Drug-induced Neurological Disorders [4th ed. 2021] 3030735028, 9783030735029

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Drug-induced Neurological Disorders Kewal K. Jain

Fourth Edition

123

Drug-induced Neurological Disorders

Kewal K. Jain

Drug-induced Neurological Disorders Fourth Edition

Kewal K. Jain Jain PharmaBiotech Basel, Basel Stadt Switzerland

ISBN 978-3-030-73502-9    ISBN 978-3-030-73503-6 (eBook) https://doi.org/10.1007/978-3-030-73503-6 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Foreword to the First Edition

When a new drug first enters preclinical studies, these are directed to determine the mechanism of primary action, pharmacokinetics, and in vivo toxicity. Though screening tests are undertaken, little information is usually obtained on secondary activities of the drug and on its interaction with other drugs. When a potential pharmaceutical compound moves from the preclinical to the clinical phase of study, this introduces another order of complexity, mainly the difference between human metabolism and that of animals. Moreover, the complexity of the human nervous system and human awareness provides the basis for a whole new series of effects and side effects. Some of these become obvious in Phase I trials in humans, but the number of subjects is always small at this stage. As the drug moves into Phase II and Phase III studies, less frequent toxicity reactions begin to be experienced. These include the development of antibodies with a host of immunologically mediated side effects. Additionally, in the human population, there are some individuals with unusual metabolisms who produce abnormal pharmacokinetics, and hence high blood levels of the drugs. Phase III and IV studies that are used to assess efficacy and the risk-benefit ratio of a medication often involve 500–5000 patients. With this number, it might be expected that most of the potential side effects of a drug would have been discovered by the end of this stage of pharmaceutical development. Unfortunately, this is not so. Some idiosyncratic reactions have an incidence of only 1 in 10,000 or 1 in 100,000 patients. If the idiosyncratic reaction is fatal, even reactions with this rarity may lead to withdrawal of the trial medication. Additionally, many of the uncommon adverse drug reactions (ADRs) go unrecognized for a considerable period after the drug is released. Reasons include that the ADR is very different in type from the primary effect of the drug, that the ADR is very similar to a spontaneous human disease, or that the ADR only results from drug interaction with other drugs or metabolic disorders. It is not until a pattern of such disorders is recognized in a cohort of patients taking a certain drug that it comes under suspicion for being responsible for an ADR. Post-marketing surveillance by pharmaceutical companies is especially important for recognition of these ADRs. Companies are generally effective in collecting and cataloging such reports. The World Health Organization maintains a registry of adverse drug reactions. The medical/scientific literature is also an important vehicle for reports of potential ADRs, for this is v

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Foreword to the First Edition

often the mechanism by which clinicians raise the first suspicions that an unusual medical complication might be an ADR. When a very unusual medical condition is first seen, it is never certain whether it is due to a drug or not. When it is seen a second and a third time in relation to treatment with a certain drug than the association becomes more likely. It is essential that physicians have a high index of suspicion. Undoubtedly, a very large number of such ADRs are missed, either because the physician was suspicious but never saw a second instance of the disorder or was too busy to report it. The rate of reporting of ADRs is undoubtedly quite low throughout the world. However, to be set against this low rate of recognition of ADRs is the fact that the literature and pharmaceutical industry data banks are full of single case reports of potential complications of every drug. A glance at the Physicians’ Desk Reference reveals the enormous range of complications of each drug that the practicing physician is warned about. One of the problems of such product information is that ADRs recognized early in the development of a drug, even though they may be extremely rare, tend to get fossilized in this information. No attempt is ever made to eliminate reference to such side effects that turn out to have extremely low frequencies. It is likely that many such reports of apparent ADRs are not due to the drug in question or are rare idiosyncratic reactions. From a scientific point of view, one would like some index of the frequency of each suggested ADR. Unfortunately, not only is the frequency of reporting low, but certainty of the causality is often absent, and the denominator of drug dose times patient years is unknown. We might hope that patient data banks in this computer age would help. Record linkage studies such as those by Mayo Clinic or in Oxford may help, but rarely are pharmaceutical agents sufficiently clearly targeted for these studies to produce information on more than the common ADRs and common drugs. Turning to the nervous system, we are all aware that over the last 15 years there has been an enormous explosion in knowledge of basic neurosciences. In particular, enormous strides have been made in the understanding of basic neurochemical mechanisms of the action of the nervous system, and the discovery of new classes of receptors, neurotransmitters, second messengers, and fields of neuronal functions. Each discovery has opened the way for the development of new, highly directed, and potent pharmaceutical agents. As the range in potency of these has increased, the potential for drug interaction has also increased exponentially. Such interactions can include the development of excessive therapeutic action, the blocking or abnormal increase in a normal neurological function, or frank neurotoxicity. Again, such changes will not be recognized as a specific ADR without the presence of a very observant neurologist with a high index of suspicion. The complexity of the nervous system and the rapid advance in the development of neuroactive substances explains why neurology is the major discipline experiencing this exponential rise in drug-induced disorders. How can we improve the dissemination of information about neurological ADRs? One source of information is the Physicians’ Desk Reference. For each drug, there are a reported series of complications divided under region of the body. Under the central nervous system, almost all drugs are reported to cause nausea, drowsiness, dizziness, and tremor. It is interesting that these

Foreword to the First Edition

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are also the most frequent side effects experienced by subjects taking placebo medication in double-blind controlled trials. Hence, they may not be due to the specific effect of the drug in question. Another source of information is to review textbooks of disease. In the field of neurology, each chapter or monograph includes some description of drug toxicity affecting this system. Textbooks of neuropharmacology and therapeutics of neurological disease often have important information but are never comprehensive. They only deal with the most common complications that are well recognized. The data banks of ADRs, such as those of the WHO and individual pharmaceutic firms, can be helpful. However, for the practicing clinician, one should have a suspicion that the unusual neurological reaction is due to a certain drug before one can approach any of these data banks. Access to pharmaceutical company reports may be difficult, for these companies are often unwilling to provide full information, and the rate at which ADRs are reported and their statistical reliability has already been discussed. Often the neurologist comes at the situation from a different direction. The patient is exhibiting an unusual neurological syndrome, and the suspicion arises whether this could be due to an ADR. It must be remembered that polypharmacy is the order of the day, particularly in the elderly, where, if there are not five different diseases each receiving three different medications, the individual is quite unusual! Hence, there is a great need for a monograph such as that of Dr. Jain. This attempts to collate the frequency of the rare drug-induced neurological disorders affecting each area of the nervous system and each of the many neurological functions within each area. Dr. Jain brings an unusual experience to this task. He is a neurosurgeon and neurologist who, for many years, has been a medical advisor to the pharmaceutical industry. He has an understanding of the records of ADRs in the pharmaceutical firms, and hence has access to many that are normally not surveyed in producing a compilation of drug-­ induced neurological disorders. He has also undertaken a very exhaustive review of the clinical literature dealing with neurological ADRs. The reader is provided with a very succinct collection of this information arranged in the clinically relevant format of individual regions of the nervous system and neurological functions. Dr. Jain well recognizes the limitations and drawbacks of the data sources concerning ADRs that I have highlighted above. His first chapter on epidemiology and clinical significance is an excellent critical review of this field. The reader will do well to come back again and again to these points in reading the remainder of the book. In summary, there is an enormous amount of information in this book that will be of great use to the practicing neurologist. Walter G. Bradley Professor and Chairman Department of Neurology, University of Miami School of Medicine, Miami, FL, USA June 1995

Preface to the Fourth Edition

During the last quarter of a century, when the first three editions of this book were published, considerable advances have taken place in pharmacovigilance at the regulatory agencies as well as the manufacturers of biopharmaceutical products. Most new drugs are biotechnology based and several new adverse reactions have been identified. There are advances in understanding pathomechanism of various diseases including those caused by drugs. This was the first book on the topic and remains the only source of information in a compact volume that is useful for neurologists, psychiatrists, and pharmaceutical physicians, particularly those involved in drug safety. In the earlier editions, attempts were made to cite the authors of case reports of adverse drug reactions, but as awareness of these has increased, the number of publications has multiplied. It would be impossible to include reference to every publication as it may come to occupy more than half of the text. References are selected and some statements are based on my recent experience and have replaced references to older publications. Retrieving old publications is not a problem as efficient search methods are universally available. Selected references are appended to each chapter and total approximately 1000. The text is supplemented with 11 figures and approximately 200 tables, which were very useful for the readers of the previous editions and elicited positive comments. The book was expanded to include many new therapies based on cell and gene therapies. Monoclonal antibodies are now used for the treatment of many diseases, particularly cancer, and side effects of these are mentioned along with other drugs. Some new areas are added such as the effects of drugs on the developing nervous system due to exposure of the fetus to drugs taken by the mother during pregnancy. A chapter is devoted to neurological effects of drug abuse. Finally, I would like to thank Gregory Sutorius, editor of medical books at Springer, for his support of this project and taking care of some of the formalities and problems of transfer of this book from the publisher of first three editions to Springer. Nisha Vetrivel, project coordinator (books) at Springer Nature, has overseen the processing of the manuscript. Basel, Switzerland January 2021

K. K. Jain

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Contents

Part I Basics of Adverse Drug Reactions of the Nervous System 1 Introduction, History, and Epidemiology of Drug-Induced Neurological Disorders��������������������������������������������������������������������   3 Introduction��������������������������������������������������������������������������������������    3 Definitions����������������������������������������������������������������������������������������    3 Historical Aspects����������������������������������������������������������������������������    3 Pharmacovigilance ��������������������������������������������������������������������������    4 Epidemiology of ADRs��������������������������������������������������������������������    4 Assessment of Adverse Drug Reactions������������������������������������������    6 Sources of Adverse Drug Reaction Data�������������������������������������    6 Systems Pharmacology Approach to Identify ADRs ������������������    6 Causality Assessment������������������������������������������������������������������    6 Diagnostic Assessment����������������������������������������������������������������    8 Behavioral Toxicity����������������������������������������������������������������������    9 Clinical Significance��������������������������������������������������������������������    9 Concluding Remarks������������������������������������������������������������������������    9 References����������������������������������������������������������������������������������������    9 2 Neurologic Symptoms as Adverse Drug Reactions ����������������������  11 Introduction��������������������������������������������������������������������������������������   11 Aphasia��������������������������������������������������������������������������������������������   11 Drug-Induced Aphasia ����������������������������������������������������������������   11 Ataxia����������������������������������������������������������������������������������������������   11 Drug-Induced Ataxia��������������������������������������������������������������������   12 Dysarthria����������������������������������������������������������������������������������������   13 Drug-Induced Dysarthria ������������������������������������������������������������   13 Dysphagia����������������������������������������������������������������������������������������   15 Drug-Induced Dysphagia ������������������������������������������������������������   15 Falls��������������������������������������������������������������������������������������������������   16 Drug-Induced Falls����������������������������������������������������������������������   16 Hiccups��������������������������������������������������������������������������������������������   17 Drug-Induced Hiccups ����������������������������������������������������������������   17 Nausea and Vomiting ����������������������������������������������������������������������   17 Drug-Induced Nausea and Vomiting��������������������������������������������   18 Neurogenic Bladder Dysfunction����������������������������������������������������   20 Drug-Induced Neurogenic Bladder����������������������������������������������   20 xi

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Tremor����������������������������������������������������������������������������������������������   20 Drug-Induced Tremor������������������������������������������������������������������   21 Yawning ������������������������������������������������������������������������������������������   22 Neuropharmacologic Regulation of Yawning������������������������������   23 Disorders Associated with Pathologic Yawning��������������������������   23 Drug-Induced Yawning����������������������������������������������������������������   23 References����������������������������������������������������������������������������������������   24 3 Role of the Blood-Brain Barrier in Effects of Drugs on the Brain��������������������������������������������������������������������������  27 Introduction��������������������������������������������������������������������������������������   27 BBB as an Anatomical as well as Physiological Barrier ������������   27 Molecular Biology of the BBB����������������������������������������������������   27 BBB as a Biochemical Barrier����������������������������������������������������   28 Regulatory Functions of the BBB������������������������������������������������   28 Other Neural Barriers������������������������������������������������������������������   28 Passage of Substances Across the BBB ��������������������������������������   29 Systems for Transport of Molecules Across the BBB ����������������   29 Blood-Brain Barrier in Neurologic Disorders����������������������������������   32 Chemical Factors That Increase the Permeability of the BBB��������   33 Drugs Action on the BBB Affecting Transport to the Brain������������   33 Amitriptyline Enhances Transport Across BBB��������������������������   33 Anticholinergic Drugs’ Enhanced Passage Across BBB Increases Neurotoxicity ��������������������������������������������������������������   34 Antiepileptic Drug Resistance in BBB����������������������������������������   34 Drug Abuse-Induced Blood-Brain Barrier Dysfunction��������������   34 Levodopa Passage Across BBB Increases in Parkinson Disease������������������������������������������������������������������������   35 Mannitol for Treatment of Cerebral Edema��������������������������������   35 Nanomedicines and BBB������������������������������������������������������������   35 Tissue Plasminogen Activator, BBB, and Hemorrhagic Complications������������������������������������������������������������������������������   35 References����������������������������������������������������������������������������������������   36 4 Pathomechanisms of Drug-­Induced Neurological Disorders������  39 Introduction��������������������������������������������������������������������������������������   39 Direct Neurotoxicity of Drugs ��������������������������������������������������������   39 Breach of BBB����������������������������������������������������������������������������   40 Retrograde Intra-axonal Transport����������������������������������������������   40 Mechanisms of Direct Neurotoxicity������������������������������������������   40 Secondary Drug-Induced Neurologic Disorders������������������������������   46 Risk Factors for Drug-Induced Neurologic Disorders��������������������   46 Risk Factors Relevant to the Patients������������������������������������������   46 Risk Factors Related to Drugs ����������������������������������������������������   51 Concluding Remarks������������������������������������������������������������������������   54 References����������������������������������������������������������������������������������������   54 5 Adverse Effects of Drugs on the Fetal Nervous System����������������  55 Introduction��������������������������������������������������������������������������������������   55 Neurological Disorders and Pregnancy��������������������������������������������   55

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Pharmacology of Drugs During Pregnancy ������������������������������������   55 Placental Barrier��������������������������������������������������������������������������   56 Fetal Blood-Brain Barrier������������������������������������������������������������   56 Epidemiology of Disorders Due to Fetal Exposure to Drugs����������   57 Effects of Maternal Drugs on Breastfeeding Infants ����������������������   57 Pharmacokinetics During Lactation��������������������������������������������   57 Precautions for Drug Use During Lactation��������������������������������   58 Effects of Drugs Used During Pregnancy on the Fetal CNS ����������   58 Anti-Parkinson’s Disease Drugs��������������������������������������������������   59 Antidepressants����������������������������������������������������������������������������   59 Antiepileptic Drugs����������������������������������������������������������������������   60 Antimigraine Drugs ��������������������������������������������������������������������   64 Biological Therapies During Pregnancy��������������������������������������   65 Drugs Used for Narcolepsy, Excessive Daytime Sleepiness, and Attention-­Deficit/Hyperactivity Disorder������������������������������   65 Drugs Used in the Treatment of Multiple Sclerosis��������������������   66 Drugs Used for Management of Cerebral Ischemia��������������������   69 Drugs for Nausea and Vomiting of Pregnancy����������������������������   70 Local Anesthetics ������������������������������������������������������������������������   70 Opioids for Pain During Pregnancy ��������������������������������������������   71 Pregabalin������������������������������������������������������������������������������������   71 Sedatives and Hypnotics��������������������������������������������������������������   71 Substance Abuse During Pregnancy��������������������������������������������   71 Neonatal Abstinence Syndrome��������������������������������������������������   74 References����������������������������������������������������������������������������������������   75 6 Principles of Management of Drug-Induced Neurological Disorders������������������������������������������������������������������������������������������  79 Introduction��������������������������������������������������������������������������������������   79 Diagnosis������������������������������������������������������������������������������������������   79 Clinical Diagnosis������������������������������������������������������������������������   79 Laboratory Diagnostic Procedures����������������������������������������������   79 Prevention of DINDs ����������������������������������������������������������������������   80 Treatment of DIND��������������������������������������������������������������������������   81 Nonpharmacological Therapies for DIND����������������������������������   81 Management of DIND in Special Groups����������������������������������������   81 Geriatric Age Group��������������������������������������������������������������������   81 Pregnancy������������������������������������������������������������������������������������   81 Concluding Remarks and Future ����������������������������������������������������   82 Development of Safer Therapies��������������������������������������������������   82 Personalized Approach to Management of DIND ����������������������   82 References����������������������������������������������������������������������������������������   86 Part II Neurological Complications of Therapies 7 Methods of Drug Delivery to the Nervous System and DIND������������������������������������������������������������������������������������������  91 Introduction��������������������������������������������������������������������������������������   91 Drug Delivery Across the BBB��������������������������������������������������������   91

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Retrograde Axonal Transport����������������������������������������������������������   97 Direct Injection into the CNS Substance or CNS Lesions��������������   97 Convention-Enhanced Delivery ��������������������������������������������������   97 Injections into the CSF Pathways������������������������������������������������   98 Intrathecal Drug Delivery������������������������������������������������������������   99 Delivery of Drugs to the Brain via the Nasal Route��������������������  100 Intra-arterial Administration of Therapeutic Substances for CNS Disorders������������������������������������������������������������������������  101 Types of Systems for Therapeutic Delivery to the Nervous System����������������������������������������������������������������������������������������������  103 Targeted Drug Delivery to the CNS������������������������������������������������  105 Nanoparticle-Based Targeted Delivery of Chemotherapy Across the BBB����������������������������������������������������������������������������  105 References����������������������������������������������������������������������������������������  106 8 Neurological Complications of Anesthesia������������������������������������ 109 Introduction��������������������������������������������������������������������������������������  109 Neurological Complications of General Anesthesia������������������������  109 Pathomechanism of Neurologic Complications of General Anesthesia������������������������������������������������������������������������������������  110 Prevention of Complications of General Anesthesia ������������������  114 Management of Neurologic Complications of Anesthesia��������������  116 Diagnosis��������������������������������������������������������������������������������������  116 Treatment ������������������������������������������������������������������������������������  116 Neurological Complications of Local Anesthesia����������������������������  118 Adverse Effects of Local Anesthetics on the Nervous System������������������������������������������������������������������������������������������  118 Neurological Complications of Epidural Anesthesia����������������������  125 Epidemiology of Neurologic Complications of Epidural Anesthesia������������������������������������������������������������������������������������  125 Pathomechanism of Neurologic Complications of Epidural Anesthesia������������������������������������������������������������������������������������  126 Safety of Epidural Anesthesia in Special Populations ����������������  128 References����������������������������������������������������������������������������������������  129 9 Neurological Complications of Cancer Therapies������������������������ 133 Introduction��������������������������������������������������������������������������������������  133 Pathomechanism of Neurological Complications of Anticancer Drugs ������������������������������������������������������������������������  133 Peripheral Neuropathies��������������������������������������������������������������  133 Neurological Complications of Biological Therapies for Cancer����������������������������������������������������������������������������������������  137 Alpha Interferon��������������������������������������������������������������������������  137 Management of Neurological Complications of Anticancer Drugs������������������������������������������������������������������������������������������������  141 Preventive Measures��������������������������������������������������������������������  141 Treatment of Neurological Complications of Immune Therapies of Cancer ��������������������������������������������������������������������  141

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Neuroprotection Against Chemotherapy-Induced Brain Damage������������������������������������������������������������������������������  142 References����������������������������������������������������������������������������������������  142 10 Adverse Effects of Biological Therapies on the Nervous System ���������������������������������������������������������������������������������������������� 145 Introduction��������������������������������������������������������������������������������������  145 Neurological Complications of Cell Therapy����������������������������������  145 Neurological Complications of CAR-T Cell Therapy ����������������  145 Complications of Cell Therapy of Neurological Disorders ������������  146 Tumor Formation After CNS Transplantation of Stem Cells������  147 Neurological Complications of Gene Therapy��������������������������������  148 Adverse Effects of Gene Therapy������������������������������������������������  148 Neurotoxicity of Gene Therapy ��������������������������������������������������  149 Adverse Effects of Vaccines on the Nervous System����������������������  150 Introduction����������������������������������������������������������������������������������  150 Adverse Effects of Vaccines on the Nervous System������������������  152 References����������������������������������������������������������������������������������������  154 Part III Drug-Induced Neurological Disorders 11 Drug-Induced Aseptic Meningitis�������������������������������������������������� 157 Introduction��������������������������������������������������������������������������������������  157 Clinical Manifestations��������������������������������������������������������������������  158 Pathomechanism������������������������������������������������������������������������������  158 Epidemiology����������������������������������������������������������������������������������  163 Prevention����������������������������������������������������������������������������������������  163 Differential Diagnosis����������������������������������������������������������������������  163 Laboratory Investigations����������������������������������������������������������������  164 Management������������������������������������������������������������������������������������  165 References����������������������������������������������������������������������������������������  165 12 Drug-Induced Intracranial Hypertension ������������������������������������ 169 Introduction��������������������������������������������������������������������������������������  169 Epidemiology����������������������������������������������������������������������������������  170 Pathophysiology of Idiopathic Intracranial Hypertension ��������������  170 Secondary Intracranial Hypertension����������������������������������������������  170 Drug-Induced Intracranial Hypertension (DIIH) ����������������������������  170 Pathogenesis of Drug-Induced Intracranial Hypertension ��������������  172 Management of DIIH����������������������������������������������������������������������  176 References����������������������������������������������������������������������������������������  177 13 Drug-Induced Encephalopathies���������������������������������������������������� 181 Introduction��������������������������������������������������������������������������������������  181 Drugs Associated with Encephalopathy������������������������������������������  182 Acyclovir��������������������������������������������������������������������������������������  182 Aluminum������������������������������������������������������������������������������������  183 Antibiotics������������������������������������������������������������������������������������  183 Antiepileptic Drugs����������������������������������������������������������������������  185

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Encephalopathies Secondary to Drug-Induced Metabolic Disorders������������������������������������������������������������������������������������������  190 Hepatic Encephalopathy��������������������������������������������������������������  190 Hypoglycemic Encephalopathy ��������������������������������������������������  192 Hyponatremic Encephalopathy����������������������������������������������������  192 Wernicke’s Encephalopathy��������������������������������������������������������  193 Drug-Induced Leukoencephalopathy������������������������������������������  193 Amphotericin B����������������������������������������������������������������������������  193 Anticancer Agents������������������������������������������������������������������������  194 Arsenicals������������������������������������������������������������������������������������  198 Corticosteroids ����������������������������������������������������������������������������  199 Heroin������������������������������������������������������������������������������������������  199 Immunosuppressive Therapy with Organ Transplantation����������  199 Interferons������������������������������������������������������������������������������������  201 Monoclonal Antibodies����������������������������������������������������������������  201 Leukoencephalopathy Secondary to Drug-Induced Hypertension��������������������������������������������������������������������������������  203 Syndromes with Encephalopathy in Which Drugs Are Implicated ����������������������������������������������������������������������������  203 References����������������������������������������������������������������������������������������  205 14 Drug-Induced Disorders of Memory and Dementia�������������������� 209 Introduction to Drug-Induced Memory Impairment������������������������  209 Definitions and Historical Note ��������������������������������������������������  209 Drugs Associated with Memory Impairment������������������������������  210 Pathomechanisms of Drug-Induced Memory Disturbances��������  216 Epidemiology������������������������������������������������������������������������������  217 Prognosis of Drug-Induced Memory Disturbances ��������������������  218 Prevention������������������������������������������������������������������������������������  218 Differential Diagnosis������������������������������������������������������������������  218 Diagnostic Workup����������������������������������������������������������������������  218 Management of Drug-Induced Memory Impairment������������������  218 Drug-Induced Dementia������������������������������������������������������������������  219 Definitions and Historical Note ��������������������������������������������������  219 Clinical Manifestations����������������������������������������������������������������  220 Drugs Associated with Dementia������������������������������������������������  220 Pathomechanism of Drug-Induced Dementia������������������������������  224 Epidemiology of Drug-Induced Dementia����������������������������������  226 Factors that Predispose to Drug-­Induced Dementia��������������������  227 Prevention of Drug-Induced Dementia����������������������������������������  227 Differential Diagnosis of Drug-­Induced Dementia����������������������  227 Diagnostic Workup����������������������������������������������������������������������  228 Management of Drug-Induced Dementia������������������������������������  228 References����������������������������������������������������������������������������������������  229 15 Drug-Induced Disturbances of Consciousness������������������������������ 233 Introduction��������������������������������������������������������������������������������������  233 Drug-Induced Syncope��������������������������������������������������������������������  233 Clinical Manifestations����������������������������������������������������������������  233

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Prognosis and Complications������������������������������������������������������  234 Pathomechanism of Syncope ������������������������������������������������������  234 Epidemiology of Drug-Induced Syncope������������������������������������  238 Prevention of Drug-Induced Syncope������������������������������������������  238 Differential Diagnosis of Syncope����������������������������������������������  238 Diagnostic Workup����������������������������������������������������������������������  239 Management of Drug-Induced Syncope��������������������������������������  239 Drug-Induced Delirium��������������������������������������������������������������������  240 History������������������������������������������������������������������������������������������  240 Terminology��������������������������������������������������������������������������������  240 Clinical Manifestations����������������������������������������������������������������  241 Drugs Associated with Delirium��������������������������������������������������  241 Underlying Disorders and Risk Factors for Delirium������������������  243 Delirium Due to Drug Withdrawal����������������������������������������������  245 Pathomechanism of Delirium������������������������������������������������������  245 Epidemiology of Drug-Induced Delirium������������������������������������  246 Prevention of Drug-Induced Delirium ����������������������������������������  247 Differential Diagnosis of Delirium����������������������������������������������  247 Diagnostic Workup����������������������������������������������������������������������  247 Management of Drug-Induced Delirium ������������������������������������  248 Coma Due to Drug Intoxication������������������������������������������������������  250 Clinical Manifestations����������������������������������������������������������������  251 Drugs that Can Cause Coma��������������������������������������������������������  252 Pathomechanism of Drug-Induced Coma������������������������������������  252 Epidemiology of Drug-Induced Coma����������������������������������������  257 Prevention of Drug-Induced Coma����������������������������������������������  257 Differential Diagnosis of Drug-­Induced Coma����������������������������  257 Diagnostic Workup����������������������������������������������������������������������  258 Management of Drug-Induced Coma������������������������������������������  259 References����������������������������������������������������������������������������������������  261 16 Drug-Induced Neuropsychiatric Disorders ���������������������������������� 265 Introduction��������������������������������������������������������������������������������������  265 Behavioral Toxicity��������������������������������������������������������������������������  265 Psychoactive Drugs and Motor Vehicle Accidents����������������������  265 Behavioral “Disinhibition”����������������������������������������������������������  266 Pathomechanisms of Drug-Induced Psychiatric Adverse Effects��������������������������������������������������������������������������������  266 Drug-Induced Depression����������������������������������������������������������������  267 Pathomechanism of Drug-Induced Depression���������������������������  267 References����������������������������������������������������������������������������������������  284 17 Neurologic Effects of Drug Abuse�������������������������������������������������� 285 Introduction��������������������������������������������������������������������������������������  285 Terminology��������������������������������������������������������������������������������  285 Epidemiology of Drug Abuse����������������������������������������������������������  285 Abused Drugs����������������������������������������������������������������������������������  286 Opioids����������������������������������������������������������������������������������������  286 Psychostimulants�������������������������������������������������������������������������  287

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Sedatives and Hypnotics��������������������������������������������������������������  288 Cannabis (Marijuana)������������������������������������������������������������������  289 Pathomechanism of Drug Abuse������������������������������������������������������  290 Neurological Adverse Effects of Illicit Drugs����������������������������������  291 Seizures in Drug Abuse����������������������������������������������������������������  291 Injuries to the Nervous System in Drug Abuse����������������������������  291 CNS Infections in Drug Abuse����������������������������������������������������  291 Stroke in Drug Abusers����������������������������������������������������������������  292 Mental Alterations in Drug Abuse ����������������������������������������������  292 Alcoholic Neurologic Disorders��������������������������������������������������  292 References����������������������������������������������������������������������������������������  293 18 Drug-Induced Sleep Disorders�������������������������������������������������������� 295 Introduction��������������������������������������������������������������������������������������  295 Clinical Features of Sleep Disorders Induced by Drugs������������������  295 Pathomechanism of Drug-Induced Sleep Disorders������������������������  296 Central Disorder of Hypersomnolence����������������������������������������  296 Drug-Induced Drowsiness������������������������������������������������������������  296 Insomnia Due to Drugs or Substances ����������������������������������������  296 Vivid Dreams and Nightmares����������������������������������������������������  298 Sleepwalking��������������������������������������������������������������������������������  298 Drug-Induced Disorders of Breathing During Sleep ������������������  299 Sleep Paralysis ����������������������������������������������������������������������������  300 Drug-Induced Enuresis����������������������������������������������������������������  300 Drug-Induced Sleep Bruxism������������������������������������������������������  300 Drug-Induced Sleep-Related Eating Disorders����������������������������  300 Drug-Induced Rapid Eye Movement Sleep Behavior Disorder����������������������������������������������������������������������������������������  301 Drug-Induced Restless Legs Syndrome��������������������������������������  301 Sleep-Related Adverse Effects of Drugs According to Therapeutic Categories����������������������������������������������������������������  301 Epidemiology of Drug-Induced Sleep Disorders������������������������  305 Prevention of Drug-Induced Sleep Disorders������������������������������  305 Differential Diagnosis of Drug-­Induced Sleep Disorders������������  305 Diagnostic Workup of Patients with Drug-Induced Sleep Disorders����������������������������������������������������������������������������  306 Management of Drug-Induced Sleep Disorders��������������������������  306 References����������������������������������������������������������������������������������������  307 19 Drug-Induced Seizures�������������������������������������������������������������������� 309 Introduction��������������������������������������������������������������������������������������  309 Clinical Manifestations��������������������������������������������������������������������  309 Pathomechanism of Drug-Induced Seizures������������������������������������  310 Drugs Associated with Seizures������������������������������������������������������  310 Anesthetics and Seizures��������������������������������������������������������������  311 Antidepressants and Seizures������������������������������������������������������  311 Antimicrobial Agents and Seizures����������������������������������������������  312 Antipsychotic Agents and Seizures����������������������������������������������  313 Aggravation of Seizures by Antiepileptic Drugs ������������������������  314

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Epidemiology of Drug-Induced Seizures����������������������������������������  318 Prevention of Drug-Induced Seizures����������������������������������������������  319 Differential Diagnosis of Drug-­Induced Seizures����������������������������  320 Diagnostic Workup of Patients with Drug-Induced Seizures����������  320 Management of Drug-Induced Seizures������������������������������������������  321 References����������������������������������������������������������������������������������������  322 20 Drug-Induced Movement Disorders���������������������������������������������� 325 Introduction��������������������������������������������������������������������������������������  325 Terminology and Classification of Movement Disorders����������������  325 Antipsychotic Drugs������������������������������������������������������������������������  326 Adverse Effects of Antipsychotic Agents����������������������������������������  326 Assessment of Neurological Status of Schizophrenic Patients��������  327 Pathomechanisms of Drug-Induced Movement Disorders��������������  328 Factors That Influence the Onset of Drug-Induced Movement Disorders������������������������������������������������������������������������������������������  328 Akathisia������������������������������������������������������������������������������������������  329 Classification of Akathisia ����������������������������������������������������������  329 Pathomechanism of Akathisia������������������������������������������������������  330 Epidemiology of Akathisia����������������������������������������������������������  330 Prevention������������������������������������������������������������������������������������  331 Differential Diagnosis������������������������������������������������������������������  331 Management of Akathisia������������������������������������������������������������  332 Akinetic Mutism������������������������������������������������������������������������������  332 Asterixis ������������������������������������������������������������������������������������������  333 Athetosis��������������������������������������������������������������������������������������  333 Ballism ����������������������������������������������������������������������������������������  334 Chorea������������������������������������������������������������������������������������������  334 Acute Dystonia����������������������������������������������������������������������������  335 Treatment of Dystonia ����������������������������������������������������������������  336 Oculogyric Crises������������������������������������������������������������������������  338 Myoclonus������������������������������������������������������������������������������������  338 Restless Legs Syndrome������������������������������������������������������������������  339 Tics��������������������������������������������������������������������������������������������������  339 Tremor����������������������������������������������������������������������������������������������  340 Drug-Induced Tremor������������������������������������������������������������������  340 Tardive Tremor����������������������������������������������������������������������������  341 Drug-Induced Parkinsonism������������������������������������������������������������  342 Epidemiology of DIP ������������������������������������������������������������������  342 Clinical Features of DIP��������������������������������������������������������������  342 Pathomechanism of DIP��������������������������������������������������������������  342 Risk Factors for DIP��������������������������������������������������������������������  343 Course and Prognosis of DIP������������������������������������������������������  343 Management of Antipsychotic-­Induced Parkinsonism����������������  344 Non-antipsychotic Drugs That Induce Parkinsonism������������������  344 Differentiation of Idiopathic PD from DIP����������������������������������  345 Extrapyramidal Disorders Due to Antipsychotics and Anti-­dementia Drugs��������������������������������������������������������������������  345 References����������������������������������������������������������������������������������������  345

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21 Tardive Dyskinesia �������������������������������������������������������������������������� 347 Introduction��������������������������������������������������������������������������������������  347 Clinical Features��������������������������������������������������������������������������  347 Rating Scales for TD��������������������������������������������������������������������  348 Epidemiology of TD��������������������������������������������������������������������  348 Risk Factors for Tardive Dyskinesia��������������������������������������������  348 Pathomechanism of TD����������������������������������������������������������������  349 Differential Diagnosis of TD ������������������������������������������������������  351 Management of TD��������������������������������������������������������������������������  353 Prevention of TD��������������������������������������������������������������������������  353 Treatment of TD��������������������������������������������������������������������������  353 Tardive Dystonia������������������������������������������������������������������������������  355 Pathophysiology��������������������������������������������������������������������������  355 Epidemiology������������������������������������������������������������������������������  356 Prognosis and Complications������������������������������������������������������  356 Management��������������������������������������������������������������������������������  356 Dyskinesias Associated with Antiparkinsonian Drugs��������������������  357 Levodopa-Induced Dyskinesias ��������������������������������������������������  357 Clinical Features of LID��������������������������������������������������������������  357 Risk Factors for PID��������������������������������������������������������������������  358 Pathophysiology��������������������������������������������������������������������������  358 Management of LID��������������������������������������������������������������������  359 Drug-Induced Extrapyramidal Syndromes����������������������������������  360 References����������������������������������������������������������������������������������������  360 22 Drug-Induced Headaches���������������������������������������������������������������� 363 Introduction��������������������������������������������������������������������������������������  363 Classification������������������������������������������������������������������������������������  363 Drugs and Other Substances Reported to Induce Headache��������  364 Clinical Features of Drug-Induced Headaches��������������������������������  365 Risk Factors of Drug-Induced Headache ����������������������������������������  366 Pathomechanism of Drug-Induced Headache����������������������������������  366 Headache Remedies That Induce Headaches������������������������������  367 Headaches Induced by Other Drugs and Substances������������������  367 Headache Due to Non-CNS Adverse Effects of Drugs��������������������  373 Hypertension��������������������������������������������������������������������������������  373 Headache Due to Myositis of Head and Neck Muscles��������������  373 Epidemiology of Drug-Induced Headaches������������������������������������  373 Diagnosis of Drug-Induced Headache ��������������������������������������������  374 Diagnosis of Drug-Induced Headache ��������������������������������������������  376 Differential Diagnosis������������������������������������������������������������������  376 Diagnostic Workup����������������������������������������������������������������������  377 Prevention of Drug-Induced Headache��������������������������������������������  377 Management of Drug-Induced Headache����������������������������������������  378 Treatment of Withdrawal Headaches ������������������������������������������  379 Prognosis of Medication Overuse Headache and Results of Therapy������������������������������������������������������������������������������������  379 Management of Headache Due to Use of Illicit Drugs����������������  380 References����������������������������������������������������������������������������������������  380

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23 Drug-Induced Cerebrovascular Disorders������������������������������������ 381 Introduction��������������������������������������������������������������������������������������  381 Clinical Manifestations��������������������������������������������������������������������  381 Pathomechanism of Drug-Induced Cerebrovascular Disease����������  382 Drug Categories and Drugs Associated with Stroke��������������������  382 Mechanisms Involved in Drug-­Induced Cerebrovascular Disease ����������������������������������������������������������������������������������������  387 Epidemiology of Drug-Induced Stroke��������������������������������������������  390 Prevention of Drug-Induced Cerebrovascular Disease��������������������  391 Differential Diagnosis������������������������������������������������������������������  391 Diagnostic Workup����������������������������������������������������������������������  391 Management of Drug-Induced Cerebrovascular Disease����������������  392 Drug-Induced Cerebrovascular Disease During Stroke��������������  392 References����������������������������������������������������������������������������������������  392 24 Drug-Induced Disorders of Cranial Nerves���������������������������������� 395 Introduction��������������������������������������������������������������������������������������  395 Drug-Induced Disorders of Eye Movements ����������������������������������  395 Combined Third, Fourth, and Sixth Cranial Nerve Palsies����������  396 Effect of Drugs on Eye Muscles��������������������������������������������������  396 Drug-Induced Ophthalmoplegia��������������������������������������������������  396 Oculomotor (III Cranial Nerve) Neuropathy ������������������������������  397 Trochlear (IV Cranial Nerve) Neuropathy����������������������������������  397 Abducent (VI Cranial Nerve)������������������������������������������������������  397 Trigeminal (V Cranial Nerve) Neuropathy����������������������������������  398 Paralysis of the VII (Facial Nerve)����������������������������������������������  398 References����������������������������������������������������������������������������������������  399 25 Drug-Induced Neurootological Disorders�������������������������������������� 401 Introduction��������������������������������������������������������������������������������������  401 Dizziness and Vertigo����������������������������������������������������������������������  401 Drugs Associated with Dizziness and Vertigo ����������������������������  401 Pathomechanisms of Drug-Induced Vertigo and Dizziness ��������  401 Management of Drug-Induced Dizziness and Vertigo ����������������  402 Ototoxicity ��������������������������������������������������������������������������������������  402 Tinnitus��������������������������������������������������������������������������������������������  402 Drug-Induced Tinnitus ����������������������������������������������������������������  402 Hearing Loss������������������������������������������������������������������������������������  403 Drug-Induced Hearing Loss��������������������������������������������������������  403 Aminoglycoside Antibiotics��������������������������������������������������������  403 Nonaminoglycoside Antibiotics��������������������������������������������������  405 Anti-inflammatory Drugs������������������������������������������������������������  406 Antimalarials��������������������������������������������������������������������������������  406 Antineoplastic Drugs ������������������������������������������������������������������  406 Loop Diuretics ����������������������������������������������������������������������������  407 Other Drugs����������������������������������������������������������������������������������  408 Prevention of Drug Ototoxicity����������������������������������������������������  409 Prevention of Drug-Induced Hearing Loss����������������������������������  409 Recurrent Laryngeal Nerve Palsy����������������������������������������������������  410 References����������������������������������������������������������������������������������������  410

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26 Drug-Induced Neuro-­ophthalmological Disorders ���������������������� 411 Introduction��������������������������������������������������������������������������������������  411 Drug-Induced Optic Neuropathy ����������������������������������������������������  411 Optic Atrophy������������������������������������������������������������������������������  411 Drug-Induced Aggravation of Age-­Related Macular Degeneration��������������������������������������������������������������������������������  412 Papilledema Due to Drug-Induced Rise of Intracranial Pressure����������������������������������������������������������������������������������������  413 Drug-Induced Retinopathies��������������������������������������������������������  413 Neuro-ophthalmic Toxicity of Drugs ������������������������������������������  413 Nystagmus������������������������������������������������������������������������������������  420 Drug-Induced Diplopia����������������������������������������������������������������  421 Drug-Induced Oculogyric Crisis��������������������������������������������������  421 Cortical Blindness����������������������������������������������������������������������������  422 Anticancer Drugs ������������������������������������������������������������������������  422 References����������������������������������������������������������������������������������������  423 27 Drug-Induced Disorders of Smell and Taste �������������������������������� 425 Introduction and Terminology ��������������������������������������������������������  425 Clinical Manifestations��������������������������������������������������������������������  425 Prognosis and Complications������������������������������������������������������  426 Drugs Reported to Induce Disorders of Taste and Smell����������������  426 Pathomechanism of Drug-Induced Disturbances of Smell and Taste������������������������������������������������������������������������������������������  426 Epidemiology of Drug-Induced Smell and Taste Disturbances������  431 Prevention of Drug-Induced Smell and Taste Disturbances������������  431 Diagnosis������������������������������������������������������������������������������������������  431 Differential Diagnosis of Drug-­Induced Smell and Taste Disturbances��������������������������������������������������������������������������������  431 Diagnostic Workup����������������������������������������������������������������������  432 Management������������������������������������������������������������������������������������  433 Future Prospects������������������������������������������������������������������������������  434 References����������������������������������������������������������������������������������������  434 28 Drug-Induced Peripheral Neuropathies���������������������������������������� 437 Introduction��������������������������������������������������������������������������������������  437 Drugs Associated with Peripheral Neuropathy��������������������������������  437 Pathophysiological Classification����������������������������������������������������  438 Pathology of Peripheral Neuropathy��������������������������������������������  438 Anatomical Classification of Peripheral Neuropathy������������������  438 Epidemiology����������������������������������������������������������������������������������  439 Pathomechanisms of Drug-Induced Neuropathies��������������������������  439 Predisposing Factors in the Peripheral Nerves����������������������������  439 Mechanisms ��������������������������������������������������������������������������������  440 Antineoplastic Agents������������������������������������������������������������������  441 Antimicrobial Agents ������������������������������������������������������������������  448 Cardiovascular Drugs������������������������������������������������������������������  453 Central Nervous System (CNS) Drugs����������������������������������������  454 Miscellaneous Drugs��������������������������������������������������������������������  456

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Prevention of Drug-Induced Peripheral Neuropathy ����������������������  463 Neuroprotective Against Anticancer Drug-Induced Peripheral Neuropathy ����������������������������������������������������������������  464 Diagnosis of Drug-Induced Peripheral Neuropathy������������������������  464 Management of Drug-Induced Peripheral Neuropathy��������������������  464 References����������������������������������������������������������������������������������������  464 29 Drug-Induced Disorders of the Autonomic Nervous System ������ 469 Introduction��������������������������������������������������������������������������������������  469 Classification of Drug-Induced Disorders of the ANS��������������������  469 Anticholinergic Syndrome ��������������������������������������������������������������  469 Clinical Manifestations����������������������������������������������������������������  469 Drug-Induced Anticholinergic Syndrome������������������������������������  471 Pathomechanism of Anticholinergic Syndrome��������������������������  471 Differential Diagnosis������������������������������������������������������������������  471 Anticholinergic Syndrome in Anesthesia������������������������������������  471 Treatment ������������������������������������������������������������������������������������  473 Cholinergic Syndrome ��������������������������������������������������������������������  473 Sympathomimetic Syndromes ��������������������������������������������������������  473 Autonomic Neuropathy��������������������������������������������������������������������  474 Drug-Induced Autonomic Neuropathy����������������������������������������  474 Autonomic Disturbances Associated with Drug Withdrawal����������  475 Reflex Sympathetic Dystrophy/Complex Regional Pain Syndrome ����������������������������������������������������������������������������������������  475 Clinical Features��������������������������������������������������������������������������  475 Causes of RSD/CRPS I����������������������������������������������������������������  476 Management of Drug-Induced RSD/CRPS 1������������������������������  477 References����������������������������������������������������������������������������������������  477 30 Drug-Induced Neuromuscular Disorders�������������������������������������� 481 Introduction��������������������������������������������������������������������������������������  481 Prolonged Duration of Neuromuscular Blockade������������������������  481 Postoperative Respiratory Depression ����������������������������������������  481 Unmasking or Aggravation of Myasthenia Gravis����������������������  481 Drug-Induced Reversible Myasthenic Syndromes����������������������  482 Pathomechanism of Drug-Induced Neuromuscular Disorders��������  482 Drugs That Impair Neuromuscular Transmission������������������������  482 Epidemiology of Drug-Induced Neuromuscular Disorders������������  489 Differential Diagnosis����������������������������������������������������������������������  489 Prevention����������������������������������������������������������������������������������������  490 Management of Drug-Induced Neuromuscular Disorders��������������  490 References����������������������������������������������������������������������������������������  490 31 Drug-Induced Myopathies�������������������������������������������������������������� 493 Introduction��������������������������������������������������������������������������������������  493 Clinical Manifestations��������������������������������������������������������������������  493 Rhabdomyolysis��������������������������������������������������������������������������  494 Critical Illness Myopathy������������������������������������������������������������  494 Prognosis and Complications������������������������������������������������������  495

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Drugs That Produce Myopathies�����������������������������������������������������  495 Pathomechanism of Drug-Induced Myopathies������������������������������  495 Direct Effect of Drugs on Muscles����������������������������������������������  496 Epidemiology of Drug-Induced Myopathy��������������������������������������  503 Prevention of Drug-Induced Myopathy ������������������������������������������  503 Differential Diagnosis����������������������������������������������������������������������  504 Diagnostic Workup��������������������������������������������������������������������������  506 Management������������������������������������������������������������������������������������  507 References����������������������������������������������������������������������������������������  508 32 Drug-Induced Spinal Disorders������������������������������������������������������ 511 Introduction��������������������������������������������������������������������������������������  511 Clinical Manifestations��������������������������������������������������������������������  511 Backache��������������������������������������������������������������������������������������  511 Drugs Affecting the Vertebral Column����������������������������������������  512 Toxicity of Intrathecal Agents������������������������������������������������������  512 Drug-Induced Myelopathy����������������������������������������������������������  515 Lesions of the Anterior Horn Cells and Anterior Nerve Roots ������������������������������������������������������������������  519 Drug-Induced Lhermitte’s Sign ��������������������������������������������������  519 Drug-Induced Spinal Hemorrhage����������������������������������������������  519 References����������������������������������������������������������������������������������������  520 33 Drug-Induced Cerebellar Disorders���������������������������������������������� 523 Introduction��������������������������������������������������������������������������������������  523 Clinical Manifestations of Cerebellar Disorders������������������������������  523 Clinical Features of Drug-Induced Cerebellar Disorders����������������  523 Drugs Associated with Cerebellar Disorders ������������������������������  524 Alcohol����������������������������������������������������������������������������������������  524 Antibiotics������������������������������������������������������������������������������������  524 Antidepressants����������������������������������������������������������������������������  525 Antiepileptic Drugs����������������������������������������������������������������������  525 Antineoplastic Drugs ������������������������������������������������������������������  527 Cyclosporine��������������������������������������������������������������������������������  528 Cimetidine������������������������������������������������������������������������������������  529 Lithium����������������������������������������������������������������������������������������  529 Vaccines ��������������������������������������������������������������������������������������  529 References����������������������������������������������������������������������������������������  529 34 Eosinophilia-Myalgia Syndrome���������������������������������������������������� 533 Introduction��������������������������������������������������������������������������������������  533 Epidemiology of EMS ��������������������������������������������������������������������  533 Risk Factors for EMS����������������������������������������������������������������������  534 Clinical and Pathological Features��������������������������������������������������  534 Differential Diagnosis����������������������������������������������������������������������  535 Idiopathic Eosinophilic Myositis ������������������������������������������������  535 Polymyositis��������������������������������������������������������������������������������  535 Toxic Oil Syndrome ��������������������������������������������������������������������  535 Peripheral Neuropathy and EMS ������������������������������������������������  535 Natural History of EMS ������������������������������������������������������������������  536

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Pathomechanism��������������������������������������������������������������������������  536 Role of Tryptophan����������������������������������������������������������������������  536 Role of Tryptophan Contamination ��������������������������������������������  537 Role of Eosinophils����������������������������������������������������������������������  537 CNS Involvement in EMS�����������������������������������������������������������  537 Treatment of EMS����������������������������������������������������������������������������  538 Concluding Remarks������������������������������������������������������������������������  538 References����������������������������������������������������������������������������������������  539 35 Drug-Induced Pituitary Disorders ������������������������������������������������ 541 Introduction��������������������������������������������������������������������������������������  541 Direct Effects of Drugs on the Pituitary������������������������������������������  541 Modification of Drug Effect by Preexisting Lesions in the Pituitary������������������������������������������������������������������������������  542 Pituitary Apoplexy ����������������������������������������������������������������������  542 Cerebrospinal Fluid Rhinorrhea (CSF) Due to Shrinking of Prolactinoma����������������������������������������������������������������������������  544 Pituitary Insufficiency������������������������������������������������������������������  544 Drug-Induced Disorders of the Pituitary Due to Disturbances of Other Endocrines ��������������������������������������������������������������������  544 Posterior Pituitary����������������������������������������������������������������������������  548 Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH)����������������������������������������������������������������������  548 References����������������������������������������������������������������������������������������  551 36 Serotonin Syndrome������������������������������������������������������������������������ 553 Introduction��������������������������������������������������������������������������������������  553 Clinical Manifestations��������������������������������������������������������������������  553 Prognosis and Complications������������������������������������������������������  554 Pathomechanism������������������������������������������������������������������������������  554 Drug Interactions ������������������������������������������������������������������������  556 Epidemiology����������������������������������������������������������������������������������  561 Prevention����������������������������������������������������������������������������������������  561 Diagnosis of Serotonin Syndrome ��������������������������������������������������  561 Differential Diagnosis������������������������������������������������������������������  561 Diagnostic Workup����������������������������������������������������������������������  562 Management������������������������������������������������������������������������������������  563 Management of Serotonin Syndrome During Pregnancy������������  564 Anesthesia and Serotonin Syndrome ������������������������������������������  564 References����������������������������������������������������������������������������������������  564 37 Drug-Induced Guillain-Barré Syndrome�������������������������������������� 567 Introduction��������������������������������������������������������������������������������������  567 Variants and Clinical Aspects of GBS ��������������������������������������������  567 Pathophysiology������������������������������������������������������������������������������  568 Drugs and Other Therapies Associated with Guillain-Barré Syndrome ����������������������������������������������������������������������������������������  568 Drugs��������������������������������������������������������������������������������������������  569 Vaccines ��������������������������������������������������������������������������������������  571

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Management of Guillain-Barré Syndrome��������������������������������������  572 References����������������������������������������������������������������������������������������  572 38 Neuroleptic Malignant Syndrome�������������������������������������������������� 575 Introduction��������������������������������������������������������������������������������������  575 Epidemiology����������������������������������������������������������������������������������  575 Pathomechanism������������������������������������������������������������������������������  575 Risk Factors for NMS������������������������������������������������������������������  576 Clinical Features and Diagnosis of NMS����������������������������������������  577 Diagnosis of NMS������������������������������������������������������������������������  577 Clinical Course of NMS��������������������������������������������������������������  579 Drugs Associated with NMS��������������������������������������������������������  579 Medical Complications of NMS��������������������������������������������������  581 Management of NMS����������������������������������������������������������������������  582 Concluding Remarks������������������������������������������������������������������������  582 References����������������������������������������������������������������������������������������  582 Index��������������������������������������������������������������������������������������������������������  585

Author’s Biography

K.  K.  Jain  is a neurologist/neurosurgeon with specialist qualifications including fellowships of the Royal Colleges of Surgeons in Australia and Canada. He has trained, practiced, and held academic positions in several countries including Switzerland, India, Iran, Germany Canada, and the USA. After retirement from neurosurgery, Prof. Jain remains a consultant in neurology. He also works in the biotechnology/biopharmaceuticals industry and is a fellow of the Faculty of Pharmaceutical Medicine of the Royal College of Physicians, UK. Currently, he is the CEO of Jain PharmaBiotech. Prof. Jain’s 484 publications include 32 books (6 as editor and 26 as author) and 50 special reports, which have covered important areas in biotechnology, gene therapy, and biopharmaceuticals. The following Jain PharmaBiotech reports are relevant to biomarkers: proteomics, molecular diagnostics, nanobiotechnology, and personalized medicine. Recent books include Handbook of Nanomedicine (Springer 2008, Chinese edition by Peking University Press 2011, 3rd ed 2017), Textbook of Personalized Medicine (Springer 2009; Japanese ed. 2012; 2nd ed Springer 2015, 3rd ed 2021), Handbook of Biomarkers (Springer 2010; Chinese ed., Chemical Industry Press 2016, 2nd ed 2017), Handbook of Neuroprotection (Springer 2011, 2nd ed 2019), Applications of Biotechnology in Cardiovascular Therapeutics (Springer 2011), Applications of Biotechnology in Neurology (Springer 2013), and Applications of Biotechnology in Oncology (Springer 2014). He has also edited Applied Neurogenomics (Springer 2015).

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Part I Basics of Adverse Drug Reactions of the Nervous System

1

Introduction, History, and Epidemiology of Drug-­ Induced Neurological Disorders

Introduction The term “drug-induced neurological disorders (DIND)” as used here refers to unintended or undesirable effects on the nervous system caused by drugs or associated with drug use. Such disorders are classified as iatrogenic disorders, a term which also covers other illnesses such as ones caused by other therapies, e.g., surgical procedures, or even neglect in carrying out treatment which results in harm or injury to the patient. The use of the word “induced” within the term DIND does not necessarily imply a proven causal relationship of the drug to the disorder. The drug may affect the nervous system directly (primary neurotoxicity) or indirectly by other systemic disturbances caused by the drug (secondary neurotoxicity). DIND includes disorders caused by inappropriate use or overdose of a drug or interaction with other drugs, but environmental and industrial toxins are excluded.

Definitions Terms that are used commonly to describe adverse effects of drugs are defined by the World Health Organization (WHO) as follows: Side effect is any unintended effect of a pharmaceutical occurring at doses normally used in humans which is related to the pharmacological properties of the drug.

Adverse event/adverse experience (AE) is any untoward medical occurrence that may present during treatment with a pharmaceutical product, but which does not necessarily have a causal relationship with this treatment. Adverse drug reaction (ADR) is an event which is related or suspected to be related to the trial medicine. An ADR is a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function. A serious adverse drug reaction (sADR) is defined as any event or reaction that results in death, a life-threatening event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly or birth defect. sADRs, such as liver failure and fatal arrhythmia, can lead to a drug being withdrawn from the market when the risks outweigh the benefits.

Historical Aspects The concept of harm resulting from medical treatment is more than 3500 years old. In the seventh century BC, the Code of Hammurabi prescribed penalties for physician errors that resulted in harm. Similarly, in the first century AD, the

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_1

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1  Introduction, History, and Epidemiology of Drug-Induced Neurological Disorders

Roman law included penalties for such harms. Great medical writers throughout the centuries have described complications of medical treatment. Around the middle of the twentieth century, with the development of pharmacotherapy, increasing attention was given to ADRs. They were not viewed merely as iatrogenic phenomena, but rather as inevitable consequences of medical progress and introduction of new drugs. Among the earliest adverse effects of therapies to be recognized were those of the nervous system. Historical landmarks of drug-induced neurological disorders (DIND) in the twentieth century are shown in Table 1.1. Surveillance systems have been developed during the past 30 years for collection and analysis of ADRs. In view of the increasing occurrence of drugs and environmentally induced neurotoxicity, the National Toxicology Program of the National Institute of Environmental Health Sciences of the United States has modified its protocol to include a more extensive histopathoTable 1.1  Historical landmarks of drug-induced neurological disorders in the twentieth century Year Landmark 1934 Polyneuropathies as complications of vaccinations were recognized in 1934 (Cathala 1934) 1949 Encephalopathies due to vaccines (Globus and Kohn 1949) Pathogenesis of iatrogenic neurologic disorders was discussed under 12 categories, 9 of which were adverse drug effects mostly associated with antibiotic and hormone therapy (Yajnik and Solanki 1972) 1962 The saga of thalidomide: neuropathy to embryopathy, with case reports of congenital anomalies (Mellin and Katzenstein 1962) 1974 Payk was the first to separate complications of treatment of neurologic disorders from neurologic complications resulting from treatment of diseases of other systems (Payk 1974) 1975 Publication of the first work expressing concern regarding the increasing number of adverse effects of the drugs with a focus on iatrogenic pathology in neurology (Arnott and Caron 1975) © Jain PharmaBiotech

logical examination of the nervous system (Rao et al. 2011).

Pharmacovigilance Pharmacovigilance is the branch of pharmaceutical science for drug safety relating to the detection, assessment, understanding, and prevention of adverse effects of medicines. It extends from the clinical trials of a drug to the post-marketing phase and long-term follow-up in medical practice. It is the responsibility of the Food and Drug Administration (FDA) in the United States, the European Medicines Agency (EMA) in the European Union (EU), and relevant healthcare authorities in other countries. The goal of pharmacovigilance is to protect patients and to disseminate knowledge among the relevant professionals.

Epidemiology of ADRs In the United States, serious ADRs (sADRs) contribute to over 100,000 deaths per year and have been one of the leading causes of mortality over the past several decades and thus impose a significant public health concern. The exact incidence of DIND among sADRs is unknown. Reported adverse effects of drugs on the nervous system form only a small proportion of all neurological disorders, but they are under-recognized and under-reported. ADRs, both from clinical trials and postmarketing surveillance, are usually reported to the manufacturers of the product involved. The manufacturers make the initial assessment of these reports and file the ADRs with the health authorities of the countries involved according to the regulatory requirements. The World Health Organization (WHO) also maintains a database for ADRs. The reporting rate of ADRs is low, and even in countries with well-organized safety surveillance systems such as

Epidemiology of ADRs

Sweden and the United Kingdom, all the ADRs are not reported. The incidence of ADRs in hospitalized patients has been determined by meta-analysis of 39 prospective studies from US hospitals (Lazarou et  al. 1998). The overall incidence of ADRs was 6.7% and of fatal ADRs was 0.32% of hospitalized patients making these the fourth leading cause of death in the United States after heart disease, cancer, and stroke. The incidence is much higher than that assumed from the spontaneous reporting system which identifies only about 1 in 20 ADRs. In a study of 18,820 hospital admissions in the United Kingdom, 1225 were related to an adverse drug reaction, giving a prevalence of 6.5%, with the adverse drug reaction directly leading to the admission in 80% of cases (Pirmohamed et al. 2004). Assessment of 1263 consecutive admissions to the neurology unit of a Swiss university hospital over 1 year revealed drug-related problems in 29% of cases, and these were the cause of admission in 0.8% (Taegtmeyer et al. 2012). For determining incidence of adverse drug reactions, a study systematically reviewed all major electronic databases for studies published from 1990 to the end of 2018 and found that the body system associated with the most adverse reactions reported was the central nervous system (Khalil and Huang 2020). The most frequent adverse drug reactions were fatigue (55%) followed by dizziness (18.4%) and tremor (15.8%). Only a small fraction of the adverse drug reactions is published as case reports or as a part of the results of clinical trials of new drugs. Most of the information received by the pharmaceutical companies is inadequate for establishing the diagnosis of drug-induced neurologic disorders, but it is used for answering questions from physicians and for making decisions for inclusions of adverse reactions in basic drug information and package inserts. Most of the products listed in the Physicians’ Desk Reference include a mention of at least 1 untoward effect that relates to the nervous system. Entries in the list of adverse reactions are

5

not always based on medical judgment but may be a measure to protect the manufacturer against legal liability by having declared that such an adverse reaction has been reported. The adverse drug reaction may not be causally related to the drug, and this information is not of significant practical value for a neurologist. Currently, the Food and Drug Administration is proposing to reduce this bulky list of all adverse events to meaningful adverse drug reactions related to the drug. The frequency of occurrence of adverse events in clinical trials can be calculated and compared with that in the placebo group. An adverse event is an adverse drug reaction only if the relation to the drug is proven or suspected. The size of clinical trials is limited and seldom involves more than 500 patients, and, therefore, rare adverse drug reactions cannot be expected to show up in these trials. Postmarketing surveillance continues for the lifetime of a drug to detect such adverse drug reactions. The frequency of occurrence of adverse drug reactions in this phase is difficult to determine because of poor reporting rate and lack of knowledge of the denominator. The number of patients exposed to the drug is sometimes estimated from the quantity of the drug sold and the standard dose for a patient. These figures are not reliable because the amount of drug used by individual patients varies a great deal, and all the drugs sold are not administered to the patients. A study from Sweden showed that fatal adverse drug reactions account for approximately 3% of all deaths in the general population and two thirds of these were due to hemorrhages, of which 29% involved the nervous system (Wester et  al. 2008). Antithrombotic agents were implicated in more than half of the fatal adverse drug reactions. Chimeric antigen receptor T cell (CAR-T-cell) therapy has become an important tool in the treatment of relapsed and refractory malignancy; however, it is associated with significant neurologic toxicity. A study has revealed that neurologic side effects were extremely prevalent for

6

1  Introduction, History, and Epidemiology of Drug-Induced Neurological Disorders

individuals undergoing CAR-T-cell therapy, with 77% of participants displaying at least one manifestation of the following (Rubin et  al. 2019): encephalopathy (57%), headache (42%), tremor (38%), aphasia (35%), and focal weakness (11%).

 ssessment of Adverse Drug A Reactions  ources of Adverse Drug Reaction S Data FDA (Food and Drug Administration)-approved drug labeling is defined by the Code of Federal Regulations (21CFR201.57) of the United States and contains 17 distinct sections (Code of Federal Regulations Title 21 (21CFR) 201.57 2020). Each section provides specific information such as drug safety, efficacy, patient information, target populations, and clinical as well as nonclinical data (Fang et al. 2016). To promote the safe use of drug products and protect public health, ADR information is collected from clinical trials and postmarketing surveillance data and summarized in FDA-approved drug labeling as boxed warnings and precautions with different level of severity and coverage. Serious warnings are about ADRs that lead to death or serious injury, whereas warnings describe clinically significant ADRs. The Medical Dictionary for Regulatory Activities (MedDRA) is the standard medical terminology developed by the International Council for Harmonization (ICH) of Technical Requirements for Pharmaceuticals for Human Use and is used worldwide to facilitate the sharing of regulatory information for medical products. MedDRA is used for coding adverse events in the FDA’s Adverse Event Reporting System (FAERS). MedDRA is widely applied in analyzing ADR report data and in mining public health data for potential safety concerns. MedDRA terminology has been successfully used to code and investigate ADRs in a variety of studies. MedDRA has also been used to analyze ADRs in FDA drug labeling, but it may not provide an

adequate assessment of drug toxicity and severity, potentially undermining the utility of drug labeling. A study has demonstrated that combining MedDRA standard terminologies with data mining techniques facilitated computer-aided ADR analysis of drug labeling and highlighted the importance of labeling sections that differ in seriousness and application in drug safety (Wu et al. 2019). Using sADRs primarily related to boxed warning sections, a prototype approach for computer-­aided ADR monitoring and studies can be applied to other public health documents.

 ystems Pharmacology Approach S to Identify ADRs ADRs vary widely in mechanism, severity, and populations affected, making ADR prediction and identification important public health concerns. However, current methods for detection of ADRs by clinical trials are limited by small sample size, and postmarket surveillance may be biased. Patients remain at risk of ADRs until sufficient clinical evidence has been gathered. Systems pharmacology, an emerging interdisciplinary field combining network and chemical biology, provides important tools to uncover and understand ADRs and may mitigate the drawbacks of traditional methods for predicting ADRs. Network analysis enables researchers to integrate heterogeneous data sources and quantify the interactions between biological and chemical entities. Recent work in this area has combined chemical, biological, and large-scale observational health data to predict ADRs in both individual patients and global populations (Boland et  al. 2016). This approach provides a framework that incorporates important data elements, such as diet and comorbidities, which are known to modulate risk of ADRs.

Causality Assessment Drug-induced neurologic disorders can mimic neurologic disorders due to other causes;

Assessment of Adverse Drug Reactions

however, when a reasonable suspicion exists of association with a drug, or a known or plausible pathomechanism for drug-induced neurologic disorders, the drug should be considered in the differential diagnosis. Questionnaires, algorithms, and computer-based Bayesian approaches are used to assess the causal relationship of the drugs to the ADRs. None of these methods have found universal application because they are tedious, time-consuming, and expensive. In practice, causality is usually assessed by global judgment, i.e., opinion of the causal relation of the drug to the event after taking into consideration the available relevant information, as shown in the questionnaire in Table 1.2. The answers are taken into consideration to allocate the ADRs to the following categories: (1) probable, (2) possible, and (3) unlikely. These are approximate terms, and the term “definite” is rarely used. “Possible” means that such a reaction can take place with the drug, and sometimes this term is used simply because the possibility cannot be excluded. Sufficient information for assessment may not be available in some cases. This approach is a practical initial triage. Assessment of a DIND in a patient receiving a multimodal treatment is difficult. Patients undergoing organ transplants are liable to neurologic complications from the primary disease, the procedure, and the drugs (that include immunosuppressants and antibiotics). Critical decisions need to be made in the case of liver and heart

Table 1.2  A questionnaire for global evaluation of causal relationship of a drug to an adverse event (1) Is there a biological explanation (pathomechanism) for the adverse event? (2) Is the adverse event temporally related to the drug? (3) Do the symptoms subside after discontinuation of the drug? (dechallenge positive) (4) Do the symptoms recur after resumption of the drug? (rechallenge positive) (5) Is the event already known and documented (in literature or in the database of the manufacturer)? (6) Is the adverse event known to occur in the course of the natural disease? (7) Is the adverse event known with the concomitant therapy? Source: Jain (1995)

7

transplants. For this, an understanding of the pathomechanism of neurologic disorders and their natural history is important. An immunosuppressant may not need to be discontinued if the evidence for causal relationship is weak and the neurologic complications are transient. Anecdotal reports of suspected adverse drug reactions involving the nervous system are common in the medical literature and play an important role in providing early warning alerts. They are, however, of limited value because confirmatory investigations are not often carried out, and this information is not systematically incorporated into commonly used drug information sources.

 aranjo Scale for Causality N Assessments of ADRs Naranjo scale is like the scale given in Table 1.1 except that there are ten questions that are answered as either Yes, No, or “Do not know.” Different point values (−1, 0, +1, or +2) are assigned to each answer (Naranjo et  al. 1981). Total scores range from −4 to +13; the reaction is considered definite if the score is 9 or higher, probable if 5–8, possible if 1–4, and doubtful if 0 or less. There are some problems with reproducibility. Exact agreement between raters’ scores on the Naranjo scale and the published adverse reaction probability scores is infrequent leading to recommendation that authors of case reports include all pertinent details of the case and that journals ensure the robustness of the causality assessment by peer review (Liang et al. 2014)  ayesian Approach to Causality B Assessment of ADRs Reported cases are considered suspected ADRs, and health authorities have adopted structured causality assessment methods, enabling the evaluation of the likelihood that a drug was the causal agent of an ADR. A Bayesian approach is used to assess the probability that an ADR is drug induced. This approach uses the background information of relative incidence of the adverse event in exposed as well as nonexposed patients, based on likelihood ratios from specific case information. A posterior probability that the drug

8

1  Introduction, History, and Epidemiology of Drug-Induced Neurological Disorders

caused the adverse event is obtained from posterior odds determined from a combination of background information and case-specific data. Computerized models are available for the evaluation of some adverse events. Bayesian data mining in the US Vaccine Adverse Event Reporting System prospectively detected the safety signal for febrile seizures after the 2010–2011 seasonal influenza virus vaccine in young children (Martin et  al. 2013). Bayesian methodology has been found to be useful during interim analyses of clinical trials. A Bayesian framework has been developed for aggregating multiple types of evidence to assess the probability of a putative causal link between drugs and side effects. The Bayesian framework has been expanded to add evidential modulators, which bear on the assessment of the reliability of incoming study results, and the overall framework for evidence synthesis (E-Synthesis) is then applied to a case study (De Pretis et al. 2019). E-Synthesis is highly flexible concerning the allowed input, while at the same time relying on a consistent computational system. Furthermore, by introducing evidential modulators, and thereby breaking up the different dimensions of evidence (strength, relevance, reliability), E-Synthesis allows them to be explicitly tracked in updating causal hypotheses.

Diagnostic Assessment ADRs are often reported as symptoms, and these should be linked to a provisional neurologic diagnosis. There are two limitations to this assessment: 1. The assessor does not have access to the patient, and further information is usually difficult to obtain. 2. Drug safety specialists are rarely neurologists, and the average medical assessor does not have adequate neurological knowledge to carry out this step. Evaluation of literature. Publications showing the association of various drugs with DINDs fall into the following categories:

• Single case reports. This is the weakest evidence particularly if the case is not well documented. Unfortunately, this constitutes the bulk of the literature on adverse reactions to drugs. Such case reports are usually not peer reviewed. Reputable journals insist on minimum essential information before publishing these reports, but many inadequately documented reports also get published in obscure journals. Whether the causal relationship is proven or not, such reports cannot be ignored. Some of these reports may encourage other physicians to submit similar unreported cases for publication. • Multiple case reports. This is a stronger evidence than that provided by single case reports. • Reports of clinical trials of new drugs. These provide a useful source of adverse events for assessment. • Drug safety reviews. These serve a useful purpose of analyzing the cumulative evidence in literature. A good review should provide a critical analysis of the information, comments on pathomechanisms of DIND, and possibly suggestion for prevention and treatment. • Toxicology studies. Animal experimental studies provide toxicological information which may or may not be relevant to human DINDs but may provide an insight into pathomechanisms. • Epidemiological studies. These are the most useful source of information, particularly if they are properly designed prospective studies. • Textbooks on adverse drug reactions. Some well-known DINDs are listed in recognized textbooks of adverse drug reactions and can be quoted even though reference to the original source is not always provided. Some authors have attempted to stratify the information on ADRs according to the strength of evidence into various levels. The major drawback is that a rigid system of evaluation cannot be applied to “soft” data that is available from drug safety literature. The quality of information available varies from one drug to another, and application of strict criteria of evaluation might exclude

References

information which may useful even though it is anecdotal. Evidence is presented as available and pathomechanisms are described where possible. Drugs frequently mentioned and reported in relation to certain disorders are marked with asterisks in various tables, and the readers are left to make their own judgment.

Behavioral Toxicity A closely related topic to DIND is behavioral toxicity, which is the study of abnormal behavior that is caused by agents such as pharmaceuticals and other chemicals. Substances can adversely affect the normal function of the CNS, and this may result in the development of behavioral changes. Adverse changes to sensory function, motor coordination, learning ability, and memory can be affected by neurotoxicants. These changes are sometimes transient, but in certain instances, the changes are irreversible.

Clinical Significance Drug-induced neurological disorders (DIND) can mimic neurological disorders due to other causes. However, when there is a reasonable suspicion of association with a drug or a known or plausible pathomechanism for DIND, the drug should be considered in the differential diagnosis. For practical purposes ADRs in the categories A (probable) and B (possible) are taken into consideration. DINDs are presented according to various neurological systems. It has the advantage that a physician or a neurologist who is investigating a patient with a neurological problem has access to information about drugs which can cause that problem. One drawback is that ADRs seldom involve only one neurological system. There may be involvement of other systems of the body or involvement of another neurological system. Assessment of a DIND in a patient receiving a multimodal treatment is difficult. Patients undergoing organ transplants are liable to neurological complications of the primary disease, the proce-

9

dure, and the drugs which include immunosuppressants and antibiotics which are liable to induce neurological disorders. Critical decisions need to be made in case of liver and heart transplants. For this an understanding of the pathomechanism of neurological disorders and their natural history is important. An immunosuppressant may not need to be discontinued if the evidence for causal relationship is weak and the neurological complications are transient. In a study on liver transplant, the time of occurrence of CNS complications and the risk factors identified suggest that the pre-transplant condition and the surgical phase are the two most critical periods for developing CNS complications. Patients undergoing liver transplant with a severe pre-­ transplant medical disorders are at higher risk of experiencing CNS complications.

Concluding Remarks Drug-induced neurological disorders may be more frequent that they have hitherto considered to be. They can mimic naturally occurring neurological disorders or induce drug-specific syndromes. The current methods of data collection and assessment of ADRs drugs are inadequate. To improve the current situation, it would be important to establish registries for drug-induced neurological disorders.

References Arnott G, Caron JC.  Iatrogenic pathology in neurology. Lille Med. 1975;20:294–8. Boland MR, Jacunski A, Lorberbaum T, et  al. Systems biology approaches for identifying adverse drug reactions and elucidating their underlying biological mechanisms. Wiley Interdiscip Rev Syst Biol Med. 2016;8:104–22. Cathala JU.  La paralysie post-serotherapie. Presse Med. 1934;42:65–7. Code of Federal Regulations Title 21 (21CFR) 201.57. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfCFR/CFRSearch.cfm?fr=201.57. last revision 1 April 2019. Accessed on 20 Nov 2020. De Pretis F, Landes J, Osimani B. E-synthesis: a Bayesian framework for causal assessment in pharmacosurveillance. Front Pharmacol. 2019;10:1317.

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1  Introduction, History, and Epidemiology of Drug-Induced Neurological Disorders

Fang H, Harris SC, Liu Z, et  al. FDA drug labeling: rich resources to facilitate precision medicine, drug safety, and regulatory science. Drug Discov Today. 2016;21:1566–70. Globus JH, Kohn JL. Encephalopathy following pertussis vaccine prophylaxis. JAMA. 1949;141:507–9. Jain KK.  A short practical method for triage of adverse drug reactions. Drug Inf J. 1995;29:339–42. Khalil H, Huang C.  Adverse drug reactions in primary care: a scoping review. BMC Health Serv Res. 2020;20:5. Lazarou J, Pomeranz BH, Corey PN.  Incidence of adverse drug reaction in hospitalized patients. JAMA. 1998;279:1200–5. Liang R, Borgundvaag B, McIntyre M, et al. Evaluation of the reproducibility of the Naranjo Adverse Drug Reaction Probability Scale score in published case reports. Pharmacotherapy. 2014;3410:1159–66. Martin D, Menschik D, Bryant-Genevier M, Ball R. Data mining for prospective early detection of safety signals in the Vaccine Adverse Event Reporting System (VAERS): a case study of febrile seizures after a 2010–2011 seasonal influenza virus vaccine. Drug Saf. 2013;36:547–56. Mellin GW, Katzenstein M.  The saga of thalidomide. Neuropathy to embryopathy, with case reports of congenital anomalies. N Engl J Med. 1962;267:1184–92.

Naranjo CA, Busto U, Sellers EM, et  al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–45. Payk TR. Iatrogenic injuries in neurology. Fortschr Neurol Psychiatr Grenzgeb. 1974;42:97–111. Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ. 2004;329:15–9. Rao DB, Little PB, Malarkey DE, Herbert RA, Sills RC. Histopathological evaluation of the nervous system in national toxicology program rodent studies: a modified approach. Toxicol Pathol. 2011;39:463–70. Rubin DB, Danish HH, Ali Basil A, et  al. Neurological toxicities associated with chimeric antigen receptor T-cell therapy. Brain. 2019;142:1334–48. Taegtmeyer AB, Curkovic I, Corti N, et al. Drug-related problems and factors influencing acceptance of clinical pharmacologists’ alerts in a large cohort of neurology inpatients. Swiss Med Wkly. 2012;142:w13615. Wester K, Jönsson AK, Spigset O, Druid H, Hägg S. Incidence of fatal adverse drug reactions: a population based study. Br J Clin Pharmacol. 2008;65:573–9. Wu L, Ingle T, Liu Z, et al. Study of serious adverse drug reactions using FDA-approved drug labeling and MedDRA. BMC Bioinf. 2019;20(Suppl 2):97. Yajnik HV, Solanki SV. Iatrogenic neurological disorders. Indian J Med Sci. 1972;26:419–27.

2

Neurologic Symptoms as Adverse Drug Reactions

Introduction An adverse drug reaction (ADR) can present with a neurologic symptom which may be a disease entity by itself with several mechanisms, and several widely differing pharmaceutical agents may be the causative agents. Symptoms are first recorded as adverse events during clinical trials and form the basis of drug safety information in the drug leaflet or Physicians’ Drug Reference manuals when the drug is approved for practice. A higher percentage of reported symptoms is often arbitrarily linked to the significance of these. Examples of drug-induced adverse effects are headache and seizure disorders (epilepsy). Symptoms presenting as ADRs of drugs and background disease are shown in Table 2.1. Some of the symptoms will be described in this chapter briefly, whereas others are included in the associated or background diseases in various chapters of this book.

aphasia (total aphasia), all language functions are severely affected, so that the patient appears mute. Aphasia is most often seen after stroke but can also follow other neurological disorders, including traumatic brain injury, brain tumors, and neurodegenerative diseases. Dysphasia means impaired language rather than loss.

Drug-Induced Aphasia Aphasia as a direct ADR of a drug is rare and most likely occurs due to drug-induced cerebrovascular disease or neurotoxicity of illicit drugs. Published case reports of drug-induced aphasia are listed in Table 2.2. In some cases of drug-induced ataxia, the pathomechanism is not clear. It may be accompanied by other enruological symptoms and signs. Management depends on the type of aphasia or dysphasia and the associated disease.

Aphasia

Ataxia

Aphasia is the inability to formulate language because of focal damage to the cerebral cortex or subcortical structures in the area of the Sylvian fissure (areas supplied by the middle cerebral artery), most prominently after damage to the left side of the brain. Several subtypes of aphasia have been described. For example, in global

Ataxia is both a symptom and a sign of incoordination. Ataxic movements are poorly organized and usually indicate dysfunction of the cerebellum or its numerous connections with other parts of the CNS.  There are several classifications of ataxia, and it is among the presenting features of several hereditary and degeneration disorders. Other

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_2

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2  Neurologic Symptoms as Adverse Drug Reactions

12 Table 2.1  Symptoms presenting as ADRs of drugs Symptom Aphasia

Ataxia Dysarthria

Dysphagia Falls

Headache Hearing loss Hiccups Insomnia Nausea and vomiting Neurogenic bladder

Smell and taste disturbances Syncope Tremor Vertigo and dizziness Visual impairment and diplopia Yawning

Comments/associated/background disorder Focal neurotoxicity of some drugs Drug-induced cerebrovascular disease Illicit drug use It is both a symptom and a sign of incoordination usually indicating dysfunction of the cerebellum or its numerous connections with other parts of the CNS Difficulty in speech due to articulation of words resulting from neurologic disturbances of function of orofacial muscles, tongue, lips, and throat in several disorders Dysphagia, difficulty in swallowing, is due to mechanical or neuromuscular causes; the latter is more relevant to neurological disorders Sudden falls or drop attacks are without loss of consciousness and are not precipitated by a specific stimulus. They occur in several neurological disorders, and the elderly are more at risk of drug-induced falls See Chap. 22 for drug-induced headache Hearing loss is both a symptom and a sign and is discussed in detail in Chap. 25 on neurootological disorders Inappropriate respiratory muscle contractions that can occur due to systemic disorders, brain stem lesions, and as adverse drug reactions See Chap. 19 for drug-induced sleep disorders Occur due to many causes and diseases involving several systems, including neurologic disorders, and as adverse drug reactions This is the term used for urinary symptoms and signs indicating lack of bladder control due to a CNS or peripheral nerve damage. It may present as underactive bladder leading to urinary retention or overactive bladder leading to increased frequency of micturition; both can be drug-induced See Chap. 27 for this topic See Chap. 16 on disturbances of consciousness The rhythmic quality distinguishes tremor from other involuntary movements. Associated with several disorders See Chap. 25 on neurootological disorders See Chap. 26 on drug-induced neuroophthalmological disorders Excessive yawning is now increasingly linked to neurologic disorders, and several drugs have been reported to induce yawning

© Jain PharmaBiotech

causes include cerebellar tumors and other lesions of the cerebellum. Toxic- or drug-related causes of ataxia are medications and recreational drugs, alcohol, and other toxic exposures such as lead, mercury, thallium, carbon monoxide, and ciguatera.

Drug-Induced Ataxia Cerebellar ataxia can be induced by several drugs. A systemic review of the literature up to 2016 and querying the national ADR register of Netherlands to identify all of the drugs that can have ataxia as an adverse effect revealed that the most common groups were antiepileptics,

benzodiazepines, and antineoplastic drugs (van Gaalen et al. 2014). A patient presenting with ataxia may have the following drug-induced causes affecting different parts of the CNS: • Cerebellar: degeneration or hemorrhage • Cerebral: encephalopathy • Spinal cord: myelopathy with posterior column involvement • Brainstem: transient ischemic attacks • Frontal lobe lesions in encephalomyelitis Drugs reported to be associated with ataxia are shown in Table 2.3.

Dysarthria

13

Table 2.2  Case reports of drug-induced aphasia Drug Cisplatin Cyclosporine A Ifosfamide Immunomodulatory drugs (thalidomide, lenalidomide, pomalidomide) Ipilimumab

Lamotrigine Metrizamide myelography Naftidrofuryl oxalate Phenylpropanolamine

Symptoms Aphasia, confusion, and agitation Aphasia Aphasia, confusion, hallucinations, and coma Expressive aphasia and dysarthria, amnesia, and reversible coma Aphasia, tremor, ataxia, myoclonus, hallucinations, anxiety, and agitation Global aphasia

Quetiapine Salazosulfapyridine

Expressive dysphasia Aphasia Nominal aphasia and acute memory loss Global aphasia Aphasia, hemiplegia

Sulfasalazine Vigabatrin

Dysphasia, seizures Aphasia

Mechanism Central neurotoxicity

Reference Higa et al. (1995)

Central neurotoxicity Central neurotoxicity

Rodriguez et al. (1992) Curtin et al. (1991)

Central neurotoxicity

Patel et al. (2015)

? Related to antithyroid antibodies

Carl et al. (2015)

EEG abnormalities

Battaglia et al. (2001) Sarno et al. (1985) Matschke (1987) Puar (1984)

Neurotoxic reaction Unclear Unclear Antidopaminergic effect Drug-induced hypersensitivity syndrome and SIADH Unclear Unclear

Chien et al. (2017) Morinaga et al. (2019) Hill et al. (1994) Gil and Neau (1995)

© Jain PharmaBiotech Abbreviation: SIADH syndrome of inappropriate secretion of antidiuretic hormone

In most patients, ataxia occurs within days or weeks after the introduction of a new drug or an increase in dose. Ataxia tends to disappear after discontinuation of the drug, but chronic ataxia has been described for some drugs.

Dysarthria Dysarthria is defined as difficulty in articulation of words due to neurologic disturbances of function of orofacial muscles, tongue, lips, and throat. Total inability to articulate is termed anarthria. It can be due to lesions at several levels from the cortex down to cranial nerves. A well-known type is ataxic dysarthria due to cerebellar lesions. Dysarthria is a manifestation of several disorders listed in Table  2.4, both sys-

temic and neurologic, that affect coordination of speech. There is an overlap of localization as well as pathology.

Drug-Induced Dysarthria Drugs associated with dysarthria as an adverse effect are listed in Table 2.5. Drugs act at different levels of the nervous system to cause dysarthria: • Cerebral cortex. Slurring of speech can be due to effect of sedative-hypnotic drugs on the cerebral control of speech. • Central anticholinergic effect of some drugs such as tricyclic antidepressants can lead to speech block, i. e., halt in normal speech patterns.

14 Table 2.3  Drugs associated with ataxia Anticholinergic agents Antiepileptic drugs  Carbamazepine  Gabapentin  Lamotrigine  Oxcarbazepine  Phenytoin  Pregabalin  Tiagabine  Topiramate  Valproic acid  Vigabatrin Anticancer agents   Cisplatin   Cytarabine   Fluorouracil   Methotrexate Sedative-hypnotics   Barbiturates   Benzodiazepines   Zolpidem Miscellaneous drugs   Amiodarone   Cyclosporine   Lithium  Nitrous oxide Alcohol Recreational drugs  Ketamine  Dextromethorphan   Phencyclidine © Jain PharmaBiotech

• Cerebellum. Scanning speech can result from drugs such as lithium and phenytoin which have a toxic effect on the cerebellum. • Neuromuscular blockade, an adverse effect of drugs such as aminoglycoside antibiotics, can produce a myasthenic syndrome and cause fatigability of speech. • Orofacial movement disorder in tardive dyskinesia due to neuroleptic therapy can make articulation difficult. Drug-induced dysarthria may be a manifestation of extrapyramidal syndrome as suggested in a case report of dysarthria following treatment with paroxetine in a 42-year-old man with pathological laughter resulting from traumatic brain injury (Park et al. 2011). Dysarthria disappeared

2  Neurologic Symptoms as Adverse Drug Reactions Table 2.4  Causes of dysarthria Neurologic disorders with dysarthria as a symptom  Stroke: cerebrovascular ischemic disorders  Neurodegenerative disorders  Complications of surgery for posterior fossa tumors  Encephalitis  Cerebral palsy  Cerebellar disorders  Brainstem disorders  Movement disorders  Epileptic disorders  Demyelinating diseases  Myopathies  Cranial nerve lesions Dysarthria in metabolic diseases with neurologic manifestations  2-Hydroxyglutaric aciduria  Ornithine transcarbamylase deficiency Dysarthria as part of syndromes with other manifestations  Fabry disease  Hereditary spastic paraparesis  Di George syndrome or 22q11.2 deletion syndrome  Dysarthria-facial paresis syndrome  Dysarthria-clumsy hand syndrome  Moebius syndrome  Niemann-Pick disease  Pompe disease  Raynaud syndrome involving the tongue   SANDO (sensory ataxic neuropathy, dysarthria, and ophthalmoplegia) Drug-induced dysarthria (see Table 2.5) Exposure to toxins and metals  Mercury poisoning  Botulism  Nerve agent poisoning

Table 2.5  Drugs associated with dysarthria as an adverse effect Anticancer agents: irinotecan (Zhen et al. 2019) Antiepileptic drugs: phenytoin Antipsychotic: aripiprazole Atropine overdose during minor procedures Benzodiazepines Lithium neurotoxicity Neuroleptic drugs Paroxetine, a selective serotonin reuptake inhibitor © Jain PharmaBiotech

following discontinuation of paroxetine. A mixed hyperkinetic-hypokinetic dysarthria has been reported in ephedrone-induced parkinsonism and

Dysphagia

is associated with marked dystonia as well as bradykinesia; it is likely due to manganese-induced damage to the basal ganglia (Rusz et al. 2014). Dysarthria developed 3 weeks after addition of aripiprazole (an antipsychotic) to a boy’s medications for attention-deficit hyperactivity disorder (Han et al. 2017). On examination, he showed curtaining of the pharyngeal wall, tongue fasciculation and deviation, and a weak gag reflex. MRI suggested lower cranial nerve involvement. Serum anti-GM1 IgG and anti-GD1b IgG antibodies were positive. After stopping aripiprazole, his bulbar symptoms improved. However, on readministration of aripiprazole 7 weeks later, dysarthria recurred and again resolved after stopping the drug. Irinotecan-induced dysarthria in a man being treated for colon cancer resolved with the ­discontinuation of irinotecan (Lee et  al. 2013). Recurrence could be prevented in this case by modifying the cycles of chemotherapy and prolonging the duration of intravenous administration of the drug. A case of acute dysarthria and delirium with suspected stroke has been reported after a dental procedure with an overdose of sublingual atropine due to miscalculation, but intravenous physostigmine completely reversed the symptoms, confirming atropine toxicity as the cause as well as providing an effective therapy (Cole et al. 2018).

Dysphagia Dysphagia is defined as the difficulty in the oral preparation of food for swallowing and as the difficulty in the passage of the food bolus through the oropharynx and esophagus to the stomach. Both definitions may be involved, but only one classification of dysphagia is based on the distinction between these two phases: (1) oropharyngeal dysphagia, or transfer dysphagia, is associated with injuries of the muscles that regulate the movement of the oral cavity and upper esophageal sphincter, whereas (2) esophageal dysphagia refers to the disordered movement of food within the esophagus. The term “swallowing apraxia” was proposed for disorders of lin-

15

gual, labial, and mandibular coordination that are observed before bolus transfer during the oral stage of swallowing. Swallowing involves a larger neural network that includes the anterior insula and cerebellum. Dysphagia can be due to mechanical or neuromuscular causes, and the latter is more relevant to neurological disorders. Causes of neuromusclar dysphagia are listed in Table 2.6.

Drug-Induced Dysphagia Neuromuscular dysphagia should be differentiated from mechanical dysphagia, which can be due to several lesions including esophagitis. Drug-induced esophagitis is esophageal mucosal injury caused by the medications and usually refers to a direct toxic effect by the offending medication. Drug-induced neurologic disorders with dysphagia are listed in Table 2.7.

Table 2.6 Classification of causes of neuromusclar dysphagia Scleroderma Dermatomyositis Hollow viscus myopathy Diffuse esophageal spasm Lower esophageal sphincter achalasia Lesions in neural network controlling swallowing: swallowing center (anterior insula and cerebellum) or brainstem involving nuclei of lower cranial nerves Cranial nerve lesions: V, VII, IX, X, XII Degenerative neurologic disorders: Parkinson disease, Huntington disease, amyotrophic lateral sclerosis CNS trauma: traumatic brain injury, cervical spinal cord injury Lower motor neuron lesions: poliomyelitis Upper motor neuron lesions: pseudobulbar paralysis Disorders of the autonomic nervous system: pandysautonomia Neuromuscular disorders: myasthenia gravis Muscle disorders: myopathies Movement disorders Local anesthetic application in oropharynx Complications of surgical procedures Drug-induced neurologic disorders with dysphagia Muscle disorders induced by toxins and drugs © Jain PharmaBiotech

16 Table 2.7 Drug-induced neurologic disorders with dysphagia Anticholinergic syndrome (see Chap. 29) Antipsychotic-induced movement disorders: tardive dyskinesia Botulinum toxin therapy Muscle relaxants impairing swallowing reflex Neuroleptic malignant syndrome (see Chap. 39) Phenytoin toxicity Sedative/hypnotic/narcotic medications: barbiturates, benzodiazepines, morphine © Jain PharmaBiotech

2  Neurologic Symptoms as Adverse Drug Reactions Table 2.8  Drugs reported to predispose to falls Anticholinergic agents Antidepressants  Nortriptyline  Venlafaxine Antiepileptic drugs Antipsychotics  Olanzapine Cardiovascular drugs  Amantadine  Beta blocking agents  Calcium channel blockers  Diuretics  Renin-angiotensin system inhibitors  Vasodilators Hypnotics and sedatives  Bromazepam  Diazepam Opioids

Dysphagia is usually relieved by discontinuation of the offending drug. A case of phenytoin-­ induced dysphagia with lack of velopharyngeal coordination and nasopharyngeal reflux combined with massive palatine tonsillar hypertrophy was relieved by discontinuation of phenytoin © Jain PharmaBiotech (Hwang 2017). However, sufficient time should be allowed for lymphoid hypertrophy to resolve ture risk. The older persons are more prone to resolution before considering surgery. falls than younger persons due to increased drug use, reduced physiological functions, and altered pharmacokinetics and pharmacodynamics. Also, Falls the relative role of specific genes and polymorphisms in old age may differ from younger peoSudden falls or drop attacks are without loss of ple. A list of drugs reported to predispose to falls consciousness that are not precipitated by a spe- is shown in Table 2.8. cific stimulus, occur with abrupt onset and withAntidepressants and anxiolytics are the most out warning, and are followed by a rapid return to frequently used drugs that increase the risk of baseline. Falls due to syncope and epileptic sei- falls, and interventions to prevent falls in elderly zures are not included as they may involve loss of patients with a focus on reducing the total numconsciousness. The following are considered in ber of drugs and withdrawing psychotropic medithe investigation of a patient with falls: cations might improve the quality of drug (Milos et  al. 2014). Most of the drug-related causes of • Adverse effects of drugs falls are due to drug intoxication although the • Cerebellar disorders underlying mechanism varies as follows: • Dementia • Movement disorders, e. g., parkinsonism • Decreased renal functioning if a patient is pre• Neuromuscular disorders: neuropathy and scribed a renally excreted drug without dose myopathy adjustment • Vestibular disorders • Decreased hepatic metabolism leading to higher serum concentration of the drug • Inherited absence of the CYP2D6 enzyme Drug-Induced Falls • Anticholinergic side effects Falls are the leading cause of injuries among older persons. Use of several types of drugs has been associated with an increased fall and frac-

Drug-related falls are potentially preventable, and therapeutic drug monitoring may help to identify persons who are at risk for falls due to

Nausea and Vomiting

drug use. Biomarkers for frailty but also genomic biomarkers might help in identifying patients at high risk for drug-induced falls. Many other factors including disease and drug-drug interactions also contribute to risk of falls (Just et al. 2017). Lowering of the dose stops the falls in most cases. However, plasma levels within the therapeutic range do not exclude the diagnosis of drug-­ induced falls (Hartholt et al. 2016).

Hiccups Hiccups are inappropriate respiratory muscle contractions that can occur due to gastrointestinal, respiratory, neurologic, and general systemic disorders as well as a sequel to surgery or adverse reaction to drugs. Among the neurologic lesions that can cause persistent hiccups, brainstem lesions figure prominently. Benign posterior fossa tumors can cause hiccups by compression of the brainstem. This is relieved following the removal of the tumors.

Drug-Induced Hiccups Drug-induced hiccups are shown in Table 2.9.

Table 2.9  Drug-induced hiccups Alcohol Anesthetics Antibiotics: beta-lactams, macrolides, fluoroquinolones Atypical antipsychotic: clozapine Benzodiazepines Barbiturates Chemotherapy Corticosteroids Digitalis Dopamine agonists used for Parkinson disease Intrathecal morphine infusion (Loomba et al. 2012) Nicotine gum Opioids Phenytoin (Asadi-Pooya et al. 2011) Sedatives Selective serotonin reuptake inhibitors, e.g., sertraline (Bilgiç 2019) Tricyclic antidepressants © Jain PharmaBiotech

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The cause of hiccup, if identified, should be treated. For example, the offending drug may be discontinued, or its administration may be modified. For example, a randomized, multicenter, phase III trial showed that hiccup intensity was significantly lower when the antiemetic corticosteroid was rotated from dexamethasone to methylprednisolone without a change in emesis intensity than that when dexamethasone was maintained (Go et al. 2017).

Nausea and Vomiting Vomiting is under the control of a “vomiting center” in the reticular formation and a chemoreceptor trigger zone in the area postrema of the floor of the fourth ventricle. Nausea and vomiting occur due to many causes and diseases involving several systems, including neurologic disorders shown in Table 2.10. Vomiting can be the initial manifestation of a neurologic disorder such as raised intracranial pressure. Investigation of vomiting includes consideration of neurologic and gastrointestinal disorders as well as system diseases or the action of drugs or toxins. The mechanisms of nausea and vomiting are often used as a basis for development of drugs to counteract the nausea and vomiting associated with surgery, chemotherapy, and radiation.

Table 2.10  Neurologic disorders associated with nausea and vomiting Abdominal migraine Autonomic epilepsy Benign intracranial hypertension Encephalopathy Hemorrhagic stroke Hydrocephalus Meniere disease Meningitis Raised intracranial pressure due to mass brain lesions Subarachnoid hemorrhage Traumatic brain injury © Jain PharmaBiotech

18 Table 2.11  Drugs that can induce nausea and vomiting A1-adrenergic receptor agonists: ephedrine Alcohol Anesthetics: postoperative vomiting Antibiotics Anticonvulsant medications Apomorphine Cardiac drugs, e.g., digitalis Chemotherapeutic agents Dopamine agonists: ropinirole Nonsteroidal antiinflammatory drugs Opioid analgesics Progesterone Radiotherapy for cancer Vasopressin

2  Neurologic Symptoms as Adverse Drug Reactions

Vasopressin  Vasopressin is produced in the supra-optic portion of the hypothalamus and transported to the posterior pituitary; it is an important hormonal mediator of nausea and vomiting. Serum levels of vasopressin are raised in motion sickness, following stimulation of the vagal afferents and after injection of apomorphine.

Progesterone  Progesterone is one of the important hormones responsible for nausea and vomiting. Its major site of action is the GABAA receptor. The secretion of progesterone is determined by the hypothalamic-pituitary-gonadal © Jain PharmaBiotech axis. Gonadotropin-releasing hormone from the arcuate nucleus of the hypothalamus controls the release of the follicle-stimulating hormone and the luteinizing hormone in the anterior pituitary. Drug-Induced Nausea and Vomiting This part of the reproductive cycle in women is Drugs and other therapeutics causing nausea and characterized by nausea and vomiting. Luteinizing hormone is responsible for the matuvomiting are shown in Table 2.11. ration of corpus luteum, which becomes an endoCorticotropin-Releasing factor  Corticotropin-­ crine organ and secretes 17-hydroxyprogesterone releasing factor is produced in the paraventricu- and later progesterone. Both these hormones are lar nuclei of the hypothalamus and controls the key factors in the occurrence of nausea and vomproduction and secretion of pro-opiomelanocor- iting in the irritable bowel syndrome. tin by the anterior pituitary. This prohormone subsequently gives rise to adrenocorticotropic hormone, beta-endorphins, and beta-melanocyte Dopamine Agonist-Induced Nausea and stimulating hormone. Adrenocorticotropic Vomiting  Ropinirole, a non-ergoline dopamine ­hormone stimulates the adrenal glands to release agonist, is commonly associated with nausea and cortisol and catecholamines, i.e., epinephrine vomiting in patients being treated for restless legs and norepinephrine, which inhibit the stomach syndrome. Nausea and vomiting represented and the small intestine and may produce nausea. nearly 50% of all adverse events reported for ropA1-adrenergic receptor agonists such as ephed- inirole (Kurin et al. 2018). rine can produce nausea by mimicking the adrenal response of catecholamine release. Nausea and Oversecretion of adrenocorticotropic hormone Chemotherapy-Induced Vomiting   Nausea and vomiting as an adverse in response to persistent stress can produce chronic nausea and vomiting. Acute nausea acti- reaction to chemotherapy are common and well vates the hypothalamo-pituitary-adrenal axis and recognized. The gastrointestinal tract and the the neurohypophyseal system. Nausea can, thus, cerebral cortex are identified as sources of afferbe the cause as well as an effect of neurohypoph- ent input to the vomiting center in chemotherapy. yseal disturbances. Production and release of The chemoreceptor trigger zone, which lacks the beta-­endorphins can have the same effect as an protective blood-brain barrier, is exposed to subinjection of morphine or another opioid, i.e., stances in the systemic circulation in addition to those circulating in the cerebrospinal fluid of the nausea and vomiting.

Nausea and Vomiting

brain. Various neurotransmitters involved in chemotherapy-­induced nausea and vomiting are dopamine, acetylcholine, histamine, and serotonin. Receptors for each of these neurotransmitters are found in the vomiting center, the chemoreceptor trigger zone, and the gastrointestinal tract. Activation of these receptors by chemotherapy, metabolites, or neurotransmitters can be responsible for nausea and vomiting. Serotonin (5-HT), which is released from the chromaffin cells in the intestinal mucosa following chemotherapy, binds to 5-HT3 receptors that are found both in the peripheral vagal nerve terminals in the gastrointestinal tract and in high concentration in the area postrema of the brain where chemoreceptor trigger zone is located. 5-HT3 antagonists do not prevent release of serotonin but bind to 5-HT3 receptors and prevent chemotherapy-­induced nausea and vomiting by preventing agonism of the 5-HT3 receptors by serotonin. Substance P is one of the four mammalian tachykinins found in neurons, which innervate the brain stem nucleus tractus solitarius and area postrema in the region of the vomiting center. Substance P produces vomiting when applied to cells of tractus solitarius. The biological actions of substance P are mediated through the neurokinin-­1 (NK-1) receptor, a G protein receptor coupled to the inositol phosphate signal transduction pathway. NK-1 receptors are highly concentrated in the brain and bind the neurokinin substance P.  Activation of NK-1 receptors plays a central role in nausea and vomiting induced by emetogenic stimuli, including certain cancer chemotherapies. NK-1 receptor antagonists have been demonstrated to improve the management of nausea and vomiting experienced by cancer patients undergoing chemotherapy. Radiotherapy-Induced Nausea and Vomiting  As many as 40–80% of patients undergoing radiotherapy will experience nausea or vomiting, depending on the site of irradiation, dose, radiotherapy techniques, and recent chemotherapy.

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 anagement of Drug-Induced Nausea M and Vomiting Diagnosis  Temporal relation with drug ingestion is the most important clue for drug-induced vomiting. Drugs may have a central emetic action or local irritant action on the gastric mucosa. Drug-induced vomiting should be differentiated from that associated with the primary disease, such as cancer. Treatment  Several methods of treatment are available for the control of nausea and vomiting. Multiple approaches with varying degrees of efficacy for management of nausea and vomiting are available. The most effective approach is administration of a 5-HT3-receptor antagonist, which reduces or prevents emesis in 50% of patients, and it increases to 70% when the agent is given in combination with dexamethasone with further increase to approximately 84% when an NK-1-­ receptor antagonist is added (Navari and Aapro 2016).

Management of Opioid-Induced Nausea and Vomiting  Approximately 40% of patients experience nausea, and 15–25% of patients may suffer from vomiting after opioid administration. Nausea often precedes vomiting, although they can occur separately. Several medications can be used to treat opioid-induced nausea and vomiting including serotonin receptor antagonists, dopamine receptor antagonists, and neurokinin-1 receptor antagonists (Mallick-Searle and Fillman 2017).

Management of Chemotherapy-Induced Nausea and Vomiting  Selective 5-HT3 antagonists, neurokinin-1 antagonists, and corticosteroids are the most effective therapeutic agents for chemotherapy-induced nausea and vomiting. A systematic review has shown that there is no significant difference between a short or long course of dexamethasone for preventing nausea or vomiting, but a short course was associated with fewer adverse effects (Raghunath et al. 2020).

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Considerable progress has been made in the prophylaxis of chemotherapy-induced nausea and vomiting with the introduction of NK-1 inhibitors. Dolasetron, granisetron, palonosetron, ondansetron, and tropisetron are agents with a high therapeutic index. Delayed nausea and vomiting after chemotherapy are best prevented by a combination of ondansetron with dexamethasone if given within the first 24 hours after start of chemotherapy. Another method is a single dose of 0.25  mg of palonosetron hydrochloride, a next generation 5-HT3 antagonist, by intravenous injection approximately 30 minutes before the start of chemotherapy. Further clinical studies of palonosetron have shown prolonged half-life and high receptor affinity, making it an effective antiemetic agent against chemotherapy-induced nausea and vomiting. Oral formulation of palonosetron is also available. A pilot study has shown the efficacy of gabapentin for controlling chemotherapy-induced nausea and vomiting (Cruz et al. 2012). Rolapitant, a potent and orally active neurokinin NK-1 receptor antagonist, is approved by the US Food and Drug Administration for prevention of delayed chemotherapy-induced nausea and vomiting in adults. Data from randomized clinical trials support the use of an olanzapine for the treatment of breakthrough chemotherapy-induced nausea and vomiting (Hocking and Kichenadasse 2014). In a randomized, double-blind, placebo-controlled phase 3 trial, olanzapine significantly improved nausea prevention as well as the completeresponse rate among previously untreated patients who were receiving highly emetogenic chemotherapy (Navari et al. 2020). Cannabidiol, a nonpsychotropic cannabinoid, reduces nausea and vomiting during chemotherapy (Mortimer et al. 2019).

Neurogenic Bladder Dysfunction Neurogenic bladder is the term used for urinary symptoms and signs indicating lack of bladder control due to a CNS or peripheral nerve damage, which may present as underactive bladder leading to urinary retention or overactive bladder leading

2  Neurologic Symptoms as Adverse Drug Reactions

to increased frequency of micturition or urinary incontinence. Neurogenic bladder may be the result of spinal cord injury, stroke, encephalitis, multiple sclerosis, dementia, Parkinson disease, or diabetes. It can also be caused by injury to nerves during major pelvic surgery. Children born with congenital malformation, e.g., spina bifida, may develop neurogenic bladder.

Drug-Induced Neurogenic Bladder A patient who presents with neurogenic bladder dysfunction can have drug-induced causes as shown in Table 2.12.

Tremor Tremor is the rhythmical involuntary oscillations of a part of body around a fixed point, usually in one plane. The rhythmic quality distinguishes tremor from other involuntary movements; its biphasic character distinguishes it from clonus. Most tremor classifications are based on four clinical features: (1) anatomical pattern; (2) the relative prominence at rest, on maintaining a Table 2.12  Drug-induced neurogenic bladder Anticholinergic drugs that cause urinary retention  Antimuscarinic agents: atropine, scopolamine, oxybutynin, tolterodine, propantheline  Antinicotinic agents: trimethaphan, mecamylamine  Neuromuscular anticholinergic agents used as muscle relaxants during surgery: e.g., tubocurarine  Other drugs with anticholinergic activity: neuroleptics, tricyclic antidepressants Drugs that induced hyperactivity of nerves  Antihypertensive drugs (particularly alpha blockers) can result in stress incontinence  Bethanechol  Botulinum toxin  Estrogen can cause both stress and urge incontinence  GABA supplements  Selective serotonin reuptake inhibitors (e.g., escitalopram) can cause urge incontinence Secondary effect of drugs that cause  Autonomic neuropathy (see Chap. 29)  Encephalopathy (see Chap. 13)  Myelopathy (see Chap. 31) © Jain PharmaBiotech

Tremor

posture, and on action; (3) frequency; and (4) amplitude. For example, tremor at rest suggests Parkinson disease, but the diagnosis depends if the patient has other signs of the disease. Resting (static) tremor occurs in a part that is supported and relaxed. It is typically found in Parkinson disease and is rare as a manifest. Action tremor is one that develops only during movement. The intention tremor of cerebellar disease is an action tremor that shows progressive exaggeration in goal-directed movements, as in finger-nose test. This type of tremor indicates cerebellar dysfunction and is rare with drugs except anticonvulsants and lithium. The most common causes of postural tremor are physiological tremor, essential tremor, and drug-induced tremor (Alty and Kempster 2011). Physiological tremor is present in all muscle groups and can rarely be seen by the naked eye. It is present throughout the waking state and in some phases of sleep as well. It ranges in frequency between 8 and 13 Hz. The amplitude of this type of tremor can be increased directly, or indirectly, by drugs. Postural tremor is the type of tremor which appears when the position of the body is actively maintained against the force of gravity. Essential tremor and Parkinson disease are clinically, pathologically, and chemically distinct. Benign familial essential tremor is an idiopathic, dominantly inherited, postural tremor of variable amplitude with frequency range like that of physiological tremor. Propranolol and primidone are useful firstline medications for essential tremor. Cardioselective beta-blockers, such as metoprolol and atenolol, may relieve essential tremor, whereas non-selective beta-blocker pindolol exacerbates it.

Drug-Induced Tremor The tremor frequency has a wide range from 3 to 12  Hz. Various drugs which induce or enhance tremor are listed Table 2.13. The most common clinical features of these tremors are enhanced physiologic tremor in patients exposed to sympathomimetics and antidepressants. Parkinsonian tremors are well

21 Table 2.13  Drugs that induce or enhance physiological tremor Anticonvulsantsa  Lamotrigine  Phenytoin  Valproic acid Antidepressantsa  Monoamine oxidase inhibitors  Selective serotonin reuptake inhibitors (see Chap. 36 on serotonin syndrome)  Tricyclic antidepressants, e.g., amitriptyline Antihyperglycemic drugsa Beta-adrenergic agonistsa Calcium channel blockersa  Cinnarizine  Flunarizine Cardiac antiarrhythmics  Amiodarone  Procainamide Chemotherapeutic agents  Cytarabine Cimetidine CNS stimulantsa  Amphetamines  Caffeine  Cocaine  Ephedrine Corticosteroidsa Cotrimoxozole Cyclosporine Dopamine receptor blocking agents  Antipsychoticsa  Domperidone  Droperidol  Metoclopramide Histamine H1-antagonists Hormones  Epinephrine  Thyroxinea Immunosuppressants  Cyclosporine  Tacrolimus Levodopaa (see levodopa-related movement disorders, Chap. 22) Lithium a Methyldopa Metoclopramide Nicotine Pindolol Reserpine Theophyllinea Tumor necrosis factor Vidarabine (continued)

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2  Neurologic Symptoms as Adverse Drug Reactions

Table 2.13 (continued)

the central component (amitriptyline). Other drugs can cause tremor, presumably by blockade of dopamine receptors in the basal ganglia (dopamine-­blocking agents), by secondary effects such as causing hyperthyroidism (amiodarone), or by other mechanisms (Morgan et al. 2017). Tremor at rest is observed in 11.2% of patients treated with valproate and is related to the burden © Jain PharmaBiotech a of valproate-induced tremor, rather than the presWell documented ence of parkinsonism (Baizabal-Carvallo and Alonso-Juarez 2019). Valproate-induced tremor known to occur with neuroleptic and dopamine may resemble that observed in patients with receptor blocking agents. Characteristically the essential tremor. In a comparative study, patients drug-induced tremors are postural although they with valproate-induced tremor were found to be can produce a typical resting parkinsonian significantly younger than those with essential tremor. Antipsychotic drugs produce a low-­ tremor and had a shorter evolution time of treatfrequency postural tremor, whereas anticonvul- ment (Alonso-Juarez and Baizabal-Carvallo sant drugs produce a high-frequency, 2018). Moreover, patients with valproate-induced low-amplitude tremor. Other drugs may enhance tremor requiring pharmacological treatment had physiological tremor when it is referred to as similar distribution, clinical rating scale for drug-induced tremor. Drug-induced tremor may tremor scores, and functional impact than those be a part of other syndromes such as serotonin with essential tremor. syndrome and drug-induced parkinsonism. The term “tardive tremor” is used for Treatment of Drug-Induced Tremor antipsychotic-­ induced tremor which persists Upon encountering a patient with tremor during after discontinuation of the offending drug and is treatment with agents known to cause tremor, it is usually accompanies by tardive dyskinesia and worthwhile to discontinue the agent if this is postardive dystonia. Tardive tremor is predominantly sible. Propranolol is frequently used for treatment postural with a frequency range of 3–5 Hz. of tremor, but it is not always effective. Valproateinduced tremor has been managed successfully by Pathomechanism of Drug-Induced adding acetazolamide to the therapy. Withdrawala  Alcohol  Barbiturates  Benzodiazepines  Beta blockers  Gamma-hydroxybutyrate  Opiates

Tremor Pathomechanism of tremor is not well understood. Several other drugs exacerbate physiological and essential tremors by different mechanisms. While the parkinsonism and tardive dyskinesia of antipsychotics are related to dopamine receptor blocking properties, the tremor-inducing effect may result from other properties. Physiological tremor may be exacerbated through the increase in catecholamines. Cimetidine is postulated to increase tremor by blockade of central H2 receptors. The mechanism underlying the genesis of slower and more complex and disabling drug-­ induced tremor is even less clear. Some medications (epinephrine) that cause enhancement of physiological tremor likely do so by peripheral mechanisms in the muscle (β-adrenergic agonists), but others may influence

Yawning A yawn is an involuntary sequence of mouth opening, retraction of the tongue, deep inspiration, brief apnea, and slow expiration. Excessive yawning, which is defined as three or more yawns per 15 minutes, is pathological and may be a sign of neurological disorder. Motor centers of the brainstem (nuclei of V, VII, IX, X, XI, and XII cranial nerves) and the spinal cord are involved in yawning, and these are further controlled by the paraventricular nucleus of the hypothalamus (Collins and Eguibar 2010). A group of oxytocin neurons situated in the parvocellular region of the paraventricular nuclei and extending toward the hippocampus

Yawning

23

facilitate yawning, in conjunction with the locus Table 2.14 Disorders associated with pathologic coeruleus and the spinal cord. The insula has also yawning been implicated as the brain region for serotonin-­ Altered states of consciousness Amyotrophic lateral sclerosis (bulbar form) mediated yawning.

Neuropharmacologic Regulation of Yawning According to earlier studies, yawning is controlled by the dopaminergic and serotonergic systems, which activate the cholinergic system. Serotonergic activation and dopaminergic inhibition may work together in the event of yawning. Later studies have shown that numerous other neurotransmitters and neurohormones are involved in the mediation of yawning, including acetylcholine, dopamine, glutamate, oxytocin, gamma-aminobutyric acid (GABA), opioids, adrenaline, nitric oxide, adrenocorticotropic hormone (ACTH), and alpha-melanocyte-­stimulating hormone. A surge in plasma ACTH levels at night and just prior to awakening from sleep is also associated in humans with yawning.

 isorders Associated with Pathologic D Yawning Disorders that are known to be associated with pathologic yawning are shown in Table  2.14. Characteristic features of these associations help in the differential diagnosis of yawning. Drug-­ induced yawning should also be considered. Prognosis of yawning depends on that of the associated disorder. Usually there are other symptoms besides yawning, and response to treatment of primary disorders varies on each manifestation. For example, yawning may remain a residual symptom during management of opioid withdrawal with buprenorphine.

Drug-Induced Yawning Yawning may be an adverse reaction to drugs, but it is rarely serious and is not usually listed in drug

Brain tumors Chiari malformation type I Drug-induced yawning Epilepsy Foix-Chavany-Marie syndrome Gilles de la Tourette syndrome Gastrointestinal disorders Hyperthermia, heat stroke Intracranial hypertension syndromes Migraine headaches Motion sickness Multiple sclerosis Multiple system atrophy Parkinson disease Progressive supranuclear palsy Psychogenic neurologic disorders Schizophrenia Sleep disorders Stroke Traumatic brain injury

© Jain PharmaBiotech Table 2.15  Drugs that induce pathological yawning Barbiturates: intravenous thiopental Benzodiazepines Dopamine and dopaminergic-receptor agonists: levodopa, apomorphine hydrochloride Methylphenidate Opioids and withdrawal from use Oxytocin Physostigmine Serotonin reuptake inhibitors: citalopram, fluoxetine, sertraline, venlafaxine, duloxetine, escitalopram © Jain PharmaBiotech

summaries (Patatanian and Williams 2011). Several drugs are reported to induce yawning, and these are listed in Table 2.15. Systemic administration of D2-like dopaminergic-­receptor agonists increases yawning. Effects of systemic administration of the D2 agonists and antagonists on yawning behavior have been studied in rats and have been correlated with the lipid myelin content in the brainstem and other areas in the CNS (Eguibar et al. 2012). Dopaminergic D2-like agonists were still able to induce yawning despite the severe myelin loss. Similarly, patients with demyelinating

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induced nausea and vomiting: a pilot study. Support Care Cancer. 2012;20:601–6. Curtin JP, Koonings PP, Gutierrez M, Schlaerth JB, Morrow CP.  Ifosfamide-induced neurotoxicity. Gynecol Oncol. 1991;42:193–6. Eguibar JR, Cortes Mdel C, Lara-Lozano M, Mendiola DM. Dopaminergic D2-like agonists produce yawning in the myelin mutant taiep and Sprague-Dawley rats. Pharmacol Biochem Behav. 2012;102:118–23. Gil R, Neau JP. Rapid aggravation of aphasia by vigabatrin. J Neurol. 1995;242:251–2. Go SI, Koo DH, Kim ST, et al. Antiemetic corticosteroid rotation from dexamethasone to methylprednisolone to prevent dexamethasone-induced hiccup in cancer patients treated with chemotherapy: a randomized, single-blind, crossover phase III trial. Oncologist. 2017;22:1354–61. Han TH, Kim DY, Park DW, Moon JH. Transient isolated lower bulbar palsy with elevated serum anti-GM1 and anti-GD1b antibodies during aripiprazole treatment. Pediatr Neurol. 2017;66:96–9. Hartholt KA, Becker ML, van der Cammen TJ.  Drug-­ induced falls in older persons: is there a role for therapeutic drug monitoring? Ther Adv Drug Saf. 2016;7:39–42. References Higa GM, Wise TC, Crowell EB. Severe, disabling neurologic toxicity following cisplatin retreatment. Ann Alonso-Juarez M, Baizabal-Carvallo JF.  Distinguishing Pharmacother. 1995;29:134–7. features between valproate-induced tremor and essenHill ME, Gordon C, Situnayake RD, Heath tial tremor. Acta Neurol Scand. 2018;138:177–81. DA.  Sulfasalazine induced seizures and dysphasia. J Alty JE, Kempster PA. A practical guide to the differential Rheumatol. 1994;21:748–9. diagnosis of tremor. Postgrad Med J. 2011;87:623–9. Asadi-Pooya AA, Petramfar P, Taghipour M.  Refractory Hocking CM, Kichenadasse G.  Olanzapine for chemotherapy-­induced nausea and vomiting: a systemhiccups due to phenytoin therapy. Neurol India. atic review. Support Care Cancer. 2014;22:1143–51. 2011;59:68. Baizabal-Carvallo JF, Alonso-Juarez M.  Valproate-­ Hwang CH.  Velopharyngeal incoordination caused by phenytoin-induced toxicity. Am J Phys Med Rehabil. induced rest tremor and parkinsonism. Acta Neurol 2017;96:e24–7. Belg. 2019:1–5. Epub ahead of print. Battaglia D, Iuvone L, Stefanini MC, et  al. Reversible Just KS, Schneider KL, Schurig M, et al. Falls: the adverse drug reaction of the elderly and the impact of pharmaaphasic disorder induced by lamotrigine in atypicogenetics. Pharmacogenomics. 2017;18:1281–97. cal benign childhood epilepsy. Epileptic Disord. Kurin M, Bielefeldt K, Levinthal DJ.  Prevalence of 2001;3:217–22. nausea and vomiting in adults using ropinirole: a Bilgiç A.  Possible sertraline-induced hiccups in a boy systematic review and meta-analysis. Dig Dis Sci. with obsessive-compulsive disorder and attention-­ 2018;63:687–93. deficit/hyperactivity disorder. Clin Neuropharmacol. Lee KA, Kang HW, Ahn JH, et al. Dysarthria induced by 2019;42:17–8. irinotecan in a patient with colorectal cancer. Am J Carl D, Grüllich C, Hering S, et al. Responsive encephaHealth Syst Pharm. 2013;70:1140–3. lopathy associated with autoimmune thyroiditis following ipilimumab therapy: a case report. BMC Res Loomba V, Gupta M, Kim D.  Persistent hiccups with continuous intrathecal morphine infusion. Clin J Pain. Notes. 2015;8:316. 2012;28:172–4. Chien CF, Huang P, Hsieh SW. Reversible global aphasia as a side effect of quetiapine: a case report and literature Mallick-Searle T, Fillman M.  The pathophysiology, incidence, impact, and treatment of opioid-induced review. Neuropsychiatr Dis Treat. 2017;13:2257–60. nausea and vomiting. J Am Assoc Nurse Pract. Cole JB, Orozco BS, Arens AM. Physostigmine reversal 2017;29:704–10. of dysarthria and delirium after iatrogenic atropine overdose from a dental procedure. J Emerg Med. Matschke RG.  Allergische Reaktion bei Therapie mit Naftidrofuryl (Dusodril). Ein Fallbericht [Allergic reac2018;54:e113–5. tion in therapy with naftidrofuryl (Dusodril). A case Collins GT, Eguibar JR. Neuropharmacology of yawning. report]. HNO. 1987;35:219–21. (article in German). Front Neurol Neurosci. 2010;28:90–106. Cruz FM, de Iracema Gomes Cubero D, Taranto P, et al. Milos V, Bondesson Å, Magnusson M, et  al. Fall risk-­ increasing drugs and falls: a cross-sectional study Gabapentin for the prevention of chemotherapy-

disorders, such as multiple sclerosis, can yawn, indicating that drugs can trigger neurons that elicit this innate behavior. Extension of the Thompson Cortisol Hypothesis proposes that the stress hormone, cortisol, is responsible for yawning and fatigue, particularly in persons with incomplete innervation such as in multiple sclerosis (Thompson 2014). Yawning is a side effect of both nonselective and selective serotonin reuptake inhibitors. Yawning has been reported as a dose-dependent side effect of escitalopram and is resolved following reduction of the dose (Roncero et  al. 2013). History of drug use helps to differentiate druginduced yawing from that associated with various diseases, and it can be confirmed by relief from yawning by discontinuation of the offending drug.

References among elderly patients in primary care. BMC Geriatr. 2014;14:40. Morgan JC, Kurek JA, Davis JL, Sethi KD. Insights into pathophysiology from medication-induced tremor. Tremor Other Hyperkinet Mov (N Y). 2017;7:442. Morinaga Y, Abe I, Minamikawa T, et  al. A case of drug-induced hypersensitivity syndrome induced by salazosulfapyridine combined with SIADH caused by interstitial pneumonia. Drug Discov Ther. 2019;13:232–8. Mortimer TL, Mabin T, Engelbrecht AM. Cannabinoids: the lows and the highs of chemotherapy-induced nausea and vomiting. Future Oncol. 2019;15:1035–49. Navari RM, Aapro M.  Antiemetic prophylaxis for chemotherapy-­induced nausea and vomiting. N Engl J Med. 2016;374:1356–67. Navari RM, Pywell CM, Le-Rademacher JG, et  al. Olanzapine for the treatment of advanced cancer-­ related chronic nausea and/or vomiting: a randomized pilot. JAMA Oncol. 2020;6:1–5. Park JK, Kang WS, Cho AR.  Paroxetine-induced dysarthria in a 42-year-old man with pathologic laughing. Aust N Z J Psychiatry. 2011;45:1096–7. Patatanian E, Williams NT.  Drug-induced yawning--a review. Ann Pharmacother. 2011;45:1297–301. Patel UH, Mir MA, Sivik JK, et  al. Central neurotoxicity of immunomodulatory drugs in multiple myeloma. Hematol Rep. 2015;7:5704. Puar HS.  Acute memory loss and nominal aphasia caused by phenylpropanolamine. South Med J. 1984;77:1604–5.

25 Raghunath A, Chandrasekara SD, Anthony SN, Markman B. Duration of dexamethasone administration for the prevention of chemotherapy-induced nausea and vomiting  – a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2020;152:103012. Rodríguez E, Delucchi A, Cano F.  Neurotoxicidad por ciclosporina A en trasplante renal en niños [Neurotoxicity caused by cyclosporin A in renal transplantation in children]. Rev Med Chil. 1992;120:300– 3. (article in Spanish). Roncero C, Mezzatesta-Gava M, Grau-López L, Daigre C. Yawning as a dose-dependent side effect of treatment with escitalopram. Neurologia. 2013;28:589–90. Rusz J, Megrelishvili M, Bonnet C, et al. A distinct variant of mixed dysarthria reflects parkinsonism and dystonia due to ephedrone abuse. J Neural Transm. 2014;121:655–64. Sarno JB. Transient expressive (nonfluent) dysphasia after metrizamide myelography. AJNR Am J Neuroradiol. 1985;6:945–7. Thompson SB. Yawning, fatigue, and cortisol: expanding the Thompson cortisol hypothesis. Med Hypotheses. 2014;83:494–6. van Gaalen J, Kerstens FG, Maas RP, et al. Drug-induced cerebellar ataxia: a systematic review. CNS Drugs. 2014;28:1139–53. Zhen DB, McDevitt RL, Zalupski MM, Sahai V. Irinotecan-associated dysarthria: a single institution case series with management implications in patients with gastrointestinal malignancies. J Oncol Pharm Pract. 2019;25:980–6.

3

Role of the Blood-Brain Barrier in Effects of Drugs on the Brain

Introduction The blood-brain barrier (BBB) is a dynamic conduit for transport between blood and brain of those nutrients, peptides, proteins, or immune cells that have access to certain transport systems localized within the BBB membranes. It has been designed to protect the brain from harmful agents, but it is damaged in several neurologic diseases exposing the brain to neurotoxic agents. Anatomy and physiology of the BBB are one of basics for understanding drug-induced neurologic disorders (DIND). This knowledge is also exploited to facilitate delivery of therapeutics intended for action on the brain across the BBB, which may be damaged during delivery of therapeutics across it by uncontrolled opening. Flooding the brain with uncontrolled drug delivery across the BBB is more likely to produce ADRs.

 BB as an Anatomical as well B as Physiological Barrier The structural basis of the BBB is the presence of “tight” junctions between endothelial cells lining the brain capillaries in contrast to the peripheral tissue capillaries that have interendothelial cleft passages. Several physiologic properties make the endothelium in the central nervous system distinct from the vasculature found in the periphery. Anatomically, blood-brain barrier-tight junc-

tions are more like epithelial-tight junctions than endothelial-tight junctions in peripheral blood vessels. The development of tight junctions depends on two primary processes: (1) the appearance of high levels of the tight junction protein “occludens” and (2) intracellular signaling processes that control the state of phosphorylation of junctional proteins. Fenestrations found in capillaries of other organs are absent in the brain, and many capillaries are “seamless.” The formation of barrier-type capillaries is induced by signals from adjacent astrocytes. If capillary integrity is compromised, a pericyte located on the wall of the capillary exercises the barrier function. The pericytes are phagocytic microglial cells that are responsible for maintenance of homeostasis between the blood and the brain. The anatomical barrier is not complete. Some regions of the brain, e.g., the circumventricular organs that include the area postrema, the neural pituitary gland, the median eminence, the pineal gland, and the organum vasculosum of the lamina terminalis have nonblood-brain barrier or “leaky” capillaries like those in the choroid plexus.

Molecular Biology of the BBB The molecular composition of the blood-brain barrier has been studied by immunocytochemistry, and the results of these studies show that the

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_3

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blood-brain barrier exhibits a specific collection of structural and metabolic properties that are also found in the tight-transporting epithelia. These conclusions are substantiated by antibodies that recognize proteins of nonblood-brain barrier origin and blood-brain barrier-specific proteins. Blood-brain barrier-specific immunoprobes have a potential application for investigating the pathomechanisms that lead to the breakdown of blood-brain barrier. Different patterns of blood-brain barrier disintegration are anticipated under different pathological conditions, e.g., inflammatory reactions versus tumors. Genes that are selectively expressed at the blood-brain barrier have been cloned. These include GLUT-1 (glucose transporter) and GGTP (gamma-glutamyl transpeptidase). The blood-­ brain barrier GLUT-1 transporter maintains the availability in the brain of glucose, and the regulation of the protein is mediated at the levels of the gene transcription, mRNA translation and stability, and posttranscriptional processes. GLUT-1 plays a role in the development of the cerebral endothelial cells with blood-brain barrier properties in vivo. Knockdown of GLUT-1 in an animal model was shown to produce loss of the cerebral endothelial cells and downregulation of the junctional proteins important for intactness of the tight junctions with resulting leaky blood-­ brain barrier and vasogenic cerebral edema (Zheng et  al. 2010). This finding suggests that research into modulation of GLUT-1 expression may lead to therapeutic strategies for preventing vasogenic cerebral edema. Molecular mechanisms of the “tight junctions” of the blood-brain barrier are just being unraveled. In addition to occludens, other molecules (such as claudins) may be responsible for the integrity of the tight junctions.

tected from systemic bursts of epinephrine. Aminopeptidases degrade plasma-borne enkephalins. However, amino acid transporters permit significant quantities of levodopa prodrug to penetrate the blood-brain barrier, and metabolized dopamine is delivered to the brain this way to treat patients with Parkinson disease.

Regulatory Functions of the BBB The term “regulatory functions” collectively describes all processes by which the unique functions of the brain are maintained. There are distinct differences in the BBB regulation of nutrients in different parts of the brain and varying degrees of activity of the brain. For example, blood-brain barrier glucose transporter is a functional participant in the cerebral glucose homeostasis. The endothelia also regulate blood-to-brain passage of nutrients and peptides as well as brain-to-blood movement of acidic compounds.

Other Neural Barriers There are some similarities, as well as structural and functional differences, between blood-brain and other neural barriers.

 lood-Cerebrospinal Fluid Barrier B The blood-cerebrospinal fluid barrier is formed by the choroid plexus, and the tight junction between the epithelial cells is involved in the functional role of this barrier. Some studies also suggest the presence of a transport system on both the blood-brain barrier and blood-­ cerebrospinal fluid barrier that is responsible for ligand efflux from the central nervous system into the blood. Together with the anatomical features, this transport system also has a functional significance in preventing the entry BBB as a Biochemical Barrier of several ligands into the central nervous sysThis barrier is constituted by certain enzymes in tem. In addition to such an efflux mechanism, the brain capillary endothelial cells. Most neu- both the ­blood-­brain barrier and blood-cerebrorotransmitters have low blood-brain barrier perme- spinal fluid barrier have functional roles in ability, which allows separation of the peripheral transporting micronutrients into the central nervous system from the blood by either a carrierfrom the central pool of neurotransmitters. Monoamine oxidases can metabolize plasma-­ or receptor-mediated mechanism. The choroid borne biogenic amines so that the brain is pro- plexus is smaller in size than the total surface

Introduction

area of the cerebral capillaries. However, the microvilli and numerous folds of the epithelium increase the surface area available for exchanges. It provides some pharmacotherapeutic opportunities that are not available via the blood-brain barrier. Cerebrospinal fluid may also act as a “third circulation,” conveying substances secreted into it rapidly to many brain regions.

Blood-Nerve Barrier In peripheral nerves, the endothelial lining of the vasa nervosum is formed by continuous, nonfenestrated endothelial cells with tight junctions, and this formation renders it impermeable to macromolecules in the circulation. The perineurium is not protected, but innermost layers of the perineural sheath isolate the interstitium in the same way as the brain is isolated by the blood-­ brain barrier. This barrier may be deficient at the posterior root ganglia. Blood-Retinal Barrier The blood-retinal barrier is formed by the retinal vascular endothelium in conjunction with tight junctions of the retinal pigment epithelium. The inner and the outer limiting membranes of retina are relative diffusion barriers; they may retain fluid and electrolytes that leak through blood-­ retinal barrier, leading to retinal edema. This may occur in retinal vascular and inflammatory diseases. Blood-Labyrinth Barrier The blood-labyrinth barrier is characterized by tight junctions lining blood vessels in the labyrinth. This regulates the transport of various substances in and out of the fluid-containing parts of the inner ear. The ability to manipulate this barrier would be useful in managing ototoxicity of some systemically administered agents, such as antibiotics and antineoplastic agents.

 assage of Substances Across P the BBB Several carrier or transport systems, enzymes, and receptors that control the penetration of molecules have been identified in the blood-brain barrier endothelium by physiological and bio-

29

chemical studies. Passage of substances across the blood brain barrier is shown in Fig. 3.1:

 ystems for Transport of Molecules S Across the BBB Transporter systems that control the penetration of molecules across the blood-brain barrier are shown in Table 3.1.

ABC Transporters These function at the blood-brain barrier as ATP-­ driven xenobiotic efflux pumps and limit delivery of small molecule drugs to the brain (Miller 2015). When ABC transporters limit neurotoxicant entry into the CNS, they are neuroprotective; but when they limit therapeutic drug entry, they are obstacles to drug delivery to treat CNS diseases. Understanding the regulation of expression and transport activity of these transporters might help in improving drug delivery to the brain. P-glycoprotein (P-gp) is the most investigated ABC (efflux) transporter and plays a critical role in drug safety and efficacy. Apart from its role as an efflux pump for drugs such as vinblastine, it is also implicated in neurodegenerative diseases such as Alzheimer disease. Altered function of P-gp can be studied in vivo using PET, but no suitable radiopharmaceutical is yet available for this purpose (Raaphorst et al. 2015). Most of the data about P-gp is available for adults. Because of the vulnerable nature of the pediatric population, future research is needed for the measurement of brain P-gp activity across age groups using PET or central pharmacodynamic responses (Nicolas and de Lange 2019). Currently, caution is advised when extrapolating adult data to children. Glucose Transporter This provides the major source of energy for the brain, i.e., glucose. More than 98% of the energy supply generated in the brain to sustain neuronal function arises from combustion of blood-borne glucose. The rate of glucose transport depends on the glucose concentration of the blood and increases until saturation is reached. The transport rate across the endothelial membrane is essentially identical in both directions.

3  Role of the Blood-Brain Barrier in Effects of Drugs on the Brain

30 BLOOD VESSEL

LUMEN

ENDOTHELIUM

BRAIN CELLS

1

CARRIER 2

RECEPTOR 3

BLOOD-BRAIN BARRIER

Fig. 3.1  Passage of substances across the blood brain barrier. Legend: (1) Passive diffusion. Fat-soluble substances dissolve in the cell membrane and cross the barrier, e.g., alcohol, nicotine, and caffeine. Water-soluble substances like penicillin have difficulty in getting through. (2) Active

transport. Substances that the brain needs such as glucose and amino acids are carried across by special transport proteins. (3) Receptor-mediated transport. Molecules link up to receptors on the surface of the brain and are escorted through, e.g., insulin. (© Jain PharmaBiotech)

Under normal conditions, blood-brain barrier glucose transport proceeds at rates approximately twofold greater than the existing glucose phosphorylation and utilization rates. However, when plasma glucose falls to hypoglycemic levels, glucose transport through the blood-brain barrier falls to levels that become limiting for glucose utilization. Glucose utilization rates are increased in the convulsing brain, but glucose utilization may be limited by blood-brain barrier glucose transport. Studies of blood-brain barrier glucose permeability and regional brain glucose metabolism show that no major adaptational changes occur in the maximal transport velocity or affinity to the blood-brain barrier glucose transporter during hyperglycemia.

thelial cells is involved in blood-brain barrier creatine transport. Certain small amino acids are synthesized in the brain and act as inhibitory neurotransmitters, e.g., gamma-aminobutyric acid. For this reason, their concentration in the brain needs to be ­ controlled constantly. A carrier system exists for this purpose and transports small amino acids out of the extracellular space of the brain along with sodium ions according to the ion gradient. The amino acids are then delivered to the blood circulation by transport systems localized in the luminal endothelial membrane. Results of experimental studies suggest that A2A adenosine receptor (AR) signaling is an endogenous modulator of blood-brain barrier permeability. Regadenoson, an FDA-approved A2A AR agonist used as a cardiac nuclear stress test, also increases blood-brain barrier permeability and facilitates CNS entry of macromole-

Other Transporters The blood-brain barrier supplies creatine to the brain for an energy-storing system, and creatine transporter localized at the brain capillary endo-

Introduction

31

Table 3.1  Transporter systems for passage of molecules across the BBB Transporters or system Energy transporters Glucose transporter GLUT 1 Monocarboxylic acid transporter MCT1 Creatine transporter CRT Amino acid transporters Excitatory amino acids EAAT 1,2,3 LAT1 CAT1 AST2 Neutral amino acid transporter/A-­system Neutral amino acid transporter/L-­system Basic amino acid transporter Neurotransmitter transporters GAT2 SERT NET Organic anions and cation transporters OAT1 OATP/OATP A oatp1 oatp2 oatp3 OCTN2

Substrates D-glucose, dehydroascorbic acid L-lactate Creatine Aspartate, glutamate Large neutral amino acids Cationic amino acids L-alanine Glycine, leucine Phenylalanine Arginine GABA Serotonin Norepinephrine

P-aminohippuric acid Bile acids, estrone sulfate Opioid agonists, glucuronide conjugates, estrone sulfate, pravastatin Digoxin, biotin, bile acids, dehydroepiandrosterone and estrone sulfate, opioid agonists Homovanillic acid, indoxyl sulfate, p-aminohippuric acid, cimetidine Carnitine ABC (adenosine triphosphate-binding cassette) transporters Vincristine, cyclosporine A ABCB1 Leukotriene C4 ABCC1 Mitoxantrone, topotecan ABCG2 P-glycoprotein efflux system Vinblastine Miscellaneous transporters and receptors Adenosine receptor Adenosine Triiodothyronine Hormones Sodium, potassium Na+-K+ ATPase Guanine Purine bases Thiamine and folic acid receptor Vitamin transporters © Jain PharmaBiotech

cules like dextrans. Thus, A2A AR modulation on blood-brain barrier endothelial cells can be fine-tuned for drug delivery to the brain (Kim and Bynoe 2016). Gamma-glutamyl transpeptidase catalyzes amino acid transfer in membranes of various organs and has been localized in brain capillaries where it serves as a part of the amino acid transport system of the brain. Cerebrovascular gamma-­ glutamyl transpeptidase protects the blood-brain barrier against the barrier-disturbing effects of leukotriene C4 by breaking it down before it can reach its receptors on the endothelial surface.

Glutamate flux from plasma into the brain is mediated by a transport system at the blood-brain barrier. Glutamate concentration in brain interstitial fluid is only a fraction of that of plasma and is maintained independent of small fluctuations in plasma concentration. Blood-brain barrier is a single component of a regulatory system that helps maintain brain interstitial fluid glutamate concentration independently of the circulation. The concentration of the sodium and potassium ions in the brain is controlled by sodium-­ potassium ATPase, which is localized in the endothelial cell membrane of the brain capillar-

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3  Role of the Blood-Brain Barrier in Effects of Drugs on the Brain

ies. The ionic pump allows upstream movement of sodium against the concentration gradient from the endothelial cytoplasm into the brain compartment and potassium movement in the reverse direction. The blood-brain barrier provides a fluid environment with low potassium content to achieve nerve conduction. An increase in blood-brain barrier mitochondria and electrical resistance along with Na+-K+ ATPase contribute to the maintenance of low potassium levels. Organic anion transporter 1 is a multispecific transporter that accepts small, organic anions such as p-aminohippurate. Organic anion transporter 1 is expected to be responsible for the uptake of the p-aminohippurate from the brain to the brain capillary endothelial cells.

 lood-Brain Barrier-Specific Enzymes B Enzymes that control the penetration of molecules across the blood-brain barrier are the following: • 1-Naphthol UDP-glucuronyltransferase (p-nitrophenol) • Aldehyde dehydrogenase (alcohol) • Aminopeptidases A and M (d-sleep inducing peptide) • Acetylcholinesterase (acetylcholine) • Catechol-O-methyltransferase (codeine, morphine) • Cytochrome P450 monooxygenase (parathion) • L-amino acid decarboxylase (levodopa) • G-glutamyl transpeptidase (leukotriene C4) • Monoamine oxidases A and B (dopamine, MPTP) • NADPH-cytochrome P450 reductase (misonidazole) An example of the mode of action of enzymes is monoamine oxidase, which provides an enzymatic barrier and hinders the influx of monoamine precursors into the brain. After their entry into the endothelial cells, monoamines are decarboxylated by cytoplasmic monoamine oxidase, thus effectively preventing a flood of peripheral monoaminergic neurotransmitters in the neuronal environments.

Receptor-Mediated Peptide and Protein Transcytosis The transport of peptides and proteins across cellular barriers, transcytosis, has been documented in several parts of the human body. Examples include the transport of IgG across the intestinal epithelium and human placenta, the transport of insulin and insulin-like growth factors across the aortic endothelium, and the transport of epidermal growth factor across the kidney epithelium. It is not surprising that transcytosis occurs across the blood-brain barrier. In addition to the unidirectional and bidirectional transport of small molecules, other macromolecules can enter the brain tissue from the blood by a receptor-­mediated process. An example of this is the transport of transferrin across the blood-brain barrier. Brain cells require a constant supply of iron to maintain their function, and brain may substitute its iron through transcytosis of ironloaded transferrin across the brain microvasculature. Other biologically active proteins such as insulin and immunoglobulin G are actively transcytosed through bloodbrain barrier endothelia.

 lood-Brain Barrier in Neurologic B Disorders Genomic and proteomic analyses have been used to study the blood-brain barrier and how it relates to the pathogenesis of major neurologic diseases. Shear stress associated with blood flow in arteries has variable effects on endothelial cells, which are modulated by induction or suppression of genes regulating endothelial physiology, e.g., formation of inter-endothelial tight junction and expression of specific carrier-mediated transporters (Cucullo et al. 2011). These findings can form the basis of developing innovative therapeutic strategies to improve the management of blood-­ brain barrier-related diseases. Disorders of the brain that involve the blood-­ brain barrier are shown in Table 3.2. Various inflammatory factors produced by perivascular cells in multiple sclerosis affect the permeability of the blood-brain barrier. One of

Drugs Action on the BBB Affecting Transport to the Brain Table 3.2  Neurologic disorders that involve the BBB AIDS-encephalopathies Chronic sleep loss Autoimmune disorders CNS injuries Cerebrovascular disease Neurodegenerative disorders Mitochondrial encephalopathies Epileptic seizures Infections: meningitis Multiple sclerosis Brain tumors Cerebral hypoxia Vasogenic cerebral edema © Jain PharmaBiotech

these, the intercellular adhesion molecule-1, binds to its leukocyte ligands and allows activated leukocyte entry into the central nervous system. According to one hypothesis, pathological reflux of venous flow in the cerebral and spinal veins increases the expression of intercellular adhesion molecule-1 by the cerebrovascular endothelium, which, in turn, could lead to increased permeability of the blood-brain barrier (Simka 2009).

 hemical Factors That Increase C the Permeability of the BBB Various chemical factors that increase the permeability of the blood-brain barrier are shown in Table 3.3.

 rugs Action on the BBB Affecting D Transport to the Brain Alteration in permeability of blood-brain barrier is an adverse effect of drugs, or the disease may lead to neurotoxicity. Psychoactive drugs such as methamphetamine and cocaine can alter the permeability of the BBB, which, in turn, may further contribute to their neurotoxicity. In case of therapeutics, facilitation of passage may enhance the desired action. Pharmacological agents that affect the permeability of the BBB are listed in Table 3.4, and some are described in the following text.

33 Table 3.3  Chemical factors that increase the permeability of the BBB Alpha-thrombin Adenosine diphosphate Adenosine monophosphate Adenosine triphosphate Arachidonic acid Bradykinin Collagenase Enkephalin Free radicals Histamine Leucine Leukotriene C4 Macrophage inflammatory proteins Nitric oxide Phospholipase A2 Platelet activating factor Serotonin Trypsin Tumor necrosis factor alpha Vascular endothelial growth factor © Jain PharmaBiotech Table 3.4  Pharmacological agents that affect the permeability of the BBB Amitriptyline Anticholinergic drugs Antiepileptic drug resistance in BBB Drug abuse: cocaine methamphetamine Levodopa Mannitol for treatment of cerebral edema Nanomedicines Tissue plasminogen activator © Jain PharmaBiotech

Amitriptyline Enhances Transport Across BBB A rat study has shown that amitriptyline, a tricyclic antidepressant, reduces basal P-glycoprotein transport activity through a distinct lysophosphatidic acid 1 (LPA) receptor-mediated signaling cascade that requires G-protein coupling, Src kinase, and ERK ½ (Banks et al. 2018). The ATP-­ binding cassette transporter P-glycoprotein contributes to limit the delivery of therapeutics by actively pumping clinical substrates back into circulation before they can reach the brain parenchyma. Ability of LPA and amitriptyline to decrease induced P-glycoprotein transport activity in a human SOD1 transgenic rat model of

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3  Role of the Blood-Brain Barrier in Effects of Drugs on the Brain

amyotrophic lateral sclerosis was also demonstrated. These findings may translate to new clinical strategies for increasing the cerebral penetration of therapeutics in patients suffering from CNS diseases marked by pharmacoresistance.

 nticholinergic Drugs’ Enhanced A Passage Across BBB Increases Neurotoxicity

carbamazepine metabolism was evaluated in vitro and ex vivo using high-performance liquid chromatography-mass spectroscopy. Accelerated mass spectroscopy was used to identify 14C metabolites deriving from the parent 14 C-carbamazepine; no drug level could not be detected in drug resistant epileptic brain ex situ; low levels of carbamazepine were detected in the brain side of the in  vitro BBB established with endothelial cells derived from the same patients; rather quinolinic acid was found, which may be a result of carbamazepine metabolism. Quinolinic acid was not detected in the brain of patients who received antiepileptic drugs other than carbamazepine prior to surgery or in brain endothelial cultures obtained from a control patient. Our data suggest that a drug-resistant BBB not only impedes drug access to the brain but may also allow the formation of neurotoxic metabolites.

There are over 600 medications that have some degree of serum anticholinergic activity. Several drugs with anticholinergic effects are in clinical use, and adverse effects are due to the chemical messenger acetylcholine being blocked from binding to the “muscarinic receptor” present in the brain and peripheral body systems. Medicines that block acetylcholine from binding to the muscarinic receptors include antidepressants, anti-­ Parkinson’s medicines, drugs for overactive bladder, antipsychotics, anti-emetics, and anti-­ Drug Abuse-Induced Blood-Brain allergics. ADRs of medicines with anticholinergic Barrier Dysfunction activity in the brain include cognitive impairment, delirium, attention deficits, behavioral excitation, Psychostimulants and nicotine are the most widely confusion, falls, and disorientation. Anticholinergic abused drugs known to induce long-term neurobesyndrome is more likely to be caused by drugs havioral deficits, and synaptic disturbances are with central anticholinergic effects that cross the well documented with chronic use of methamBBB and block muscarinic cholinergic receptors phetamine, cocaine, and nicotine. Use of psycho(Salahudeen and Nishtala 2016). stimulants can disrupt BBB integrity/function, leading to an increased risk of brain edema and neuroinflammation. Neurovascular complications of drug abuse are attributed to oxidative stress Antiepileptic Drug Resistance in BBB (Sajja et al. 2016). Changes in tight junction proAntiepileptic drugs and their metabolites may tein and cytoskeleton induced by drug abuse proproduce adverse effects by several mechanisms, mote glial activation, enzyme potentiation, and including biotransformation by P450 enzymes, BBB remodeling, which affect neuroinflammatory which are not exclusively expressed by hepato- pathways (Pimentel et al. 2020). Synergistic pathological impact of psychocytes but also by endothelial cells in brain from epileptics. It is possible that the effect of systemi- stimulants and human immunodeficiency virus cally administered antiepileptics can be modu- (HIV) encephalitis on blood-brain barrier integlated by metabolic activity at the BBB. Surgical rity further points to the unifying role of endothebrain specimens and blood samples (ex vivo) lial oxidative stress. This mechanistic framework were obtained from drug-resistant epileptic sub- would guide further investigations on specific jects receiving the antiepileptic drug carbamaze- molecular pathways to accelerate therapeutic pine prior to temporal lobectomies, and an approaches for the prevention of neurovascular in  vitro BBB model was then established using deficits by drugs of abuse. Methamphetamine alters the BBB integrity, primary cell culture derived from the same brain specimens (Ghosh et  al. 2012). The pattern of increasing susceptibility to CNS infection. Using

Drugs Action on the BBB Affecting Transport to the Brain

a murine model of methamphetamine administration, a study demonstrated that methamphetamine alters BBB integrity and modifies the expression of tight junction and adhesion molecules (Eugenin et  al. 2013). Additionally, it showed that BBB disruption accelerates transmigration of the neurotropic fungus Cryptococcus neoformans into the brain parenchyma after systemic infection. Furthermore, methamphetamine-­ treated mice displayed increased mortality as compared to untreated animals. These findings provide novel evidence of the impact of methamphetamine abuse on the integrity of the cells that comprise the BBB and protect the brain from infection.

 evodopa Passage Across BBB L Increases in Parkinson Disease Chronic treatment with levodopa in rats increases BBB permeability and uncouples CBF from CMR in the striatum, the globus pallidus, and the primary motor cortex. Entry of levodopa into the brain is regulated by endothelial cells at the BBB.  Moreover, vascular smooth muscle contraction is regulated to a substantial degree by dopamine D1 receptors. At doses required for treatment of Parkinson disease, dopamine binding to vasculature receptors is likely to result in vasodilation and local blood flow increases, which is not beneficial in the long term. In both patients with Parkinson disease and rodent models, dyskinesias have been associated with larger increases in striatal extracellular levels after levodopa administration (Hong et al. 2014).

 annitol for Treatment of Cerebral M Edema Mannitol, first described in the early 1960s, remains part of the routine medical management of cerebral edema, which is available as a 20% solution and administered on a weight-based bolus dosing schedule. Continuous infusions of mannitol are no longer used clinically, as rebound cerebral edema due to mannitol deposition in the compromised BBB. The mechanism of action for

35

mannitol is through direct osmotic effects on astrocytes and neurons with intact BBB, as well as opening tight junctions within the BBB to enhance osmotic pull of intracellular cerebral fluid into the intravascular space. Although the osmotic diuresis seen with mannitol does facilitate reduction in cerebral edema, redistribution of the cerebral plasma volume ultimately leads to increased cerebral blood flow and a concomitant vasoconstrictive response of the intracerebral vasculature that decreases intracerebral pressure (Halstead and Geocadin 2019).

Nanomedicines and BBB Nanoparticles, because of their nanosize, cross the BBB easily. Some nanoparticles are used as nanomedicines for CNS disorders and administered intravenously. However, uncontrolled passage of some nanomedicines into the brain is undesirable and might lead to neurotoxicity; therefore, controlled delivery techniques such as receptor-mediated endocytosis for targeted drug delivery are preferred (Jain 2017).

 issue Plasminogen Activator, BBB, T and Hemorrhagic Complications Tissue plasminogen activator (tPA) is an enzyme that catalyzes the conversion of plasminogen to plasmin for clot breakdown. Therefore, it is approved for the treatment of embolic or thrombotic stroke, but use is contraindicated in hemorrhagic stroke. Several clinical trials have shown that intravenous thrombolytic therapy for ischemic stroke using tPA within a “therapeutic window” treatment time of 3 hours is the best available approach to improve the clinical outcome safely. TPA has been administered effectively as late as 6 hours after the onset of stroke. There is still some concern about hemorrhagic complications. In a 4-year study, use of intravenous tPA therapy was associated with symptomatic intracranial hemorrhage rate of 2.2% (Orlando et  al. 2016). Despite this complication, treatment offered significantly better odds of achieving a favorable functional outcome compared to no therapy. The

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3  Role of the Blood-Brain Barrier in Effects of Drugs on the Brain

hemorrhagic complication of tPA may be due to impairment of BBB integrity resulting from activation of latent platelet-derived growth factorCC.  Treatment of mice with the platelet-derived growth factor antagonist imatinib, an approved drug for leukemia, reduces both cerebrovascular permeability and hemorrhagic complications associated with late administration of thrombolytic plasminogen activator following ischemic stroke (Su et al. 2008). Imatinib may, thus, have potential clinical application in prevention of hemorrhagic complications associated with tissue plasminogen activator. Various studies suggest that tPA- and rtPA-­ mediated permeabilization of the BBB is species specific. Mouse tPA appears to disrupt the BBB only from within the CNS, whereas human rtPA induces BBB permeabilization when it is given intravenously as well. However, the effect of human rtPA on BBB integrity and cerebral vasodilation does not require its catalytic activity and provide an opportunity to develop agents that isolate its beneficial effect on fibrinolysis, prolong its therapeutic window, and have the potential to improve the management of patients with stroke. A phase II randomized trial has shown that imatinib is safe and tolerable and may reduce neurologic disability in patients treated with intravenous thrombolysis after ischemic stroke (Wahlgren et al. 2017). A randomized study has shown that use of ginsenoside (a traditional Chinese medicine) with tPA therapy reduces symptomatic intracerebral hemorrhage by promoting transforming growth factor-β1 (Chen et al. 2016). • Cerebral edema. Cerebral edema associated with stroke may also be aggravated by thrombolysis. Forced reperfusion of already irreversibly damaged tissue increases edema formation and enlarges developing infarcts with an increase of intracranial pressure. • Animal studies have reported neurotoxicity after tPA thrombolysis, but there is no evidence that tPA administration can increase ischemic injury in human patients. • Post-stroke seizures occur in one out of ten patients. However, clinical studies have not shown that incidence of seizures is higher in

those treated with tPA than treatment-naive patients. Current noninvasive vascular imaging tests such as CT angiography and MRI angiography can diagnose vascular occlusions safely, quickly, accurately, and specifically. At centers with facilities for MRI, fluid-attenuating inversion recovery scans, T2-weighted MRI, and multivariate regression analysis, exclusion brain hemorrhage, definition of ischemic areas, and identification of occluded arteries can all be performed prior to thrombolysis to reduce hemorrhagic complications. The likelihood of a poor outcome after thrombolysis is proportional to the extent of hemorrhage seen on pretreatment CT scans. Despite an increased risk of symptomatic intracranial hemorrhage, tPA has not been reported to increase mortality.

References Banks DB, Chan GN, Evans RA, et al. Lysophosphatidic acid and amitriptyline signal through LPA1R to reduce P-glycoprotein transport at the blood-brain barrier. J Cereb Blood Flow Metab. 2018;38:857–68. Chen J, Bai Q, Zhao Z, Sui H, Xie X.  Ginsenoside represses symptomatic intracerebral hemorrhage after recombinant tissue plasminogen activator therapy by promoting transforming growth factor-β1. J Stroke Cerebrovasc Dis. 2016;25(3):549–55. Cucullo L, Hossain M, Puvenna V, Marchi N, Janigro D. The role of shear stress in blood-brain barrier endothelial physiology. BMC Neurosci. 2011;12:40. Eugenin EA, Greco JM, Frases S, et al. Methamphetamine alters blood brain barrier protein expression in mice, facilitating central nervous system infection by neurotropic Cryptococcus neoformans. J Infect Dis. 2013;208:699–704. Ghosh C, Marchi N, Hossain M, et al. A pro-­convulsive carbamazepine metabolite: quinolinic acid in drug resistant epileptic human brain. Neurobiol Dis. 2012;46:692–700. Halstead MR, Geocadin RG.  The medical management of cerebral edema: past, present, and future therapies. Neurotherapeutics. 2019;16:1133–48. Hong JY, Oh JS, Lee I, et al. Presynaptic dopamine depletion predicts levodopa-induced dyskinesia in de novo Parkinson disease. Neurology. 2014;82:1597–604. Jain KK. Handbook of nanomedicine. 3rd ed. New York: Springer/Humana; 2017. Kim DG, Bynoe MS. A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-­ brain barrier. J Clin Invest. 2016;126:1717–33.

References Miller DS. Regulation of ABC transporters at the blood-­ brain barrier. Clin Pharmacol Ther. 2015;97:395–403. Nicolas JM, de Lange ECM.  Mind the gaps: ontogeny of human brain P-gp and its impact on drug toxicity. AAPS J. 2019;21:67. Orlando A, Wagner JC, Fanale CV, Whaley M, McCarthy KL, Bar-Or D. A four-year experience of symptomatic intracranial hemorrhage following intravenous tissue plasminogen activator at a comprehensive stroke center. J Stroke Cerebrovasc Dis. 2016;25(4):969–76. Pimentel E, Sivalingam K, Doke M, Samikkannu T. Effects of drugs of abuse on the blood-brain barrier: a brief overview. Front Neurosci. 2020;14:513. Raaphorst RM, Windhorst AD, Elsinga PH, et  al. Radiopharmaceuticals for assessing ABC transporters at the blood-brain barrier. Clin Pharmacol Ther. 2015;97:362–71. Sajja RK, Rahman S, Cucullo L. Drugs of abuse and blood-brain barrier endothelial dysfunction: a focus on the role of oxidative stress. J Cereb Blood Flow Metab. 2016;36:539–54.

37 Salahudeen MS, Nishtala PS.  Examination and estimation of anticholinergic burden: current trends and implications for future research. Drugs Aging. 2016;33:305–13. Simka M.  Blood-brain barrier compromise with endothelial inflammation may lead to autoimmune loss of myelin during multiple sclerosis. Curr Neurovasc Res. 2009;6:132–9. Su EJ, Fredriksson L, Geyer M, et  al. Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nat Med. 2008;14:731–7. Wahlgren N, Thorén M, Höjeberg B, et al. Randomized assessment of imatinib in patients with acute ischaemic stroke treated with intravenous thrombolysis. J Intern Med. 2017;281:273–83. Zheng PP, Romme E, van der Spek PJ, et  al. Glut1/ SLC2A1 is crucial for the development of the blood-­ brain barrier in vivo. Ann Neurol. 2010;68:835–44.

4

Pathomechanisms of Drug-­ Induced Neurological Disorders

Introduction Pathomechanisms of drug-induced neurological disorders (DIND) vary considerably, and most of them remain unexplored. The mechanisms of toxicity associated with drugs can be grouped into pharmacologically mediated and those that are nonpharmacological. Pharmacologically mediated mechanism is defined as the interaction of the drug with its intended target or relevant receptor. Interaction with this intended target can result in an anticipated biological effect, such as the reduction in blood glucose by insulin, or in a previously unanticipated effect. Nonpharmacological effects are those unrelated to the interaction with the intended target, e.g., hypersensitivity reactions secondary to an immune response to the drug. It is sometimes difficult to draw a line between desirable and undesirable effects of a drug for neurological disorder. For example, intravenous diazepam may control status epilepticus but will make the patient drowsy for a while. Such transient neurological disturbances are considered a minor inconvenience, leave no permanent sequelae, and are overweighed by the therapeutic benefits of the drug. On the other hand, the central nervous system (CNS) may be affected by drug for disorders of other systems. Various pathomechanisms of DIND will be discussed under the following three categories:

1. Direct mechanisms or primary neurotoxicity. 2. Indirect mechanisms, i. e., neurotoxicity is due to drug-induced disturbances of other organs. 3. Predisposing or risk factors for DIND: (i) related to the patient or (ii) related to the drug. These mechanisms are discussed briefly in this chapter, and further details are given in chapters dealing with individual disorders.

Direct Neurotoxicity of Drugs Because some of the drugs used for treatment of neurologic disorders target receptors in the nervous system, there remains the possibility of direct neurotoxic effect. For example, dopamine receptors, which are profusely expressed in the caudate-putamen area of the brain, represent the molecular target of several drugs used in the treatment of neurologic disorders such as Parkinson disease. Although such drugs are effective in alleviating the symptoms of the disease, their long-term use could lead to the development of severe side effects. Neurotoxicant-induced changes in protein level, function, or regulation could have a detrimental effect on neuronal viability. Direct oxidative or covalent modifications of individual proteins by various drugs are likely to lead to disturbance of tertiary structure and a loss of function of

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_4

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4  Pathomechanisms of Drug-Induced Neurological Disorders

neurons. The proteome and the functional determinants of its individual protein components are, therefore, likely targets of neurotoxicant action, and resulting characteristic disruptions could be critically involved in corresponding mechanisms of neurotoxicity. Neuroproteomic studies can provide an overview of cell proteins and, in the case of neurotoxicant exposure, can provide quantitative data regarding changes in corresponding expression levels and/ or post-­translational modifications that might be associated with neuron injury.

Breach of BBB Two important considerations for direct neurotoxicity are (1) breech of the blood-brain barrier (BBB), which usually prevents the access of drugs to the fluid spaces of the brain (see Chap. 3), and (2) retrograde axonal transport. For direct neurotoxic effects, the drugs must cross the blood-brain barrier. Despite this barrier, lipid-­ soluble molecules as benzodiazepines readily enter the brain. Damage to the BBB facilitates the passage of drugs that normally do not cross it. Diseases in which the BBB is damaged, such as multiple sclerosis, malignant brain tumors, and meningitis, would facilitate the direct neurotoxic effect of drugs. There is a risk of neurotoxicity of nanomedicines based on metallic nanoparticles as they can easily cross the BBB and exert toxic effect via several possible mechanisms, such as oxidative stress, lysosome dysfunction, and activation of certain signaling pathways (Feng et al. 2015). This can be avoided by use of relatively nontoxic nanoparticles such as those made of polymers and using targeted delivery to the lesion.

Retrograde Intra-axonal Transport

the patient to drug-induced neurologic disorders when a neurotoxic drug is administered. Adriamycin, when injected into the cerebral ventricles of mice, passes into the surrounding parenchyma and is detected in the nuclei of both neurons and neuroglia. Therefore, it can be assumed that when Adriamycin is given to patients with disturbance of BBB, the drug may spread to the brain in the same way It is a well-established fact that neurons have the capacity to incorporate substances at the periphery of the axons and that material can be transported within the axons to the perikaryon by means of retrograde axonal transport. When toxic substances are picked up by axons and transported to perikaryon, death or degeneration of the neuron results, a phenomenon called “suicidal axonal transport.”

Mechanisms of Direct Neurotoxicity Various direct mechanisms of neurotoxicity are listed in Table 4.1. Table 4.1  Direct mechanisms of neurotoxicity Disturbances of brain energy metabolism  ATP synthetase inhibition, e.g., oligomycin  Uncoupling, i.e., dissociation of oxidative phosphorylation, e.g., by barbiturates  Disturbances of oxygen consumption  Enzymatic dysfunction, e.g., theophylline leading to convulsions by inhibiting adenosine  Selective vulnerability of the central nervous system Sequelae of disturbances of brain energy metabolism  Ca2+ ion entry in the cell  Oxygen free radical formation  Excitatory amino acids Ion channel disturbances  Mitochondrial dysfunction, e.g., zidovudine-induced mitochondrial myopathy  Neurotransmitter disturbances, e.g., atropine produces memory impairment by reducing acetylcholine  Metabolite-mediated toxins, e.g., MPTP neurotoxicity to dopamine cell in the substantia nigra Drug-induced selective cell death  Unknown mechanisms Disturbance of the proteome  Alterations of individual protein structure by drugs leading to loss of neuronal function

Drugs may bypass the BBB by retrograde intra-­ axonal transport. In the case of peripheral nerves, the BBB may be deficient in posterior root ganglia and perineurium, making them susceptible to peripheral neuritis. Damage to the BBB can occur in several diseases, which can predispose © Jain PharmaBiotech

Direct Neurotoxicity of Drugs

 isturbances of Brain Energy D Metabolism These play an important role in drug-induced neurotoxicity. Various disturbances of brain energy metabolism are as follows: ATP Synthetase Inhibition  Adenosine triphosphate (ATP) plays an important role in the brain. Under normoxic conditions ATP is synthesized almost exclusively by oxidative phosphorylation in the mitochondria, and only a small portion comes from glycolysis. The rate of ATP production varies with rapid synthesis in areas of higher functional activity. ATP level is a reliable indicator of pathological events such as hypoxia, ischemia, hypoglycemia, seizures, and toxic effects of drugs which may disrupt the homeostasis of brain metabolism by hindering energy production or enhancing energy consumption. Oligomycin is an example of a drug which inhibits ATP synthetase. Uncoupling  There must be an adequate rate of electron flow and oxygen delivery as well as efficient coupling between electron transport and oxidative phosphorylation to maintain a balance between energy production and utilization. Uncoupling is dissociation of oxidative phosphorylation following its inhibition, for example, by barbiturates. Disturbance of oxygen consumption  Oxygen deficiency whether due to hypoxia, ischemia, or drug effects leads to depletion of glycogen stores and impaired mitochondrial respiration. ATP production is decreased. The resulting neuronal damage may be transient, reversible, or irreversible depending on the duration and extent of hypoxia. Oxygen transport from the blood to the tissues becomes impaired after chronic exposure to ethanol resulting in oxygen deficiency which restricts the synthesis of ATP. Enzymatic disturbances  Adenosine which is formed by enzymatic dephosphorylation of adenosine monophosphate (AMP) has an inhibitory effect on the central nervous system. The action of this enzyme is inhibited by

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theophylline convulsions.

intoxication

leading

to

Selective vulnerability of the CNS  Brain cells are selectively vulnerable because they express specifications which mediate essential functions, for example, neurotransmitter uptake. Neurons at specific sites are more vulnerable than those in other areas.

 equelae of Disturbances of Brain S Energy Metabolism Sequelae of metabolic disturbances of the brain are Ca2+ entry into neurons, free radical formation, and excitatory amino acids. Ca2+ entry in neurons  Ca2+ normally acts as a second messenger and plays an important role in membrane stabilization and regulation as well as neurotransmitter release. However, it can also cause cell death under certain circumstances. Ca2+ enters the postsynaptic neurons mostly through receptor-operated calcium channels which lie on dendrites. The most important transmitters are glutamate and related amino acids. The best known is N-methyl-D-aspartate [Methyl-D-aspartate]> (NMDA) receptor linked to calcium channels. Stimulation of this receptor allows mainly Ca2+ and some Na+ to enter the cell. Inside the neuron Ca2+ is a signal which is changed into various cell responses. During energy deficit Ca2+ may rise manifold and set off metabolic reactions with formation of free fatty acids (FFA) and cell destruction. Increased level of Ca2+ in mitochondria activates various dehydrogenases and alters the metabolic flux into the citric acid cycle. Cell viability is threatened when calcium homeostasis fails and calcium-activated reactions run out of control. There is considerable evidence for a link between Ca2+ influx and neuronal necrosis. Free radicals  A free radical is an agent with an unpaired electron in its orbit. Oxygen radicals are produced by normal cellular metabolism but are usually kept under control by several defense mechanisms. Such defense mechanisms may be overwhelmed when there is increased production

4  Pathomechanisms of Drug-Induced Neurological Disorders

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of oxygen free radicals by hypoxia and disturbance of cellular metabolism. The central nervous system is particularly vulnerable to free radical damage because of its high lipid content. Superoxide radical is water soluble, but it can cross membranes through the anion channels and enter the extracellular space. Seizures are one manifestation of the attack of free radicals on neuronal membranes. Drug-induced seizures lead to increase of brain levels of FFA. Superoxide may arise from further metabolism of FFA. Oxygen radicals may also increase the permeability of BBB. Free radical mechanisms may contribute significantly to the expression of harmful properties of diverse, unrelated neurotoxic agents. Excitatory amino acids  Current evidence suggests that poorly controlled release of these amino acids, their insufficient clearance from the extracellular space, and breakdown of surrounding GABA-ergic inhibition transform the excitatory transmitters into potential toxins.

Fig. 4.1 Pathogenesis of excitotoxic cell damage

Pathogenesis of excitotoxic cell damage is shown in Fig. 4.1.

Mitochondrial Dysfunction Mitochondrial DNA is susceptible to mutations by endogenous as well as exogenous factors. Increased sensitivity to mutagenic factors may account for the mitochondrial DNA polymorphism within ethnic groups and mitochondrial disease associated with all mitochondrial DNA mutations, including DNA depletion. Mitochondrial damage is known to be caused by classic poisons such as cyanide and carbon monoxide. Neurotransmitter Disturbances Neurotransmitter disturbances are an important pathomechanism of adverse reactions of several drugs such as antidepressants which are aimed at manipulating this system for therapy. Neurotransmitters involved in DIND include serotonin (5-HT), norepinephrine (NE), dopamine (DA), and acetylcholine (ACh).

EXCITATORY AMINO ACIDS (EAA)

NMDA receptors

Depolarization

Ca+ entry

EEA release

Ca+ ion release

Neuronal injury

Non-NMDA receptors

Depolarization

Na+ entry

Passive Cl−/H2O entry

Cellular edema

Direct Neurotoxicity of Drugs

Serotonin (5-HT)  Both excess and depletion of this neurotransmitter can produce neurological disorders. Examples of drugs which produce depletion of serotonin are substituted amphetamine derivatives: 3,4-­methylenedioxyamphetamine (MDMA, ecstasy), p-chloramphetamine (PCA), and fenfluramine. All these drugs release serotonin and cause depletion of 5-HT from most axon terminals in the forebrain. Decrease in brain levels of serotonin is due to drug-induced degeneration of 5-HT neurons or their projections to the brain. Anatomical and neuroimmunocytochemical studies have provided evidence for the axonal degeneration as well as reinnervation, but it is not known if a normal pattern is established. MDMA use has been shown to produce depletion of dopamine and produce parkinsonism. There is controversy regarding the effect of fenfluramine. Low doses of this drug which are effective in suppressing food intake in rats do not have effect on the integrity of the 5-HT terminals in spite of increase in brain levels of 5-HT.  Higher doses, however, deplete brain 5-HT and produce toxic effects. Dexfenfluramine, a drug used as an appetite suppressant, was withdrawn from the market as an antiobesity drug. The drug is said to “prune” neurons and result in depletion of serotonin in the brain. Antidepressants, which block serotonin uptake increase levels of serotonin in the brain, may produce serotonin syndrome. Pathogenesis of serotonin syndrome by drug-­induced excess of serotonin is described in Chap. 37.

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Acetylcholine  ACh binding sites on cholinergic nerve terminals or sites postsynaptic to cholinergic neurons (nicotine receptors) are well-known targets of neurotoxins. Atropine is an example of such a drug which can produce memory impairment by reducing ACh in the brain.

Metabolite-Mediated Neurotoxicity The best example of metabolite-mediated neurotoxicity is the use of designer drugs containing the contaminant MPTP (1-methyl-4-phenyl1,2,5,6-tetrahydropyridine). Their use results in severe parkinsonian syndrome. MPTP leads to selective destruction of dopamine cell bodies in the substantia nigra and the loss of the striatonigral pathways. MPTP is not a neurotoxin itself; it is converted in the glia to 1-methyl-4-­ phenylpyridinium ion (MPP+) by monoamine oxidase B (MAO B) via the intermediate MPDP.  MPP+ is a substrate for the dopamine reuptake systems and accumulates within dopaminergic neurons, where it binds to neuromelanin, a black pigment found in the nigral nerve cells of primates. MPP+ is then concentrated in the mitochondria where it is thought to inhibit oxidative phosphorylation, leading to ATP depletion and changes in intracellular calcium concentration with subsequent cell death.

Norepinephrine  Blockage of NE uptake by antidepressants can cause tremor.

Astrogliosis Traditionally the induction of gliosis has been regarded as relatively late step in the cascade of events that follow neural cell damage. Gliosis, as measured by an increase in glial fibrillary acidic protein, can coincide with the earliest evidence of cell damage, often within hours of toxin exposure. Perhaps a signal common to a variety of toxicants initiates this response, and further investigations are worthwhile for determining the common mediators of neurotoxicity.

Dopamine  Blockage of dopamine uptake by antidepressants can lead to psychomotor activation and aggravation of psychoses. Dopamine depletion may result from enhanced metabolism of dopamine via MAO activity. This may explain why neurotoxicity of levodopa can be reduced by MAO-B inhibitor deprenyl.

 rug-Induced Selective Cell Death D Drugs may induce death of a selective population of neurons. Cyclosporine-induced selective cell death of oligodendrocytes in cortical cell cultures may help to explain the involvement of brain white matter in cyclosporine toxicity in humans. Pharmacological strategies such as the use of

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4  Pathomechanisms of Drug-Induced Neurological Disorders

neurotrophic factors may prove useful in enhancing the benefit-risk ratio of using this drug.

Unknown Mechanisms Some drugs such as fluorinated quinolone antibiotics are associated with neurotoxicity, but PET scanning shows no abnormality of cerebral blood flow and metabolism. The mechanism of several other DINDs remains unknown.  ultiple Mechanisms of Neurotoxicity M from Drugs An example of this is neurotoxicity of amphetamine. Mechanisms that mediate this damage involve oxidative stress, excitotoxic mechanisms, neuroinflammation, the ubiquitin proteasome system, as well as mitochondrial and neurotrophic factor dysfunction (Yamamoto et  al. 2010). These mechanisms are also involved in the toxicity associated with chronic stress and HIV infection, both of which have been shown to enhance the toxicity to methamphetamine. Repetitive use of methamphetamine causes sustained elevations of central monoamines that can manifest as a variety of neurologic disorders such as cognitive disorders, drug-induced psychosis, and movement disorders (Rusyniak 2011). Drug-induced perturbations of cholesterol homeostasis cause mitochondrial DNA disorganization, whereas mitochondrial DNA aggregation in the genetic cholesterol trafficking disorder Niemann-Pick type C disease further corroborates the interdependence of mitochondrial DNA organization and cholesterol with involvement of the ATAD3 gene as well (Desai et  al. 2017). Thus, the dual problem of perturbed cholesterol metabolism and mitochondrial dysfunction may play an important role in the causation of neurologic disorders. Another example is that of highly active antiretroviral therapy (HAART), which has increased survival rates of patients infected by HIV, but HIV-associated neurocognitive disorders (HAND) may persist. An experimental study to examine the effect of highly active antiretroviral therapy on biomarkers of senescence in primary cultures of human has shown that it induces inhibition or arrest of cell cycle, senescence-­associated beta-

galactosidase, reactive oxygen species, as well as upregulation of mitochondrial oxygen consumption. These changes in mitochondria correlate with increased glycolysis in highly active antiretroviral therapy drug-treated astrocytes (Cohen et al. 2017). Taken together, these results indicate that highly active antiretroviral therapy drugs induce the senescence program in human astrocytes and that highly active antiretroviral therapy may play a role in the neurocognitive impairment observed in HIV-infected patients.

 ethods of Assessing Neurotoxicity M Study of adverse effects of chemical, physical, or biological factors on the function and/or structure of the nervous system is called neurotoxicology and is a branch of toxicology. Most of the studies on neurotoxicology have taken place within the last two decades. Most of the studies in neurotoxicology concern exposure to environmental and industrial chemicals and measurement of effect in experimental animals. The information accumulated in this fashion is not necessarily relevant to the study of neurological adverse effects resulting from the use of therapeutic substances in human patients. Nevertheless, the methods used are important for the investigation of the potential neurotoxicity of a drug. Some of these methods are used for testing neurotoxicity in the preclinical stage of drug development. These methods are listed in Table 4.2. A discussion of these methods of assessing neurotoxicity is beyond the scope of this work. Some of the approaches will be mentioned briefly here. Immunohistochemistry  This is a powerful tool for evaluating neurotoxic effect of drugs. It allows one to demonstrate neurotoxic effects of a substance through altered morphology or loss of stained structure as in the classical methods of histochemistry. In addition, it can reveal the neurochemical identity of the affected structures. This technique has been used for demonstrating neurotoxicity of fenfluramine. It is a versatile and sensitive technique for localizing antigens of interest in the central nervous system with a high degree of resolution. Depletion of antibodies may not necessarily indicate neu-

Direct Neurotoxicity of Drugs Table 4.2  Methods for testing neurotoxicity during preclinical drug development Animal studies The neurotoxicology of cognition: attention, learning, and memory Behavioral changes Effect on motor function Electrophysiological studies: EEG and evoked potentials Effect of neurotoxicants on brain chemistry: neurotransmitter changes Metabolic mapping with deoxyglucose autoradiography Morphological changes in the nervous system  Axonal degeneration detected by silver stains  Developmental neurotoxicology: effect on neurodevelopment Cell cultures as alternatives to conventional animal toxicity as in vitro models Molecular biological approaches Genetic and molecular analysis of proteins using DNA technology In situ hybridization Ion channel neurotoxicity: receptor and ligand binding neuronal injury Study of myelin injury Immunological methods  Immunohistochemistry  Study of cell adhesion and proliferation Biomarkers of neurotoxicity Glial fibrillary acidic protein (GFAP) Single-stranded DNA as a biomarker of neuronal apoptosis Human studies Clinical neurological examination Neuropsychological tests Behavioral test batteries EEG and action potentials NMR imaging to evaluate drug concentration and metabolism Positron emission tomography (PET) Brain imaging studies for detection of lesions: CT and MRI scans © Jain PharmaBiotech

rotoxicity, and this is a limitation of this technique. Immunohistochemistry is also being used to examine functional neuroanatomy by elucidating changes in the expression of proteins which appear to relate to drug treatment or neuronal injury. In situ hybridization histochemistry  This method utilizes standard physicochemical rules for DNA and RNA duplex formation, allowing

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one to form hybrids between mRNA molecules and labeled probes with complementary nucleotide sequences within the tissues. This technique is reviewed in more detail elsewhere (Jain 2021). This technique provides a new window into the brain and a view of protein synthetic machinery of individual brain cells. The practical utility of this method in elucidating the drug action in the brain is still limited till the techniques are refined. Neurotoxicoproteomics  Neurotoxicant-induced changes in protein level, function, or regulation could have a detrimental effect on neuronal viability. Direct oxidative or covalent modifications of individual proteins by various drugs are likely to lead to disturbance of tertiary structure and a loss of function of neurons. The proteome and the functional determinants of its individual protein components are, therefore, likely targets of neurotoxicant action, and resulting characteristic disruptions could be critically involved in corresponding mechanisms of neurotoxicity. Neuroproteomic studies can provide an overview of cell proteins and, in the case of neurotoxicant exposure, can provide quantitative data regarding changes in corresponding expression levels and/ or post-translational modifications that might be associated with neuron injury. Biomarkers of neurotoxicity  A variety of classic proteomic techniques (e.g., LC/tandem mass spectroscopy, 2DG image analysis) as well as more recently developed approaches (e.g., two-­ hybrid systems, antibody arrays, protein chips, isotope-coded affinity tags, ICAT) are available to determine protein levels, identify components of multiprotein complexes, and detect post-­ translational changes. Proteomics, therefore, offers a comprehensive overview of cell proteins and, in the case of neurotoxicant exposure, can provide quantitative data regarding changes in corresponding expression levels and/or post-­ translational modifications that might be associated with neuron injury. Human embryonic stem cell (hESC)-based test systems, based on neuronal differentiated murine ESCs and quantitative differential pro-

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4  Pathomechanisms of Drug-Induced Neurological Disorders

teomic display techniques, can be used to identify biomarkers for neurotoxicity. Results are superior to those of conventional array technologies (nucleic acids) because the proteomic analysis covers post-translational modifications. It is possible to identify toxicity biomarkers without using animal-based in  vitro or in vivo systems. To circumvent serious neurotoxicity, while taking advantage of the antitumor activities of the platinum agents, efforts to identify mechanism-­ b ased biomarkers are under investigation. These data from study of genetic biomarkers associated with neurotoxicity induced by single-agent and combination platinum chemotherapy have the potential for broad clinical implications if mechanistic associations lead to the development of toxicity modulators to minimize the noxious sequelae of platinum chemotherapy (McWhinney et al. 2009). Glial fibrillary acidic protein as biomarker of neurotoxicity  The glial reaction, gliosis, represents a hallmark of all types of nervous system injury. Therefore, biomarkers of gliosis can be applied for assessment of neurotoxicity. The astroglial protein, glial fibrillary acidic protein (GFAP), can serve as one such biomarker of neurotoxicity in response to a panel of known neurotoxic agents. Qualitative and quantitative analysis of GFAP has shown this biomarker to be a sensitive and specific indicator of the neurotoxicity. The implementation of GFAP and related glial biomarkers in neurotoxicity screens may serve as the basis for further development of molecular signatures predictive of adverse effects on the nervous system. Single-stranded DNA as a biomarker of neuronal apoptosis  Single-stranded DNA (ssDNA) is a biomarker of apoptosis and programmed cell death, which appears prior to DNA fragmentation during delayed neuronal death. A study investigated the immunohistochemical distribution of ssDNA in the brain to investigate apoptotic neuronal damage as the cause of death in medicolegal autopsy cases

(Michiue et  al. 2008). Neuronal immunopositivity for ssDNA was globally detected in the brain, independent of the age, gender of subjects, and postmortem interval, and depended on the cause of death. Higher positivity was typically found in the pallidum for delayed brain injury death and fatal carbon monoxide intoxication and in the cerebral cortex, pallidum, and substantia nigra for drug intoxication. For mechanical asphyxiation, a high positivity was detected in the cerebral cortex and pallidum, while the positivity was low in the substantia nigra. The neuronal ssDNA increased during the survival period within about 24h at each site, depending on the type of brain injury, and in the substantia nigra for other blunt injuries. The neuronal positivity was usually lower for drowning and acute ischemic disease. Topographical analysis of ssDNA-positive neurons may contribute to investigating the cause of brain damage and survival period after a fatal insult.

Secondary Drug-Induced Neurologic Disorders The central nervous system is affected by changes in other organs. Many of the neurologic disorders are secondary to diseases of other organs. Similarly, the nervous system is affected by adverse drug reactions affecting other body systems. Such DINDs are referred to as secondary to distinguish them from primary DINDs for discussion of pathomechanisms. Examples of secondary drug-induced neurologic disorders according to the primary system involved are shown in Table 4.3.

 isk Factors for Drug-Induced R Neurologic Disorders Risk Factors Relevant to the Patients Risk factors that predispose a patient to the development of drug-induced neurologic disorders are shown in Table 4.4.

Risk Factors for Drug-Induced Neurologic Disorders

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Table 4.3  Examples of secondary drug-induced neurologic disorders

Table 4.4  Conditions that predispose a patient to drug-­ induced neurologic disorders

Drug-induced cardiovascular disorders  Drug-induced cardiac arrhythmias can lead to dizziness, syncope, and cerebral ischemia  Severe drug-induced hypotension may lead to cerebral ischemia  Drug-induced hypertension may lead to hypertensive encephalopathy and facial nerve palsy Drug-induced hematological disorders  Coagulation disorders can lead to cerebral hemorrhage or thrombosis  Drug-induced respiratory disorders  Respiratory disorders can lead to decreased ventilation and cerebral hypoxia Drug-induced renal disorders  Renal failure can lead to uremia and uremic encephalopathy Drug-induced hepatic disorders  Hepatic disorders can lead to hepatic encephalopathy Drug-induced electrolyte and metabolic disorders  Drug-induced hyponatremia and hypoglycemia can lead to convulsions  Hyponatremia can produce cerebral edema Drug-induced vitamin deficiency  Drug-induced vitamin deficiency can lead to neurologic disorders such as peripheral neuropathy Drug-induced endocrine disorders  Drug-induced hypothyroidism can lead to decline of mental function, ataxia, and seizures  Hyperthyroidism can produce tremor and myopathy

Genetic predisposition: pharmacogenetic factors Epigenetics Patients with a history of neurologic disorders Use by normal subjects of drugs indicated for neurologic disorders Compromised brain function  Degenerative brain disease  Intracranial space-occupying lesions  Brain damage, e.g., stroke or head injury Systemic diseases, e.g., those involving the kidneys and the liver, AIDS Noncompliance Old age Nocebo effect Pregnancy: risk to the offspring from prenatal exposure to drugs

© Jain PharmaBiotech

Pharmacogenetics Pharmacogenetics is the study of influence of genetic factors on the action of drugs and is relevant to ADRs. One reason for the high incidence of serious and fatal ADRs is that existing drug development does not incorporate genetic variability in pharmacokinetics and pharmacodynamics of new drug candidates. Polymorphisms in the genes that code for drugmetabolizing enzymes, drug transporters, drug receptors, and ion channels can affect an individual’s risk of having an adverse drug reaction, or they can alter the efficacy of drug treatment in that individual. Genetic aberrations associated with adverse reactions are of two types. Most of these arise from classical polymorphism in which the abnormal gene has a prevalence of more than 1% in the general population. Toxicity

© Jain PharmaBiotech

is likely to be related to blood drug concentration and, by implication, to target organ concentration resulting from impaired metabolism. The other type is rare, and only 1 in 10,000 to 1 in 100,000 persons may be affected. Most idiosyncratic drug reactions fall into the latter category. Examples of adverse reactions with a pharmacogenetic basis are malignant hyperthermia and extrapyramidal movement disorders in psychiatric patients on neuroleptic therapy. Enzymes controlling the drug metabolism are relevant to pharmacogenetics. The cytochrome P450 enzyme system consists of a large family of proteins that are involved in the synthesis and/or degradation of a vast number of endogenous compounds as well as the metabolism of exogenous toxins. P450 enzymes can alter, abolish, or enhance drug metabolism. Most of the clinically used drugs are cleared through the action of P450 enzymes: CYP2D6, CYP3A4, and CYP2C19. Drugs used in neurology and psychiatry practice, which are metabolized by CYP2D6, include the following: • • • • •

Amitriptyline Clomipramine Clozapine Codeine Fluoxetine

4  Pathomechanisms of Drug-Induced Neurological Disorders

48

• • • • • • • • • • • •

Fluvoxamine Haloperidol Imipramine Mexiletine Nortriptyline Olanzapine Paroxetine Phenacetin Risperidone Sertraline Tramadol Venlafaxine

CYP2C19 is the gene encoding S-mephenytoin hydroxylase, and its mutations lead to poor metabolism of various drugs that include amitriptyline, citalopram, clomipramine, diazepam, imipramine, and mephenytoin. AmpliChip CYP450 microarray enables clinical diagnostic laboratories to identify polymorphisms in CYP2D6 and CYP2C19, which play a major role in drug metabolism (Jain 2005). Expression of ATP-dependent efflux transporter, P-glycoprotein, at the level of the BBB limits the entry of many drugs into the central nervous system. Single nucleotide polymorphisms in P-glycoprotein are a potential determinant of interindividual variability in efficacy and toxicity of drugs on the CNS. Genotyping may be able to identify individuals at risk of reactions to certain drugs, but multiple genes involved in drug reactions may be difficult to detect. A patient may have a life-­ threatening reaction due to other factors that influence the onset of drug reactions, such as drug-disease interaction and drug-drug interaction. Although genetic associations with individual idiosyncratic ADRs have been identified, further studies are needed to provide insights into the mechanism of drug interaction with the gene variant that leads to a phenotype, which can manifest in several clinical forms with variable severity. Peripheral neuropathy is a side effect of proteasome inhibitor bortezomib used for the treatment of multiple myeloma, which may limit its use in some patients. A genome-wide associa-

tion study on multiple myeloma patients treated with bortezomib has revealed four new single nucleotide polymorphisms (SNPs) for bortezomib-­ induced peripheral neuropathy at 4q34.3 (rs6552496), 5q14.1 (rs12521798), 16q23.3 (rs8060632), and 18q21.2 (rs17748074), suggesting a genetic basis for neurotoxicity (Campo et  al. 2018). Further research is needed to clarify the mechanism of action of the identified single nucleotide polymorphisms in the development of drug-induced peripheral neuropathy.

Epigenetic Factors Gene regulation by genetics involves a change in the DNA sequence, whereas epigenetic regulation involves alteration in chromatin structure and methylation of the promoter region, representing a means of inheritance without associated DNA sequence alterations (Csoka and Szyf 2009). Epigenetic factors may explain changes in gene expression that persist long after drug exposure has ceased. One hypothesis proposes that some iatrogenic diseases, such as tardive dyskinesia, are epigenetic in nature. Drug-Drug Interaction Drug-to-drug interactions contribute significantly to ADRs. There may be unpredictable potentiation of synergistic effect resulting in neurotoxicity if two drugs with similar mechanisms of action are used concomitantly. The interaction of a drug acting on the nervous system with a drug acting on another system that interferes with the metabolism of the CNS drug may lead to neurotoxicity. Anticonvulsants have clinically significant interactions with other drugs used in brain tumor patients. A drug interaction can result in elevated phenytoin levels after initiation of erlotinib therapy. In polypharmacy there may be a combination of drug-drug and drug-disease interactions. An example is serotonin syndrome that developed after the use of tramadol and ziprasidone in a patient with an indwelling deep brain stimulator for Parkinson disease (El-Okdi et al. 2014).

Risk Factors for Drug-Induced Neurologic Disorders

 se by Normal Subjects of Drugs U Indicated for Neurologic Disorders Drugs given to modulate brain function counteract an abnormal function and aim to achieve a balanced neurologic status. Use of such drugs by volunteers in studies and misuse by persons without neurologic disease may produce disturbances of neurologic function. Neurologic patients who have been taking certain medications for long periods usually develop tolerance to minor adverse reactions seen at the start of the therapy. Another mechanism, seen, for example, in epileptic patients on antiepileptic drugs, is enhanced metabolism by hepatic p450 enzyme. Nonepileptic patients taking these drugs for the first time may show adverse effects after doses that are well tolerated by patients on chronic antiepileptic drug therapy.  atients with a History of Neurologic P Disorders Patients who have had neurologic signs and symptoms in the past are more likely to have a recurrence of these as an ADR.  Patients with compromised brain function are more susceptible to DIND.  The human brain has a considerable reserve capacity and plasticity, which enables it to function without obvious deficits even after parts of it are rendered inactive; however, any further insult, such as drug toxicity, may lead to decompensation and manifestations of neurologic disorders. Some examples are as follows: Degenerative brain diseases  Patients with Alzheimer disease show an exaggerated response to sedative and hypnotic drugs. Patients with underlying organic brain disease are more prone to CNS depressant effects of benzodiazepines. Severe neuroleptic sensitivity has been described in patients with senile dementia of the Lewy body type, and more than half of these patients show this reaction. Intracranial space occupying lesions  Patients with a unilateral large chronic subdural hematoma may not show any hemiplegia, but on intravenous injection of valium, such patients have been observed to manifest hemiplegia from

49

which they recover after the effect of valium wears off. This unmasking of occult neurological deficit was made during cerebral angiography under local anesthesia in the pre-CT era (Jain 1974). Sedatives can unmask focal neurological deficits. Preoperative midazolam or fentanyl in patients with brain tumor or stroke can cause exacerbation of pre-existing neurological deficit. The sedative-­induced changes range from unilateral mild weakness to complete hemiplegia but are transient in nature. Brain damage  Adolescents with brain damage are more prone to develop carbamazepine neurotoxicity. Patients with stroke are subject to increased lithium neurotoxicity. Disturbances of BBB  Conditions which disrupt BBB such as head injury, infections, and cerebrovascular accidents may allow systemic drugs that normally do not cross BBB to reach the brain tissues and produce toxic effects. Patients with meningitis are more liable to develop neurotoxicity of antibiotics due to penetration of BBB.

 atients Suffering from Systemic P Diseases Patients suffering from systemic diseases are more prone to develop adverse reactions to drugs. Drug-induced neurologic disorders are more likely to develop in patients with diseases of the kidneys and liver. Several cases of neurotoxicity resulting from treatment of herpes zoster with acyclovir or valacyclovir have been reported in patients with renal failure, whereas this is a rare side effect of these drugs in patients with normal renal function (Ruiz-Roso et al. 2012). Patients with AIDS have multiple diseases and impairment of the immune system. They have a disproportionate share of adverse drug reactions including those involving the nervous system. These patients do not tolerate tricyclic antidepressants well because of the anticholinergic effects of these drugs. They are more prone to develop drug-induced peripheral neuropathy with zidovudine (see Chap. 28).

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4  Pathomechanisms of Drug-Induced Neurological Disorders

Old Age The elderly are frequently on multi-drug therapy and are two to three times more likely than young persons to experience ADRs. Some of the changes with aging which predispose the aged to adverse effects of drugs are: • Reduction in lean body mass. • Albumin, which binds to drugs, decreases by about 25% in the elderly, making a higher level of free drug available in the serum. • Decreases in liver blood flow and hepatic cell and enzyme function result in decreased drug metabolism. • Decreases in the blood flow to the kidneys and in the number of functional glomeruli result in decreased creatinine clearance. • Age-related changes in the brain include the loss of neurons, decreased dendritic connections between neurons, decreased cerebral blood flow, and decreased number of neurotransmitters. To some extent these changes offer additional explanation why the elderly are susceptible to psychotropic drugs. Elderly patients are particularly prone to adverse effects of psychotropic agents, including benzodiazepines because of the altered pharmacokinetics. Memory and psychomotor impairments are more pronounced in the elderly on benzodiazepine treatment as compared with younger controls. The elderly are susceptible to the central effects of drugs. It is known that geriatric patients are at greater risk of neurological complications during surgical procedures, due in part to altered response to anesthetic drugs. The aged are sensitive to and require smaller doses of anesthetics to produce anesthesia. Aging potentiates the cerebral metabolic depression produced by midazolam. Triazolam causes a greater degree of sedation and psychomotor impairment in healthy elderly persons than in younger persons who receive the same dose. This is due to reduced clearance and higher plasma concentration of triazolam rather than due to increased intrinsic sensitivity to the drug. The elderly are frequent users of antirheumatic agents and are more prone to show CNS

toxicity of these agents. Tinnitus is a well-known reversible ADR of salicylates. Because the early symptoms may be overlooked, an elderly patient with salicylate intoxication may present with encephalopathy: confusion, agitation, slurred speech, hallucinations, seizures, and coma. The incidence of tardive dyskinesia is higher among the elderly patients than in young patients on neuroleptic therapy, and this complication is more likely to be irreversible in older patients. Parkinsonian side effects are more common in the younger patients than in the older ones, but choreiform side effects increase with age.

 regnancy and Prenatal Exposure P to Drugs Exposure of the fetus to certain drugs in the earlier phases of pregnancy may produce congenital malformations of the nervous system (see Chap. 5). Prenatal exposure to drugs, both therapeutic and recreational, has been documented to produce cognitive disturbances in early childhood. These may be subtle developmental abnormalities that may not be detected at birth but manifest later in childhood. Some tests such as Fagan’s Test of Infant Intelligence which evaluates visual recognition memory can detect abnormalities in infants between the ages of 6 and 12 months who have a history of in utero exposure to drugs. These abnormalities are predictive of neuropsychological deficits that manifest later in childhood and enable their identification before the children reach school age. Cognitive performance in adult age has been documented to be impaired due to in utero exposure to phenobarbital given for the treatment of epilepsy.  ole of Nocebo Effect in ADRs R In a placebo (I shall please) response, a sham medication or procedure has a beneficial health effect because of a patient’s expectation. Sugar pills, e.g., can improve depression if the patient believes them to be antidepressants. Nocebo (I shall harm) is the reverse phenomenon, i.e., negative expectations of treatment can lead the patient experience adverse effects, which can cause harm. Nocebo is at least as important as the placebo effect, as it is a biochemical and physiological process that involves pain and

Risk Factors for Drug-Induced Neurologic Disorders

stress pathways in the brain. Nocebo effect plays a role in some DINDs. Nocebo effects lead to significant number of patients in placebo groups to drop out of clinical trials because of side effects from an inert treatment. A meta-analysis has revealed the significant impact of the nocebo effect in 18 clinical trials of drugs for fibromyalgia; 11% of patients in the placebo arm dropped out of the study because of side effects including dizziness and nausea (Häuser et  al. 2012). Whereas the study investigators aim to reduce placebo response, clinicians often utilize placebo effects. There is a need for development of strategies to reduce nocebo responses in clinical trials as well as in practice.

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Drug Interactions A drug-drug interaction occurs when pharmacologic action of a drug is altered by coadministration of second drug. This may result in an increase or decrease of the known effect of either drug or a new effect which is seen with neither of the drugs. Drug-drug interactions are classified according to the primarily involved mechanisms as follows:

• Pharmacokinetic interactions occur as the drug is transported to and from its site of action, and the result is a change in plasma level or tissue distribution of the drug. • Pharmacodynamic interactions occur at biologically active (receptor) sites and result in a change in the pharmacologic effect of a given Risk Factors Related to Drugs plasma level of the drug. • Idiosyncratic interactions occur unpredictably Factors related to the drugs that influence neuroin a small number of patients and are unextoxicity are as follows: pected from known pharmacologic actions of individual drugs. Their mechanisms are gen• Some of the neurotoxic effects are dose-­ erally unclear but may be based on genetic related, and some occur only as an overdose susceptibility. effect. Management of non-neurotoxic side effects of drugs enables higher doses of these Factors which increase the likelihood of clinidrugs to be given, leading to neurotoxicity. cally significant interactions with psychotropic An example of this is high-dose chemother- drugs are as follows: apy enabled by the addition of granulocyte colony-­stimulating factor (filgrastim), which • Use of drugs that induce or inhibit hepatic counteracts neutropenia. Eventually, neuromicrosomal enzymes toxicity becomes the limiting factor with this • Drugs that have a low therapeutic index approach. • Drugs that have multiple pharmacologic • Rate of drug delivery, e.g., faster rates of intraactions venous delivery of some drugs, may produce • High-risk patients (elderly, medically ill, etc.) transient neurologic disturbances. • Route of administration of some drugs, which Interactions leading to DIND usually occur usually do not cross the BBB, has neurotoxic under the following circumstances: effects only when applied directly to the CNS such as by intrathecal or intraventricular routes. • Enhancement of neurotoxicity of drug for • Drug interactions may occur with concomiCNS disorders interacting with another CNS tant medications. drug or a non-CNS drug which affects its • Drug-disease interaction. Drugs may unfavormetabolism ably influence the course of the neurologic • Enhancement of potential neurotoxicity by condition being treated. interaction between drugs for non-CNS • Drug withdrawal after prolonged use may prodisorders duce neurologic disorders.

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4  Pathomechanisms of Drug-Induced Neurological Disorders

Drug-Disease Interactions Drugs for CNS disorders  A drug may have an unfavorable effect on the course of the neurological disease that is the indication for its use. There are several such happenings particularly in degenerative disorders. It is difficult to determine whether the adverse effect is the natural course of the disease or if the drug induces neurological deterioration. One example would be an epileptic patient with an organic brain lesion whose seizures continue to deteriorate with antiepileptic therapy. Optimal doses of the drug may not be able to control seizure activity due to progression of the underlying lesion. Interferon-beta has been approved as a therapy for multiple sclerosis, but active lesions may develop during the first 3 months in treated patients. The rate of appearance of new lesions declined after active treatment was stopped indicating that interferon-beta causes activation of the disease process. Long-­ term interferon-beta therapy, however, downregulates interferon gamma production and decreases clinical activity. There may be unpredictable potentiation of synergistic effect resulting in neurotoxicity if two drugs with similar mechanisms of action on the CNS are used concomitantly. The concentration of drugs for CNS disorders may rise to toxic levels because of concomitant drugs which interference with drug metabolism and clearance. One of the common mechanisms is that plasma levels of a CNS drug are raised by other drugs which inhibit the hepatic microsomal p450 metabolism. Anticonvulsants have clinically significant interactions with other drugs used in brain tumor patients. A drug interaction can result in elevated phenytoin levels after initiation of erlotinib therapy in a patient who is receiving phenytoin. Some of the important drug interactions are shown in Table 4.5, and further interactions are mentioned in various other chapters. The use of two CNS drugs can have adverse interactions. Such an interaction can take place if one drug is substituted for the other after an inadequate washout period. Hypertension with stupor is known to occur after a switch of two monoamine oxidase (MAO) inhibitors isocarboxazid and phenelzine.

Drugs for non-CNS indications  Interaction of two such drugs can raise the plasma levels of one of these which is known to cause DIND.  For example, addition of a quinolone raises theophylline serum levels by more than 100% and can lead to seizures in one-third of the patients. Neurological disorders have been reported in elderly patients where chloroquine was used concomitantly with NSAIDs. Although each of these drugs can cause neurologic adverse effects, a pharmacodynamic and/or pharmacokinetic interaction was considered to have contributed to these cases.

Drug Withdrawal Discontinuation of several drugs after prolonged therapeutic use may produce a withdrawal reaction with neuropsychiatric symptoms. This is to be distinguished from withdrawal syndromes seen in drug dependence. Manifestations of withdrawal of several drugs will be mentioned in various chapters of this book. Withdrawal phenomena are particularly associated with antidepressants and antipsychotics. Antidepressants  Withdrawal phenomena following abrupt or progressive cessation of antidepressant medications are well recognized. These occur after all types of antidepressants including tricyclics, monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors. Mood changes resulting from withdrawal are difficult to distinguish from the symptoms of depression, but other symptoms such as sleep disturbances, delirium, and movement disorders may also occur. Incidence of antidepressant withdrawal syndrome varies from 16% to 80% in various studies. Risk factors for the development of this syndrome include long-term use of the drug and concomitant discontinuation of a centrally acting comedication such as anticonvulsant carbamazepine. Pathophysiology of this syndrome varies according to the type of antidepressant. Tricyclic antidepressants (TCAs)   The most well-documented hypothesis of pathophysiology is the effect on cholinergic system. Most of the symptoms are explained as a cholinergic rebound because TCAs produce musca-

Risk Factors for Drug-Induced Neurologic Disorders

53

Table 4.5  Neurological disorders due to drug interactions of psychopharmaceuticals Drug Interaction with Antipsychotic 1/clozapine Antipsychotic 2/ lithium Benzodiazepines (BZD) Omeprazole Carbamazepine (CBZ)

Erythromycin

Clozapine

Benzodiazepines/ lorazepam Sumatriptan

Ergotamine

Lithium MAO inhibitor: moclobemide Phenytoin (PHT)

Diuretic Fluoxetine (SSRI)

Selective monoamine oxidase inhibitor/ selegiline Tricyclic antidepressants (TCA)/imipramine

Pethidine

Fluoxetine

SSRI/fluoxetine

Neurological ADRs Mechanism Disorientation, tremor, Combined neurotoxicity of two ataxia, seizures Ataxia Increase of plasma levels of BZD by p450 inhibition antipsychotics Neurotoxicity of Increase of plasma levels of CBZ by carbamazepine p450 inhibition Excessive sedation, Pharmacodynamic ataxia Increased peripheral Pharmacodynamic interaction at 5-HT vasospasm in migraine postsynaptic level between an agonist and an antagonist Lithium neurotoxicity Decreased renal clearance of lithium Serotonin syndrome Accumulation of serotonin due to inhibition of degrading effect of MAO Neurotoxicity of Increase of plasma levels of PHT by phenytoin p450 inhibition Restlessness, Dopamine is implicated irritability, delirium Accentuation of antidepressant effect

rinic cholinergic receptor blockade resulting in development of tolerance and increase in postsynaptic density of muscarinic receptors. Movement disorders may be due to disturbance of cholinergic-­d opaminergic balance in the nigrostriatal and mesocortical systems, respectively. Parkinsonism may be associated with dopamine receptor blockade. Because TCAs also affect the noradrenergic system, abrupt withdrawal increases noradrenaline turnover which explains anxiety and agitation.

Increase of plasma levels of TCA by p450 inhibition

vertigo, and tremor. Psychiatric withdrawal symptoms more likely to be seen with fluoxetine include nervousness, anxiety, depression, suicide attempt, psychotic depression aggression, and agitation. Because the psychiatric symptoms of antidepressant discontinuation include changes in mood, affect, appetite, and sleep, they are sometimes mistaken for signs of a relapse into depression. The mechanism of withdrawal reactions is not well understood, but it is postulated that discontinuation events result from a sudden decrease in the availability of synaptic serotonin in the face of downregulated serotonin receptors. In addition, other neurotransmitters, such as dopamine, norepinephrine, or gamma-aminobutyric acid (GABA), may also be involved. Individual patient sensitivity may also be a factor in SSRI discontinuation phenomena.

• Monoamine oxidase inhibitors (MAOIs) can exert an amphetamine-like effect and explains the similarity of MAOI withdrawal to amphetamine overdose. MAOIs downregulate and subsensitize alpha2 adrenergic receptors in animals and humans. These effects provide a theoretical basis for MAOI withdrawal-­ induced psychosis. • CNS withdrawal symptoms of selective sero- Antipsychotics  A variety of symptoms follow tonin reuptake inhibitors (SSRIs) are usually the discontinuation of phenothiazines, thioxanseen with paroxetine which as a short half- thenes, and butyrophenones. The most common life and rarely with fluoxetine and sertraline. are nausea, vomiting, anorexia, paresthesias, CNS withdrawal symptoms include dizzi- anxiety, agitation, restless, and insomnia. Patients ness, headache, seizures, paresthesias, may experience vertigo, paresthesias, myalgia,

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4  Pathomechanisms of Drug-Induced Neurological Disorders

and tremor. Symptoms usually appear a few days after discontinuation of the drug and resolve in 1–2 weeks. The pathophysiology of antipsychotic withdrawal may involve drug-induced supersensitivity of muscarinic cholinergic and dopaminergic systems because antipsychotics bind to dopaminergic, muscarinic, and adrenergic receptors. Long-term treatment with antipsychotic agents may result in dopaminergic rebound in the chemoreceptor trigger zone which may account for withdrawal-associated nausea and vomiting. Management of antipsychotic agent withdrawal phenomena is symptomatic. Anxiety and agitation should be watched carefully as this may progress to psychosis and require increase in the dose of antipsychotic.

Cohen J, D'Agostino L, Wilson J, Tuzer F, Torres C.  Astrocyte senescence and metabolic changes in response to HIV antiretroviral therapy drugs. Front Aging Neurosci. 2017;9:281. Csoka AB, Szyf M.  Epigenetic side-effects of common pharmaceuticals: a potential new field in medicine and pharmacology. Med Hypotheses. 2009;73:770–80. Desai R, Frazier AE, Durigon R, et  al. ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism. Brain. 2017;140:1595–610. El-Okdi NS, Lumbrezer D, Karanovic D, et al. Serotonin syndrome after the use of tramadol and ziprasidone in a patient with a deep brain stimulator for Parkinson disease. Am J Ther. 2014;21(4):e97–9. Feng X, Chen A, Zhang Y, et al. Central nervous system toxicity of metallic nanoparticles. Int J Nanomedicine. 2015;10:4321–40. Häuser W, Sarzi-Puttini P, Tölle TR, Wolfe F.  Placebo and nocebo responses in randomised controlled trials of drugs applying for approval for fibromyalgia syndrome treatment: systematic review and meta-­analysis. Clin Exp Rheumatol. 2012;30(6 Suppl 74):78–87. Jain KK. Use of diazepam in carotid angiography. Can J Discontinuation syndromes  The existence of Neurosci. 1974;1:141–2. discontinuation syndromes following treatment Jain KK.  Applications of AmpliChip CYP450. Mol Diagn. 2005;9:119–27. with neuroleptic (antipsychotic) drugs was first Jain KK.  Molecular Diagnostics. Basel: Jain outlined in the mid-1960s, but the effects of such PharmaBiotech Publications; 2021. syndromes have been neglected since then. There McWhinney SR, Goldberg RM, McLeod HL.  Platinum neurotoxicity pharmacogenetics. Mol Cancer Ther. is evidence for the existence of discontinuation 2009;8:10–6. syndromes after cessation of treatment with antiMichiue T, Ishikawa T, Quan L, et  al. Single-stranded psychotics/neuroleptics which may involve feaDNA as an immunohistochemical marker of neuronal tures other than motor dyskinesias. damage in human brain: an analysis of autopsy material with regard to the cause of death. Forensic Sci Int. 2008;178:185–91. Ruiz-Roso G, Gomis A, Fernández-Lucas M, et  al. Concluding Remarks Aciclovir and valaciclovir neurotoxicity in patients with renal failure. Nefrologia. 2012;32:114–5. Knowledge of the pathomechanism of drug-­ Rusyniak DE. Neurologic manifestations of chronic methamphetamine abuse. Neurol Clin. 2011;29:641–55. induced neurological disorders (DINDs) is help- Yamamoto BK, Moszczynska A, Gudelsky GA. ful in their assessment. More is known about this Amphetamine toxicities: classical and emerging mechanisms. Ann N Y Acad Sci. 2010;1187:101–21. subject than is generally assumed. Several

hypotheses still need further investigation. Better understanding of the pathomechanisms of DINDs will improve their management.

References Campo C, da Silva Filho MI, Weinhold N, et  al. Bortezomib-induced peripheral neuropathy: a genome-wide association study on multiple myeloma patients. Hematol Oncol. 2018;36:232–7.

5

Adverse Effects of Drugs on the Fetal Nervous System

Introduction Safety of drugs during pregnancy is an important subject and beyond the scope of this chapter, but an excellent book is available on this topic (Briggs et al. 2017). The fetus is exposed to drugs used during pregnancy for action on the nervous system, particularly those that cross the blood-­ brain barrier (BBB) and the placental barrier. This may result in premature babies, underweight babies, stillborn births, or congenital malformations including those involving the nervous system or neurodevelopmental disorders. Some neurological problems in adults are being traced back to exposure to drugs at the fetal stage. Exposure to recreational drugs and alcohol before birth has been proven to cause behavior problems in early childhood. Even coffee is sometimes considered to be a drug during pregnancy. Use of drugs during pregnancy is not recommended except when there is no alternative, e.g., use of antiepileptic drugs (AEDs) during pregnancy.

Neurological Disorders and Pregnancy A brief discussion of neurological disorders that occur in pregnant women and neurological complications of pregnancy is relevant to the topic of this chapter as the diseases as well as the drugs used for their treatment may affect the fetal brain.

Examples of neurological complications of pregnancy are: • Wernicke’s encephalopathy due to intractable vomiting, which urgent administration of thiamine. • Eclampsia occurs when seizures or coma develops in a patient with preeclampsia. • Various manifestations of stroke such as hypertensive intracerebral hemorrhage, subarachnoid hemorrhage, and venous sinus thrombosis may occur during pregnancy. • Posterior reversible encephalopathy syndrome is characterized by headache, encephalopathy, visual disturbances, and seizures associated with reversible vasogenic edema seen on CT or MRI. • Neurological complication of general anesthesia.

 harmacology of Drugs During P Pregnancy Pregnancy is associated with profound changes in the physiology of every organ in the body, which affect the pharmacokinetics and pharmacodynamics of medications. Some important changes during pregnancy are as follows (Costantine 2014): • Absorption of orally administered drugs may be affected by a decrease in gastrointestinal

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_5

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5  Adverse Effects of Drugs on the Fetal Nervous System

56

•

•

•

•

•

•

motility leading to a decrease in maximum concentration and time to maximum concentration. Maternal blood volume increases by 40–50% during pregnancy, and water within the body expands the volume of distribution of hydrophilic substances. Maternal fat stores increase tenfold leading to a larger volume of distribution of lipophilic drugs. For some drugs, a larger volume of distribution could lead to a decreased peak serum concentration, which may necessitate a higher initial and maintenance dose to obtain therapeutic plasma concentrations. Because of the decrease in serum albumin during pregnancy, highly protein-bound compounds, such as digoxin, midazolam, and phenytoin, display higher free levels, which increases their peak plasma concentrations and thus risks of ADRs. Drug elimination, especially for renally cleared medications, is enhanced by the increased renal blood flow and glomerular filtration rate in pregnancy, which can lead to a significant increase in the elimination rates of renally cleared medications, leading to shorter half-lives and risk of sub-therapeutic concentrations. Drug metabolism is also affected by the increase or decrease in the expression and activity of various metabolizing enzymes.

Despite all of these, pregnant women are still considered therapeutic orphans as most of the current therapeutics were never studied in pregnancy. A review pointed out the urgent need to increase the support of pharmacokinetic trials in pregnancy through private-/government-funding organizations and to support current or future networks to perform obstetric-fetal pharmacology studies (Ayad and Costantine 2015).

Placental Barrier The placenta is a lipid membrane that allows bidirectional transfer of substances between the

mother and the fetus rather than acting as a true barrier for the transfer of most drugs and xenobiotics from mother to fetus. In humans the placental barrier consists of the trophoblastic epithelium, covering the villi, the chorionic connective tissue, and the fetal capillary endothelium. The average thickness of the barrier varies from 20 to 30 μm in the first trimester to 2–4 μm in the third trimester. Development of the fetus depends on the placental passage of gases, nutrients, hormones, and waste products via passive diffusion, carrier-­ mediated cellular uptake and efflux, and transcytosis pathways. The same mechanisms additionally control the rate and extent of transplacental transfer of drugs taken by the pregnant mother. Essentially all drugs cross the placenta to a certain extent, and some accumulate in the placenta itself at levels that can even exceed those in maternal plasma. Hence, even drugs that are not efficiently transferred across the placenta may indirectly affect fetal development by interfering with placental function (Tetro et al. 2018). The rate and extent of diffusion across placenta differ for various compounds and are determined by the maternal-fetal drug gradient, uterine and umbilical blood flow, molecular weight (MW) of drug/toxicant, protein binding, lipid solubility, and degree of ionization. Metabolic processes in the mother or the placenta can biotransform high-MW chemicals into low-MW chemicals, thus allowing them to cross the placental barrier. Human placenta, by having a significant butyrylcholinesterase activity, metabolizes cocaine and thereby serves as a metabolic barrier to protect the fetus.

Fetal Blood-Brain Barrier Efflux mechanisms in the blood-brain barrier (BBB) play a role in protective mechanisms in the adult human brain (see Chap. 3) and in the embryo, fetus, and newborn brain. The belief that the BBB is absent or immature in the fetus and newborn has led to many statements with potential clinical implications (Saunders et al. 2019). The immature brain is more vulnerable to damage by drugs and

Effects of Maternal Drugs on Breastfeeding Infants

toxins as some developmentally regulated normal BBB mechanisms probably contribute to this vulnerability. The functional status of brain barrier efflux mechanisms should be investigated at different stages of brain development to provide a rational basis for the use of drugs in pregnancy and in newborns, especially in those prematurely born, where protection usually provided by the placenta is no longer present.

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and/or there is positive evidence of human fetal risk based on ADR from investigational or marketing experience, and the risks involved in the use of the drug in pregnant women clearly outweigh potential benefits.

 ffects of Maternal Drugs E on Breastfeeding Infants

Use of drugs by the mother during pregnancy does not pose significant problems in breastfeeding. A century-old concept suggested that “… it is possible to show that drugs … when given to a There are no precise figures available for the mother, rarely affect the milk injuriously, and prevalence or incidence of sequelae of fetal drug almost never the babe to a marked degree” (Reed exposure to the brain. Prescription drug use is 1908). It has not been refuted. Moreover, most generally associated with 2–3% incidence of lactating women take few medicines. Further, congenital malformations. ADRs of drugs during although drugs are transferred into the breast milk pregnancy are difficult to study as pregnant to some extent, the amount of drug is usually women are not enrolled in clinical trials. Post-­ small and unlikely to cause an ADR in the baby. market safety of drug use during pregnancy is assessed by enrolling the patients in pregnancy registries. Pharmacokinetics During Lactation The use of medications in pregnancy has been increasing over the past few decades both in the Drugs enter milk by passive diffusion, but there is USA and in other developed countries. The aver- a correlation between maternal plasma-drug conage number of medications used by pregnant centration and milk-drug concentration. A high women in the USA increased by 68%, from 2.6 in volume of distribution of a drug, e.g., sertraline, 1976–1978 to 4.2  in 2006–2008, and >80% of leads to a lower maternal plasma concentration pregnant women use four or more drugs at some and a subsequent lower concentration in milk. point during their pregnancy (Lupattelli et  al. Drug transfer into breast milk is also influ2014). In addition to prescription medications, enced by the extent to which the drug is bound by pregnant women are also self-medicating them- maternal plasma proteins. Drugs with lower proselves with over-the-counter drugs and herbal tein binding such as venlafaxine diffuse readily products for which there is limited information in and produce higher concentration of the drug in pregnancy. A review of >150,000 pregnancies the milk, but highly protein-bound drugs will be revealed that while the majority (78%) of preg- minimally transferred to the breastfed baby. nant women are exposed to either class B or C The size of the drug molecule influences the drug, 1.1% and 3.4% are exposed to either a class concentration in milk. Most drug molecules, X or D (Andrade et al. 2008). Class D indicates including alcohol, nicotine, and caffeine, are that there is positive evidence of human fetal risk small enough to enter the milk. Exceptions are based on ADR data from investigational or mar- drugs with high molecular weights such as hepaketing experience or studies in humans, but rins and insulin. Drugs cross membranes in a potential benefits may warrant the use of the drug non-ionized form. Milk is generally slightly more in pregnant women despite potential risks, acidic than the mother’s plasma and attracts weak whereas class X indicates that studies in animals organic bases such as oxycodone and codeine, or humans have demonstrated fetal abnormalities which become ionized and “trapped” in the milk.

Epidemiology of Disorders Due to Fetal Exposure to Drugs

5  Adverse Effects of Drugs on the Fetal Nervous System

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Conversely, weak organic acids such as penicillin tend to be ionized and held in maternal plasma. Lipid-soluble drugs such as citalopram are more likely to be secreted in milk by dissolution in the fat droplets. Pharmacogenetic factors also play a role. In ultra-rapid metabolizers of codeine, the drug is variably metabolized to morphine by the cytochrome P450 (CYP) 2D6 enzyme. Repeated codeine doses produce significant amounts of morphine that is transferred from maternal plasma to the milk resulting in CNS depression and may be lethal. Codeine should be avoided during breastfeeding and alternative analgesia is recommended, such as paracetamol or ibuprofen.

 recautions for Drug Use During P Lactation Considering the number of drugs available, relatively few known ADRs occur in babies, and it is generally not necessary to suspend breastfeeding because of the mother’s medication. However, the number of drugs in use is increasing and the following are contraindicated during lactation because of general ADRs, but not for neurotoxicity: • Amiodarone, an iodine-containing molecule, may affect thyroid function in infant. • Anticancer agents may cause bone marrow suppression and leukopenia. • Gold salts may cause nephritis and hematological abnormalities. • Iodine in high doses (>150 μg daily) has a risk of hypothyroidism in the infant. • Retinoids (oral) have a potential for serious adverse effects. Precautions for drug use during lactation are: • If a drug is needed, the lowest effective dose should be used. • Drugs with a relatively short half-life, such as sertraline rather than fluoxetine, should be chosen to minimize drug exposure in milk. • The infant should be fed before the mother takes her medicine so that the drug concentration in milk will be at its lowest.

 ffects of Drugs Used During E Pregnancy on the Fetal CNS Drugs used during pregnancy that have effects on the fetal CNS are listed in Table 5.1 and described in the following text. According to the US FDA, drugs used in pregnancy are assigned to categories (https://chemm. nlm.nih.gov/pregnancycategories.htm): Category A. Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters). Category B. Animal reproduction studies have failed to demonstrate a risk to the fetus and Table 5.1  List of CNS-active drugs used in pregnancy that affect the fetus Drugs used for the treatment of neurological disorders Anti-Parkinson’s disease drugs Antidepressants Antiepileptic/anticonvulsant drugs: fetal anticonvulsant syndrome Antimigraine drugs Antipsychotic drugs Drugs used in the treatment of multiple sclerosis Drugs used for the management of cerebral ischemia Drugs for nausea and vomiting Lithium Opioid analgesics Psychostimulants Sedatives and hypnotics Other drugs during pregnancy with effect on the fetus Antiallergics Antiasthmatics, e.g., albuterol (Ventolin) Antibiotics Anticancer drugs Anticoagulants Antihypertensive drugs Aspirin Chemotherapy Fluconazole (Diflucan) for yeast infections Ibuprofen Immunosuppressants Isotretinoin for acne Local anesthetics Systemic corticosteroids Substance abuse during pregnancy Alcohol: fetal alcohol syndrome Cocaine Marijuana (cannabis) © Jain PharmaBiotech

Effects of Drugs Used During Pregnancy on the Fetal CNS

there are no adequate and well-controlled studies in pregnant women. Category C. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Category D. There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant the use of the drug in pregnant women despite potential risks. Category X. Studies in animals or humans have demonstrated fetal abnormalities, and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in the use of the drug in pregnant women clearly outweigh the potential benefits.

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mals, including teratogenicity. There is an association between topiramate use early in pregnancy and the risk of oral clefts (Hernandez-Diaz 2014). It should be used in pregnancy only if the potential benefits outweigh the potential risks. Serum concentrations of topiramate decline gradually throughout pregnancy, and therapeutic drug monitoring may be useful (Westin et al. 2009).

Antidepressants

Selective Serotonin Reuptake Inhibitors (SSRIs)  Antidepressant use during pregnancy is associated with increased risks of miscarriage, birth defects, preterm birth, newborn behavioral syndrome, persistent pulmonary hypertension of the newborn, and possible longer-term neurobehavioral effects (Domar et al. 2013). In pregnant women, SSRIs cross the placenta and have the potential to affect newborns. Sertraline and paroxetine have been associated with congenital malformations. SSRIs have also Anti-Parkinson’s Disease Drugs been associated with neonatal complications, such as neonatal abstinence syndrome and persisLevodopa  The safety of levodopa in women tent pulmonary hypertension. The risk of persiswho are or may become pregnant has not been tent pulmonary hypertension of the newborn is established. Doses more than 200 mg/kg per day usually low, but the use of SSRIs in late preghave an adverse effect on the postnatal growth of nancy increases that risk more than twofold, and the offspring. Levodopa should not be used in this seems to be a class effect (Kieler et al. 2012). nursing mothers. According to a warning from the FDA in 2006, physicians prescribing SSRIs to pregnant women Selegiline  No teratogenic effects were observed must discuss with them the potential risks. in a study of embryo-fetal development in A comparative study of cohorts of children of Sprague-Dawley rats (at oral doses 35 times the women with and without different antidepressant human therapeutic dose). No adequate and well-­ exposures before and during pregnancy failed to controlled studies have been administered in reveal an association with congenital heart anompregnant women. Selegiline should be used dur- alies (Petersen et al. 2016). This study also found ing pregnancy only if the potential benefit justifies an increased risk of congenital heart anomalies in the potential risk to the fetus. This is usually not a children of older women and in children of problem in practice as Parkinson’s disease usually women with diabetes, obesity, and a history of occurs in women beyond the childbearing period. alcohol and drug abuse independent of the The manufacturer of the selegiline transder- ­prescription of antidepressants. The authors of mal patch recommends that breastfeeding is not this study cautioned that, based on existing evirecommended during treatment and for 5  days dence, advising women to stop antidepressant treatment in pregnancy may be counterproducafter the final dose. tive. Paroxetine is contraindicated in pregnancy Topiramate  This drug has demonstrated selec- and is classified as category D/X due to its teratotive developmental toxicity in experimental ani- genic effects in causing cardiovascular defects,

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specifically cardiac malformations, if prescribed in the first trimester. Elevated platelet serotonin levels found in approximately one third of children with autism have led to the belief that dysfunctional serotonin signaling may be a causal mechanism for the disorder and has raised concern about the developmental effects of prenatal exposure to SSRIs (Harrington et  al. 2013). A cohort study of all singleton live births in Denmark from 1996 through 2005 with follow-up to 2009 failed to detect a significant association between maternal use of SSRIs during pregnancy and autism spectrum disorder in the offspring (Hviid et al. 2013). According to one review, the absolute risks of SSRIs used in pregnancy are low and may be outweighed by the risks of untreated depression, particularly in the perinatal period (Susser et al. 2016). These drugs fall in category C of the US FDA classification regarding safety of use during pregnancy. Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans. SSRIs are usually compatible with breastfeeding, but individual variations in infant exposure may occur. Fluoxetine  Fetal development studies in rats and rabbits have shown no evidence of teratogenicity following administration of fluoxetine, a SSRI, in doses equivalent to the maximum recommended human dose throughout organogenesis; however, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first week postpartum occurred following maternal exposure to fluoxetine during gestation and lactation. Symptoms such as irritability, respiratory distress, and muscular hypotonia have been reported in newborns after third trimester exposure. A meta-analysis indicates that maternal fluoxetine use is associated with a slightly increased risk of cardiovascular malformations in infants, and the risk-benefit must be weighed when making decisions about whether to treat with fluoxetine during pregnancy (Gao et al. 2017). No significant malformations were reported involving the nervous system, eye, urogenital system, digestive system,

5  Adverse Effects of Drugs on the Fetal Nervous System

respiratory system, or musculoskeletal system. The mean combined dose of fluoxetine and its metabolite norfluoxetine transmitted to infants through breast milk is usually below the 10% level of concern, but it may be greater than 10% in some cases. Adverse effects have been observed in breastfed infants and, thus, nursing when on fluoxetine treatment is not recommended. Usual doses of fluoxetine result in relatively low concentrations of fluoxetine during pregnancy, which are partly due to increased demethylation of fluoxetine by cytochrome P450 2D6, which may explain undertreatment of depression in pregnancy and therapeutic failure. The positive effects of treatment of depression during pregnancy and the perinatal period generally outweigh the risks of possible adverse effects of fluoxetine.

Antiepileptic Drugs There is concern about teratogenicity as the incidence of congenital malformations in offspring of women treated with anticonvulsants during pregnancy is somewhat higher than in offspring of women not exposed to these drugs. Most anticonvulsant drugs fall into category C of the US FDA. Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans. Longterm developmental effects of antiepileptic drugs in children as they grow older are still uncertain. Potential benefits may warrant use of antiepileptic drugs in pregnant women despite potential risks. Scientific data are now becoming available for the use of second-generation antiepileptic drugs during epilepsy. Lamotrigine and levetiracetam are considered to have low risks for both anatomical and behavioral teratogenesis (Meador and Loring 2016). Although safety issues are favorable for lamotrigine, its therapeutic concentration may be difficult to maintain during pregnancy as its clearance from the body during pregnancy is increased due to being metabolized by uridine-­ diphosphate glucuronosyltransferase (Reimers and Brodtkorb 2012). Analysis of 20-year data from the Australian Pregnancy Register of women on antiepileptic

Effects of Drugs Used During Pregnancy on the Fetal CNS

drugs for epilepsy as well as other indications showed that polytherapy did not increase fetal hazard unless valproate or topiramate was involved in the combination (Vajda et al. 2019). The use of these two drugs should be avoided in pregnancy unless absolutely required for seizure control. For women on anticonvulsant therapy who are breastfeeding, there are still limited data regarding the degree to which anticonvulsants penetrate breast milk. In general, women with epilepsy can breastfeed their babies safely with some cautions. Phenobarbital and primidone should be avoided, and with ethosuximide, levetiracetam, lamotrigine, topiramate, and zonisamide, there is a potential for significant breast milk concentrations. Carbamazepine  Experimental studies have shown no teratogenic effect of carbamazepine on the fetus, but epidemiological studies suggest that there may be an association of carbamazepine use during pregnancy with congenital malformations of the fetus, including spina bifida. Carbamazepine should be used during pregnancy only if the potential benefits outweigh the risks. Studies have shown the role of folic acid deficiency in the causation of congenital malformations such as spina bifida. Medications that lower folic acid should be avoided, and folic acid supplementation during pregnancy is recommended. Gabapentin  Gabapentin has been shown to be fetotoxic in rodents, but this is not necessarily predictive of human toxicity. It should be used in pregnancy only if the benefits outweigh the potential risks. A review of published pregnancy registries shows that maternal gabapentin use is associated with roughly equivalent rates of premature birth and birth weight after correction for gestational age at delivery and maternal hypertension/eclampsia as those that have been reported in the general population (Guttuso Jr et  al. 2014). Although these data support the safety of gabapentin use in pregnancy, the number of exposures so far is still small, and further studies are needed. Withdrawal symptoms from gabapentin, administered to mothers during pregnancy, have

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been reported in neonates. As in adults, gabapentin should be gradually tapering off in neonates over weeks to months (Carrasco et al. 2015). The transfer of gabapentin to breast milk is extensive, but plasma concentrations appear to be low in suckling infants and no adverse effects have been reported in neonates. Lacosamide  This drug produces increased developmental neurotoxicity in rats following administration during pregnancy. A woman with status epilepticus due to cerebral venous thrombosis in early pregnancy was treated with levetiracetam, lacosamide, and enoxaparin throughout the pregnancy (Ylikotila et al. 2015). At full-term delivery, levetiracetam and lacosamide were present in the cord blood of the infant in levels like those in maternal blood, resulting in sleepiness, which resolved after 2  weeks. The infant was breastfed, and lacosamide level in milk was low. There are no adequate and well-controlled studies in pregnant women. Lacosamide should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. Lacosamide is excreted in human milk, and the decision whether to discontinue nursing or to discontinue lacosamide should consider the importance of the drug to the mother. A study from a large epilepsy center suggests a good level of efficacy and safety for lacosamide throughout pregnancy and breastfeeding without teratogenicity or toxicity (Lattanzi et al. 2017). Lamotrigine  Although lamotrigine is not teratogenic in pregnant rats, it reduces fetal folate concentration, which is a factor known to be associated with teratogenesis in animals as well as in humans. The rate of lamotrigine excretion into the human breast milk is like that observed with other antiepileptic drugs. A review of 18 years of the International Lamotrigine Pregnancy Registry did not detect an appreciable increase in major congenital malformation frequency following first-trimester lamotrigine monotherapy exposure (Cunnington et  al. 2011). Lamotrigine is among the safest antiepileptic medications in terms of fetal malformations and postpartum cognitive development, making it probably the first choice for treatment of an epileptic woman

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who wishes to become pregnant (Moore and Aggarwal 2012). However, increased risk of an isolated cleft palate or cleft lip deformity has been reported in infants exposed to lamotrigine in the first trimester of pregnancy (Holmes et al. 2008). It should be used in pregnancy only if potential benefits outweigh the risks. Lamotrigine levels in serum correlate strongly with the lamotrigine levels in amniotic fluid and umbilical cord blood, indicating the fetus is exposed to the drug administered to a woman during pregnancy (Paulzen et  al. 2015). Lamotrigine clearance is markedly elevated during the first trimester, and an average dose increase by 250% is required to obtain therapeutic serum levels (Fotopoulou et al. 2009). Levetiracetam  A study based on registers of epilepsy and pregnancy in the UK and Ireland showed a low risk for major congenital malformations with levetiracetam monotherapy as compared to its use as a part of polytherapy regimen (Mawhinney et  al. 2013). Another retrospective study showed that the use of levetiracetam as monotherapy during pregnancy has the same risk level for fetal malformations as the group who never used antiepileptic drugs and that the risk increased when it was used as a part of polytherapy (Koc et al. 2018). No controlled studies have been performed in pregnant women. Because of the potential risk to the fetus during pregnancy, levetiracetam should be used only if the benefits outweigh the risks. Perampanel  It is designated pregnancy category C. Administration of perampanel to pregnant rats throughout organogenesis resulted in an increase in visceral abnormalities. No controlled study of use of perampanel in pregnancy in humans has been published so far. Perampanel is generally not recommended for women of childbearing age without contraception, and reduced efficacy of progesteronecontaining oral contraceptives by interaction with perampanel should be considered (Rohracher et al. 2016). Potential benefits may warrant the use of the drug in pregnant women despite potential risks, but perampanel should be used only if clearly needed and the benefit

5  Adverse Effects of Drugs on the Fetal Nervous System

outweighs the potential risk. Pregnant patients taking perampanel should enroll in the North American Antiepileptic Drug Pregnancy Registry. Perampanel is excreted into animal milk, but it is not known whether it is distributed in human breast milk. The effects in nursing infants are unknown. Phenytoin/Fosphenytoin  Precautions for pregnant women using phenytoin are as follows: • An increase of seizure frequency may occur during pregnancy because of altered phenytoin absorption or metabolism. Periodic measurements of phenytoin levels to guide dosage adjustment are recommended. • Several reports suggest an association between the use of antiepileptic drugs, including phenytoin, in pregnancy and a higher incidence of birth defects. • Neonatal coagulation defects have been reported within the first 24  hours in babies born to mothers receiving phenytoin. Vitamin K has been shown to correct or prevent this defect. • Only small amounts of phenytoin are found in breast milk and usually cause no difficulties in breastfed infants. Breastfeeding during phenytoin monotherapy has not been reported to adversely affect infant development. If phenytoin is required by the mother, breastfeeding need not be discontinued. Tiagabine  Because teratogenic effects were seen in the offspring of rats exposed to maternally toxic doses of tiagabine, and because experience in humans is limited, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Because of the possibility that tiagabine may be excreted in breast milk, and because there is very limited published experience with tiagabine during breastfeeding, other antiepileptic agents may be preferred. Valproic Acid  Maternal exposure to valproic acid (VPA) during the first trimester of pregnancy significantly increased the risk of major malforma-

Effects of Drugs Used During Pregnancy on the Fetal CNS

tions (Jentink et al. 2010). Tests for the detection of neural tube defects and other congenital malformations should be carried out as a part of routine prenatal care. In utero exposure to valproate, as compared with other commonly used antiepileptic drugs, is associated with an increased risk of impaired cognitive function at 3 years of age (Meador et al. 2009). VPA exposure in rats leads to autistic-like behavior in their offspring, including social and communication deficits, but this animal model of autism, although valid, has limitations in translation to a clinical setting (Roullet et al. 2013). A study on pregnant rats has shown neurotoxic effect of prenatal VPA on the cerebellar cortex, especially on Purkinje cells of the offspring where the cells appeared shrunken, reduced in density, disorganized, and surrounded by empty haloes (Shona et  al. 2018). Administration of folic acid was shown to retain the normal architecture of Purkinje cells with their axons and nuclei. This study confirmed the protective role of folic acid against the cerebellar neurotoxic effects of VPA prenatal exposure. It is recommended that folic acid supplements should be given to every epileptic pregnant mother if she needs to be treated with VPA. In 2014, the European Medicines Agency (EMA) recommended that valproate not be used to treat epilepsy or bipolar disorder or for prevention of migraine in girls and women who are pregnant or who can become pregnant unless other treatments are ineffective or not tolerated. The EMA’s data show that children exposed to valproate in the womb are at an approximately 11% risk for malformations at birth such as neural tube defects and cleft palate compared with a 2–3% risk among children in the general population. EMA further recommends that women for whom valproate is the only option should use effective contraception. Valproic acid is excreted in breast milk, and caution should be exercised when valproic acid is administered to a nursing woman. Vigabatrin  Vigabatrin exerts its antiepileptic effect by inhibiting the breakdown of GABA, thereby increasing the concentration of this inhibitory neurotransmitter at the synapses. It increases the concentration of GABA in the

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brains of experimental animals and in the CSF of patients in a dose-dependent manner. Vigabatrin can cause congenital malformations in animal studies, but no human data are available. Vigabatrin may be used in pregnant women if potential benefits exceed the possible risks to the fetus. The amount of vigabatrin transferred through the placenta is small. Excretion of the drug in the milk of nursing mothers is also small; however, according to the manufacturer’s instructions, breastfeeding is not recommended for women on vigabatrin therapy. Zonisamide  Zonisamide is chemically classified as a sulfonamide and is unrelated to other antiepileptic drugs. Women of childbearing age who are given zonisamide should be advised to use effective contraception. Zonisamide was t­ eratogenic in mice, rats, and dogs and embryolethal in monkeys when administered during the period of organogenesis. These findings suggest that the use of zonisamide during pregnancy in humans may present a significant risk to the fetus. Zonisamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Zonisamide serum concentrations may fall by more than 40% during pregnancy, which may worsen seizure control, and therapeutic drug monitoring with dose adjustments is a useful measure to cope with this (Reimers et al. 2018).

 etal Anticonvulsant Syndrome F Fetal anticonvulsant syndrome is a cluster of congenital malformations in infants exposed to AEDs in utero, which include cardiac and neural tube defects, orofacial clefts, and hypospadias, and minor malformations such as craniofacial dysmorphisms. Effect may occur during the first 3 months or later in the gestation period: The syndromes that have been named after the AED are fetal hydantoin/phenytoin syndrome, fetal phenobarbital syndrome, fetal primidone syndrome, fetal trimethadione syndrome, and fetal valproate syndrome. For multiple AEDs, terms such as hydantoin-barbiturate-­ carbamazepine embryofoetopathy may be used. Prevention of Congenital Malformations Associated with the Use of AEDs During

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Pregnancy  There is a need for the ongoing register collection of risks associated with newer AEDs which lack substantial (major) data. Choosing these newer medications can create a dilemma for physicians, particularly when seizures are not well controlled or where treatment options are limited. A multidisciplinary team approach to managing women with epilepsy has been recommended so that pregnancies in such women can be well managed in an optimum and individualized fashion (Whelehan and Delanty 2019).

Antimigraine Drugs Dihydroergotamine  No evidence of teratogenicity exists in animal reproductive studies. Dihydroergotamine crosses the placenta in small amounts, and the vasoconstrictive effect, which can lead to reduced placental flow, may cause fetal growth retardation. A case-control study of adverse events showed that other than for prematurity, risk of dihydroergotamine use during pregnancy was like that of triptan use but was smaller than the risk associated with the use of nonsteroidal anti-inflammatory drugs (Berard and Kori 2012). Dihydroergotamine is excreted in the milk and may cause an adverse reaction in the fetus. Nursing during dihydroergotamine treatment is not recommended. Sumatriptan  This drug is lethal to embryos in experimental animals, but teratogenicity has not been demonstrated in humans. The risk of all major birth defects following first-trimester exposure to sumatriptan is reported to be 4.6% (Cunnington et al. 2009). Current information is not sufficient to rule out the risk for birth defects with the use of sumatriptan, and caution should be exercised in making a recommendation for the use of sumatriptan during pregnancy. Sumatriptan is secreted in human milk, and caution should be exercised when administering sumatriptan to nursing mothers.

Antipsychotic Drugs Antipsychotics are being increasingly prescribed during pregnancy and in the postpartum period. Analysis of data from the National Birth

5  Adverse Effects of Drugs on the Fetal Nervous System

Defects Prevention Study (1997–2011), a US population-­based case-control study to examine the risk factors for major structural birth defects, observed that atypical antipsychotic use during pregnancy was more common among women with pre-­ pregnancy obesity and women who reported illicit drug use before and during pregnancy, smoking during pregnancy, alcohol use during pregnancy, or use of other psychiatric medications during pregnancy (Anderson et al. 2020). The investigators found high associations between early pregnancy atypical antipsychotic use and congenital malformations. These findings support the close clinical monitoring of pregnant women using atypical antipsychotics. Preventive Measures  Women treated with atypical antipsychotics generally access healthcare services before pregnancy; efforts to reduce correlates of atypical antipsychotic use might improve maternal and infant health in this population. The ability of antipsychotics to enter the fetal, newborn, and infant circulation varies considerably among antipsychotics. Given sampling constraints of other methods, measuring antipsychotic concentrations in maternal blood may represent the least expensive, most readily available, and reliable estimate of fetal/infant exposure (Schoretsanitis et al. 2020). Ideally, the use of antipsychotics during pregnancy should be avoided, particularly during the first trimester. If absolutely indicated, the use of low doses of haloperidol may be considered. Haloperidol is excreted into the breast milk. Risperidone  The teratogenic potential of risperidone has been studied in rats, but there are no conclusive results that can be transposed to human beings. There are no adequate well-­ controlled studies of teratogenesis in pregnant women exposed to risperidone. Risperidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It has been demonstrated that risperidone and 9-hydroxyrisperidone are excreted in human breast milk. Therefore, women receiving risperidone should not breastfeed.

Effects of Drugs Used During Pregnancy on the Fetal CNS

Biological Therapies During Pregnancy Nusinersen  Nusinersen is a splice-modulating antisense oligonucleotide indicated for the treatment of spinal muscular atrophy. Nusinersen is approved for intrathecal use. There are inadequate data on the developmental risk associated with the use of nusinersen in pregnant women. No adverse effects on embryo development were observed in animal studies in which nusinersen was administered by subcutaneous injection to mice and rabbits during pregnancy. There are no data on the presence of nusinersen in human milk or the effects on the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for nusinersen.

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comparative, multicenter observational study suggest that methylphenidate does not seem to increase the risk for major malformations, but further studies are required to establish its safety in pregnancy and its possible association with miscarriages (Diav-Citrin et al. 2016). Methylphenidate is excreted in breast milk only in small amounts, and there are no reports of breastfed infants demonstrating any adverse effects, but there are no adequate studies of long-­ term neurodevelopmental effects (Marchese et al. 2015).

Modafinil  Animal studies to assess the effects of modafinil on reproduction and the developing fetus have not been conducted. Due to drug interaction, an increased risk of pregnancy exists when using steroidal contraceptives (including depot or implantable contraceptives) with modafinil tablets. This increased risk continues for 1  month after discontinuation of modafinil Drugs Used for Narcolepsy, Excessive therapy. Daytime Sleepiness, and Attention-­ Deficit/Hyperactivity Disorder Results of the analysis of a prospective cohort study using the US Provigil/Nuvigil Pregnancy This is a diverse group of drugs. The mechanism Registry from 2010 to 2019 demonstrate that there of action varies and is not known in some cases. is a potential increased risk of major congenital malformations following in utero exposure to Methylphenidate  This is a mild CNS stimulant modafinil and/or armodafinil compared with the used for the treatment of attention-deficit/hyper- general population (Kaplan et  al. 2021). This activity disorder and narcolepsy. Adequate ani- potential risk is not likely due to the underlying mal reproduction studies to establish safe use of condition of narcolepsy, because previous data methylphenidate during pregnancy have not been suggest that narcolepsy does not increase the risk conducted. The FDA has assigned methylpheni- of abnormal pregnancy outcomes. These findings date to pregnancy category of C. Methylphenidate are consistent with a previously published Danish should not be used by women of childbearing age retrospective database study reporting an absolute unless the potential benefits outweigh the possi- risk of 12% for major congenital malformations in ble risks. In a study of 180 children exposed to first-trimester pregnancy exposure to modafinil methylphenidate in utero during the first trimes- (Damkier and Broe 2020). Because no specific ter, 4 children with major malformations were organ malformation pattern was identified, a clear identified (Dideriksen et al. 2013). According to causal association between the use of modafinil the authors, methylphenidate exposure during and/or armodafinil and major congenital malforpregnancy does not appear to be associated with mations cannot be established. a substantial, i.e., more than twofold, increased No adequate and well-controlled trials have risk of congenital malformations. A further study been administered with modafinil in pregnant by these authors also concluded that first-­ women, and this drug should be used during trimester in utero exposure to methylphenidate is pregnancy only if the potential benefit outweighs not associated with a substantially increased the potential risk. overall risk of major congenital malformations It is not known whether modafinil or its (Pottegård et al. 2014). Results of a prospective, metabolites are excreted in human milk. Caution

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should be exercised when modafinil tablets are administered to a nursing woman. Sodium Oxybate  This is a medical formulation of gamma-hydroxybutyrate (GHB), which occurs naturally in many human tissues as a metabolite of gamma-amino butyric acid. It is a CNS depressant with anticataplectic activity in patients with narcolepsy. Its precise mechanism of action is unknown. Reproductive studies in pregnant animals have not shown any evidence of teratogenicity. There are no adequate studies in pregnant women, and this drug should be used during pregnancy only if clearly needed. It is not known whether sodium oxybate is excreted in human milk, and caution should be exercised when sodium oxybate is administered to a nursing woman. Despite its short half-life, GHB concentrations remained two to five times higher than endogenous levels 4 hours after both nighttime doses, and to prevent excessive GHB exposure, breastfeeding mothers who take sodium oxybate are advised to express and discard their morning milk (Barker et al. 2017).

 rugs Used in the Treatment D of Multiple Sclerosis Multiple sclerosis (MS) is an autoimmune disease of the CNS, involving the brain, spinal cord, and optic nerves. MS presents in two clinical forms: relapsing MS, manifesting with inflammatory attacks causing deterioration of neurological symptoms, and progressive MS, defined as the constant worsening of neurological function. Pregnancy substantially reduces disease activity, although for some patients, severe relapses could appear while pregnant. MS is considered to not have an impact on the woman’s ability to conceive and carry a fetus to term, as well as MS diagnosis does not increase the rates of premature or stillbirth, birth defects, cesarean delivery, or spontaneous abortions. According to the US FDA, most of the drugs approved for treatment of MS are labeled as class C, meaning data of adverse effect was obtained in animal reproduction studies; however, despite the possible risk, pregnant women may benefit from

5  Adverse Effects of Drugs on the Fetal Nervous System

the drug, but there are not enough reliable evidence and well-controlled studies in humans. The most frequently used drugs included interferon-β, natalizumab, fingolimod, and dimethyl fumarate. Alemtuzumab  It is a humanized IgG1 monoclonal antibody used to treat relapsing-remitting MS. Alemtuzumab targets CD-52, resulting in the depletion of B and T lymphocytes. Animal studies report increased embryo lethality and reduced levels of B and T lymphocytes in offspring when pregnant mice were exposed to alemtuzumab during the period of organogenesis. The use of alemtuzumab in women of childbearing age who desire pregnancy or are not on reliable birth control is not recommended because of potential risks to the fetus (Langer-Gould 2019). Antibodies, including anti-CD52 and autoantibodies, may be transferred from the mother to the fetus during pregnancy, and placental transfer of antithyroid antibodies may result in neonatal Graves’ disease. Corticosteroids  Because adequate human reproduction studies have not been done with corticosteroids, the use of these drugs in pregnant women, nursing mothers, or women of childbearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and embryo or fetus. A case of neonatal acute adrenal insufficiency manifesting as hypoglycemia and seizures has been reported following maternal exposure to moderate doses of corticosteroids during pregnancy (Saulnier et al. 2010). Little prednisone is excreted in breast milk. Dalfampridine  Oral administration of dalfampridine in studies on rats did not cause any adverse effects on fertility. There are no adequate and well-controlled studies of dalfampridine in pregnant women. Administration of dalfampridine to animals during pregnancy and lactation resulted in decreased offspring viability and growth at doses comparable to the maximum recommended human dose of 20  mg/day. Dalfampridine should be used during pregnancy

Effects of Drugs Used During Pregnancy on the Fetal CNS

only if the potential benefit justifies the potential risk to the fetus. Voltage-gated potassium channels regulate uterine muscle contractibility and blocking of these channels could affect uterine contraction. The effect of dalfampridine on labor and delivery in humans is unknown. It is not known whether dalfampridine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from dalfampridine, a decision should be made whether to discontinue nursing or to discontinue the drug. Dimethyl Fumarate  At the highest dose tested in rats, data of increased lethalness, delayed ossification and sexual maturity, lower birth, and testicular weight were obtained. In human studies, results of the pregnancy outcomes when exposed to dimethyl fumarate early in pregnancy did not indicate increased fetal abnormalities (Gold et al. 2015). This drug is designated pregnancy category C.  There are no adequate and well-controlled studies in pregnant women. In animals, adverse effects on offspring were observed when dimethyl fumarate was administered during pregnancy and lactation at clinically relevant doses. Dimethyl fumarate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether this drug is excreted in human milk; therefore, caution should be exercised when it is administered to a nursing woman. Fingolimod  No information is available, as pregnant and nursing women were excluded from clinical trials of fingolimod for MS. The number of pregnancies reported in women exposed to fingolimod in completed or ongoing clinical studies is small and does not allow firm conclusions to be drawn about fetal safety of fingolimod in humans. Because of the known risks of teratogenicity in animals, contraception is recommended in women on fingolimod therapy and for 2 months after discontinuation (Karlsson et al. 2014). Glatiramer Acetate  No adverse effects on fetal development have been observed in experimental animals. With regard to its use by pregnant

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women with MS, it is a FDA category B drug. Although a retrospective study showed no deleterious effects from glatiramer acetate in pregnant women with MS or in their offspring, use of glatiramer acetate during pregnancy should be restricted to the most difficult cases where the benefits clearly outweigh the risks (Fragoso et al. 2010). A prospective, observational, multicenter study showed that a mother’s exposure to glatiramer is not associated with a higher frequency of spontaneous abortion, or other negative pregnancy and fetal outcomes, implying that it can be used safely during pregnancy (Giannini et  al. 2012). It is not known if glatiramer is excreted in human milk. Caution should, therefore, be exercised when the drug is used by nursing mothers. Infliximab  Infliximab does not actively cross the placenta during the first trimester of pregnancy, but some transfer during the late second and third trimesters leads to detectable levels in the infant’s serum for several months after birth (Djokanovic et al. 2011). Immunological effects of this are unknown, but live vaccination should be avoided until infliximab is undetectable in the serum. Infliximab is not transferred from mother to child by excretion through breast milk (Kane et al. 2009). Therefore, mothers receiving infliximab may be allowed to breastfeed their babies. Interferon Beta 1a  This drug is contraindicated for pregnant women and should not be used unless the potential benefit justifies the potential risk to the fetus. However, a review of outcomes of women exposed to subcutaneous interferon beta 1a during pregnancy revealed normal live births (Sandberg-Wollheim et al. 2011). The rates of spontaneous abortion and major congenital anomalies in live births were in line with those observed in the general population. Results of a study on women chronically receiving intramuscular interferon beta 1a suggest that interferon beta 1a does not enter the milk compartment significantly and that levels in milk are below those required to produce pharmacological effects (Hale et al. 2012). No side effects were observed in any of the breastfed infants.

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Interferon Beta 1b  Use of this drug is contraindicated for pregnant women. The rates of spontaneous abortions and birth defects in a study with the largest number of interferon beta 1b-exposed pregnancies do not differ from available population estimates, and no pattern of specific birth defects was observed (Romero et  al. 2015). However, the number of cases is not large enough to make a final assessment of the safety of interferon beta 1b during pregnancy. It is not known if interferon beta is excreted in human milk. Nursing mothers should either discontinue nursing or interferon beta treatment. Glatiramer Acetate  No adverse effects on fetal development have been observed in experimental animals. With regard to its use by pregnant women with MS, it is a FDA category B drug. Although a retrospective study showed no deleterious effects from glatiramer acetate in pregnant women with MS or in their offspring, use of glatiramer acetate during pregnancy should be restricted to the most difficult cases where the benefits clearly outweigh the risks (Fragoso et  al. 2010). A prospective, observational, multicenter study showed that a mother’s exposure to glatiramer is not associated with a higher frequency of spontaneous abortion, or other negative pregnancy and fetal outcomes, implying that it can be used safely during pregnancy (Giannini et al. 2012). It is not known if glatiramer is excreted in human milk. Caution should, therefore, be exercised when the drug is used by nursing mothers.

5  Adverse Effects of Drugs on the Fetal Nervous System

adequate and well-controlled studies in pregnant women. If the drug is used during pregnancy or the patient becomes pregnant during treatment, the patient should be apprised of the potential hazard to the fetus. Women of childbearing age should be advised to avoid becoming pregnant. The only documented case of mitoxantrone therapy in the first trimester of pregnancy resulted in an underweight baby at full term who was delivered by cesarean section but without congenital malformations (De Santis et al. 2007). A study on MS patients, previously treated with mitoxantrone, showed that the drug does not affect the ability to conceive or pregnancy outcomes (Frau et al. 2018). There were no differences in pregnancies, abortions, or miscarriages before and after mitoxantrone. All the babies born were healthy until the end of follow-up. Mitoxantrone is excreted in human milk in significant concentrations for 28  days after the last administration. Because of the potential for serious adverse reactions in infants from mitoxantrone, breastfeeding should be discontinued before starting the treatment.

Infliximab  Infliximab does not actively cross the placenta during the first trimester of pregnancy, but some transfer during the late second and third trimesters leads to detectable levels in the infant’s serum for several months after birth (Djokanovic et al. 2011). Immunological effects of this are unknown, but live vaccination should be avoided until infliximab is undetectable in the serum. Infliximab is not transferred from mother to child by excretion through breast milk (Kane et al. 2009). Therefore, mothers receiving infliximab may be allowed to breastfeed their babies.

Mycophenolate  All immunosuppressant agents have potential adverse effects during pregnancy. Animal studies with mycophenolate have shown teratogenic effect. A study from a group of different European teratogen information services has provided evidence of a specific mycophenolate embryopathy with patterns that include external ear anomalies ranging from hypoplastic pinna to complete absence of pinna, cleft lip, with or without cleft palate, and ocular anomalies as iris or chorioretinal coloboma and anophthalmia/ microphthalmia (Perez-Aytes et al. 2017). There are no adequate or well-controlled studies of the mycophenolate therapy during pregnancy, and its use is not recommended unless the benefits of treatment outweigh the risks. Contraception is used during mycophenolate treatment in women of childbearing age. Women on mycophenolate therapy should be aware of the potential risk of this drug to cause a specific embryopathy and the need of interrupting the treatment at least 6 weeks before becoming pregnant.

Mitoxantrone  It may cause fetal harm when administered to pregnant women. There are no

Natalizumab  Natalizumab is a IgG4 humanized monoclonal antibody against α4-integrin

Effects of Drugs Used During Pregnancy on the Fetal CNS

(cell adhesion molecule). It is considered that natalizumab does not enter the fetal circulation until 13–14 weeks of gestation when the placenta is formed, but it actively crosses the placenta’s barrier during the second and third trimesters. Discontinuation of natalizumab severely increases relapse rate, which normally manifests 12–16 weeks after treatment termination. Women with a severe risk of MS reactivation would benefit from the continuation of treatment with natalizumab, as the latest data on the use of natalizumab have demonstrated that continued treatment during pregnancy was related to a decreased risk of MS relapses during the pregnancy and postpartum period (Varytė et al. 2020). There are no adequate and well-controlled studies of natalizumab therapy in pregnant women. This drug should be used during pregnancy only if clearly needed. Before starting natalizumab treatment, women of childbearing age must be informed of the risk of recurrence of disease activity when the drug is discontinued even though pregnancy is considered as p­ rotective for women with multiple sclerosis (De Giglio et al. 2015). An analysis from the Tysabri® (natalizumab) pregnancy exposure registry showed that although the incidence of birth defects was higher than the population without drug exposure, the pattern did not suggest drug-induced malformations (Friend et al. 2016). The spontaneous abortion rate in this study was consistent with that of the general population. Natalizumab can be considered as a therapeutic option in patients with highly active multiple sclerosis during pregnancy, but anemia and thrombocytopenia may occur in newborns exposed to natalizumab during the third trimester (Haghikia et al. 2014). It is not known whether natalizumab is excreted in human milk. A decision should be made whether to discontinue nursing or natalizumab, considering the importance of therapy to the mother. Ocrelizumab  Ocrelizumab, a fully humanized monoclonal antibody, is designed to selectively target CD20-positive B cells, which are key contributors to myelin and axonal damage that can lead to disability in patients with multiple sclerosis. There are no studies of ocrelizumab

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therapy in pregnant women. There are no data on B-cell levels in human neonates following maternal exposure to ocrelizumab. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. Ocrelizumab can cross the placental barrier. This drug should be used during pregnancy only if clearly needed. It is not known whether ocrelizumab is excreted in human milk. Women of childbearing potential should use contraception while receiving ocrelizumab and for 6  months after the last infusion of ocrelizumab.

 rugs Used for Management D of Cerebral Ischemia Clopidogrel  Toxicity studies in rats and rabbits have not revealed any evidence of impaired fertility or fetotoxicity due to clopidogrel. According to a review of the limited data available in the literature, clopidogrel use in pregnancy has not shown significant toxicity to either the mother or the newborn (Reilly et al. 2014). There are, however, no adequate and well-controlled studies in pregnant women. Clopidogrel should be used during pregnancy only if clearly needed. Studies in rats have shown that clopidogrel and its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration the importance of the drug to the nursing woman. Nimodipine  The mechanism of nimodipine’s beneficial effect in patients with subarachnoid hemorrhage is not fully understood. It may have a preferential cerebral vasodilator action or a direct effect involving prevention of calcium overload in neurons by a blocking action on L-type voltage-sensitive calcium channels. Nimodipine may have a neuroprotective effect by entering the cell and inhibiting excessive calcium ion influx into the mitochondria.

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5  Adverse Effects of Drugs on the Fetal Nervous System

Animal studies have shown no consistent evidence of teratogenic activity in the fetus during pregnancy. Nimodipine has the potential to produce fetal hypoxia associated with maternal hypotension. There are no adequate and well-­ controlled studies in pregnant women to directly assess the effect on human fetuses. Nimodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nimodipine itself has been shown to appear in human breast milk; therefore, nursing mothers are advised not to breastfeed their babies when taking the drug.

and Gynecologists and public health authorities recommend advising pregnant women and those considering becoming pregnant to avoid using marijuana or other cannabinoids to treat their nausea as concerns exist regarding fetal safety (American College of Obstetricians and Gynecologists Committee on Obstetric Practice 2015).

Local Anesthetics

Local anesthetics can cross the placenta by diffusion and may cause fetal CNS and respiratory depression. Hypotension due to spinal anesthesia for caesarian section may reduce the uteroplacenDrugs for Nausea and Vomiting tal flow and contribute to fetal hypoxia. Generally, of Pregnancy local and regional anesthesia in pregnancy is safe and has a good safety record. However, neonatal Nausea with or without vomiting is common in lidocaine intoxication, with manifestations early pregnancy. Severe vomiting resulting in including seizures, may occur following maternal hypovolemia and weight loss is termed hyper- pudendal block during delivery. No evidence emesis gravidarum and occurs infrequently. shows that local anesthetics have any teratogenic Symptoms usually resolve by midpregnancy effect when used during the first trimester of regardless of severity and need for therapy. pregnancy. Several nonpharmacological measures have been Inadvertent intrathecal injection of local anesused and some of the drugs used with remarks on thetic has been reported in a patient undergoing safety during pregnancy are mentioned here. epidural block for delivery and resulted in motor block of lower extremities and shortness of breath Doxylamine Succinate and Pyridoxine  This (Ting and Tsui 2014). This was successfully was proven modestly effective for the treatment managed with cerebrospinal lavage using CSF of nausea and vomiting of pregnancy in a meta-­ exchange for an equal volume of normal saline analysis of placebo-controlled randomized trials resulting in successful delivery. and appears to be more effective than either drug alone. It was the formulation for Bendectin, which was voluntarily withdrawn from the mar- Opioids for Pain During Pregnancy ket in 1983 due to lawsuits alleging teratogenicity, although scientific evidence supports its There is a recent increase in opioid use in the safety and efficacy. A meta-analysis of controlled general population in the USA with a reported studies on outcome of pregnancies exposed to fivefold increase during pregnancy between 2000 Bendectin reported no increase in the incidence and 2009 (Prince and Ayers 2020). Among those of birth defects. admitted to facilities for treatment of opioid abuse, the rate of pregnant females rose from 2% Marijuana  Its use among pregnant women has to 28% between 1992 and 2012. This poses a been increasing to alleviate nausea and vomiting serious risk for the mother as well as the baby. of pregnancy. Although marijuana has been used to mitigate nausea and vomiting in nonpregnant Management  A systematic review of randomindividuals, the American College of Obstetricians ized controlled trials and meta-analyses of stud-

Effects of Drugs Used During Pregnancy on the Fetal CNS

ies on opioid use during pregnancy has concluded that to minimize risk, opioid agonist pharmacotherapy should replace the continued use of opioids or detoxification (Rausgaard et  al. 2020). Various guidelines recommend methadone and buprenorphine equally for pain management, but recent studies indicate that buprenorphine has advantages over methadone.

Tapentadol  This is a novel analgesic with combined opioid and adrenergic activity that was developed to fulfill some of the unmet needs in the management of acute pain and reduce the adverse effects of opioids. It may provide ­effective analgesic therapy for acute pain with both nociceptive and neuropathic components. There are no adequate and well-controlled studies of tapentadol use in pregnant women. Tapentadol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Tapentadol is not recommended for use in women during and immediately prior to labor and delivery. Neonates whose mothers have been taking tapentadol should be monitored for respiratory depression. Tapentadol should not be used during breastfeeding.

Pregabalin Pregabalin is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and as adjunctive therapy for adults with partial onset seizures. Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity have been observed in pregnant experimental animals. Findings of a cohort study nested in the US Medicaid Analytic eXtract did not confirm the suggested teratogenic effects of exposure to pregabalin during the first trimester, although the possibility of a small effect was not ruled out (Patorno et al. 2017). There are no adequate and well-controlled studies in pregnant women. Pregabalin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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Sedatives and Hypnotics Benzodiazepines  An increased risk of congenital malformations associated with benzodiazepines during the first trimester of pregnancy has been suggested in several studies. Use of diazepam during this period should be avoided. There is a moderate association between exposure to benzodiazepine anxiolytics and child internalizing problems (internal distress) at the ages of 1.5 and 3  years that are not likely due to confounding factors, whereas exposure to nonbenzodiazepine hypnotics was not associated with any adverse outcomes after adjustment (Brandlistuen et al. 2017). Injectable diazepam is not recommended for obstetrical use. An analysis of data from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications has shown that infants of mothers with psychiatric disorders who were exposed to benzodiazepines during pregnancy have an increased risk of neonatal intensive care unit admissions and small head circumferences (Freeman et al. 2018).

Substance Abuse During Pregnancy Recreational drugs that a woman may use during pregnancy include the following: • • • • •

Alcohol Cannabis Cocaine Hallucinogens Tobacco

Effects of these drugs on the adult brain are described in Chap. 17. Effects on the human fetus, when consumed by the mother during pregnancy, are described here.

 etal Alcohol Syndrome F Fetal alcohol syndrome is one of the five disorders under the broad term of fetal alcohol spectrum disorders (FASD), which is the constellation of developmental defects in the offspring that results from maternal alcohol abuse during pregnancy.

5  Adverse Effects of Drugs on the Fetal Nervous System

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1. Fetal alcohol syndrome (FAS) 2. Partial fetal alcohol syndrome (PFAS) 3. Alcohol-related neurodevelopmental disorder (ARND) 4. Neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE) 5. Alcohol-related birth defect (ARBD) as alcohol is a strong teratogen Currently in the USA, the prevalence of FASD ranges from 24 to 48 cases per 1000, and FUS ranges from six to nine cases per 1000. Neurological features of FASD are: • Attention-deficit/hyperactivity (ADHD) • Behavioral problems • Developmental delay • Epilepsy • Intellectual disability • Microcephaly • Speech problems

disorder

Pathomechanism  Many of the behavioral deficits in children with fetal alcohol syndrome are due to alcohol-induced neuronal death, which plays a central role in the pathogenesis and outcome of fetal alcohol syndrome. In chick embryos, exposure to 2% ethanol induces craniofacial defects by downregulating Ap-2ɑ, Pax7, and HNK-1 expressions by cranial neural crest cells (Zhang et al. 2017). Management  There is no cure for FASD and the best treatment is prevention. Some measures can be taken to mitigate the effects of FASD by a personalized approach to individuals. The aim should be to tailor specific therapies to reinforce and address any delays or deficiencies in neurobehavioral development with additional education, practice, and reminders (Vorgias and Bernstein 2020). Nicotinamide can prevent some of the deleterious effects of ethanol on the developing mouse brain when given shortly after ethanol exposure. These results suggest that nicotinamide, which has been used in humans for the treatment of diabetes and bullous pemphigoid, may hold promise

as a neuroprotective and preventive therapy of FAS.

 ongenital Cocaine Syndrome C Cocaine is one of the commonly abused drugs, and its use by the pregnant women can be deleterious to the fetus as the fetal brain is particularly vulnerable. Cocaine interacts with the monoaminergic synapses in the developing brain of the fetus to induce short-term and long-term changes in neurophysiology and anatomy. Cocaine can also alter maternal behaviors, thus disrupting maternal-fetal interactions, which may contribute to the neurodevelopmental problems of the offspring. Pathomechanism  Cocaine affects the fetal brain in several ways including the following: • Cocaine is a potent vasoconstrictor, and many of the medical and neurologic problems of children exposed to cocaine in utero are due to compromised blood flow through placental and cerebral vasculature. • In experimental systems, acute and long-term abnormalities have been detected in tissue dopamine levels, receptor-binding densities, receptor-binding affinities, and subcellular receptor location (Riley et al. 2018). • In the prenatal brain cocaine reduces GABAergic inhibition as well as the ratio of GABAergic-­to-projection neurons in the cerebral cortex (McCarthy and Bhide 2012). These physiological changes impair the balance between excitatory and inhibitory neurotransmission, enhance epileptogenicity, and lead to long-term changes in synaptic plasticity. In the striatum, prenatal cocaine enhances GABA interneuron function, which depresses corticostriatal activity leading to imbalances within the striatal microcircuitry, which has adverse effects on motor control, cognition, and learning (Wang et al. 2013). • Cocaine delays the maturation of glutamatergic synaptic transmission in the developing brain by inhibiting dopamine transporters on the dopaminergic neurons in the ventrotegmental area, which project to and enhance the

Effects of Drugs Used During Pregnancy on the Fetal CNS

maturation of glutamatergic neurons throughout the cortex (Bellone et al. 2011). • Exposure of the developing neurons to cocaine can induce an overgrowth of cortical neuron dendrites, and dendritic trees of cortical neurons exposed to cocaine have greater branch length and branch number (Lu et al. 2012). • Prenatal cocaine exposure can disrupt neuronal migration during brain development in the second trimester that takes neurons to their ultimate location in the developed functioning brain. • Cocaine exposure also induces abnormal wiring of neural circuitry, which plays key roles in directing axons toward their target cells and in the establishment and stability of synapses. Cocaine substantially alters the expression of multiple families of axon guidance molecules, including the semaphorins, Ephs, ephrins, and neuropilins, within the mesolimbic dopamine system. Epigenetic Changes  Cocaine may also exert some of its neuroteratogenic effects via epigenetic mechanisms. Insulin-like growth factor II (Igf-II) is an imprinted gene that plays an important role in learning and memory. In a mouse model, prenatal cocaine exposure altered the methylation status of Igf-II and decreased expression of the gene in the hippocampus (Zhao et al. 2015). These molecular changes were accompanied by impaired performance on the Morris water maze and open field tasks. Furthermore, the cognitive deficits were reversed through the hippocampal injection of recombinant Igf-II. Thus, epigenetic changes in gene expression may underlie at least some of the neurobehavioral deficits of prenatal cocaine exposure. Epigenetic changes induced by cocaine can occur not only in the fetus during pregnancy but also in sperm prior to pregnancy. Mouse models of paternal cocaine abuse have shown that offspring of cocaine-exposed sires have memory formation deficits and associated reductions in NMDA receptor-mediated hippocampal synaptic plasticity (Wimmer et al. 2017). This appears to be due to epigenetic changes in histone proteins regulating NMDA receptors in the hippocampus of progeny mice. Based on these findings in mice, it is feasible that the adverse effects of cocaine in

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humans are due not only to maternal cocaine use during pregnancy but also to paternal use prior to pregnancy. Endoplasmic Reticulum Stress Response   Evidence suggests that prenatal cocaine induces at least some of its damaging effects on the developing brain by triggering the endoplasmic reticulum stress response, which plays an important role in processing and folding newly synthesized proteins (Tsai et al. 2019). Several chemicals and drugs can disrupt endoplasmic reticulum protein folding, which can lead to an endoplasmic reticulum stress response, which activates a set of signaling pathways that aim to promote cell survival. However, the endoplasmic reticulum stress response, when prolonged and unresolved, can also promote apoptosis. In addition, when the endoplasmic reticulum stress response in neural tissue is initiated at high intensity or for prolonged periods, it can lead to aberrant neuronal differentiation and impaired dendritic outgrowth. Gene profiling studies in the developing brain have shown that cocaine upregulates endoplasmic reticulum stress genes, which leads to disruption of glutamate and dopamine receptor activation. In addition, cocaine-induced endoplasmic reticulum stress inhibits neural progenitor proliferation, causing premature neuronal differentiation and microglial cell death (Lee et al. 2017).

 ffects on the Fetus of Cannabis E (Marijuana) Use During Pregnancy A 2019 survey in the USA has revealed that 5.4% of pregnant women 15 through 44  years of age have used marijuana in the past month, compared with 14.7% of nonpregnant women in the same age group (National Survey on Drug Use and Health 2020). The use of marijuana (cannabis) is increasing for recreational as well as medical purposes. Cannabis (marijuana) is now legal for either medicinal use or recreational use in 33 states with more states considering legalization for medicinal and/or recreational use. More women planning pregnancy, pregnant, or breast-

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5  Adverse Effects of Drugs on the Fetal Nervous System

feeding will present with exposure to marijuana. However, there is very little information on the physiological effects of cannabis during pregnancy on the mother or the fetus, partly because cannabis is an illicit drug. Moreover, most of the data reflect cannabis administered by smoking and not cannabis exposure through other routes of administration.

much greater than what has been reported to date. A workshop reached the following conclusions on this topic (National Academies of Sciences, Engineering, and Medicine 2017):

Moreover, the cohort studies were conducted when the available marijuana had a much lower potency than what is available today, which raises concern that the adverse consequences of prenatal exposure in currently pregnant women may be

 eonatal Opioid Withdrawal Syndrome N As the global prevalence of opioid use has alarmingly increased, so has the incidence of neonatal opioid withdrawal syndrome (NOWS). NOWS can manifest with varying severity or not at all, for

• There is substantial evidence of a statistical association between maternal cannabis smoking and lower birth weight of the offspring. • There is limited evidence of a statistical assoPathomechanism  The fetus is exposed to the ciation between maternal cannabis smoking effects as the active compounds in marijuana and complications for the mother during pregcross the placenta rapidly and are excreted in nancy and admission of the infant to the neobreast milk for the infant. Results of studies of natal intensive care unit. the effects of marijuana on a developing fetus and • There is insufficient evidence to support or neonate are conflicting, but researchers have refute a statistical association between materidentified chronic marijuana exposure as a risk nal cannabis smoking and later outcomes in factor for preterm birth and small-for-gestational-­ the offspring, e.g., sudden infant death synage infants (Fantasia 2017). A discussion of studdrome, cognition/academic achievement, and ies of marijuana use among pregnant and lactating later substance use. women about the effects of marijuana on fetal development and later neurodevelopmental as A more recent review has concluded that canwell as behavioral outcomes made the following nabis and associated product use has the potential remarks (Ryan et al. 2018): for adverse maternal, fetal, and long-term childhood development and its use should be discour• Many of these studies included pregnant aged during pregnancy and lactation (Joseph and women who used other substances in addition Vettraino 2020). to marijuana, such as tobacco, alcohol, or other drugs, and analytic methods were used to control for the confounding effects of these Neonatal Abstinence Syndrome other substances. • For outcomes such as later childhood and ado- In the case of psychotropic medications such as lescent cognition and behavior, studies were opioids, antidepressants, antiepileptics, and antilimited in the environmental and sociodemo- psychotics, a withdrawal syndrome or “neonatal graphic variables that the authors could con- abstinence syndrome” is caused by the discontrol, which could be expected to influence tinuation of the drug transfer from the mother to development across childhood and the newborn after delivery, with symptoms that adolescence. may include tremors, irritability, hypotonia/ • Despite these limitations and the relative pau- hypertonia, vomiting, and persistent crying, city of research in this area, the findings which can occur a few hours to 1  month after regarding growth variables and neurodevelop- delivery (Convertino et al. 2016). Neonatal neumental and behavioral outcomes can be used rologic and behavioral effects can also be caused to suggest that marijuana use during preg- by residual drug in the blood and tissues of the nancy may not be harmless. newborn.

Effects of Drugs Used During Pregnancy on the Fetal CNS

unknown reasons, but is likely to be associated with multiple factors, both maternal (e.g., smoking and additional substance exposures) and neonatal (gestational age, sex, and genetics). Care for the infant with NOWS begins with addressing the issues experienced by pregnant women with opioid use disorder. Co-occurring mental illness, economic hardship, intimate partner violence, infectious diseases, and limited access to care are common in these women and can result in poor maternal and neonatal outcomes. Although there is no consensus regarding optimal NOWS management, nonpharmacological interventions (such as breastfeeding and rooming-in of the mother and the baby) have become a priority, as they can ameliorate symptoms without the need for further opioid exposure (Coyle et al. 2018). Untreated NOWS can be associated with morbidity in early infancy, and the long-term consequences of fetal opioid exposure are only beginning to be understood according to the concept that development fundamentally represents the emergence of more complex and integrated forms of self-regulation over the lifespan, which serves to regulate the infant’s own functioning as well as caregiver behaviors and responses. Management  Primary management of NOWS should be nonpharmacologic assessment and care, which begins prenatally or at birth and continues throughout the infant’s hospitalization, regardless of the requirement for pharmacologic treatment. It also necessitates assessment of and treatment for the mother (Jansson and Patrick 2019).

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76 Domar AD, Moragianni VA, Ryley DA, Urato AC.  The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond. Hum Reprod. 2013;28(1):160–71. Fantasia HC. Pharmacologic Implications of Marijuana Use During Pregnancy. Nurs Womens Health 2017;21:217–23. Fotopoulou C, Kretz R, Bauer S, et al. Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation and the neonatal period. Epilepsy Res. 2009;85:60–4. Fragoso YD, Finkelsztejn A, Kaimen-Maciel DR, et  al. Long-term use of glatiramer acetate by 11 pregnant women with multiple sclerosis: a retrospective, multicentre case series. CNS Drugs. 2010;24:969–76. Frau J, Coghe G, Casanova P, et al. Pregnancy planning and outcomes in patients with multiple sclerosis after mitoxantrone therapy: a monocentre assessment. Eur J Neurol. 2018;25:1063–8. Freeman MP, Góez-Mogollón L, McInerney KA, et  al. Obstetrical and neonatal outcomes after benzodiazepine exposure during pregnancy: results from a prospective registry of women with psychiatric disorders. Gen Hosp Psychiatry. 2018;53:73–9. Friend S, Richman S, Bloomgren G, Cristiano LM, Wenten M.  Evaluation of pregnancy outcomes from the Tysabri® (natalizumab) pregnancy exposure registry: a global, observational, follow-up study. BMC Neurol. 2016;16(1):150. Gao SY, Wu QJ, Zhang TN, et  al. Fluoxetine and congenital malformations: a systematic review and meta-analysis of cohort studies. Br J Clin Pharmacol. 2017;83(10):2134–47. Giannini M, Portaccio E, Ghezzi A, et al. Pregnancy and fetal outcomes after Glatiramer Acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study. BMC Neurol. 2012;12:124. Gold R, Phillips JT, Havrdova E, et  al. Delayed-release dimethyl fumarate and pregnancy: preclinical studies and pregnancy outcomes from clinical trials and postmarketing experience. Neurol Ther. 2015;4:93–104. Guttuso T Jr, Shaman M, Thornburg LL. Potential maternal symptomatic benefit of gabapentin and review of its safety in pregnancy. Eur J Obstet Gynecol Reprod Biol. 2014;181:280–3. Haghikia A, Langer-Gould A, Rellensmann G, et  al. Natalizumab use during the third trimester of pregnancy. JAMA Neurol. 2014;71(7):891–5. Hale TW, Siddiqui AA, Baker TE.  Transfer of interferon β-1a into human breastmilk. Breastfeed Med. 2012;7(2):123–5. Harrington RA, Lee LC, Crum RM, et  al. Serotonin hypothesis of autism: implications for selective serotonin reuptake inhibitor use during pregnancy. Autism Res. 2013;6(3):149–68. Hernandez-Diaz S. Evidence accumulates on the association between topiramate use early in pregnancy and the risk of oral clefts. Pharmacoepidemiol Drug Saf. 2014;23(10):1026–8.

5  Adverse Effects of Drugs on the Fetal Nervous System Holmes LB, Baldwin EJ, Smith CR, et al. Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy. Neurology. 2008;70(22 Pt 2):2152–8. Hviid A, Melbye M, Pasternak B.  Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism. N Engl J Med. 2013;369(25):2406–15. Jansson LM, Patrick SW. Neonatal abstinence syndrome. Pediatr Clin N Am. 2019;66(2):353–67. Jentink J, Loane MA, Dolk H, EUROCAT Antiepileptic Study Working Group, et al. Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med. 2010;362(23):2185–93. Joseph P, Vettraino IM. Cannabis in pregnancy and lactation – a review. Mol Med. 2020;117(5):400–5. Kane S, Ford J, Cohen R, Wagner C. Absence of infliximab in infants and breast milk from nursing mothers receiving therapy for Crohn’s disease before and after delivery. J Clin Gastroenterol. 2009;43(7):613–6. Kaplan S, Braverman DL, Frishman I, Bartov N. Pregnancy and fetal outcomes following exposure to modafinil and armodafinil during pregnancy. JAMA Intern Med. 2021;181(2):275–7. Karlsson G, Francis G, Koren G, et  al. Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis. Neurology. 2014;82(8):674–80. Kieler H, Artama M, Engeland A, et  al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries. BMJ. 2012;344:d8012. Koc G, Keskin Guler S, Karadas O, et al. Fetal safety of levetiracetam use during pregnancy. Acta Neurol Belg. 2018;118(3):503–8. Langer-Gould AM.  Pregnancy and family planning in multiple sclerosis. Continuum (Minneap Minn). 2019;25(3):773–92. Lattanzi S, Cagnetti C, Foschi N, et al. Lacosamide during pregnancy and breastfeeding. Neurol Neurochir Pol. 2017;51:266–9. Lee CT, Chen J, Kindberg AA, et al. CYP3A5 mediates effects of cocaine on human neocorticogenesis: studies using an in-vitro 3D self-organized hPSC model with a single cortex-like unit. Neuropsychopharmacology. 2017;42(3):774–84. Lu R, Liu X, Long H, Ma L. Effects of prenatal cocaine and heroin exposure on neuronal dendrite morphogenesis and spatial recognition memory in mice. Neurosci Lett. 2012;522(2):128–33. Lupattelli A, Spigset O, Twigg MJ, et al. Medication use in pregnancy: a cross-sectional, multinational web-­ based study. BMJ. 2014;4:e004365. Marchese M, Koren G, Bozzo P.  Is it safe to breastfeed while taking methylphenidate? Can Fam Physician. 2015;61(9):765–6. Mawhinney E, Craig J, Morrow J, et al. Levetiracetam in pregnancy: results from the UK and Ireland epilepsy and pregnancy registers. Neurology. 2013;80:400–5.

References McCarthy DM, Bhide PG.  Prenatal cocaine exposure decreases parvalbumin-immunoreactive neurons and GABA-to-projection neuron ratio in the medial prefrontal cortex. Dev Neurosci. 2012;34(2–3):174–83. Meador KJ, Loring DW.  Developmental effects of antiepileptic drugs and the need for improved regulations. Neurology. 2016;86(3):297–306. Meador KJ, Baker GA, Browning N, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med. 2009;360(16):1597–605. Moore JL, Aggarwal P.  Lamotrigine use in pregnancy. Expert Opin Pharmacother. 2012;13:1213–6. National Academies of Sciences, Engineering, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and ­recommendations for research. Washington, DC: The National Academies Press; 2017. National Survey on Drug Use and Health. Available at: https:// www.samhsa.gov/data/data-­we-­collect/nsduh-­national-­ survey-­drug-­use-­and-­health. Accessed 20 Dec 2020. Patorno E, Bateman BT, Huybrechts KF, et al. Pregabalin use early in pregnancy and the risk of major congenital malformations. Neurology. 2017;88(21):2020–5. Paulzen M, Lammertz SE, Veselinovic T, et  al. Lamotrigine in pregnancy – therapeutic drug monitoring in maternal blood, amniotic fluid, and cord blood. Int Clin Psychopharmacol. 2015;30:249–54. Perez-Aytes A, Marin-Reina P, Boso V, Ledo A, Carey JC, Vento M.  Mycophenolate mofetil embryopathy: a newly recognized teratogenic syndrome. Eur J Med Genet. 2017;60(1):16–21. Petersen I, Evans SJ, Gilbert R, Marston L, Nazareth I.  Selective serotonin reuptake inhibitors and congenital heart anomalies: comparative cohort studies of women treated before and during pregnancy and their children. J Clin Psychiatry. 2016;77(1):e36–42. Pottegård A, Hallas J, Andersen JT, et al. First-trimester exposure to methylphenidate: a population-based cohort study. J Clin Psychiatry. 2014;75:e88–93. Prince MK, Ayers D.  Substance use in pregnancy. In: StatPearls [Internet]. Treasure Island: StatPearls Publishing; 2020. Rausgaard NLK, Ibsen IO, Jørgensen JS, et  al. Management and monitoring of opioid use in pregnancy. Acta Obstet Gynecol Scand. 2020;99:7–15. Reed CB.  A study of the conditions that require the removal of the child from the breast. Surg Gynecol Obstet. 1908;6:514–27. Reilly CR, Cuesta-Fernandez A, Kayaleh OR. Successful gestation and delivery using clopidogrel for secondary stroke prophylaxis: a case report and literature review. Arch Gynecol Obstet. 2014;290(3):591–4. Reimers A, Brodtkorb E. Second-generation antiepileptic drugs and pregnancy: a guide for clinicians. Expert Rev Neurother. 2012;12(6):707–17. Reimers A, Helde G, Becser Andersen N, et  al. Zonisamide serum concentrations during pregnancy. Epilepsy Res. 2018;144:25–9. Riley E, Maymi V, Pawlyszyn S, et  al. Prenatal cocaine exposure disrupts the dopaminergic system and its

77 postnatal responses to cocaine. Genes Brain Behav. 2018;17(4):e12436. Rohracher A, Brigo F, Höfler J, et al. Perampanel for the treatment of primary generalized tonic-clonic seizures in idiopathic generalized epilepsy. Expert Opin Pharmacother. 2016;17(10):1403–11. Romero RS, Lünzmann C, Bugge JP. Pregnancy outcomes in patients exposed to interferon beta-1b. J Neurol Neurosurg Psychiatry. 2015;86(5):587–9. Roullet FI, Lai JK, Foster JA.  In utero exposure to valproic acid and autism--a current review of clinical and animal studies. Neurotoxicol Teratol. 2013;36: 47–56. Ryan SA, Ammerman SD, O’Connor ME, Committee on Substance Use and Prevention; Section on Breastfeeding. Marijuana use during pregnancy and breastfeeding: implications for neonatal and childhood outcomes. Pediatrics. 2018;142:e20181889. Sandberg-Wollheim M, Alteri E, Stam Moraga M, Kornmann G. Pregnancy outcomes in multiple sclerosis following subcutaneous interferon beta-1a therapy. Mult Scler. 2011;17:423–30. Saulnier PJ, Piguel X, Perault-Pochat MC, Csizmadia-­ Bremaud C, Saulnier JP.  Hypoglycaemic seizure and neonatal acute adrenal insufficiency after maternal exposure to prednisone during pregnancy: a case report. Eur J Pediatr. 2010;169:763–5. Saunders NR, Dziegielewska KM, Møllgård K, Habgood MD. Recent Developments in Understanding Barrier Mechanisms in the Developing Brain: Drugs and Drug Transporters in Pregnancy, Susceptibility or Protection in the Fetal Brain? Annu Rev Pharmacol Toxicol. 2019;59:487–505. Schoretsanitis G, Westin AA, Deligiannidis KM, et  al. Excretion of antipsychotics into the amniotic fluid, umbilical cord blood, and breast milk: a systematic critical review and combined analysis. Ther Drug Monit. 2020;42:245–54. Shona SI, Rizk AA, El Sadik AO, et al. Effect of valproic acid administration during pregnancy on postnatal development of cerebellar cortex and the possible protective role of folic acid. Folia Morphol (Warsz). 2018;77:201–9. Susser LC, Sansone SA, Hermann AD.  Selective serotonin reuptake inhibitors for depression in pregnancy. Am J Obstet Gynecol. 2016;215(6):722–30. Tetro N, Moushaev S, Rubinchik-Stern M, Eyal S.  The placental barrier: the gate and the fate in drug distribution. Pharm Res. 2018;35:71. Ting HY, Tsui BC.  Reversal of high spinal anesthesia with cerebrospinal lavage after inadvertent intrathecal injection of local anesthetic in an obstetric patient. Can J Anaesth. 2014;61:1004–7. Tsai SA, Bendriem RM, Lee CTD.  The cellular basis of fetal endoplasmic reticulum stress and oxidative stress in drug-induced neurodevelopmental deficits. Neurobiol Stress. 2019;10:1–12. Vajda FJE, Graham JE, Hitchcock AA, Lander CM, O’Brien TJ, Eadie MJ. Antiepileptic drugs and foetal

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5  Adverse Effects of Drugs on the Fetal Nervous System Wimmer ME, Brian LA, Fant B, et al. Paternal cocaine taking elicits epigenetic remodeling and memory deficits in male progeny. Mol Psychiatry. 2017;22(11):1653. Ylikotila P, Ketola RA, Timonen S, et al. Early pregnancy cerebral venous thrombosis and status epilepticus treated with levetiracetam and lacosamide throughout pregnancy. Reprod Toxicol. 2015;57:204–6. Zhang P, Wang G, Lin Z, et al. Alcohol exposure induces chick craniofacial bone defects by negatively affecting cranial neural crest development. Toxicol Lett. 2017;281:53–64. Zhao Q, Hou J, Chen B, et al. Prenatal cocaine exposure impairs cognitive function of progeny via insulin growth factor II epigenetic regulation. Neurobiol Dis. 2015;82:54–65.

6

Principles of Management of Drug-Induced Neurological Disorders

Introduction

was caused by an antiemetic drug, prochlorperazine (Kawanishi et al. 2007).

Only general principles of management of drug-­ induced neurological disorders (DIND) are described in this chapter. Other chapters in this L  aboratory Diagnostic Procedures book deal with specific management of various disorders. Laboratory studies of patients with neurologic disorders induced by drugs are like those used for nondrug-induced disorders. For example, brain Diagnosis imaging techniques can directly or indirectly assess many mechanisms of anticancer drug-­ Clinical Diagnosis induced neurotoxicity. Functional MRI, diffusion tensor imaging, and MR spectroscopy are noninA careful history of drug use and a high index of vasive techniques that can yield important comsuspicion are important factors in the diagnosis plementary data regarding the nature of neural of DINDs. The physician should obtain a com- changes after chemotherapy. A noninvasive plete list of current medications, medications the nucleic acid-based MRI technique that enables patient has taken previously, as well as other pos- real-time assessment of gene transcription prosible offending medications that might be avail- files in the living brain could provide useful able from family members and other sources. information, not only about naturally occurring Drugs most likely to cause such disorders should diseases but about drug-induced neurologic disbe considered first. For example, among drug-­ orders as well (Liu and Liu 2011). induced movement disorders, antipsychotic MRI lesions of the splenium can develop in drugs and other dopamine-receptor blocking some epileptic patients after rapid anticonvulsant agents should be high on the list of suspected withdrawal. CAR-T cell therapy-induced neurodrugs. logic deficits are not always easily observable Drug-induced neurologic disorders should be clinically, and MRI is mostly normal, but diagconsidered in assessment of neuropsychiatric nostic studies that more directly evaluate neuroproblems in cancer patients. In a prospective nal functioning, like EEG and PET scan, can study, akathisia, a drug-induced movement disor- reliably detect and predict neurologic dysfuncder, was found in 4.8% of cancer patients and tion (Rubin et al. 2019).

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_6

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In drug-induced neurodegeneration, reactive glial cells at the site of degeneration are characterized by an abundance of peripheral benzodiazepine receptors as compared to surrounding neurons and provide an indirect biomarker for reliable estimation of central nervous system damage. Increased binding of ligands to peripheral benzodiazepine receptors can be measured by in vivo positron emission tomography. Single-photon emission computed tomography using (123)I-ioflupane or (123) I-iodobenzamide or both can be used to differentiate between idiopathic Parkinson disease and drug-induced parkinsonism. Detection of biomarkers of neurotoxicity may be useful for detection of toxic effects of drugs in the absence of clinical features or any clues in routine laboratory studies and imaging procedures. Detection of genetic biomarkers associated with neurotoxicity induced by single-agent and combination platinum chemotherapy can be useful in reducing the adverse effects of chemotherapy for cancer (McWhinney et al. 2009). Cognitive safety assessment is important at all stages of drug development, particularly during clinical trials. The Clinical Trials Information System Adverse Effects device, an iPad-tablet product on cloud computing, is available for measurement of cognitive impairment in phase I clinical trials. This provides fast, sensitive, and reproducible data that enables early informed decisions to be made about the cognitive safety of drugs, reducing the risk of costly failure in late-­ stage clinical trials.

Prevention of DINDs This is the most important approach to reduce the incidence of adverse reactions. When several therapeutic alternatives are available, the one with the least neurotoxicity should be selected, particularly in susceptible patients with risk factors. Dose-related adverse effects may be reduced by stepwise increase dosage over a longer period, allowing the patient to tolerate the dose.

Epidemiological studies indicate that antithrombotic agent-associated cerebral hemorrhages constitute a significant proportion of adverse drug reactions. Preventive measures should be considered to reduce these fatalities. The availability of an in vitro model of stem cell-derived human neural cell lines enables investigators to study molecular mechanisms of various drugs that produce early developmental apoptosis of neurons in humans (Bosnjak 2012). Use of this model will enable identification of drugs that are less likely to cause death of neurons. Adverse drug reactions may be reduced by newer methods of targeted controlled drug delivery, particularly genetically engineered cell-­ based therapy. Genotyping may identify patients who would develop adverse reactions to certain drugs; those drugs should be avoided in these subsets of patients. Application of pharmacogenetics, by individualizing treatment to patients for whom it is safe, provides a rational framework to minimize the uncertainty in outcome of drug therapy and should significantly reduce the risk of adverse reactions to drugs. Improved understanding of the molecular mechanisms of drug-induced neurologic disorders can lead to strategies for prevention by devising better therapies. One example is antipsychotic-­induced extrapyramidal disorders, which are due to blocking of dopamine receptors involved in drug action. Preclinical studies in the search for new drugs with fewer extrapyramidal side effects suggest the role of 5-­hydroxytryptamine (serotonin)-1A and 2A/2C receptors in the modulation of dopaminergic neurotransmission that will improve therapeutic strategies for schizophrenia with safer drugs (Shireen 2016). Neuroprotective agents can prevent neurotoxicity induced by chemotherapeutic agents used for the treatment of cancer. An experimental study in rats has shown that dl-3-n-butylphthalide has a therapeutic potential against neurotoxicity induced by doxorubicin, an anticancer agent, by attenuating oxidative stress, inflammatory reaction, and neural apoptosis (Liao et al. 2018).

Management of DIND in Special Groups

Treatment of DIND Usually, the first step is discontinuation of the responsible drug in case of severe adverse drug reactions. Symptomatic treatment may be given for persisting symptoms. The specific treatment is based on knowledge of pathomechanism of the drug-induced neurologic disorder. For example, management of drug-induced movement disorders in the older patient requires careful consideration of the contraindications imposed by such agents as anticholinergics, which can induce dementia in this patient population. In the case of secondary drug-induced disorders, the primary cause should be corrected. A boy who developed hypertension due to atomoxetine therapy for ADHD presented with facial palsy but recovered following discontinuation of the drug and normalization of blood pressure (Kobayashi et al. 2019).

Nonpharmacological Therapies for DIND Because dicontinuation of pharmacotherapy and replacement with an equally effective alternative are sometimes a problem, nonpharmacological therapies may be tried. Acupuncture and hyperbaric oxygen are two examples. Acupuncture is recognized as a viable treatment option for medication overuse headache and for headache secondary to diseases such as druginduced aseptic meningitis (Rudra et  al. 2020). Furthermore, acupuncture should also be considered as a nonpharmacological modality to be used when tapering a patient off high doses of opioids. Hyperbaric oxygenation (HBO) involves the use of 100% oxygen under pressure greater than that found on earth’s surface at sea level and has proven useful in treatment of several diseases and DINDs (Jain 2017a). It is useful as an alternative to drug therapy in diseases such as multiple sclerosis as well as for treatment of neurotoxicity due to a variety of poisons. In 85% of AIDS patients with drug-induced peripheral neuropathy, 85% show significant improvements in sensory disturbances following HBO treatment.

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 anagement of DIND in Special M Groups Patients with preexisting neurologic disorders, renal insufficiency, and advanced age may be particularly susceptible to neurotoxicity of antibiotics, and this can be reduced by dosage adjustments in high-risk populations (Grill and Maganti 2011).

Geriatric Age Group The elderly are frequently on multidrug therapy and are two to three times more likely to experience adverse reactions to drugs than young people. The brain is an especially sensitive drug target in old age. Elderly patients are particularly prone to adverse effects of psychotropic agents, including benzodiazepines, because of the altered pharmacokinetics. Memory and psychomotor impairments are more pronounced in the elderly on benzodiazepine treatment as compared with younger controls. The elderly are also more susceptible to antimuscarinic effects of some antidepressants and neuroleptic drugs and may manifest agitation, confusion, and delirium. These drugs should be used sparingly in elderly patients. If their use is essential, the dosage should be titrated to a clearly defined clinical or biochemical therapeutic goal starting from a low initial dose.

Pregnancy The potential of drugs used by the pregnant mother to harm the fetus is well known, with risk of teratogenicity. This topic is described in detail in Chap. 5. Antiepileptic therapy in pregnancy is most often implicated in the etiology of malformations of the neural tube. There is a controversy about the causal relationship of drugs to congenital malformations. However, prenatal antiepileptic drug exposure in the setting of maternal epilepsy is associated with developmental delay and later childhood morbidity in addition to congenital malformations. Valproic acid use as an antiepileptic in pregnant women is associated

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with neural tube defects in the offspring. Underlying genetic susceptibility is a factor in the etiology of this adverse effect. Drugs used for other diseases can also have adverse effects and produce neurologic disorders in the offspring that may not manifest clinically until later in infancy or childhood. Prenatal exposure to drugs has also been implicated in the development of neurologic disorders in later life, and epigenetic factors may be involved. Analysis of transcriptome data from in vitro models has enabled prediction of toxicity patterns of drugs in humans (Balmer and Leist 2014). Changes in the histone methylation pattern could explain how drug-induced changes are perpetuated over time even after washout of the drug, enabling transformation of an early insult to an adverse effect later in life. In the case of psychotropic medications such as opioids, antidepressants, antiepileptics, and antipsychotics, a withdrawal syndrome or “neonatal abstinence syndrome” is caused by the discontinuation of the drug transfer from the mother to the newborn after delivery, with symptoms that may include tremors, irritability, hypotonia/hypertonia, vomiting, and persistent crying, which can occur a few hours to 1  month after delivery (Convertino et  al. 2016). Neonatal neurologic and behavioral effects can also be caused by residual drug in the blood and tissues of the newborn.

Concluding Remarks and Future Development of Safer Therapies Advances in pharmaceutical technologies and development of biological therapies have enabled safer and more effective therapies. Targeted drug delivery now reduces exposure of normal tissues to the drug. These technologies also introduce new adverse reactions but provide tools to manage these. Drug safety is now attended to at earlier stages of drug development. New CNS drugs are being designed based on experience gained from DINDs, which are less likely to produce adverse effects. Despite all these measures, some ADRs may not manifest until after the drug has passed clinical trials and is approved for clinical use and has been in use for several months.

However, we are better prepared to deal with the DINDs now than a few decades ago. There is more information about preventive measures. Increasing awareness of ADRs and sensitive diagnostic technologies have enabled early detection of disease including DIND and taking timely therapeutic measures.

Personalized Approach to Management of DIND  asics of Personalized Neurology B Increasing acceptance of personalized medicine during the past decade has impacted the practice of neurology including management of DINDs. Personalized neurology is the application of principles of personalized medicine, i.e., the prescription of specific therapeutics best suited for an individual taking into consideration both genetic and environmental factors that influence response to therapy. The aim is to improve the efficacy and reduce the adverse effects of various therapies. Pharmacogenetics is particularly important for drug safety. Several biotechnologies are being integrated to develop personalized medicine. Besides omics, e.g., neurogenomics and neuroproteomics, nongenomic technologies such as cell therapy and nanobiotechnology are also used. Biomarkers and integration of diagnostics with therapeutics are important for the selection and monitoring of treatments. Personalized medicine is the best way to integrate new biotechnologies into medicine for improving the understanding of the pathomechanism of diseases and for management of patients (Jain 2021). The broad scope of personalized medicine parallels that of systems biology and covers predictive, preventive, and participatory aspects as well. Integration of various technologies for the development of ­personalized medicine and application to DINDs is shown in Fig. 6.1. Neurogenomics  This is improving our understanding of neurologic diseases, which is an important basis for the development of rational therapies in integrated healthcare of the future. Neurogenomics has contributed to pharmacoge-

Concluding Remarks and Future

83 Molecular diagnostics

Biochips/biosensors Wearable devices Nanobiotechnology

Electronic health records

Biomarkers Point-of-care diagnostics

Companion diagnostics

NG sequencîng SNP genotyping

Digital medicine Bioinformatics

Genetic screening Molecular imaging Early diagnosis

Personalized medicine/ drug-induced neurological disorders

Panomics: genomics, epi-genomics, proteomics metabolomics, etc. Understanding of molecular pathology Virtual clinical trials Pharmacogenomics Pharmacogenetics Therapeutic drug monitor. Drug delivery Cell therapy

Disease prevention

Synthetic biology

Translational medicine

Gene therapy RNAi, antisense Systems biology

Fig. 6.1  Integration of technologies for the development of personalized medicine. (© Jain PharmaBiotech)

netics, the term applied to the influence of genetic factors on the action of drugs, i.e., which drugs work best on which patients and the genetic basis of susceptibility to adverse reactions of drugs. This term should be distinguished from pharmacogenomics (an offshoot of genomics), which usually refers to the application of genomic technologies to drug discovery and development. Significant contributions of neurogenomics to personalized neurology include the following: • The availability of low-cost genomic sequencing will expand the use of genomic information in the practice of neurology. • Sequencing of the genome is enabling genetic redefinition of several neurologic disorders as well as better insight into their pathomechanism to improve our understanding and facilitate early detection by molecular methods. • An increase in the ability to anticipate diseases rather than just reacting to them after onset may enable the institution of preventive measures.

• The precision and effectiveness of drugs are increased. If patients can be diagnosed in terms of DNA mutations, alleles, or ­polymorphisms pertaining to a specific disease, their responses to treatment can be vastly improved. • Drugs can be better targeted to diseases in some patients based on genotype information. • Toxicity will be predictable in most cases prior to drug administration. • The development of more effective drugs may enable treatment with drugs rather than surgery in some chronic disorders. Epigenomics/epigenetics  The epigenome is a record of the chemical changes to the DNA and histone proteins of an organism, which can be inherited by an organism’s offspring. The epigenome is involved in regulation of gene expression, development, and tissue differentiation. Unlike the underlying genome, which is largely static within an individual, the epigenome can be altered by environmental conditions. Changes in

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the epigenome can result in changes in the function of the genome. Epigenetics refers to the study of changes in the regulation of gene activity and expression that are not dependent on gene DNA sequence. Whereas epigenetics often refers to the study of single genes or sets of genes, epigenomics refers to more global analyses of epigenetic changes across the entire genome. Neurologic disorders are associated not only with genomic mutations and transcriptomic dysregulations but with changes in the epigenome as well. Among the various types of epigenomic modifications, DNA methylation, histone modifications, and expression levels of microRNAs have been the most widely studied. DNA methylation is implicated in the development of the human brain as well as plasticity underlying learning and memory. Widespread reconfiguration occurs in the methylome, and conserved non-CG methylation accumulates in the neuronal genome during development (Lister et al. 2013). Targeting the complete mitochondrial exome provides a greater potential to identify rare variants that disrupt normal mitochondrial function, enabling an exact diagnosis in a large proportion of patients that remain undiagnosed by other methods. Over 95% of the target bases can be sequenced to an average coverage of 400×, providing highly accurate and sensitive results.

• By classifying patients as responders and nonresponders, this approach may accelerate personalized drug development. • Protein biomarkers facilitate integration of diagnostics with therapeutics, from development stages to translation into clinical applications. Neuroproteomics studies show that neurodegenerative diseases share many common molecular mechanisms, including misfolding of proteins. Further understanding of these mechanisms may lead to strategies for the prevention of neurodegenerative diseases and the development of effective drugs. Identification of neurodegeneration-associated changes in protein expression will facilitate the identification of novel biomarkers for the early detection of neurodegenerative diseases and targets for therapeutic intervention. Applications of proteomics technologies will facilitate a more comprehensive analysis of novel therapeutic strategies for central nervous system disorders. This will also accelerate development of specific diagnostic and prognostic disease biomarkers for the personalized management of neurologic disorders.

Neurometabolomics  Metabolomics plays an important role in personalized medicine. Neurometabolomics is the study of metabolites in the nervous system, many of which are biomarkers of disease. Neurons in the human central Neuroproteomics  Insight into the protein-based nervous system perform a wide range of motor, mechanisms of neurologic disorders will provide sensory, regulatory, behavioral, and cognitive more relevant targets for drug discovery as well functions, which requires diverse neuronal as as development for central nervous system disor- well as non-neuronal cell types. Metabolomics ders. Pharmacoproteomics, the application of can help in assessing the specificity of metabolic proteomics to pharmacology, has the following traits and their alterations in the brain and in fluadvantages for the development of personalized ids such as cerebrospinal fluid and plasma. Current applications of metabolomics include the medicines (Jain 2016): discovery of potential biomarkers of aging and • Pharmacoproteomics is a more functional rep- neurodegenerative diseases (Jové et  al. 2014). resentation of patient-to-patient variation than Neurometabolomics will improve our understanding of the physiology as well as pathology that provided by genotyping. • Because it includes the effects of post-­ of the nervous system and facilitate the developtranslational modification, pharmacopro- ment of personalized neurology by providing teomics connects the genotype with the biomarkers for disease monitoring as well as for targets for therapeutics. phenotype.

Concluding Remarks and Future

Role of biomarkers in the development of personalized neurology.  A biomarker—DNA, RNA, or protein—is defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention (Jain 2017b). Biomarkers play an important role in the development of personalized medicine. An example of the usefulness of biomarkers in the development of personalized medicine is biomarkers for Huntington disease. Genome-wide gene expression profiles from blood samples of Huntington disease patients have identified changes in blood mRNAs that clearly distinguish Huntington disease patients from controls. The elevated mRNAs are significantly reduced in Huntington disease patients involved in a dose-finding study of the histone deacetylase inhibitor sodium phenylbutyrate. These alterations in mRNA expression correlate with disease progression and response to experimental treatment. Such biomarkers may provide clues to the state of Huntington disease and may be of predictive value in clinical trials. Role of therapeutic drug monitoring in the development of personalized neurology  Therapeutic drug monitoring is the measurement of drug concentrations in blood to optimize pharmacological therapy and identify the high interindividual variability of pharmacokinetics of patients, which enables personalized pharmacotherapy (Unterecker et al. 2019). Role of functional imaging of the brain in the development of personalized medicine  The combination of PET and fMRI in hybrid PET/ MRI scanners enhances the significance of both modalities for research in biomarkers and molecular bases of neurologic disorders, which will facilitate stratification procedures for the development of personalized medicine (Mier and Mier 2015). Role of synthetic biology in the development of personalized medicine  Techniques of synthetic biology enable the growth of living systems using parts that are not derived from nature but designed

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and synthesized in the laboratory. Genes as well as proteins can be synthesized. Advances in sequencing can be used to combine synthetic biology with personalized medicine. Therapeutic systems can be based on a synthetic genome using an expanded genetic code and can be designed for specific personalized drug synthesis as well as delivery and activation by a pathological signal (Jain 2013). The ability to control expression in target areas within a genome is important for the use of synthetic biology in designing personalized medicines. Role of nanobiotechnology in the development of personalized neurology  Nanotechnology is the creation and utilization of materials, devices, and systems through the control of matter on the nanometer-length scale, i.e., at the level of atoms, molecules, and supramolecular structures. It is the popular term for the construction and utilization of functional structures with at least one characteristic dimension measured in nanometers (a nanometer is 1 billionth of a meter (10−9 m). Nanobiotechnology is the application of nanotechnology in the life sciences; applications in medicine are referred to as nanomedicine (Jain 2017c). Nanomedicine covers all specialties of medicine, including neurology, which is termed “nanoneurology.” Nanobiotechnology contributes to personalized medicine by refinement of molecular diagnosis, integration of diagnostics with therapeutics, and improvement of targeted drug delivery, e.g., across the blood-brain barrier for cerebral lesions. Neurotechnologies  Wearable devices are being used for monitoring of signs and biomarkers of neurologic disorders. These are useful, not only for diagnosis but also for the integration of diagnosis with therapeutics for personalized neurology. These devices enable assessment of patients in daily situations. For example, tasks can be focused on examining the exact types of memory disabilities in the heterogeneous group of cognitive impairments by remote use of devices and enable a virtual reality approach to personalized neurorehabilitation (Slyk et  al. 2019). Use of remote monitoring devices into a patient-centric

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virtual clinical trial design enables collection of real-time information at each stage of the trial as well as monitoring of endpoints, which would be suitable for evaluation of personalized therapies. Role of neuroinformatics in personalized neurology  Neuroinformatics is the integration of computational biology or bioinformatics with neurosciences. Enormous amounts of data from neuroimaging and structural as well as functional studies of the brain can be used to construct a “virtual brain” as a basis for disease-specific models, which can be applied to personalize therapy of neurologic disorders at the individual level (Falcon et al. 2016). Personalized biological therapies for neurologic disorders  Biological therapies particularly relevant to personalized treatment of neurologic disorders are uses of autologous stem cells for the treatment of neurologic disorders or immunotherapies of brain tumors involving tumor cells taken from a patient’s tumor. The patient’s own somatic cells, genetically engineered to release therapeutic substances, are also in clinical trials. This approach overlaps with gene therapy. Ex vivo gene therapy involves the genetic modification of the patient’s cells in vitro, mostly by use of viral vectors, prior to reimplanting these cells into the tissues of the patient’s body. This is a form of individualized therapy. Apart from infectious diseases involving the nervous system, therapeutic vaccines are in development for malignant tumors such as glioblastoma, autoimmune disorders such as multiple sclerosis, and degenerative disorders such as Alzheimer disease. Cancer vaccination involves attempts to activate immune responses against antigens to which the immune system has already been exposed. Most of the personalized cancer vaccines are cell-based, and these were the earliest forms of personalized medicine (Jain 2010). Monoclonal antibodies play an important role in personalized neurology, both as diagnostic and therapeutic agents. Designed to bind to specific receptors, monoclonal antibodies can be used to guide passage of nanomedicines across the

blood-brain barrier to specific targets in the brain, such as glioblastoma, a malignant brain tumor.

 ersonalized Management of DINDs P Pharmacogenetics and pharmacogenomics have enabled prevention of DINDs by prediction of ADRs from genotyping. This impact might be highest in the drugs that cannot be easily monitored or that do not provoke mild ADR symptoms quickly, which itself could lead to treatment modifications and dose adaptation that prevent serious ADRs. Therefore, particularly patients that require the intake of such drugs with known pharmacogenomic variability such as clopidogrel might benefit mostly from pharmacogenomic testing to prevent those serious ADRs (Just et al. 2020). Due to differences in genetic make, individual patients respond differently to diseases, and this should be considered in matching the right tratement to the right patients. A personalized approach, whereever applicable, will be pointed out in various chapters deling with DINDs.

References Balmer NV, Leist M.  Epigenetics and transcriptomics to detect adverse drug effects in model systems of human development. Basic Clin Pharmacol Toxicol. 2014;115(1):59–68. Bosnjak ZJ.  Developmental neurotoxicity screening using human embryonic stem cells. Exp Neurol. 2012;237(1):207–10. Convertino I, Sansone AC, Marino A, et  al. Neonatal adaptation issues after maternal exposure to prescription drugs: withdrawal syndromes and residual pharmacological effects. Drug Saf. 2016;39(10):903–24. Falcon MI, Jirsa V, Solodkin A. A new neuroinformatics approach to personalized medicine in neurology: the virtual brain. Curr Opin Neurol. 2016;29(4):429–36. Grill MF, Maganti RK. Neurotoxic effects associated with antibiotic use: management considerations. Br J Clin Pharmacol. 2011;72(3):381–93. Jain KK. Personalized cancer vaccines. Expert Opin Biol Ther. 2010;10(12):1637–47. Jain KK.  Synthetic biology and personalized medicine. Med Princ Pract. 2013;22(3):209–19. Jain KK. Role of proteomics in the development of personalized medicine. Adv Protein Chem Struct Biol. 2016;102:41–52. Jain KK. Textbook of hyperbaric medicine. 6th ed. Cham: Springer; 2017a.

References Jain KK. The handbook of biomarkers. 2nd ed. New York: Springer; 2017b. Jain KK.  The handbook of nanomedicine. 3rd ed. New York: Springer; 2017c. Jain KK.  Textbook of personalized medicine. 3rd ed. Cham: Springer; 2021. Jové M, Portero-Otín M, Naudí A, Ferrer I, Pamplona R.  Metabolomics of human brain aging and age-­ related neurodegenerative diseases. J Neuropathol Exp Neurol. 2014;73(7):640–57. Just KS, Dormann H, Schurig M, et al. Adverse drug reactions in the emergency department: is there a role for pharmacogenomic profiles at risk?—Results from the ADRED study. J Clin Med. 2020;9(6):1801. Kawanishi C, Onishi H, Kato D, et  al. Unexpectedly high prevalence of akathisia in cancer patients. Palliat Support Care. 2007;5(4):351–4. Kobayashi H, Fujii K, Kobayashi M, et  al. Facial nerve palsy associated with atomoxetine-induced hypertension. Brain and Development. 2019;41(3):310–2. Liao D, Xiang D, Dang R, et al. Neuroprotective effects of dl-3-n-butylphthalide against doxorubicin-induced neuroinflammation, oxidative stress, endoplasmic reticulum stress, and behavioral changes. Oxidative Med Cell Longev. 2018;2018:9125601. Lister R, Mukamel EA, Nery JR, et al. Global epigenomic reconfiguration during mammalian brain development. Science. 2013;341(6146):1237905.

87 Liu PK, Liu CH.  Gene targeting MRI: nucleic acid-­ based imaging and applications. Methods Mol Biol. 2011;711:363–77. McWhinney SR, Goldberg RM, McLeod HL.  Platinum neurotoxicity pharmacogenetics. Mol Cancer Ther. 2009;8(1):10–6. Mier W, Mier D. Advantages in functional imaging of the brain. Front Hum Neurosci. 2015;9:249. Rubin DB, Danish HH, Ali Basil A, et  al. Neurological toxicities associated with chimeric antigen receptor T-cell therapy. Brain. 2019;142(5):1334–48. Rudra RT, Gordin V, Xu L. Acupuncture in the management of medication overuse and drug-induced aseptic meningitis headache: a case report. J Acupunct Meridian Stud. 2020;13(2):58–60. Shireen E.  Experimental treatment of antipsychotic-­ induced movement disorders. J Exp Pharmacol. 2016;8:1–10. Slyk S, Zarzycki MZ, Kocwa-Karnaś A, Domitrz I.  Virtual reality in the diagnostics and therapy of neurological diseases. Expert Rev Med Devices. 2019;16(12):1035–40. Unterecker S, Hefner G, Baumann P, et  al. Therapeutic drug monitoring in neuropsychopharmacology: summary of the consensus guidelines 2017 of the TDM task force of the AGNP. Nervenarzt. 2019;90(5):463–71.

Part II Neurological Complications of Therapies

7

Methods of Drug Delivery to the Nervous System and DIND

Introduction Drugs used for the central nervous system (CNS) disorders are delivered by methods best suited for action on the brain or the spinal cord. Furthermore, it is ideal if the drugs reach the target without acting on the rest of the CNS. However, unintended effects do occur on the nervous system, which may be related to the method of delivery. The role of drug delivery in drug-induced neurological disorders (DINDs) will be examined in this chapter. Table 7.1 shows a classification of available strategies for CNS drug delivery; most of these involve circumventing the blood-brain barrier (BBB). It is desirable if the drugs reach the target site of action in the brain without acting on the rest of the CNS. Drug delivery to CNS will be described in this chapter to provide the background for understanding the important role it plays in drug safety. Examples will be given where DINDs are related to drug delivery.

Drug Delivery Across the BBB Role of the BBB in DIND was described in Chap. 3. Table  7.2 lists strategies for drug delivery across the BBB. Several CNS disorders as well as drugs affect the permeability of the BBB, making adjustment of the therapeuic drug dose diffi-

cult. Insufficient drug delivery to the CNS may manifest as lack of efficacy, e.g., breakthrough seizures in case of epilepsy despite maintenance dose of an antiepileptic drug. Increased permeability of the membrane may lead to neurotoxicity by delivery of excessive amount of drug to the brain. Some of the recommendations by participants of a workshop on the topic of crossing the blood-­ brain barrier for CNS drug delivery included the following issues that are relevant for approval of drugs and devices (National Academies of Sciences, Engineering, and Medicine 2018): • Areas of major concern to regulatory agencies include off-target effects, safety of long-term dosing, immunogenicity, and unintended adverse effects. • Technologies that disrupt the blood-brain barrier raise safety concerns regarding exposure of the brain to chemicals or toxins. • Evaluation of the safety profile of biologics can be particularly challenging as they may combine multiple components that are delivered to the brain. • The acceptable safety threshold and the risk-­ benefit ratio for a therapeutic will vary depending on the condition being treated. • Focused ultrasound introduces many regulatory challenges because it combines a device, microbubbles, the therapeutic agent, and an imaging agent.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_7

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Table 7.1  Strategies for drug delivery to the CNS Systemic administration of therapeutic substances for CNS action  Intravenous injection for targeted action in the CNS  Transdermal delivery for introduction into systemic circulation for action on CNS Direct administration of therapeutic substances to the CNS  Introduction into cerebrospinal fluid pathways: intraventricular, subarachnoid pathways, intrathecal  Introduction into the cerebral arterial circulation  Introduction into the brain substance  Direct positive pressure infusion  Intranasal instillation for introduction into the brain along the olfactory tract Drug delivery by manipulation of the blood-brain barrier (see Table 7.2) Drug delivery using novel formulations  Conjugates  Gels  Liposomes  Microspheres  Nanoparticles Chemical delivery systems Drug delivery devices  Pumps  Catheters  Implants releasing drugs  Controlled-release microchip Use of microorganisms for drug delivery to the brain  Bacteriophages for brain penetration  Bacterial vectors Cell therapy  CNS implants of live cells secreting therapeutic substances  CNS implants of encapsulated genetically engineered cells producing therapeutic substances  Cells for facilitating crossing of the blood brain barrier Gene therapy Direct injection into the brain substance Targeting of CNS by retrograde axonal transport © Jain PharmaBiotech

Osmotic opening of the blood-brain barrier  Hypertonic solutions can disrupt the blood-­brain barrier both when applied directly to the surface of the brain and when infused on the blood side of the blood-brain barrier. Electron microscopic studies in experimental animals show that such reversible opening is mediated by increased permeability of the interendothelial tight junctions to tracers such as horseradish peroxidase. It is possible that such opening is due to a shrinking of endothelial

Table 7.2  Strategies for drug delivery to the CNS across the BBB Increasing the permeability (opening) of the BBB Cerebral vasodilatation: stimulation of the sphenopalatine ganglion, nitric oxide inhalation Chemical opening Disruption of blood-brain barrier by focused ultrasound Osmotic opening of the blood-brain barrier Pharmacological strategies to facilitate transport across the BBB Chimeric peptides Inhibition of efflux transporters that impede drug delivery Modification of the drug to enhance its lipid solubility Monoclonal antibody fusion proteins Nanoparticle-based technologies Neuroimmunophilins Prodrug bioconversion strategies Trojan horse approach Use of transport/carrier systems Bypassing the BBB Direct introduction of drugs into the brain or the CSF Using an alternative route of delivery, e.g., injection into epidural venous plexus © Jain PharmaBiotech

cells, leading to a widening of spaces between the cells. Entry of neutral, water-soluble drugs into the brain can be predicted by a model that takes into consideration the effective pore size, pore density, and time course for bulk water flow. In addition to this, the molecular size and molecular charge of the drug also play a role in the entry of drugs into the brain. A negative surface charge associated with the pores can restrict the passage of negatively charged molecules more than their neutral or positively charged counterparts. This strategy may be useful to facilitate the entry into the brain of drugs that are bound tightly to plasma proteins. A temporary increase of blood-brain barrier permeability would allow the entry of both the free and the bound forms of the drug. Whereas the free part of the drug would have an immediate effect, the bound portion would have to dissociate from the protein before producing its effect, which would cause a delay. In experimental animals, the osmotic opening method has been used to obtain wide access of water-soluble drugs, such as peptides, boron compounds for neutron capture

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their ability to penetrate the blood-brain barrier. The addition of methyl groups in a series of barbiturates improves lipophilicity and brain Chemical opening of the blood-brain bar- penetration, leading to increased hypnotic rier  This is more selective and controllable action. It is also possible to generate a lipothan osmotic opening. Bradykinin given by philic prodrug that is broken down to release intracarotid injection opens the brain tumor the more active drug within the brain. An examcapillaries without affecting the capillaries in ple of this is heroin, which enters the brain readily due to its lipophilicity but, after entry, the normal brain. hydrolyses to morphine, which is less lipophilic Disruption of blood-brain barrier by focused and less likely to diffuse back across the bloodultrasound  Low-frequency, MRI-guided, brain barrier, leading to prolongation of durafocused ultrasound has been shown to induce tion of its action on the brain. Ester formation is localized and reversible disruption of the blood-­ another approach for increasing the lipophilicbrain barrier without undesired long-term effects ity of polar molecules exhibiting poor CNS in experimental animals. A frequency range of penetration. Several investigators have explored approximately 260  kHz enables the passage of the lipophilic-ester concept for improving the ultrasound through the skull and produced focal CNS delivery of antiviral agents. An example disruption of blood-brain barrier without extrava- of this is improvement of the blood-­brain barsation of red blood cells (Vykhodtseva 2010). The rier penetration of GABA (gamma-­aminobutyric exact mechanism is not known, but ultrasound-­ acid), an anticonvulsant agent with poor CNS induced microbubbles may temporarily expand penetration, by use of lipophilic esters. the capillary wall and open the tight junctions. Although increasing lipophilicity generally This noninvasive technique offers a potential increases penetration across the blood-brain barmethod for targeted drug delivery in the brain rier, it may also result in reduction of biological aided by a relatively simple low-frequency device. action due to drug-receptor interaction, drug metabolism, or binding to plasma proteins, as in Neurostimulation  This produces an indirect the case of barbiturates. Therefore, optimization effect, i.e., opening of the blood-brain barrier to rather than maximization of both lipophilicity facilitate drug delivery to the brain. One device, and rate of bioconversion is required. Vascular Enabled Integrated Nanosecond Lipid-binding carriers may reduce the binding (VEIN) pulse, involves insertion of minimally of neurotrophic factors to serum lipids and invasive electrodes into diseased brain tissue increase transport across the blood-brain barrier. and application of multiple bursts of nanosec- Liposomes have been considered, but their size is ond pulses with alternating polarity that disrupt too large to cross the blood-brain barrier. tight junction proteins responsible for maintaining the integrity of the blood-brain barrier Use of transport or carrier systems  Of the variwithout causing damage to the surrounding tis- ous carrier systems, those for glucose and neutral sue (Arena et al. 2014). amino acids have high enough transport capacity to hold promise for significant drug delivery to Modification of the drug to enhance its lipid the brain. Approaches for drug delivery across solubility  There is a good correlation between the blood-brain barrier include the prodrug stratthe lipid solubility of a drug and the blood- egy whereby drug molecules are conjugated to brain barrier penetration in vivo. The lipophilic glucose transporter substrates or encapsulated in pathway also provides a large surface area for nano-enabled delivery systems (e.g., liposomes, drug delivery. It is approximately 12  m2 in an micelles, nanoparticles) that are functionalized to average human brain. Therefore, the addition of target glucose transporters (Patching 2017). hydrophobic groups to molecules increases Glucose transporters have the limitation that only therapy, and viral vectors for gene therapy, to the brain.

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molecules closely resembling D-glucose are transported. Neutral amino acids are less specific. Entry via this carrier may explain the central effects of the muscle relaxant baclofen. Transport systems for peptides may prove to be effective targets for peptide drugs required to control natural peptide hormones. Drugs used to treat neurologic disorders appear to cross the blood-brain barrier more easily when an ascorbic acid molecule is attached. Ascorbic acid works like a shuttle and, theoretically, could transport any compound into the brain. The ascorbic acid SVCT2 transporter, which is believed to play a major role in regulating the transport of ascorbic acid into the brain, provides a targeted delivery to the brain. Potential applications include drugs to treat neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, and epilepsy.

disease by 55-fold compared to the parent antibody.

Inhibition of efflux transporters  Efflux transport system at the blood-brain barrier provides a protective barrier function by removing drugs from the brain or CSF and transferring them to the systemic circulation. Therefore, modulation of these efflux transporters by design of inhibitors and/or design of compounds that have minimal affinity for these transporters may enhance the treatment of neurologic disorders. Concomitant use of inhibitors of P-glycoprotein, an efflux transporter, also enhances the delivery of drugs to the CNS. In a clinical experimental study, administration of the experimental oncology drug tariquidar (a potent P-glycoprotein inhibitor) along with radiolabeled verapamil in healthy volunteers showed that total distribution volume of verapamil in whole brain grey matter increased about 300% Receptor-mediated transport  Receptor-­ on PET scans (Bauer et al. 2015). mediated transcytosis employs the vesicular trafficking machinery of the endothelium to Trojan horse approach  Attaching an active transport substrates between the blood and drug molecule to a vector that accesses a spebrain. If appropriately targeted, this approach cific catalyzed transporter mechanism creates a can also be used to shuttle a wide range of ther- Trojan horse-like deception that tricks the apeutics into the brain in a noninvasive manner. blood-brain barrier into welcoming the drug Sophisticated cell culture models of the blood- through its gates. Transport vectors, such as brain barrier have enabled the identification, endogenous peptides, modified proteins, or characterization, and validation of a novel tar- peptidomimetic monoclonal antibodies, are a geted drug delivery technology, designated way of tricking the brain into allowing these 2B-Trans, for the receptor-­mediated uptake and molecules to pass. The therapeutic peptide or transport of drugs across the blood-brain bar- protein drug is fused to a molecular Trojan rier (Gaillard and de Boer 2008). Differential horse, which may be a monoclonal antibody drug targeting or delivery approach based on that binds to a specific receptor on the bloodreceptor-mediated transport is recommended brain barrier and enables receptor-­ mediated for the treatment of CNS diseases that are delivery of the fusion protein across the barrier related to the blood-brain barrier alone as well to exert the desired pharmacological effect on as for CNS diseases that are related to both the the brain (Pardridge 2015). The Trojan horse brain and the blood-brain barrier. approach has been applied to delivery of nonviA “Brain Shuttle module” has been developed ral gene and RNAi therapeutics, ­particularly in by manipulating the binding mode of an antibody lysosomal storage disorders and Parkinson disfragment to the transferrin receptor (TfR), which ease (Boado and Pardridge 2011). can be engineered into a standard therapeutic antibody for successful transcytosis across the Inhibition of carriers that impede drug blood-brain barrier (Niewoehner et al. 2014). A delivery  P-glycoprotein active drug efflux monovalent binding mode to the TfR anti-­ transporter is present at high densities in the amyloid beta antibody increases delivery to beta luminal membranes of brain endothelium. It amyloid target in a mouse model of Alzheimer pumps out some cytotoxic agents used to treat

Drug Delivery Across the BBB

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brain tumors and excludes them from the brain. P-glycoprotein inhibitors enhance the effects of cytotoxic agents and have the potential of enhancing chemotherapeutic effects on the brain. Transport of small molecules across the blood-­brain barrier  Lipid-soluble small molecules with a molecular mass of less than 400– 600  d are transported readily through the blood-brain barrier in  vivo via lipid-mediated transport. However, other small molecules lacking these molecular properties, antisense drugs, and peptide-based pharmaceuticals ordinarily undergo negligible transport through the bloodbrain barrier in pharmacologically significant amounts. Some small-­ molecule neuroprotective agents have failed in human trials due to poor transport of these agents across the bloodbrain barrier. Strategies that enable drug transport through the blood-brain barrier arise from knowledge of the molecular and cellular biology of blood-brain barrier transport processes.

binding the drug to the peptide is cleaved, and the drug binds to a receptor at the neuron. Receptor-­ mediated endocytosis is more adequately described as transcytosis and is depicted in Fig.  7.1. The nontransportable drug is attached to a protein or peptide vector, which is accepted by the receptor at the luminal side of the BBB and endocytosed. After exocytosis in the brain interstitial fluid, the chemical link binding the drug to the peptide is cleaved, and the drug binds to a receptor at the neuron. The high level of expression of transferrin receptors on the surface of endothelial cells of the blood-brain barrier has been widely utilized to deliver drugs to the brain. This approach has been explored for the delivery of citicoline, a neuroprotective drug for stroke, which does not readily cross the blood-brain barrier because of its strong polar nature.

Chimeric peptides  Under normal conditions, vesicular transport that involves receptor-­ mediated endocytosis is responsible for only a small amount of molecular trafficking across the Receptor-mediated endocytosis  In this blood-brain barrier, but it may be suitable for the approach, the nontransportable drug is attached delivery of agents that are too large to use other to a protein or peptide vector, which is accepted routes. This approach involves forming a chimeby the receptor at the luminal side of the blood-­ ric peptide by coupling an otherwise nontransbrain barrier and endocytosed. After exocytosis portable drug to a blood-brain barrier transporter in the brain interstitial fluid, the chemical link vector by a disulfide bond. The chimera is then Endocytosis

Exocytosis

RV Drug

Cleavage

RV Vector

Vector

Drug

Vector

Drug Receptor binding

Blood

Blood-brain barrier

Neuron Brain

Fig. 7.1  Use of receptor-mediated transcytosis to cross the BBB. RV, receptor for the vector. (© Jain PharmaBiotech)

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endocytosed by the capillary endothelial cells and transported to the brain where it can be cleaved by disulfide reductase to release the pharmacologically active compound. Blood-brain barrier peptide receptor systems include those for insulin, insulin-like growth factor, transferrin, and leptin. Kinin analogs for modification of bloodbrain barrier  In vivo imaging studies in animal models of glioma have shown that kinin B1 (B1R) and B2 receptor (B2R) agonists increase the blood-brain barrier penetration of chemotherapeutic doxorubicin to glioma sites, with additive effects when applied in combination (Sikpa et al. 2020). B2R agonist also promoted the selective delivery of co-injected diagnostic MRI agent gadopentetate dimeglumine in irradiated brain areas, depicting increased vascular B2R expression. These findings suggest potential use of kinin analogs to facilitate access of drugs to the brain. Monoclonal antibody fusion proteins  These involve conjugation of a drug to a transport vector. These have diagnostic and therapeutic applications for the treatment of brain tumors. Nontransportable specific antigen-binding monoclonal antibodies such as IgG3 have been attached to a transport vector such as insulinlike growth factor. The bifunctional molecule can cross the blood-brain barrier through interaction with the receptor for insulin-like growth factor. Transferrin is a specific receptor for molecules that are not synthesized in the brain but play an essential biological role. This transfer mechanism can be exploited in an approach in which antiferritin receptor antibodies are covalently linked to nerve growth factor, resulting in a substantial transfer of biologically active nerve growth factor across the blood-brain barrier into the CNS. Nerve growth factor can be transported across the blood-brain barrier by conjugating with OX-2, an antibody directed against the transferrin receptor. Prodrug bioconversion strategies and their CNS selectivity  A wide range of prodrug

options can be explored in improving the CNS delivery of low molecular weight drugs. Site-­ specific delivery to the CNS via the prodrug approach can be achieved only if the basic criteria of this approach are fulfilled. Prodrug strategies for increasing the blood-brain barrier transport of small hydrophilic molecules include chemical modification to more lipophilic derivatives, carrier-mediated prodrug transport, and prodrug bioconversion strategies. Carrier-mediated prodrug transport involves the use of a carrier that is a substrate for one of the transporters within the blood-brain barrier. A classic example of this approach is the improvement of CNS delivery of the neurotransmitter dopamine, which is poorly transported across the blood-brain barrier and is rapidly degraded in the endothelial cells by the action of the enzyme monoamine oxidase. Prodrug L-dopa is readily transported across the blood-brain barrier via the large neutral amino acid transporter and is decarboxylated to dopamine by L-amino acid decarboxylase, which is localized in the capillary endothelium. Several other drugs are transported to the brain via the neutral amino acid transporter (L-system) such as baclofen, melphalan, and buthionine sulfoximine. Similarly, many beta-­ lactim antibiotics including benzylpenicillin, ceftriaxone, and the anticonvulsant valproic acid are transported by the monocarboxylic acid carrier. Several peptide transporter systems have also been described. Parent drug efflux from the CNS and metabolism in brain tissue are important factors limiting drug efficacy. Combined prodrugs containing both the active agent and an inhibitor of the enzyme that metabolizes the parent compound is a more effective approach. Additional research is necessary before CNS delivery can be truly designed into a molecule via the prodrug approach. Activated T lymphocytes  T lymphocytes can cross the blood-brain barrier and can be engineered to produce nerve growth factor in quantities comparable to those produced by genetically engineered fibroblasts. Engineered

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T lymphocytes have been used as vehicles to deliver nerve growth factor across the endothelial blood-nerve barrier to attenuate experimental autoimmune neuritis.

cedures, implantation of cells or tissues, or the use of special devices. Injection into the arterial circulation of the brain. There is considerable clinical experience with injections into the arterial circulation of the brain (Joshi 2010). Neuroradiologists manipulate catheters in the circulation and inject contrast agents for angiography.

Neuroimmunophilins  These small-molecule neurotrophic factors can be administered orally and can cross the blood-brain barrier. Neuroimmunophilin ligands are small molecules that can repair and regenerate damaged nerves without affecting normal, healthy nerves and may have application in the treatment of a broad range of diseases, including Parkinson disease, spinal cord injury, traumatic brain injury, and peripheral nerve injuries. The immunosuppressants tacrolismus (FK-506) and cyclosporine are in clinical use for the treatment of allograft rejection following organ transplantation. Immunophilins can regulate neuronal survival and nerve regeneration although the molecular mechanisms are poorly understood. Endothelial sphingosine 1-phosphate (S1P) receptor-1 S1P receptor-1, a G protein-coupled receptor, promotes the barrier function in peripheral vessels. Experimental studies in mice suggest that brain endothelial S1P1 maintains the blood-brain barrier by regulating the proper localization of tight junction proteins (Yanagida et  al. 2017). Thus, endothelial S1P1 inhibition may be a strategy for transient blood-brain barrier opening and delivery of small molecules into the CNS.

Retrograde Axonal Transport In experimental animals with transected peripheral nerve roots, targeted axonal import has been shown to deliver protein cargo into spinal cord motor neurons after intramuscular injection (Sellers et al. 2016). Nonviral-mediated delivery of functional proteins into the spinal cord indicates the clinical potential of this technology. Invasive neurosurgical approaches. This can be achieved by special delivery methods that involve direct introduction of the therapeutic substances into the brain substance or into the CSF.  These methods involve neurosurgical pro-

 irect Injection into the CNS D Substance or CNS Lesions Stereotactic techniques used in modern neurosurgery enable placement of electrodes or probes in precise locations in the brain with minimal invasion. Drugs injected this way can spread over a wider area by convection currents and achieve a high and uniform concentration in the interstitial space of the brain. Direct positive pressure-­ controlled infusion has potential for the delivery of pharmacologic agents, viral vectors, and oligonucleotides to the brain. In the case of brain tumors, surgical removal of the tumor provides an opportunity to pack the tumor cavity with therapeutic substances in such a way that they do not escape into the systemic circulation. Brain abscesses can be aspirated through a cannula inserted by a minimally invasive technique, and antibiotics can be injected after aspiration of the infected material.

Convention-Enhanced Delivery This is a potentially useful method for significantly circumventing the blood-brain barrier and increasing delivery of water-soluble drugs to the brain. Important advances have been made to optimize the unique ability of convention-­ enhanced delivery to locally deliver high doses of powerful chemotherapeutics to gliomas for maximal tumor destruction with minimal neurologic and systemic side effects (Ding et  al. 2010). Direct convection delivery can also be used to deliver an infusate and distribute macromolecules in a predictable, homogeneous manner over significant volumes of naive and traumatized spinal

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cord. These characteristics make direct convection delivery a valuable tool in the investigation of the therapeutic potential of various compounds for the treatment of spinal cord injury. Development of surrogate imaging tracers that are co-infused during drug delivery now permit accurate, noninvasive real-time tracking of convective infusate flow in nervous system tissues (Lonser et al. 2015).

Injections into the CSF Pathways Delivery of drugs by lumbar puncture or direct intraventricular injection can bypass the blood-­brain barrier by direct introduction into the CSF. The layers of cells that line the fluid spaces of the brain are permeable to molecules introduced this way. Various problems with this approach are as follows: • The procedure of lumbar puncture is relatively simple, but intraventricular injection is a neurosurgical procedure. • The diffusion distance from the CSF to the drug target can be several centimeters, and an insufficient amount of the drug may reach the intended site. • The flow of CSF is from the microvessels of the brain toward the CSF spaces, opposite to the direction of the drug diffusion. • CSF has a high turnover rate, and it is replaced within few hours when the injected drug is continuously cleared back into the blood. Controlled-release formulations and drug-­ delivery devices are required for overcoming these disadvantages. Depot cytarabine (DTC 101) contains cytarabine encapsulated in microscopic spherical particles and has extended use of the therapeutic drug concentrations after a single dose given by lumbar puncture or by intraventricular injection. Delivery of drugs into CSF is via implanted catheters, reservoirs, and pumps. Various catheters are inserted into the CSF compartments (lumbar subarachnoid space, cisterns, and ventricles). These are connected to reservoirs and pumps and left in place during the duration of

therapy for continuous or pulsatile drug infusions. The main objectives of these devices are as follows: • To provide an access to various compartments of the CNS without repeated neurosurgical procedures • To prevent leakage of active principle to other organs • To obtain samples of CSF for monitoring the results of therapy • To enable treatment on an outpatient basis The earliest of such devices is Ommaya™ reservoir (constructed of a synthetic material). It is implanted subcutaneously and connected to an intraventricular catheter. Drugs can be injected into the reservoir (access port) at required intervals. Several improvements on this have appeared since then. These can be continuous flow pumps or programmable pumps. Continuous flow pumps  The delivery mechanism of the pump is based on the expansion of Freon gas at 37  °C that pushes a diaphragm “plunger/pusher” plate. Usually, the pump reservoir is implanted subcutaneously and is connected to the catheter implanted into the nervous system to deliver the therapeutic molecules. The reservoirs are refilled by subcutaneous injection of the solution containing the bioactive molecules. A well-known example of this technique is the intrathecal pump delivery of the GABAergic drug baclofen for spasticity. Programmable pumps  These are electromechanical pumps of peristaltic type powered by batteries. Their built-in electronics can be remotely controlled from an external programming unit. An example is SynchroMed system (Medtronic Inc.). The infusion can be programmed in various modes: continuous hourly infusions, repeated bolus infusions with a specified delay, multiple doses over a programmed interval, or a single bolus infusion. The use is restricted to a hospital with a relevant programming unit. The patient cannot switch the pump off and on.

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Intrathecal Drug Delivery Intrathecal drug administration means the introduction of a therapeutic substance by lumbar puncture into the subarachnoid space of the spinal cord. It is part of the broader term of neuraxial drug administration, which describes techniques that deliver drugs in proximity to the spinal cord and include epidural administration into the fatty tissues surrounding the dura, by injection or infusion. This approach was initially developed in the form of spinal anesthesia but has evolved to include a wide range of techniques for administration of several different drugs. Some of the devices used are referred to in the preceding section.

 pplications of Intrathecal Drug A Delivery • An intrathecal approach, with various types of implanted pumps, has been used for administration into the CSF of morphine for cancer pain and baclofen for spasticity. Targeted intrathecal drug delivery systems are an option for the treatment of patients with moderate to severe chronic refractory pain when more conservative approaches fail (De Andres et  al. 2014). • Therapeutic recombinant proteins can be introduced into the brain via this route. • Implantation of genetically engineered encapsulated cells producing ciliary neurotrophic factor in the spinal subarachnoid space is an example of gene delivery into the CNS via this route. Deposition of transgenic constructs into the subarachnoid space or the ventricular system is likely to be an efficient route for not only transducing the subependymal region but also for disseminating products of gene expression into the brain.  dverse Effects of Intrathecal Drug A Administration Adverse effects due to intrathecally administered drugs and biologicals include the following: • The most well-known adverse effect with intrathecal therapy is drug-induced aseptic or chemical meningitis due to direct irritation of

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the meninges by the drug. This usually resolves on discontinuation of the drug. Chemical meningitis accounts for half of the serious complications of an intrathecal injection of methylprednisolone. Reactions to preservative solutions can produce arachnoiditis. The intrathecal administration of solutions preserved with benzyl alcohol has been shown to increase the risk of adverse neurologic events. Spinal injection should not contain any preservatives (such as benzyl alcohol or polyethylene glycol). Granulomatous masses can develop at the tip of the intrathecal catheter of the morphine infusion systems. Respiratory depression can occur with intrathecal opioids, but kappa receptor agonists produce analgesia with little or no respiratory depression. The mechanism of adverse effects after spinal administration is distinctly different for morphine, as morphine is water soluble compared to more lipid-soluble opioids. The systemic absorption of morphine after intrathecal or epidural administration is slow, resulting in long duration of analgesia and low plasma concentrations, whereas lipid-soluble opioids are rapidly absorbed into the circulation and redistributed to the brain. Loss of opioid tolerance due to delayed intrathecal pump refill may lead to development of severe respiratory depression; therefore, refilling pumps in these patients should be done properly when their pumps are completely empty (Ruan et al. 2010). High concentrations of local anesthetics in the cerebrospinal fluid are neurotoxic. Pruritus is a frequent and annoying side effect of intrathecal opioids, but the mechanism is not clear. Several drugs, including antihistamines, nonsteroid antiinflammatory drugs, and droperidol, have been tried for pruritus associated with intrathecal opioids. Other reported complications of intrathecal administration of drugs include transverse myelitis, cauda equina syndrome, lumbar radiculitis, and urinary retention.

Complications of intrathecal administration of drugs are not meant to be given by this route of

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administration. Severe neurologic complications have been reported to be associated with inadvertent administration of methadone by means of implanted intrathecal catheters to a group of patients. Some safeguards that should be used to hinder the use of certain intrathecal drugs include the following: • Cytotoxic drugs should be given only by appropriately trained staff. • Intrathecal drugs should be administered in a designated area (e.g., an operating theater). • Drugs for intrathecal use should be delivered directly from the pharmacy to the point of use and shipped separately from other drugs. • Cytotoxic drugs should be delivered to, and stored in, such a designated area.

 omplications of Long-Term Intrathecal C Therapy Using Devices Most of the therapy-related safety issues associated with intrathecal drug delivery are due to inadequate patient monitoring, inflammatory granuloma at catheter tip, wound healing, dosing errors, pump fills or refills, and interaction with concomitant systemic medications. These complications can be prevented by adequate clinician training and implementation of best practices (Prager et al. 2014). Complications of long-term intrathecal therapy may be related to pumps or catheters placed in the intrathecal space that may malfunction or get obstructed, requiring invasive intervention for correction. The most bothersome complication is infection. Cancer patients receiving cytotoxic therapies are particularly susceptible to infectious complications because they are immunocompromised. The incidence of infectious complications varies from 2% to 8% and frequently requires prolonged antibiotics and device revision or removal (Engle et al. 2013). Chronic headache due to loss of CSF may occur in patients with an implanted drug delivery pump. Radioisotope cisternography may be a useful diagnostic procedure to determine the exact location of CSF leak. Spinal fluid leak can be stopped with a blood patch, but if it fails, epidural fibrin glue can be used (Freeman et al. 2014).

Catheter-tip masses are a complication of implantable drug delivery device usage in less than 3% of all patients with intrathecal catheters (Medel et al. 2010). These require removal to prevent neurologic complications. In one case, air trapped within an arachnoid cyst at the tip of the catheter due to long-term use of intrathecal morphine led to lower extremity paresis, which recovered after surgical decompression (Atencio et al. 2012). CSF analysis should be performed in patients chronically treated by intrathecal infusion who develop a rapid increase in pain, usually due to aseptic arachnoiditis. In a patient who developed pain after long-term treatment with intrathecal morphine infusion, the symptoms resolved on switch to ziconotide (Codipietro and Maino 2015). Migration of intrathecal catheter 5 months following placement for management of pain due to arachnoiditis and extensive epidural scarring and manifested by reduction of pain relief has been reported in one patient requiring repositioning of the catheter (Anitescu et  al. 2012). High-­ resolution 3D CT with volume rendering technique is a noninvasive method that can identify complications of intrathecal drug delivery devices such as catheter obstruction, displacement, or leakage more precisely than axial CT and fluoroscopy (Morgalla et al. 2016). In a retrospective study of patients who required surgery for complications associated with removal of the ­ intrathecal catheter, retained catheter was the cause of complications in half of the cases, and persistent cerebrospinal fluid leak was the next most common complication that required an external drainage system (Frizon et al. 2018).

 elivery of Drugs to the Brain via D the Nasal Route The intranasal route consists of two pathways (Crowe et al. 2018): 1. The intracellular pathway starts with endocytosis by olfactory sensory cells, followed by axonal transport to their synaptic clefts in the olfactory bulb where the drug is exocytosed. This process is repeated by olfactory neurons, thereby distributing the drug to other brain regions.

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2. In the extracellular mechanism, drugs are transported directly into the cerebral spinal fluid by first passing through the paracellular space across the nasal epithelium and then through the perineural space to the subarachnoid space of the brain.

Intra-arterial Administration of Therapeutic Substances for CNS Disorders

The olfactory nerve is the target when direct absorption into the brain is the goal because it is the only site in the human body where the CNS is directly expressed on the nasal mucosal surface (Gizurarson 2012). Although the traditional blood-brain barrier is not present at the interface between nasal epithelium and brain, P-glycoprotein and other barrier transporters are expressed at this interface, which can be modulated with nasal administration of appropriate inhibitors. Nasal administration of two prodrugs (L-dopa butyl esters) has been reported to result in higher CSF levels of L-dopa than those observed after intravenous administration. The percentage of the applied dose that passes to the brain and CSF is about 2–3%. This indicates that a nasal route may be a viable method for the delivery of peptides, analgesics, and other drugs for the treatment of CNS disorders. Preferential uptake of intranasally administered apomorphine directly into the cerebral spinal fluid has been demonstrated in a phase I study, and this opens the possibility of treating neurologic disorders with intranasal apomorphine. A wide variety of therapeutic compounds can be delivered intranasally, including relatively large molecules such as peptides and proteins, particularly in the presence of permeation enhancers (Costantino et  al. 2008). Direct nose-­to-­brain delivery is still limited by low efficiency and low volume of delivery. However, future studies are expected to achieve a detailed understanding of pharmacokinetics and mechanisms of delivery to optimize formulations and fully exploit the noseto-brain interface to deliver proteins for the treatment of neurologic diseases (Malerba et al. 2011). Intranasal route facilitates the delivery of large molecules, which fail to effectively cross the blood-brain barrier. Therefore, intranasal delivery is an efficient method of administration for neurotrophic factors, hormones, neuropeptides, and even stem cells (Chapman et al. 2013).

• Acrylic and thrombosis inducing material for occluding arteriovenous malformations • Thrombolytic agents such as tissue plasminogen activator for treatment of arterial thrombosis in stroke patients. The approved method of administration is intravenous, but the intra-­ arterial route is under investigation. • Vasodilators such as papaverine for treatment of vasospasm of cerebral arteries • Diazepam has been administered intra-­ arterially as an anesthetic during cerebral angiography and was found to be safe. • Direct injection of gene vectors into the arterial circulation of the brain • Intra-arterial administration of chemotherapy for brain tumors

Examples of intra-arterial introduction of drugs in the brain are as follows:

Intra-arterial administration of tissue plasminogen activator in stroke patients  The method of administration of thrombolytic agents such as tissue plasminogen activator is important for evaluating the results of treatment in stroke patients. Although the approved method is intravenous administration, considerable experience exists with the use of intra-arterial thrombolysis in patients in whom the lesions have been demonstrated by angiography prior to thrombolysis. Angiography is necessary for monitoring clot lysis during treatment, and a specially trained physician is required to maneuver the catheter to the site of occlusion. Despite this limitation and the risk of the complications of angiography, hemorrhages are less common with intra-arterial treatment because less of a drug is generally used. Physical manipulation of the clot may aid thrombolysis, and more of a drug can be delivered to and within the clot. Occlusion of the internal carotid artery in the neck does not respond well to intravenous thrombolysis if the stroke is due to embolization of the carotid clot to block the middle cerebral artery. Neck occlusion diminishes the

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amount of intravenously administered drug that can reach the middle cerebral artery clots under these circumstances. The intra-­arterial approach may be more successful in these situations. Anti-HIV drug delivery for treatment of AIDS encephalopathy  The blood-brain barrier hinders the penetration of anti-HIV drugs into the brain, promoting viral replication, the development of drug resistance, and, ultimately, subtherapeutic concentrations of drugs reaching the brain, leading to therapeutic failure. A penetration-­ effectiveness ranking concept for quantifying antiretroviral drug penetration into the CNS clearly could be considered as a guide for selecting relatively more effective treatment strategies from the available drugs. The specificity and efficiency of anti-HIV drug delivery can be further enhanced by using nanocarriers with specific brain-targeting, cell-penetrating ligands (Wong et al. 2010). Drug delivery to the brain in Parkinson disease  Glial cell line-derived neurotrophic factor (GDNF) is potentially useful in the treatment of Parkinson disease, but penetration into brain tissue from either the blood or the cerebrospinal fluid is limited. Although safety and potential efficacy of unilateral intraputaminal glial cell line-derived neurotrophic factor infusion via a catheter in patients with advanced Parkinson disease have been demonstrated in pilot clinical studies, the method has not been adopted in clinical practice because of the invasive nature. Drug delivery to the brain in Alzheimer disease  Several routes of drug delivery other than oral have been explored for the management of Alzheimer disease. Transdermal rivastigmine maintains steady drug levels in the bloodstream, improving tolerability and allowing a higher proportion of patients to receive therapeutic doses compared to the capsule form of the medication. Several studies are exploring the nasal route of drug delivery for Alzheimer disease. Biological therapies for the treatment of Alzheimer disease that exploit mechanisms of

penetration of the blood-brain barrier include peptides, vaccines, antibodies, and antisense oligonucleotides. Currently, the use of nanotechnology-­ based drug delivery systems appears to be a promising direction for therapy of Alzheimer disease (Wong et al. 2019). An experimental study demonstrated that the brain-targeting efficiency of intravenously injected rivastigmine encapsulated in hybrid polymer nanoparticles can be enhanced 5.4-fold compared to the drug solution (Omar et al. 2020). The results suggest that the fabricated biohybrid delivery system was able to circumvent the blood-brain barrier and is expected to minimize systemic side effects of rivastigmine. Drug delivery in epilepsy  Special methods of drug delivery would improve the control of seizures, reduce toxic effects, and increase compliance in patients with epilepsy, such as by use of long-acting formulations and subcutaneous implants. In emergency situations, administration via intravenous, rectal, nasal, or buccal mucosa can deliver the drug more quickly than oral administration. Early termination of prolonged seizures with intravenous administration of benzodiazepines is known to improve outcomes. Results of a double-blind, randomized noninferiority trial show that for subjects in status epilepticus, intramuscular midazolam is at least as safe and effective as intravenous lorazepam for prehospital seizure cessation (Silbergleit et  al. 2012). Antiepileptic drugs have been delivered effectively to seizure foci through programmed infusion pumps, which are triggered to act in response to computerized EEG seizure detection. Cell and gene therapies may prove to be more effective forms of drug delivery in epilepsy. Overexpression of P-glycoprotein and other efflux transporters in the cerebrovascular endothelium, in the region of the epileptic focus, may also lead to drug resistance in epilepsy. This hypothesis is supported by the findings of elevated expression of efflux transporters in epileptic foci in patients with drug-resistant epilepsy, induction of expression by seizures in animal models, and experimental evidence that some

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are potentially useful for the treatment of neurologic disorders. Peptides act by binding to specific cell surface receptors. The ideal therapeutic peptide should have a small molecular mass, should be a chemical mimic of the receptor, and should get to the site of action after oral administration. Types of Systems for Therapeutic Delivery to the Nervous System Most peptides, however, cannot be administered orally, as gastrointestinal enzymes rapidly In addition to the usual advances in drug delivery, inactivate them, so subcutaneous or intravenous biotechnology has been used for improving drug administration is required. Therefore, research is delivery as listed in Table 7.3. focusing on alternative routes of delivery, includProducts of biotechnology also face drug-­ ing inhaled, buccal transmucosal, intranasal, and delivery problems. Techniques such as gene ther- transdermal routes, as well as novel formulations apy, which includes implantation of genetically with liposomes. Another approach is to make the engineered cells, provide an opportunity to pro- peptides more stable and longer acting so that duce proteins in  vivo. These technologies have injections are required infrequently. Various been described in detail elsewhere (Jain 2021), strategies for delivering peptides into the CNS and their adverse effects are discussed in Chap. 11. are like approaches for delivery of proteins and applied to neurotrophic factors. The delivery of Methods of delivery of peptides for neuro- neurotrophic factors for CNS disorders involves logic disorders  Peptides regulate most physi- microencapsulation and gene therapy. ological processes, acting at some sites as For targets in the brain, delivering neuropependocrine signals and, at others, as neurotrans- tides to the site of action is problematic because mitters or growth factors. Alterations in the of the blood-brain barrier. However, polypeptides storage, release, and metabolism of neuropep- not only have the potential to serve as carriers for tides are associated with many diseases of the selective therapeutic agents, but they themselves CNS.  Various peptides native to the CNS, as may directly cross the blood-brain barrier after well as synthetic peptides and peptide analogs, delivery into the bloodstream to become potential treatments for a variety of CNS disorders, includTable 7.3  Various types of systems for drug delivery to ing neurodegeneration, autoimmune diseases, the nervous system stroke, depression, and obesity. Artificial hydroDrug delivery using novel formulations phobization of peptides can facilitate their deliv Conjugates ery across the blood-brain barrier. commonly used antiepileptic drugs are substrates. Further studies to delineate the exact role, if any, of P-glycoprotein and other efflux transporters in drug-resistant epilepsy are warranted.

 Gels  Liposomes  Microspheres  Nanoparticles Chemical delivery systems Biomaterial-based drug delivery systems Drug delivery devices  Pumps  Catheters  Implants releasing drugs  Controlled-release microchip Cell and gene therapies (see Chap. 11) Intranasal instillation for introduction into the brain along the olfactory tract Targeting of CNS by retrograde axonal transport

© Jain PharmaBiotech

Liposome-mediated drug delivery to the CNS  Liposomes have been used as nonviral vectors for gene therapy. Currently, the in vivo use of liposome particles is limited to the nanometric range, and the circulation depends on the size. Larger liposomes are cleared faster. The action of neuroactive agents (e.g., neurotrophic factors) is mostly achieved by their coupling to a receptor on the plasma membrane, causing an intracellular cascade of events. Therefore, the formulation of these molecules for delivery must allow for sustained extracellular release. Sterically stabilized liposomes,

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which are taken up by endocytosis, are unsuitable for this purpose. Because of the frequent potent nature of the neuroactive agents, sustained drug release requires extended in  vivo stability of the delivery system, which is difficult to achieve with liposomes. Therefore, liposomes are currently unsuitable for long-term administration of drugs to the nervous system unless they are adequately stabilized. Multivesicular liposomes enable encapsulation of drugs with greater efficiency, ensuring reliable, steady, and prolonged drug release. DepoDur (morphine sulfate extended-release liposome injection), an approved formulation, contains morphine for single epidural injection in the treatment of postoperative pain. Although animal studies confirm that epidural injection of DepoDur results in the sustained release of morphine into CSF, the CSF pharmacokinetics have not been determined in humans. Implantation of biodegradable microspheres  Controlled drug release in the CNS has been carried out by using implantable polymeric vectors. The biocompatibility of Poly (DL-lactide-­ co-glycolide), a biodegradable polymer, implanted into the CNS provides support for its use in a wide range of new therapeutic applications for sustained and localized drug delivery to the brain. Polymeric controlled release can provide high, localized doses of rhNGF in the brain. Microencapsulation methods allow the production of microparticles or nanoparticles loaded with neuroactive drugs. Biodegradable microspheres can be implanted stereotactically in the brain. Stereotactic procedures on the brain involve guiding a probe into discrete and precise target areas based on anatomical and functional landmarks without causing damage to the surrounding structures. Currently, this method is most frequently applied for the treatment of brain tumors and neurodegenerative disorders such as Parkinson disease. However, the potential applications of drug targeting by stereotactic implantation of drug-loaded particles are unlimited. Nanoparticles  The use of nanoparticles to deliver drugs to the brain across the blood-brain barrier

may provide a significant advantage over current strategies (Jain 2012; Silva 2010). Very small nanoparticles may simply pass through the bloodbrain barrier, but this uncontrolled passage is not desirable. Controlled passage of drugs across the blood-brain barrier can be enhanced by nanotechnology. Nanoparticles open the tight junctions between endothelial cells and enable the drug to penetrate the blood-brain barrier either in free form or together with the nanocarrier. By enabling controlled drug release in the brain, nanoparticle carrier technology decreases neurotoxicity. Various factors that influence transport include the type of polymer or ­surfactant used, nanoparticle size, and the drug molecule. Nanoparticles conjugated with specific ligands that can target receptors in the brain microvasculature can carry the drugs to the brain through the receptor-mediated transcytosis. Organically modified silica nanoparticles can be used as nonviral vectors for efficient in  vivo gene delivery without toxic effects and with efficacy equaling or exceeding that obtained by using a viral vector. Different polymer nanoparticles can be targeted to specific ligands to enhance the specificity of drugs delivered to the CNS. Glucocorticoids have shown efficacy in neuroinflammatory disorders such as multiple sclerosis. However, their side effects are dose limiting. CNS delivery of methylprednisolone across the blood-brain barrier has been enhanced by use of targeted pegylated liposomes conjugated to the brain-targeting ligand glutathione, and this method has potential for clinical development (Gaillard et al. 2012). Superparamagnetic nanoparticles used for magnetic resonance navigation, when exposed to a low radiofrequency field, release energy in the form of heat to their surroundings and temporarily open the blood-brain barrier (Tabatabaei et al. 2015). These nanoparticles can be chemically engineered to specifically target the surface of the vascular endothelium by means of adhesion antibodies. This strategy could deliver only the required drug-nanoparticle concentration at the target site and reduce side effects. Increased permeability of the blood-brain is reversible and is not associated with an increase in brain immune response.

Targeted Drug Delivery to the CNS

Chemical delivery systems  Improvements in the properties of the drugs as related to their brain specificity and prolonged effects are required. Drug targeting to specific receptors has been one of the main objectives of medicinal chemistry for several years. Chemical delivery systems consist of biologically inert molecules that enhance drug delivery to a certain organ and require several steps of chemical or enzymatic reactions. Chemical delivery systems are unique in that after reaching the brain, the dihydropyridine carrier portion of the molecule oxidizes enzymatically to give rise to a quaternary pyridinium salt. This substance, because of its hydrophilic character, is trapped in the CNS and releases the drug by hydrolysis. Pyridinium salt is rapidly excreted. The chemical delivery systems concept is a step ahead of the prodrug concept. Although prodrug is a direct chemical predecessor of the drug, it cannot solve the organ and site specificity problems. This concept has been applied to several drugs including antibiotics, neurotransmitters, anticancer drugs, antidepressants, and antiepileptic drugs. Biomaterials for local drug delivery in the central nervous system  Local drug delivery in the tissues of the central nervous system provides a solution for the problems of physiological barriers and systematic toxicity of drugs. Local drug delivery systems using biomaterials are being developed using biomaterials such as biodegradable polymers for sustained release, local parameter-­ responsible release, and regional cell-­selective active targeting release in the central nervous system (Chen et al. 2019). Cell-based drug delivery and gene therapy  Apart from their use as therapeutic agents, cells are also used as carriers of therapeutic agents for delivery, and genes are used as medicines. A special example is that of genetically engineered cells that continue to release therapeutic proteins after implantation in the body. Adverse effects of cell and gene therapy are described in Chap. 11. Controlled-release microchip  The conventional controlled drug release from polymeric materials is in response to specific stimuli such

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as electric and magnetic fields, ultrasound, light, enzymes, etc. Microchip technology has been applied to achieve pulsatile release of liquid solutions. Solid-state silicon microchips have been developed that incorporate micrometer-scale pumps and flow channels to provide controlled release of single or multiple chemical substances on demand. The release mechanism is based on the electrochemical dissolution of thin anode membranes covering microreservoirs filled with chemicals in various forms. Various amounts of chemical substances in solid, liquid, or gel form can be released either in a pulsatile or continuous manner or a combination of both. The entire device can be mounted on the tip of a small probe or implanted subcutaneously in the body. In the future, proper selection of a biocompatible material may enable the development of an autonomous controlled-release implant that has been dubbed as “pharmacy-on-a-chip” or a highly controlled tablet (“smart tablet”) for drug delivery in CNS disorders. A successful human clinical trial with an implantable, wirelessly controlled, and programmable microchip-based drug delivery device has been conducted in osteoporosis patients receiving the drug teriparatide. Drug delivery for multiple sclerosis with the same device is in preclinical development. Such a device would also be useful in the treatment of conditions such as Parkinson disease.

Targeted Drug Delivery to the CNS Drug delivery should be targeted to the desired site of action and avoid exposure of the normal tissues to the toxic effects of the drug. This is particularly important in case of anticancer drugs. An example is given of the desirable approach for chemotherapy of a malignant brain tumor.

Nanoparticle-Based Targeted Delivery of Chemotherapy Across the BBB Some of techniques used for facilitating transport of therapeutic substances across the BBB involve

7  Methods of Drug Delivery to the Nervous System and DIND

106 BBB

Blood

Brain

MAb N

R

Trojan horse approach

BBB N

Fig. 7.2  Targeted drug delivery to glioblastoma across the BBB. (© Jain PharmaBiotech) Legend. Nanoparticle (N) combined with a monoclonal antibody (MAb) for receptor (R) crosses the bloodbrain barrier (BBB) into the brain by Trojan horse

damage to the BBB, which is not desirable. Untargeted delivery would expose the normal brain tissues to the anticancer agents. Technologies based on nanoparticles enable targeted delivery of anticancer drugs across the BBB. A concept of targeted drug delivery to glioblastoma across the BBB is shown in Fig. 7.2. A limitation of this approach is specificity of receptors in target lesions. For example, if the therapy is targeted at EGFR found in glioblastoma after systemic administration, it may end up in other organs with EGFR. One strategy that is currently being pursued is to target a combination of two or more recepters in glioblastoma that are unlikely to be found in another organ or tumor.

References Anitescu M, DaSilva AN, Frim DM. Intrapleural migration of a spinal catheter in a patient with arachnoiditis and extensive epidural scarring after tethered cord release: a case report and review of literature. Neuromodulation. 2012;15(3):200–3. Arena CB, Garcia PA, Sano MB, et al. Focal blood-brain-­ barrier disruption with high-frequency pulsed electric fields. Technology. 2014;2:206–13. Atencio DC, Gachiani JM, Richter EO. Air embolus to arachnoid cyst as a rare delayed complication of

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N Cancer Cell in GBM

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the BBB by receptor-mediated transcytosis. Ligand docks on a cancer cell receptor and N delivers anticancer payload to the cancer cell in glioblastoma (GBM) intrathecal medication delivery. Neuromodulation 2012;15(1):35–8. Bauer M, Karch R, Zeitlinger M, et al. Approaching complete inhibition of P-glycoprotein at the human blood-­ brain barrier: an (R)-[11C]verapamil PET study. J Cereb Blood Flow Metab. 2015;35(5):743–6. Boado RJ, Pardridge WM.  The Trojan horse liposome technology for nonviral gene transfer across the blood-­ brain barrier. J Drug Deliv. 2011;2011:296151. Chapman CD, Frey WH 2nd, Craft S, et  al. Intranasal treatment of central nervous system dysfunction in humans. Pharm Res. 2013;30(10):2475–84. Chen JC, Li LM, Gao JQ.  Biomaterials for local drug delivery in central nervous system. Int J Pharm. 2019;560:92–100. Codipietro L, Maino P. Aseptic arachnoiditis in a patient treated with intrathecal morphine infusion: symptom resolution on switch to ziconotide. Neuromodulation. 2015;18(3):217–20. Costantino HR, Leonard AK, Brandt G, Johnson PH, Quay SC. Intranasal administration of acetylcholinesterase inhibitors. BMC Neurosci. 2008;9(Suppl 3):S6. Crowe TP, Greenlee MHW, Kanthasamy AG, Hsu WH.  Mechanism of intranasal drug delivery directly to the brain. Life Sci. 2018;195:44–52. De Andres J, Asensio-Samper JM, Fabregat-Cid G.  Intrathecal delivery of analgesics. Methods Mol Biol. 2014;1141:249–78. Ding D, Kanaly CW, Brady MW, et  al. Convection-­ enhanced drug delivery to the brain. In: Jain KK, editor. Drug delivery to the central nervous system. New York: Humana/Springer; 2010. p. 291–318. Engle MP, Vinh BP, Harun N, Koyyalagunta D. Infectious complications related to intrathecal drug delivery sys-

References tem and spinal cord stimulator system implantations at a comprehensive cancer pain center. Pain Physician. 2013;16(3):251–7. Freeman ED, Hoelzer BC, Eldrige JS, Moeschler SM.  Fibrin glue to treat spinal fluid leaks associated with intrathecal drug systems. Pain Pract. 2014;14(6):570–6. Frizon LA, Sabharwal NC, Maiti T, et  al. Removal of intrathecal catheters used in drug delivery systems. Neuromodulation. 2018;21(7):665–8. Gaillard PJ, de Boer AG. 2B-trans technology: targeted drug delivery across the blood-brain barrier. Methods Mol Biol. 2008;437:161–75. Gaillard PJ, Appeldoorn CC, Rip J, et al. Enhanced brain delivery of liposomal methylprednisolone improved therapeutic efficacy in a model of neuroinflammation. J Control Release. 2012;164(3):364–9. Gizurarson S. Anatomical and histological factors affecting intranasal drug and vaccine delivery. Curr Drug Deliv. 2012;9(6):566–82. Jain KK.  Nanobiotechnology-based strategies for crossing the blood-brain barrier. Nanomedicine. 2012;7(8):1225–33. Jain KK.  Drug delivery to the central nervous system. Basel: Jain PharmaBiotech Publications; 2021. Joshi S.  Intracarotid drug delivery. In: Jain KK, editor. Drug delivery to the central nervous system. New York: Humana/Springer; 2010. p. 155–74. Lonser RR, Sarntinoranont M, Morrison PF, Oldfield EH. Convection-enhanced delivery to the central nervous system. J Neurosurg. 2015;122(3):697–706. Malerba F, Paoletti F, Capsoni S, Cattaneo A.  Intranasal delivery of therapeutic proteins for neurological diseases. Expert Opin Drug Deliv. 2011;8(10):1277–96. Medel R, Pouratian N, Elias WJ. Catheter-tip mass mimicking a spinal epidural hematoma. J Neurosurg Spine. 2010;12(1):66–71. Morgalla M, Fortunato M, Azam A, Tatagiba M, Lepski G. High-resolution three-dimensional computed tomography for assessing complications related to intrathecal drug delivery. Pain Physician 2016;19(5):E775–80. National Academies of Sciences, Engineering, and Medicine. Enabling novel treatments for nervous system disorders by improving methods for traversing the blood-brain barrier: proceedings of a workshop. Washington, DC: The National Academies Press; 2018. Niewoehner J, Bohrmann B, Collin L, et  al. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron. 2014;81(1):49–60.

107 Omar SH, Osman R, Mamdouh W, Abdel-Bar HM, Awad GAS.  Bioinspired lipid-polysaccharide modified hybrid nanoparticles as a brain-targeted highly loaded carrier for a hydrophilic drug. Int J Biol Macromol. 2020;165(Pt A):483–94. Pardridge WM.  Targeted delivery of protein and gene medicines through the blood-brain barrier. Clin Pharmacol Ther. 2015;97(4):347–61. Patching SG. Glucose transporters at the blood-brain barrier: function, regulation and gateways for drug delivery. Mol Neurobiol. 2017;54(2):1046–77. Prager J, Deer T, Levy R, et al. Best practices for intrathecal drug delivery for pain. Neuromodulation. 2014;17(4):354–72. Ruan X, Couch JP, Liu H, Shah RV, Wang F, Chiravuri S.  Respiratory failure following delayed intrathecal morphine pump refill: a valuable but costly lesson. Pain Physician. 2010;13(4):337–41. Sellers DL, Bergen JM, Johnson RN, et al. Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration. Proc Natl Acad Sci U S A. 2016;113(9):2514–9. Sikpa D, Whittingstall L, Savard M, et al. Pharmacological modulation of blood-brain barrier permeability by kinin analogs in normal and pathologic conditions. Pharmaceuticals (Basel). 2020;13(10):E279. Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366(7):591–600. Silva GA.  Nanotechnology applications and approaches for neuroregeneration and drug delivery to the central nervous system. Ann N Y Acad Sci. 2010;1199:221–30. Tabatabaei SN, Girouard H, Carret AS, Martel S. Toward nonsystemic delivery of therapeutics across the blood-brain barrier. Nanomedicine (Lond). 2015;10(14):2129–31. Vykhodtseva N.  Disruption of blood-brain barrier by focused ultrasound for targeted drug delivery to the brain. In: Jain KK, editor. Drug delivery to the central nervous system. New  York: Humana/Springer; 2010. p. 35–62. Wong HL, Chattopadhyay N, Wu XY, Bendayan R.  Nanotechnology applications for improved delivery of antiretroviral drugs to the brain. Adv Drug Deliv Rev. 2010;62(4–5):503–17. Wong KH, Riaz MK, Xie Y, et al. Review of current strategies for delivering Alzheimer’s disease drugs across the blood-brain barrier. Int J Mol Sci. 2019;20(2):381. Yanagida K, Liu CH, Faraco G, et al. Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1. Proc Natl Acad Sci U S A. 2017;114(17):4531–6.

8

Neurological Complications of Anesthesia

Introduction Various methods of anesthesia have been applied during the evolution of medicine. The era of modern general anesthesia started in 1945 by William Morton with the administration of ether anesthesia for a general operation at the Massachusetts General Hospital, Boston (Falconer and Keys 1965). Hepatotoxicity of chloroform was recognized early, but neurologic complications of anesthesia have not been a subject of special interest until recent years. Part of the reason for this is that anesthesia is closely tied with surgery; some of the complications are difficult to attribute to anesthetics alone. However, adverse effects of anesthetics are well recognized and are more obvious with some local anesthetics. Various types of general anesthesia with the commonly used agents are as follows: • Inhalation: nitrous oxide (most widely used), halothane, enflurane, isoflurane, and sevoflurane. • Intravenous: barbiturates, benzodiazepines, propofol, and ketamine. • Narcotics: opioids, fentanyl. It has been argued that narcotics should not be classified as anesthetics because their action is subcortical rather than cortical even though loss of consciousness occurs with large doses of fentanyl.

• Muscle relaxants: depolarizing.

polarizing

and

Complications of anesthesia will be described under general anesthesia and local anesthesia. This chapter will first focus on complications of general anesthesia. Neurologic complications of local anesthesia and epidural anesthesia are described later.

Neurological Complications of General Anesthesia Most neurologic complications of general anesthesia manifesting in the postoperative period are due to CNS dysfunction and peripheral nerve injuries. Common CNS changes are cognitive impairment and delirium. Seizures are uncommon with general anesthetics, although the association with local anesthetics is well established. Myelopathies and strokes are less frequent complications. Delirium may occur in the immediate postoperative period or days later. It is characterized by impairment of consciousness, disorientation, and hallucinations. Duration is variable and may linger on for weeks. Neuromuscular blockade usually manifests as postoperative respiratory depression. A duration of neuromuscular blockade that is longer and

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_8

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more pronounced than intended would be considered a complication. Postoperative delirium usually clears up but may persist up to several weeks. Patients who develop delirium have longer hospital stays and a higher rate of major complications and of discharge to long-term care facilities. Seizures are managed easily by use of medications and do not have any significant long-term morbidity. Peripheral nerve injuries usually clear up in 90% of the patients. The prognosis of stroke depends on the mechanism and the extent of ischemic damage. Of all the various neurologic complications, myelopathy is more likely to leave permanent neurologic deficits. Prognosis for recovery of function after paraplegia is poor.

Pathomechanism of Neurologic Complications of General Anesthesia Neurologic complications of general anesthesia are shown in Table 8.1. Patients with some preexisting neurologic disorders may develop complications during anesthesia. Some examples of complications of anesthesia that may result from neurologic dysfunction or that may aggravate neurologic status are listed here: • Patients with Parkinson disease may develop dyskinesia or muscle rigidity following general anesthesia. • The potential for bulbar dysfunction and muscle weakness in patients with Kennedy disease places them at risk for perioperative complications from anesthesia. • Complications may occur in Huntington disease due to interactions between anesthetics and psychiatric medications frequently used by these patients. Measures should also be taken to reduce the risk of pulmonary aspiration following anesthesia because bulbar dysfunction may occur in Huntington disease. • Patients with muscular dystrophy may develop disease-related cardiac complications or, rarely, a malignant hyperthermia-like syndrome on exposure to inhaled anesthetics.

8  Neurological Complications of Anesthesia Table 8.1  Neurologic anesthesia

complications

of

general

(1) Preoperative  Adverse effects of premedications  Complications of endotracheal intubation and insertion of other monitoring devices    Recurrent laryngeal nerve palsy    Hypoglossal nerve paralysis (Hong and Lee 2009)  Aneurysm rupture due to gagging during intubation  Exaggerated response to neuromuscular blocking agents in neurologic disorders (2) Intraoperative  Due to anesthetic agents: e.g., malignant hyperthermia  Interaction of surgery and anesthesia: cerebral ischemia due to hypotension  Interaction of anesthetics with other drugs  Due to positioning of the patient:   Pressure palsies   Ischemic myelopathy in patients with cervical spondylosis (3) Postoperative  Cognitive disorders   Delirium   Memory disturbances  Prolonged residual sedation and drowsiness  Seizures  Stroke  Prolonged neuromuscular blockade (4) Long term  Susceptibility to develop alcohol use disorder in adulthood after exposure during adolescence

An evaluation of the adverse effects of general anesthesia requires an understanding of the effect of anesthesia on the brain. Unfortunately, there is no universally accepted definition of when the brain is anesthetized. Obviously, general anesthesia must alter neuronal functions from their normal physiological state to produce analgesia with unconsciousness. A study in fruit flies has shown that inhaled anesthetics (chloroform, isoflurane, diethyl ether, xenon, and propofol) activate TREK-1 (TWIK-­ related K+ channels) through disruption of phospholipase D2 (PLD2) localization to lipid rafts and subsequent production of signaling lipid phosphatidic acid (PA), which robustly blocks anesthetic TREK-1 currents, rendering the TRAAK channel sensitive, a channel that is otherwise insensitive to anesthetics (Pavel et  al. 2020). Results of this study establish a membrane-­

Neurological Complications of General Anesthesia

mediated target of inhaled anesthetics, which cross the blood-brain barrier, and suggest that physician assistants help set thresholds of anesthetic sensitivity in vivo to induce reversible loss of consciousness. Inactivation of structures in the limbic system, which normally participate in maintaining consciousness, potentiates the response to a general anesthetic. Both inhalational and intravenous anesthetics affect the CNS and the cardiorespiratory systems in a dose-related manner. Neuronal inhibition results in a decreasing level of consciousness and depression of the medullary vital centers, which can lead to cardiorespiratory failure.

 lcohol Use Disorder After Exposure A to General Anesthesia in Adolescence Adolescent alcohol abuse can lead to behavioral dysfunction and chronic, relapsing alcohol use disorder (AUD) in adulthood. However, not all adolescents that consume alcohol will develop an AUD; therefore, investigations are being carried out to identify neural and environmental risk factors that contribute to increases in susceptibility to AUDs following adolescent alcohol exposure. Adolescent rats exposed to isoflurane, a general anesthetic, exhibited decreases in sensitivity to negative properties of alcohol such as its aversive, hypnotic, and socially suppressive effects, as well as increases in voluntary alcohol intake and cognitive impairment (Landin et  al. 2020). Select behaviors were noted to persist into adulthood following adolescent isoflurane exposure. Similar exposure in adults had no effects on alcohol sensitivity. These findings suggest that general anesthetic exposure during adolescence may be an environmental risk factor contributing to an enhanced susceptibility to developing AUDs in an already vulnerable population.  ostoperative Cognitive Dysfunction P The brain is susceptible to anesthetic neurotoxicity at the extremes of ages. In the developing brain of the neonate, anesthetics can induce excessive apoptosis, whereas in the aging brain, subtle cognitive dysfunction can persist long after clearance of the drug.

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Postoperative cognitive dysfunction is a common complication in older adults, but its cause remains unclear. In an aged rat model of postoperative cognitive dysfunction, VEGF expression was increased in the hippocampus after isoflurane exposure, suggesting that inhalation anesthesia induces hippocampal VEGF overexpression in aged rats (Cao et al. 2019). Inhibition of VEGF significantly attenuated the isoflurane-induced cognitive deficits in the Morris water maze task, which suggests that therapeutic strategies involving VEGF should take into consideration its role in the pathogenesis of postoperative cognitive dysfunction.

 ffect on Cerebral Circulation E and Metabolism Most of the volatile anesthetic agents depress cerebral metabolism but increase cerebral blood flow to a varying extent. A disturbed coupling between regional cerebral blood flow and metabolic rate of oxygen has been observed in humans at a moderate depth of anesthesia. Propofol reduces regional cerebral blood flow and metabolic rate of oxygen comparably. Sevoflurane reduces regional cerebral blood flow less than propofol but reduces regional metabolic rate of oxygen to an extent like propofol. Despite depression of excitability of neurons, seizure complexes are frequently observed on EEG under anesthesia with enflurane. Delirium Although delirium is reported frequently after general anesthesia, randomized, controlled trials suggest that no significant difference is seen in the incidence of delirium when general anesthesia and regional anesthesia are compared. The cause of delirium after anesthesia is due to a persistence of the anesthetic agent interacting with certain risk factors, which include the following: • Preexisting cognitive disorders or brain damage • Over 70 years of age • Drug addiction • Use of concomitant medications, such as narcotics and high doses of corticosteroids

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• Use of anticholinergic premedications such as atropine • Surgical procedures associated with high risk of postoperative delirium, such as coronary artery bypass • Intraoperative disturbances such as hypoxia, acidosis, and hypoventilation • Postoperative disturbances of electrolytes, fever, and sepsis Intravenous agents, such as sodium thiopental, have a shorter duration of action and delirium. Ketamine is more likely to induce delirium accompanied by hallucinations and disorientation. Dreams and hallucinations. Dreams and hallucinations under sedation or anesthesia are well documented, e.g., with use of propofol. Sexual hallucinations may be difficult to disprove and may lead to false allegations of sexual molestation (Schneemilch et al. 2012).

Seizures Certain anesthetic agents, like enflurane, are known to induce seizures and have been used to activate epileptic foci during epilepsy surgery. EEG abnormalities following enflurane anesthesia can persist for several days after exposure, and delayed convulsions can occur. Ketamine lowers the threshold for seizures in epileptic patients. Fentanyl, an opioid used for induction of general anesthesia in patients, has been reported to induce myoclonic activity. The following are some of the explanations for abnormal motor activity following use of fentanyl: • Fentanyl represents myoclonus or clonus due to blocking of cortical inhibitory pathways that allow the lower cerebral structures to express unsuppressed excitability. • Opioid-induced motor activity represents a form of exaggerated muscle rigidity, which may sometimes resemble seizures. • Opioid-induced abnormal motor activity represents subcortical seizures, which are unlikely to be detected by surface electrodes. • In patients with complex partial seizures, fentanyl has been reported to induce cortical sei-

8  Neurological Complications of Anesthesia

zure activity from the healthy temporal lobe contralateral to the one from which seizures have been shown to arise. Factors that predispose to perioperative seizures are as follows: • Use of concomitant drugs known to predispose to seizures. • Oxygen toxicity. • Discontinuation of antiepileptic medications in the perioperative period. • Metabolic abnormalities such as hyponatremia, hypocalcemia, and hypoglycemia. • Hypothermic circulatory arrest for more than 1 hour increases the likelihood of seizures. Propofol can induce seizures in susceptible patients. Although rare, cases have been reported of abnormal movements such as myoclonus resulting from intravenous propofol anesthesia.

Stroke Cerebral ischemia may occur during general anesthesia, but perioperative strokes are more likely to occur due to embolic events. Factors that predispose patients to stroke during or after general anesthesia are the following: • A history of hypertension and heart disease. • Hypotension during general anesthesia. • Advanced age with a history of transient ischemic attacks, marked carotid stenosis, or both. • Surgical procedures under general anesthesia associated with a high risk of stroke include open heart surgery, thoracoabdominal aortic surgery, and carotid endarterectomy. Nonrandomized studies have shown that local anesthetic is associated with a significant reduction in the odds of stroke in the perioperative period following carotid endarterectomy. General anesthesia using remifentanil ­conscious sedation in carotid endarterectomy remarkably lowers the risk of intraoperative stroke as it combines advantages of both general anesthesia and local anesthesia with ease of evaluation of neurologic status (Marcucci et al. 2011). The incidence of a cerebrovascu-

Neurological Complications of General Anesthesia

lar accident during anesthesia for noncardiac nonvascular surgery is as high as 1% depending on risk factors. There is a case report of a patient who had an episode of cerebral ischemia while under general anesthesia for dental alveolar surgery (Cooke et al. 2014). • Bilateral visual loss resulting from anesthesia due to ischemic optic neuropathy associated with hypotension. • Head rotation or hypertension during intubation, which may produce vertebrobasilar ischemia. Vertebral artery dissection can occur due to abnormal neck position under anesthesia. The effect of anesthetic agents on the ischemic brain has been studied to evaluate the neuroprotective effect. The protective effect of barbiturates is believed to rest on depression of the cerebral metabolic rate.

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the aorta during some procedures, and hyperlordotic (hyperextension) position during surgery. Anterior spinal artery syndrome may occur. Inferior vena cava flow may be obstructed in this position leading to increased venous pressure in the intraspinal veins, which results in venous infarction of the spinal cord. Perioperative spinal cord stroke with paraplegia is rare, and procedures that increase the risk are aortic, lumbar disc, and scoliosis surgery. Atlantoaxial instability in patients with trauma, cervical osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and Down syndrome places them at high risk for cervical spinal cord injury during intubation and surgical positioning. Neurologic injuries during anesthesia in children with Down syndrome are rare but severe. Although the role of preoperative screening remains controversial, all children with Down syndrome undergoing surgery should be considered at risk for neurologic injury due to confirmed or undiagnosed atlantoaxial or atlantooccipital instability and should be transferred and positioned with caution (Husnudinov et  al. 2018). Children with instability should be referred for neurosurgical opinion for preoperative stabilization to mitigate perioperative risk. Subluxation of the atlantoaxial joint with impingement on the cord may lead to quadriplegia. An analysis of the American Society of Anesthesiologists Closed Claims database revealed that most cervical spinal cord injuries during general anesthesia occurred in the absence of spinal trauma, instability, or airway difficulties; spine procedures or procedures in sitting position, particularly for cervical spondylosis, were the most common cause (Hindman et  al. 2011).

 ognitive Dysfunction and Dementia C Some patients suffer transient postoperative decline in cognitive function, but they usually recover spontaneously. In one study, cognitive impairment could be objectively identified at 1 week after surgery with general anesthesia in 40% of patients, regardless of age, and this risk was reduced slightly by using loco-regional anesthesia (Pain and Laalou 2009). There is a concern that inhaled anesthetics may contribute to neurocognitive dysfunction in Alzheimer disease. Animal experimental studies indicate that inhaled anesthetics influence cognition and amyloidogenesis, but the mechanistic relationship remains unclear (Bianchi et  al. 2008). Whether long-term exposure to halothane can induce dementia has not been established. Other factors may be involved in cognitive impairment after general anesthesia. Vitamin B12 deficiency has been identified as a cause of cognitive impairment after general anesthesia using nitrous oxide with improvement followed by vitamin B12 replacement.

 eripheral Nerve Injuries P These can occur during general anesthesia; the various causative and contributing factors are as follows:

Myelopathy Myelopathy may occur due to various mechanisms. Ischemia to the spinal cord may occur from prolonged hypotension, cross clamping of

• Improper positioning of the patient during lengthy surgical procedures (most common). • Unusual stretch on the nerves in the limbs during various maneuvers.

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• Nerve ischemia due to vascular disturbances and compression. • Toxic neuropathy due to drugs. • Systemic diseases (diabetes mellitus, uremia, and atherosclerosis) predispose to the development of neuropathy in the perioperative period.

Torticollis Torticollis has been observed following head and neck surgical procedures under general anesthesia and may be due to atlantoaxial rotatory fixation. It can be detected by CT scan and treated successfully. A retrospective analysis of an intravenous remifentanil and propofol general anesthetic for craniotomy before awake functional brain mapping revealed that 3 out of 98 patients experienced intraoperative seizures (Keifer et al. 2005). Movement Disorders Prolonged neuromuscular blockade. Various causes for prolonged duration of neuromuscular weakness following anesthesia are the following: • Pseudocholinesterase normally hydrolyzes acetylcholine as well as muscle relaxants like succinylcholine and mivacurium. Therefore, in inheritable disorders such as pseudocholinesterase deficiency, there is an abnormally prolonged muscle relaxation if succinylcholine and mivacurium are administered as these drugs are not hydrolyzed. • Systemic diseases with hepatic and renal impairment lead to impaired metabolism and excretion of neuromuscular blocking agents and prolong their action. • Patients with neuromuscular diseases such as myasthenia gravis and Lambert-Eaton syndrome are at risk. • Patients with amyotrophic lateral sclerosis may show increased response to vecuronium under general anesthesia with sevoflurane. • Certain drugs such as anticholinesterases and monoamine oxidase inhibitors can decrease the activity of pseudocholinesterase and prolong neuromuscular weakness.

8  Neurological Complications of Anesthesia

Spastic Paraparesis Nitrous oxide anesthesia has been implicated in the development of myeloneuropathy. The pathomechanism is inactivation of cobalamin, the active form of vitamin B12 essential for methionine synthetase activity in the CNS and the resulting demyelination. Symptoms and signs of B12 deficiency are variable, but severe deficiency may cause serious neurologic disease, such as spastic paraparesis. Nitrous oxide anesthesia is a particular risk (Walter 2011). Cases have been reported of use of nitrous oxide leading to ataxia and walking difficulty due to dorsal column lesions demonstrated by MRI, and the patient usually recovers after discontinuing nitrous oxide inhalation. In cases with low serum B12 levels, vitamin B12 injections are helpful in recovery after discontinuation of nitrous oxide.

Prevention of Complications of General Anesthesia Prevention of complications requires proper attention to various conditions by both the anesthetists and the physicians caring for the patients. Prone position with extreme posturing of head and neck should be avoided, as this is associated with a high incidence of neurologic complications. The following measures are suggested to reduce the neurologic complications resulting from general anesthesia.

Prevention of Delirium Avoid comedications known to be associated with a high risk of delirium. Maintain adequate oxygenation, perfusion, and ventilation during anesthesia. The use of anesthetic agents (such as ketamine) in elderly subjects with brain damage and at high risk for delirium should be minimal. Prevention of Seizures The following measures have been suggested to reduce the possibilities of seizures: • Avoidance of drugs known to cause seizures. • Monitoring to detect and correct metabolic abnormalities such as hyponatremia and hypoglycemia.

Neurological Complications of General Anesthesia

• Maintenance of antiepileptic drug levels in epileptic patients. The drug may be given on the morning of surgery and as soon as the patient wakes up after surgery. If the patient is unable to take orally, it may be supplemented parenterally. • In nonepileptic patients who are suspected to be at high risk of developing perioperative seizures, consideration should be given to starting prophylactic antiepileptic therapy preoperatively. • Prolonged neuromuscular blockade. Neuromuscular monitoring is essential in the administration of nondepolarizing neuromuscular blocking agents (vecuronium) to patients with amyotrophic lateral sclerosis. • Prevention of malignant hyperthermia. Patients with neuromuscular disorders are at a high risk for developing malignant hyperthermia during general anesthesia, particularly with administration of succinylcholine and volatile anesthetics. Volatile anesthetics should be avoided in most neuromuscular disorders, and succinylcholine is contraindicated, except in myasthenia gravis. Neuromuscular function and body temperature should be monitored in such patients.

 revention of Cognitive Deficits P Due to Anesthetic Agents Cognitive deficits following cardiovascular surgery have been correlated with techniques, but a consideration should also be given to the anesthetics used. Several anesthetic agents are considered to have neuroprotective properties: propofol, isoflurane, and xenon. A comparison of the effects of propofol and fentanyl shows that propofol preserves cerebral oxygenation state estimated by jugular venous oxygenation during cardiopulmonary bypass but does not prevent postoperative cognitive dysfunction. Preclinical studies show that commonly used general anesthetics have dual effects of both neuroprotection and neurotoxicity via differential regulation of intracellular Ca(2+) homeostasis (Wei and Inan 2013). Studies in cultured cells and animals show that commonly used inhalation anesthetics may

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induce changes consistent with Alzheimer disease, e.g., beta-amyloid protein accumulation (Xie and Xu 2013). Impact of anesthetic administration on aberrant tau hyperphosphorylation as well as the subsequent development of neurofibrillary pathology and degeneration may be one of the factors in the pathogenesis of Alzheimer disease (Whittington et al. 2013). Because of the high prevalence of Alzheimer disease and frequent exposure of large populations to surgical procedures, the association between the two requires further study (Seitz et al. 2013). A prospective analysis of community-dwelling members with long-term follow-up found that exposure to anesthesia for surgery was not associated with dementia or Alzheimer disease in older adults (Aiello Bowles et al. 2016). There is still controversy about postoperative cognitive decline, and the following suggestions have been made (Hu and Xu 2016): • There is need for higher-quality prospective evidence about the relationship between exposure to anesthesia and postoperative cognitive decline, which is important for the prevention of dementia. • Patients should be informed about potential long-term cognitive sequelae when undergoing surgical procedures, and perioperative care of older adults who are at risk of ­postoperative cognitive dysfunction should be optimized. • Randomized controlled trials of perioperative therapies to prevent postoperative cognitive decline should be carried out. Patients with brain tumors are more sensitive to anesthetics than the general population and are, therefore, more likely to develop postoperative neurocognitive dysfunction. Sevoflurane or propofol combined with remifentanil is a widely used general anesthetic for neurosurgery, but neither regimen has been shown to be superior to the other in terms of neuroprotective efficacy. A prospective, single-center, randomized parallel arm equivalent clinical trial, which is registered and approved by the Chinese Clinical Trial Registry (ChiCTR-IOR-16009177), will compare the

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impacts of sevoflurane-remifentanil and propofol-­ remifentanil anesthesia on short-term postoperative neurologic function in patients with supratentorial gliomas undergoing craniotomy (Xing et al. 2020). Concomitant use of drugs that interact with anesthetic agents. Attention should be paid to drugs that are contraindicated for use during general anesthesia or require special precautions, particularly in the case of drugs with effects on the central nervous system. Monitoring of depth of anesthesia. It is important to maintain appropriate level of anesthesia required for a procedure to avoid undue depth of anesthesia. A novel automated method for assessing the depth of anesthesia extracts several features from EEG signal and applies an algorithm with accuracy of 92% for classification into awake, light, and deep- anesthesia Shalbaf et al. (2018).

Management of Neurologic Complications of Anesthesia Diagnosis Patients at risk for developing neurologic complications should have a neurologic assessment prior to anesthesia. If a patient develops neurologic complications following an operative procedure, the outline of the investigations is as follows: • Thorough review of the operative record of anesthesia and monitoring procedures. • Laboratory: hematology and biochemistry. • Neurologic examination. It should be noted that patients just recovering from anesthesia may have absent pupillary reflexes, hyperreflexia, and clonus without any neurologic basis. These changes are usually bilateral. Asymmetry of reflexes would warrant further investigation. • Neuropsychological examination, which may reveal deficits in patients who do not have gross neurologic impairment. • Basic standard neurologic investigations according to the nature of the complication. Neuroimaging studies, EEG, and lumbar puncture may be indicated.

8  Neurological Complications of Anesthesia

• Findings of animal studies indicate that isoflurane-­ induced neuronal apoptosis occurs in the developing retina and provide a basis for development of a noninvasive imaging technique to detect anesthesiainduced neurotoxicity in infants and children (Cheng et  al. 2015). It has not been established whether similar toxicity occurs in human infants. Such techniques are not yet available for clinical use.

Treatment Neurologic complications are usually detected in the recovery room as the patient starts to wake up following the procedure. However, seizures may occur during anesthesia. Treatment varies according to the manifestation. Prolonged residual sedation and drowsiness  Modafinil significantly reduces prolonged drowsiness and improves feelings of alertness and energy in postoperative patients recovering from general anesthesia. Delirium  The approach to management involves correction of hypoxia and hypoventilation in postanesthetic patients. Physostigmine can reverse delirium due to atropine, naloxone can improve cognition in narcotized patients, and flumazenil can be used to antagonize the effects of benzodiazepines. Seizures  Prevention of anesthetic drug-related seizures includes the following measures: (1) avoiding sevoflurane; (2) prophylaxis with adjunctive benzodiazepines; and (3) using EEG monitoring to detect early signs of epileptiform activity. Usually, most of the seizures are self-limiting and do not result in any sequelae. However, in patients who have undergone surgery, it is not desirable to have a convulsive movement. The management of perioperative seizures is like that of seizures due to other causes. Seizures due to an overdose of anticholinergic agent respond to physostigmine if standard anticonvulsants are not effective.

Management of Neurologic Complications of Anesthesia

Prolonged neuromuscular weakness  This may require continued mechanical ventilation or replacement of the endotracheal tube.

 nesthesia in Pregnancy and Early A Childhood In experimental studies, administration to newborn rats of a combination of drugs commonly used in pediatric anesthesia (midazolam, nitrous oxide, and isoflurane) caused widespread apoptotic degeneration in the brain with persistent learning impairment. Such studies led to questioning the safety of general anesthesia in pregnant women over the past decade. Results of a clinical study on pregnant women indicate that children exposed to anesthesia before the age of 3 had a higher relative risk of language and abstract reasoning deficits at the age of 10 than unexposed children (Ing et al. 2012). In 2017 (updated on August 3, 2018), the FDA issued an update on general anesthesia for children under 3 years of age and pregnant patients in their third trimester (https://www.fda.gov/Drugs/ DrugSafety/ucm532356.htm). Specifically, the FDA advised caution in exposures lasting more than 3 hours or with multiple procedures with cumulative exposure. The FDA has also issued new labeling requirements for these drugs, which include inhalational agents (e.g., halothane, desflurane) and intravenous sedatives (e.g., propofol, ketamine, pentobarbital). The FDA warning also states that “additional high quality research is needed to investigate the effects of repeated and prolonged anesthesia exposures in children, including vulnerable populations” (Andropoulos and Greene 2017). There is a concern about the effect of anesthetics on cognitive development in children as data from animal studies suggest that exposure to anesthetic agents during the period of rapid brain growth produces neuronal apoptosis with possible long-term functional sequelae (Yu and Liu 2013). Experimental studies in early postnatal laboratory animals have shown long-term neurologic disabilities following exposure to commonly used anesthetics, which have raised concerns about the safety of anesthetic drugs in children, particularly infants (Lei et al. 2014). A single-episode neonatal exposure to general anesthetic sevoflurane has

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a significant effect on the expression of specific miRNAs of the whole brain and the hippocampus that is both immediate, directly after neonatal treatment, and long-­lasting during adulthood (Lin et al. 2018). Thus, miRNAs are an epigenetic or molecular bridge linking general anesthetic’s effect with neurologic disability. There is suggestion of learning disabilities in some retrospective studies of children who have undergone surgical procedures under general anesthesia, but no conclusions can be drawn about the causal relationship. Prospective, randomized clinical trials are underway to answer the question of whether anesthetic use in children poses a risk to their development (Rappaport et al. 2011). One trial at Columbia University in New York will study cognitive function of children exposed to anesthetic agents within the first 3 years of life at ages 8–15 years and compare them to sibling pairs who did not have exposure to general anesthesia during surgery. The FDA collaboration SmartTots recommends undertaking large-scale clinical studies and ­ avoiding nonurgent surgical procedures requiring anesthesia in children younger than 3 years of age (Rappaport et al. 2015). A panel of experts in various pediatric surgical specialties has discussed the appropriate timing of surgery and associated exposure to anesthesia with the recommendation to adopt shorter, less risky procedures for disorders requiring neurosurgery to reduce the duration of exposure to anesthetic compounds as well as the risk of reoperation (Ko et al. 2016). The measures of minimal anesthetic exposure, maximum operative efficiency, and absolute surgical indication for an infant in the prenatal as well as postnatal period will now be supplemented with testing for neurodevelopmental injury to a child (Kolcun et  al. 2017). The FDA fully supports research on association of general anesthetic and sedative agent exposure in utero in human fetuses with postnatal neurodevelopmental outcomes (Andropoulos and Greene 2017). Findings of a retrospective review suggest that general anesthesia, induced via inhalation and maintained with volatile anesthetic via mask or supraglottic airway, is a safe and effective option for pediatric patients with Niemann-

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Pick disease type C undergoing serial intrathecal injections of 2-hydroxypropyl-beta-cyclodextrin, supporting this technique as a viable option for anesthetic care in these patients (Ulloa et al. 2020).

 dverse Effects of Local Anesthetics A on the Nervous System

Geriatric age group  A retrospective review of elderly patients above 65 years of age who underwent elective craniotomies showed that intraoperative and perioperative complications were increased in those with congestive heart failure, history of smoking, chronic steroid use, longer anesthesia time, and blood loss (Johans et  al. 2017).

 ocal Manifestations Related to Cranial L Nerves An analysis of 108 ophthalmologic complications following intraoral local anesthesia for dental procedures in 65 cases showed that the most common were those involving cranial nerves (von Arx et al. 2014). The most common complication was diplopia (39.8%), mostly resulting from paralysis of the lateral rectus muscle; others were ptosis, dilated pupil, and loss of vision. Most of these resolved within a few hours as the effect of anesthetic wore off. Temporary blindness has been reported after an inadvertent overdosage of lidocaine during a regional anesthetic procedure. Diplopia, transient unilateral loss of vision, and strabismus due to paralysis of the extrinsic muscles of the eye have been reported following block of inferior dental nerve or posterior superior alveolar nerve with local anesthetic for dental procedures (Aguado-Gil et  al. 2011). The pathomechanism of visual loss due to oral nerve block is not known, but there was partial recovery of visual function in a reported case (Ko et  al. 2015). Transient blurred vision and diplopia have been reported following a Gow-Gates mandibular block injection in dentistry, and the possible mechanisms are inadvertent intravenous injection or diffusion through tissue planes from the site of injection to the orbit (Fa et al. 2016). Diplopia, loss of vision, or ophthalmoplegia can rarely occur following inferior alveolar nerve block, which is one of the common procedures in dentistry. Cases of drooping eyelid due to paralysis of the levator palpebrae superioris muscle with acute pain and numbness in the infraorbital area on the same side as infiltration of a local anesthetic in buccal vestibule have been explained by inadvertent injection of the anesthetic solutions in the extraosseous branch of posterior superior alveolar artery through to the infraorbital artery (Scarano et al. 2018). In another case, transient diplopia was due to retro flow of local

 eurological Complications of Local N Anesthesia This section focuses on the neurologic complications of drugs used for local anesthesia as well as the procedures involved. Local anesthetics are substances that produce a reversible loss of sensation or analgesia when applied to body tissues. This is achieved by interference with nerve conduction in the peripheral nerves. Local anesthesia is used widely in most branches of medicine and is generally considered to be safer than general anesthesia. However, serious neurologic complications can occur. Use of local anesthetics is limited by their duration of action and the dose-dependent adverse effects on the cardiac and central nervous systems. Local anesthetics may cause adverse effects either by action on the nerves and muscles or neurotoxicity following systemic absorption. Local anesthetics include the following: lidocaine, ropivacaine, bupivacaine, mepivacaine, tetracaine, prilocaine, procaine, procainamide, and benzocaine. Complications may occur due to use of adjuvant agents for potentiating the effect of local anesthetics by synergism or to prolong the duration of anesthesia and limit the cumulative dose required (Swain et  al. 2017). Drugs used to potentiate the effect of local anesthetics include opioids, epinephrine, alpha-2 adrenergic antagonists, steroids, antiinflammatory drugs, midazolam, ketamine, remifentanil, and dexmedetomidine.

Adverse effects of local anesthetics involving the nervous system are shown in Table 8.2.

Neurological Complications of Local Anesthesia Table 8.2  Adverse effects of local anesthetics involving the nervous system CNS excitation manifested by: Restlessness Tremors Light-headedness Syncope Tinnitus Nausea and vomiting Slurring of speech Irrational conversation Seizures that may be followed by CNS depression CNS depression manifested by: Drowsiness Respiratory arrest Coma Complications related to peripheral and cranial nerves: Numbness and tingling in the territories of the blocked nerves Phantom limb pain Peripheral nerve palsies Cranial nerve palsies Complications associated with spinal anesthesia: Irritation of spinal nerve roots Complications of leakage of cerebrospinal fluid Cauda equina syndrome Paraplegia due to toxic or ischemic myelopathy Meningitis Epidural hematoma Effect on muscles: myonecrosis following local injection into muscles Neuroophthalmologic complications: Reduction of visual acuity following retrobulbar anesthesia Horner syndrome Extraocular muscle palsies Neurologic manifestations of systemic toxicity of local anesthetics: Numbness of the tongue and perioral region Temporary blindness Tinnitus and hearing disorders Triggering of porphyria with progressive porphyric neuropathy Hypoglycemia with coma © Jain PharmaBiotech

anesthetic agent through the inferior alveolar artery and indirectly to the ophthalmic artery paralyzing the lateral rectus muscle with recovery after 1 hour (Sargunam et al. 2019). In such cases recovery takes place spontaneously without any sequelae. Cranial nerve palsies can occur after procedures involving local anesthetic

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blocks, e.g., of branches of trigeminal nerve. Ptosis has been reported after stellate ganglion block. Facial nerve paralysis has been reported after a superficial cervical plexus block.

 ocal Manifestations Related L to Peripheral Nerves Phantom limb pain can occur following a continuous popliteal nerve block after foot surgery with alleviation and recurrence corresponding to cessation and resumption of the local anesthetic infusion. Carotid endarterectomy performed under local anesthesia may cause temporary ipsilateral vocal cord paralysis. There were no significant differences in operating time or volume or ­frequency of anesthetic administration in patients with temporary vocal cord paralysis compared with those without.  ffect of Local Anesthetics on Muscles E Local anesthetics injections in muscles for relief of muscle pain have a detrimental effect on mesenchymal stem cells, which have an important role in the treatment of degenerative disorders of muscles (Wu et al. 2018). These were in vitro studies, and in vivo studies are needed to confirm these findings.  anifestations of CNS Toxicity of Local M Anesthetics Initial symptoms of local anesthetic CNS toxicity are those of excitation, which may be manifested by restlessness and dizziness. Other manifestations are tremors, slurring of speech, and irrational conversation. This may proceed to a seizure or CNS depression. Ropivacaine is considered safer for the central nervous system, but a few published reports still implicate ropivacaine as being associated with convulsions. Seizures  Seizures are an adverse effect of an overdosage of local anesthetics and are likely to occur if the injection is made inadvertently into a blood vessel. Seizure activity following the administration of local anesthetic in pediatric dentistry is the most common adverse event, suggesting intravascular administration or a toxic dose, but there were no cases of permanent damage or fatal outcomes (Townsend et al. 2020).

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A direct correlation exists between clinical symptoms and blood levels of lidocaine: as the level increases to 8–12 mg/L, the probability of seizure also increases. Central nervous system toxicity can develop even after accidental intraarterial injection of low concentrations of local anesthetics into peripheral arteries during peripheral nerve block. Convulsions have been reported after left superior laryngeal nerve block to facilitate endotracheal intubation. The possible cause may be accidental injection of the local anesthetic into the vertebral artery. Seizures may also occur as a complication of peripheral nerve block with a local anesthetic without inadvertent blood vessel puncture. Neonatal seizures have been reported following lidocaine administration for circumcision. Apart from infiltration, local anesthetics may be given intravenously for regional anesthesia. According to a review of publications on intravenous regional anesthesia, the lowest dose of local anesthetic associated with a seizure is 1.4 mg/kg for lidocaine, 4 mg/kg for prilocaine, and 1.3 mg/ kg for bupivacaine (Guay 2009). Miscellaneous manifestations  Initiation excitation may be followed by depression of the CNS with drowsiness, respiratory arrest, and coma. Concomitant myocardial depression may produce hypotension, disturbances of cardiac rhythm, and cardiac arrest. Neurologic complications of spinal anesthesia  The most frequent complication of spinal anesthesia is spinal nerve root irritation. Cases have been reported of transient radicular irritation following intrathecal anesthesia with mepivacaine. This complication manifests from several hours to 1 day following the procedure and is characterized by sharp and bilateral radiating pain, usually involving the lower extremities. Usually no neurologic deficits arise, and the pain resolves within 1 week. Cauda equina syndrome is rare and is likely to occur with continuous spinal anesthesia through a microspinal catheter. Other complications of spinal anesthesia are due to leakage of spinal fluid through the lumbar puncture site with intracranial hypotension.

8  Neurological Complications of Anesthesia

These include headache, diplopia, and transient hearing loss. Sixth cranial nerve palsy may occur due to ischemic or traction injury (Cain et  al. 2013). The risk of developing transient neurologic symptoms after spinal anesthesia with lidocaine is significantly higher than when bupivacaine, prilocaine, or procaine is used. The prognosis of recovery from complications of local anesthesia is generally good. Recovery from seizures and transient neurologic deficits occurs within a matter of hours or days. Prognosis of neurologic deficits following spinal anesthesia is guarded, particularly in rare cases of paraplegia due to spinal cord ischemic infarction.

 athomechanism of Local Anesthetic-­ P Induced Neurologic Disorders Neurologic complications have been reported with all currently used local anesthetics. Complications may result from the local effect on nerves, the neurotoxic effect of systemic absorption, overdosage, or inadvertent injection into the circulation. Some of the complications are due to injection, which may injure the nerve directly or compress it due to the formation of a hematoma. The causes of neurologic damage associated with spinal anesthesia include the following: • Trauma of lumbar puncture with subarachnoid hemorrhage • Chemical and bacterial contamination of the local anesthetic solution • Toxic reaction to the local anesthetic Because local anesthetics act through reversible binding at sodium channels, manifestations of toxicity include central nervous system as well as cardiovascular effects. Cumulative toxicity of local anesthetics depends directly on the concentration achieved in plasma, whereas CNS toxicity depends largely on the membrane-stabilizing effect of the drug. Factors affecting plasma concentration and, thus, toxicity, include the site and rate of injection, concentration and total administered dose, absorption, degree of tissue binding, and rate of metabolism and excretion. The extent of absorption depends on tissue vascularity, sites and techniques of application, and the patient’s

Neurological Complications of Local Anesthesia

disease state. Lidocaine is eliminated mainly by the liver, and both the drug and its toxic metabolite can accumulate in congestive heart failure and liver disorders, producing neurotoxicity at low drug concentrations. Absorption from mucous membranes is usually more rapid than from subcutaneous tissues. Seizures are associated with lidocaine after topical administration for airway anesthesia for bronchoscopy. Seizures have been reported following local application of lidocaine to the oropharyngeal region and following ureteral stone manipulation with lidocaine. Complication of procedures  Examples of technical factors leading to neurologic complications are the following: • Accidental intrathecal injection of local anesthetic during trigger point injection therapy, resulting in respiratory depression and hemiplegia. • Positioning of patients. Lithotomy position during hyperbaric spinal anesthesia predisposes to neurologic complications. • Paralysis of diaphragm, due to upward migration of local anesthetic after brachial block.

Risk factors  Patients with a history of epilepsy are predisposed to seizures as an adverse effect of local anesthetics. Patients with underlying mechanical, ischemic, or metabolic neurologic derangements are considered to be at increased risk of progressive neural injury following peripheral nerve block, but axillary blockade in patients with ulnar neuropathy undergoing ulnar nerve transposition is considered to be a safe procedure. Drug interactions. Complications of local anesthetics may be enhanced by interactions with other drugs. These interactions may be pharmacokinetic or pharmacodynamic. The following pharmacokinetic interactions increase the toxicity of local anesthetics: • Calcium antagonists reduce the protein binding and increase the free fraction of local anesthetics.

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• Beta blockers decrease clearance of local anesthetics. • Pethidine (meperidine) and phenytoin increase the free fraction of bupivacaine by displacing it from plasma proteins. • Cimetidine decreases the metabolism of lidocaine, thus increasing its toxicity. • Acetazolamide prolongs the half-life of procaine. The following pharmacodynamic interactions increase the neurotoxicity of local anesthetics: • Baclofen lowers the threshold for seizures. • Flumazenil may increase the convulsive activity of bupivacaine. Most of the studies reported in the literature have used lidocaine as the prototype for examining the effects of local anesthetics on the nervous system. The main action of local anesthetics on neural tissues is a depressant effect on the conduction of nerve impulse, due to the blocking of sodium channels. Lidocaine can also close the chloride channels at the synaptic cleft; the resultant chloride ion flow hyperpolarizes the membrane and enhances synaptic transmission. Pathomechanism of local anesthetic-induced seizures. CNS toxicity of local anesthetics may be due to the depression of subcortical inhibitory control of gamma-aminobutyric acid over normally occurring excitatory activity. The convulsant effect of local anesthetics is due to an imbalance in brain activity because excitatory pathways are more resistant than are inhibitory pathways. The course of events, i.e., initial excitation of the CNS followed by depression, is explained by selective blockade of inhibitory cortical synapses by local anesthetics. One explanation of local anesthetic-induced seizures is blocking of sodium channels, which is for achieving local anesthesia but can lead to neurotoxicity when spread to the systemic circulation and central nervous system, particularly in children (Lonnqvist 2012). One theory of pathomechanisms of neurotoxicity of local anesthetics is based on Twik-related, pH-sensitive K+ channels, which generate neuronal potassium “leak” currents, membrane depolarization, and

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increased neuronal excitability (Mahajan and Derian 2019). As these channels are expressed throughout the brain, this is the suggested mechanism for seizures in this setting. Seizures have been reported after transversus abdominis plane block, which is commonly used for postcesarean section analgesia due to systemic absorption of the large amount of local anesthetic required for a successful block (Weiss et al. 2014). Pathomechanism of neurotoxicity  The toxic effect of local anesthetics on nerves has been studied. Local anesthetics precipitate nerve edema, increase endoneural nerve pressure, reduce nerve blood flow, and lead to nerve ischemia. Bupivacaine, ropivacaine, and mepivacaine are the least neurotoxic, whereas lidocaine is moderately toxic and procaine is the most damaging to the nerves. Ropivacaine promoted cell death in an in vitro study on PC12 cells as well as in animal spinal cords in a treatment group compared with a sham-operated group (Sun et  al. 2012). This study showed that ropivacaine neurotoxicity in vivo and in vitro is mediated by the Akt (protein kinase B) signaling pathway, and that may explain its adverse neurologic effects. Amitriptyline, an antidepressant sodium ion channel blocker with prolonged local anesthetic effect, produces Wallerian degeneration with destruction of nerve fibers and a hyperalgesic pain state following application to peripheral nerves. In clinical use, it has no advantage over bupivacaine regarding efficacy and should not be used as a local anesthetic. An overload of intracellular calcium is involved in the neurotoxic effect of some anesthetics. Results of a study suggest that T-type calcium channels, which lower the threshold of action potentials, may be involved in bupivacaine neurotoxicity, but specific subtypes of these channels have not yet been identified (Wen et al. 2013). An experimental study on SH-SY5Y cells has shown that nicotinamide adenine dinucleotide (NAD+) depletion contributes to bupivacaine-­ induced neurotoxicity, which is attenuated by NAD+ repletion (Zheng et al. 2013). An experimental study has shown that bupivacaine-induced

8  Neurological Complications of Anesthesia

neurotoxicity involves reactive oxygen species-­ induced mitochondrial damage and endoplasmic reticulum stress leading to apoptosis, which can be attenuated by ginkgolide B, an active component of Ginkgo biloba through its antioxidant property (Li et al. 2013).

 pidemiology of ADRs of Local E Anesthetics The exact frequency of occurrence of adverse reactions to local anesthetics is difficult to determine, as only a small fraction of these are reported to health authorities. Those published are even fewer. Local anesthetics comprised 5–10% of the cases reported to the National Adverse Anesthetics Reactions Advisory Service in the United Kingdom. More than one-fourth of all adverse reactions reported to the United Kingdom Medicines Control Agency were due to local anesthetics. An analysis of 1157 adverse reactions of local anesthetics in 721 patients, reported to the French Pharmacovigilance System, showed that 21.1% involved the nervous system (Fuzier et al. 2009). Seizures were the most frequent neurologic complications, leading to death in four cases. In the United States, systemic toxicity from the injection or overdose of local anesthetics is a rare but potentially fatal complication that occurs in less than 1 in 1000 patients (Wadlund 2017). The reported risk of permanent neurologic injury with local anesthesia is less than 5 per 10,000 cases and systemic toxicity to 1 in 10,000 cases. The most common complication of procedures performed as outpatient with local anesthesia is syncope, which occurs in 1 in 160 patients. Perineural catheters with administration of local anesthetics are used widely for the treatment of postoperative pain. If performed carefully, this procedure has a low rate of neurologic complications—less than 1 in 2000 cases. Prevention of Neurological Complications of Local Anesthesia The following measures are suggested to prevent neurological complications of local anesthesia: • Use of local anesthetics with lower risk of CNS toxicity. Levobupivacaine has similar potency to bupivacaine, but a lower risk of

Neurological Complications of Local Anesthesia

•

•

•

•

•

CNS.  A prospective randomized study has shown that ropivacaine is an alternative for deep topical anesthesia, as it has a better safety margin and lesser toxicity effect than other comparable local anesthetic agents (Kashyap et al. 2018). The use of cocaine-containing topical anesthetics is no longer recommended because of high cost and potential adverse effects; these should be replaced by noncocaine-containing topical anesthetics. Transient neurologic symptoms commonly follow lidocaine spinal anesthesia but are relatively uncommon with bupivacaine or tetracaine. The manufacturer of lidocaine recommends diluting lidocaine 5% with an equal amount of cerebrospinal fluid and limiting the dose to a maximum of 100 mg. Some of the complications of regional anesthesia for pain relief in children are procedural related to perineural infusion of local anesthetics. The success of nerve blocks can be improved, and the risks reduced through the use of nerve mapping and ultrasound. Neural injury during spinal injection of local anesthetic in the operating room can be minimized by careful patient positioning. Following a procedure under spinal anesthetic, patients should be observed closely to detect potentially treatable neurologic complications such as expanding spinal hematoma.

Ultrasound-guided nerve blocks  It is generally recognized that real-time, needle-nerve visualization during ultrasound guided nerve block can prevent nerve injury. A review of cases of neuropathy as a complication of peripheral nerve block indicates that half of these complications can be prevented by use of ultrasound-guided nerve block (Hashimoto et al. 2011). Despite this precaution, a severe brachial plexus injury has been reported after combined ultrasound and nerve stimulator-guided supraclavicular brachial plexus block (Reiss et  al. 2010). Intraneural injection during ultrasound-guided interscalene block resulted in a neurologic complication manifested by weakness and dysesthesias in the arm, which took 2 weeks to resolve (Cohen and Gray

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2010). In a case of ultrasound-guided stellate ganglion block, inadvertent intra-arterial injection of a local anesthetic agent led to a tonic-­ clonic seizure, which could be minimized under the ultrasound guidance with various protective strategies, including the determination of any prior variation, optimizing the block route, maintaining a constant probe pressure, and using saline for the test dosage (Lu et  al. 2019). This case resulted in the implementation of new protocols of the ultrasound-guided stellate ganglion block in the authors’ institution. In an open study, for ultrasound-guided stellate ganglion block for patients with postherpetic neuralgia and complex regional pain syndrome of the upper extremity, a 2 mL dosage of 0.5% mepivacaine was found to be sufficient for block, which was as successful as that achieved by conventional larger volumes of local anesthetic, but produced fewer adverse effects such as dysphagia and upper arm weakness due to a less extensive spread of the anesthetic solution (Lee et al. 2012). The American Society of Regional Anesthesia and Pain Medicine’s Practice Advisory on Neurologic Complications Associated with Regional Anesthesia and Pain Medicine offers recommendations to aid in the understanding and potential limitation of complications associated with mechanical, ischemic, or neurotoxic injury of the neuraxis or peripheral nervous system, which may arise during the practice of regional anesthesia and/or interventional pain medicine (Neal et al. 2015). It focuses on the preventive role of various monitoring technologies such as ultrasound guidance and injection pressure monitoring. New clinical recommendations focus on emerging concerns including nerve blocks in deeply sedated patients or those with preexisting neurologic disease and inflammatory neuropathies.

Diagnosis Complications of local anesthesia need to be differentiated from other causes of similar complaints. Differential diagnosis of peripheral neuropathy following local anesthesia should include consideration of other causes, although the history of local anesthetic makes the diagnosis straightforward.

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In the case of seizures, other causes that may have predisposed the patient to a seizure should be considered. These may include intracranial lesions, a history of epilepsy, or other drugs that may interact with local anesthetics to cause seizures. In the case of patients presenting with cranial nerve lesions, the possibility of a previous local anesthetic should be considered in the differential diagnosis, and the patient should be questioned regarding any procedure that may have been carried out previously. This is particularly relevant in minor procedures on the head and neck with local anesthetic infiltration. However, the possibility of a cranial nerve lesion as a complication of spinal anesthetic should also be kept in mind. A patient with neurologic complications of local anesthetics should have a blood sample examined for serum concentration of the suspected anesthetic, as well as a normal hematological examination to assess the effects of local anesthetics on platelets, leukocytes, and the morphology of erythrocytes. Blood gas analysis should be done for detection, and correction of acidosis is important in management. Cardiovascular complications may require monitoring of blood pressure and electrocardiography. An electroencephalogram may be performed as a part of the investigation of a seizure, but it does not have any value in predicting the onset of neurotoxicity prior to a seizure. Peripheral neuropathy may require electromyography and nerve conduction studies.

Management of Neurological Complications of Local Anesthetics Control of seizures is the most important part of the neurologic management of adverse reactions to local anesthetics. The following measures are useful: The patient should receive 100% oxygen. Diazepam or barbiturates should be used for the control of seizures. Intravenous suxamethonium (succinylcholine) 2 mg/kg is used to facilitate intubation. Acidosis increases the amount of unbound drug, thus increasing its toxicity. Hypoxia and hypercapnia increase cerebral blood flow and, therefore, carry more lidocaine to the brain. Correcting the acidosis and hypoxia in

8  Neurological Complications of Anesthesia

cases of lidocaine overdosage is important for seizure control. Although low-dose propofol has been recommended for the control of seizures, it should be noted that propofol has also been implicated in seizures due to general anesthetics. Lipid emulsions have been infused to reverse systemic toxicity, including seizures and cardiac arrest resulting from the administration of levobupivacaine, ropivacaine, bupivacaine, or mepivacaine. The optimal dose has not been established and risks of administering too high a dose are uncertain. Neurologic and cardiovascular symptoms associated with systemic toxicity of local anesthetics usually resolve following infusion of a lipid emulsion. Intravenous lipid infusion was also used successfully with full recovery in a case of ropivacaine-induced neurotoxicity manifested by restlessness and limb-twitching during emergence from anesthesia (Mizutani et al. 2011). Clinical trials have shown that phentolamine mesylate injection can accelerate reversal of soft tissue anesthesia and the associated functional deficits resulting from an intraoral submucosal injection of a local anesthetic containing a vasoconstrictor used for dental procedures (Hersh et al. 2008). The American Society of Regional Anesthesia and Pain Medicine has updated its algorithm on management of systemic toxicity of local anesthetics and commented that lipid emulsions may currently be underutilized (Vasques et al. 2015).

 pecial Considerations in Vulnerable S Groups Local anesthesia in patients with neurologic disorders  Peripheral regional anesthesia can be safely used in patients with spinal cord injury, multiple sclerosis, Guillain-Barre disease, neurofibromatosis, diseases of the neuromuscular junction, and Charcot-Marie-Tooth disease without neurologic complications (McSwain et al. 2014). In a single-blind study on patients undergoing transforaminal lumbar surgery, no significant difference in neurologic complications was observed between the epidural anesthesia and the local anesthesia groups (Fang et al. 2016). Patients with myasthenia gravis have historically represented a significant challenge to achiev-

Neurological Complications of Local Anesthesia

ing appropriate anesthesia and analgesia during surgical procedures. Due to the lack of fully functional acetylene choline receptors, these patients typically have abnormal reactions to neuromuscular blocking agents. They may have increased respiratory complications and prolonged need for mechanical ventilation. The stress of surgery can induce myasthenic crisis (Blichfeldt-Lauridsen and Hansen 2012). Additionally, neuromuscular blockade may be difficult to reverse if the patient is on an acetylcholinesterase inhibitor. However, this concern may be alleviated by the increased use of sugammadex, a reversal agent for the neuromuscular blockade induced by rocuronium and vecuronium, which appears to prevent residual blockade in myasthenic patients. A patient with postpolio syndrome developed cauda equina syndrome after combined spinal anesthesia and postoperative epidural analgesia (Tseng et al. 2017). Needle- or catheter-induced trauma, spinal hematoma, spinal ischemia, intraneural anesthetic injection, or infection was ruled out, leading to suspicion of neurotoxicity of bupivacaine and ropivacaine. Pregnancy  Local anesthetics can cross the placenta by diffusion and may cause fetal CNS and respiratory depression. Hypotension due to spinal anesthesia for caesarian section may reduce the uteroplacental flow and contribute to fetal hypoxia. Generally, local and regional anesthesia in pregnancy is safe and has a good safety record. However, neonatal lidocaine intoxication, with manifestations including seizures, may occur following maternal pudendal block during delivery. No evidence shows that local anesthetics have any teratogenic effect when used during the first trimester of pregnancy. Inadvertent intrathecal injection of local anesthetic has been reported in a patient undergoing epidural block for delivery and resulted in motor block of lower extremities and shortness of breath (Ting and Tsui 2014). This was successfully managed with cerebrospinal lavage using CSF exchange for an equal volume of normal saline resulting in successful delivery. Pediatrics   Local anesthetic systemic toxicity has the highest incidence in infants less

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than 6 months of age and is associated with bolus dosing and penile nerve blocks (Boretsky 2019). It is treated by securing the airway, control of seizure activity, and cardiopulmonary resuscitation if required. Administration of intralipid (intravenous lipid emulsion) should be started at the first sign of toxicity.

Neurological Complications of Epidural Anesthesia Epidural anesthesia is introduction of local anesthetic or analgesic agents in lumbar epidural space for central neuraxial block by reversible inhibition of sodium channels that enables variable and prolonged temporary interruption of neuronal signaling, including autonomic, sensory, and motor transmission. It is used alone as well as in combination with general anesthesia for surgery, postoperative pain control, obstetrics, and management of chronic pain. It is a relatively safe procedure, but neurological complications may occur. Direct neurotoxic effects of anesthetics can occur at high concentrations that are sometimes reached during epidural anesthesia. Breakdown of the blood-brain or blood-nerve barrier, such as with intraneural or subarachnoid injection, may lead to neurotoxicity at lower concentrations of local anesthetics.

Epidemiology of Neurologic Complications of Epidural Anesthesia Most studies of the frequency of neurologic complications of epidural anesthesia have been reported by anesthesiologists and range from 0 to 0.1%. Cerebral venous thrombosis is rare after epidural anesthesia, and intracranial hypotension is postulated as the cause of compensatory venous dilatation and resultant thrombosis (Yildiz et al. 2010). Most of neurologic complications are reversible, and the patients make a complete recovery. The frequency of accidental dural puncture and subarachnoid injection is estimated to be about 0.6%.

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Pathomechanism of Neurologic Complications of Epidural Anesthesia Several mechanisms play a role in neurologic complications of lumbar epidural anesthesia and analgesia. Neurologic complications of lumbar epidural anesthesia with corresponding pathomechanisms are shown in Table 8.3. Major problems related to neuraxial blocks are rare. Epidural or combined spinal and epidural techniques result in more complications than spinal procedures. Many of the neurologic complications result from accidental subarachnoid injection of anesthetic or analgesic agent. Epidural anesthesia differs from spinal anesthesia (intended subarachnoid administration of anesthetics) in that higher concentrations and volumes, and repeated injections of medications or local anesthetics, are administered. When unintended subarachnoid administration of medications occurs during intended epidural anesthesia, the higher doses of medications, the larger needle used, and the insertion of a catheter all increase the risks of neurologic complications. Inadvertent subarachnoid injection may have occurred because of migration of the catheter tip through the dura or migration from the subdural space to the subarachnoid space. Prognosis of neurologic complications of lumbar epidural anesthesia or analgesia depends on the mechanism of injury and the location and severity of the neurologic lesion. Radiculopathy  The most common complication is lumbosacral radiculopathy or polyradiculopathy, and it must be differentiated from focal neuropathy or plexopathy due to surgical positioning, childbirth, lithotomy position, or other causes unrelated to epidural anesthesia. MRI of the lumbosacral spine reveals hematomas, abscesses, or mass lesions. EMG can confirm radiculopathies. Cauda equina syndrome  Severe polyradiculopathies and cauda equina syndrome following epidural anesthesia have been associated with spinal stenosis, which is a significant risk factor. Cauda equina syndrome may have developed in these

8  Neurological Complications of Anesthesia Table 8.3  Pathomechanisms of neurologic complications of epidural anesthesia Neurologic complication Radiculopathy

Pathomechanism(s) Anesthetic neurotoxicity Nerve root trauma by injecting needle or catheter Cauda equina syndrome Accidental subarachnoid injection Neurotoxicity of anesthetic or other medication Spinal stenosis as a predisposing factor Myelopathy Arachnoiditis Epidural abscess Epidural fibrosis Epidural/subdural hematoma Ischemia due to hypotension or vasospasm Neurotoxicity of anesthetic or other medications Coma Subarachnoid injection and high spinal block Accidental dural puncture Intracranial with CSF leak hypotension and its sequelae:  Cranial nerve VI palsy  Headache  Subdural hematoma Seizures Intravascular injection of local anesthetic Bacterial meningitis External contamination due to CSF leak Guillain-Barre Delayed immune reaction syndrome © Jain PharmaBiotech

patients because of injection of fluid into a space of limited volume or the development of edema leading to compression of the spinal nerve roots. Alternatively, chronic spinal stenosis may have resulted in increased susceptibility of the nerve roots to the toxic effects of anesthetics because of breakdown of the blood-nerve barrier at that level. Because spinal stenosis may be asymptomatic, it is difficult to exclude all patients with spinal stenosis from receiving epidural anesthesia. Inadvertent subarachnoid injection has been reported to cause cauda equina syndrome, which likely resulted from toxic effects of the medication rather than mechanical injury or structural lesions. Prognosis of cauda equina syndrome depends on initial severity of neurologic deficits

Neurological Complications of Epidural Anesthesia

and the degree of axonal loss as quantified by EMG evaluation. Greater initial severity and greater axonal loss are associated with poor prognosis. Myelopathy  This is one of the most dreaded and severe complications of epidural anesthesia. Clinical presentations and causes vary, but all have in common the hallmarks of a thoracic or lumbar myelopathy, i.e., paraparesis, a sensory loss level, urinary and fecal incontinence, and loss of sexual function. Prognosis varies from near complete recovery to severe residual neurologic deficits depending on the initial severity of the lesion and reversibility of the cause. Spinal cord infarction associated with epidural anesthesia is one of the causes of acute myelopathy. Patients with paraparesis, loss of pin and temperature sensation with preservation of vibratory and proprioceptive sensation, and urinary and fecal incontinence have been found to have spinal cord infarct in the anterior spinal artery distribution. Other patients may have spinal cord infarction beyond the anterior spinal artery distribution. The pathophysiology of spinal artery occlusion or hypoperfusion is uncertain. Contributing factors may include preexisting atherosclerosis or vasculitis, anesthesia-induced hypotension, arterial vasospasm from epinephrine, or arterial compression from large volumes of injected solution in the epidural space. Acute myelopathy can occur following complete spinal block. Inadvertent subarachnoid injection may occur from one of two mechanisms: (1) the catheter may migrate from the epidural space through a previously punctured dura; or (2) the catheter may have been in the subdural space initially, with subsequent migration into the subarachnoid space. Subdural injection may occur during intended epidural anesthesia. Patients under general anesthesia are at particular risk for unintended subarachnoid injection because they cannot be monitored for progressive spinal block. After recovering from complete spinal block, usually within a day, patients awaken with a myelopathy. The likely mechanism of myelopathy is direct toxicity from high doses of anesthetic agent within the subarachnoid space.

127

Spinal cord compression from a hematoma can present either acutely or subacutely. Epidural and subdural hematomas occur most frequently in patients who are anticoagulated or in those with a coagulopathy. However, hematomas have also occurred in patients without any obvious bleeding (Horlocker et al. 2018). The mechanism of bleeding is presumably from puncture of venous blood vessels in the epidural space or dura. Arterial bleeding is unlikely given the paucity of and lateral location of arteries within the epidural space. Epidural or subdural spinal hematoma is a medical emergency that requires immediate MRI or CT and appropriate medical (e.g., steroids) and surgical intervention. Despite reports of hematomas associated with anticoagulation and antiplatelet therapy, studies suggest that the frequencies of bleeding complications from epidural anesthesia are low in patients receiving low molecular weight heparin, preoperative antiplatelet therapy, or anticoagulation following placement of the catheter. Epidural abscess constitutes another cause of myelopathy associated with epidural anesthesia. With improved aseptic techniques, infectious complications from epidural anesthesia are relatively rare. Patients present acutely or subacutely with fever, back pain, local tenderness, and neurologic symptoms and signs of myelopathy or cauda equina syndrome. The mechanism of infection may be from external contamination or hematogenous source. An epidural abscess is a medical emergency, and its suspicion requires immediate MRI, antibiotics, and possibly medical and surgical intervention for spinal cord compression. Chronic progressive myelopathy can be due to arachnoiditis associated with epidural anesthesia. Pathomechanisms include dural puncture and leaking of epidural anesthetics into the subarachnoid space, contamination of the injected solution with detergent, or meningeal reaction from the anesthetic agent or epinephrine. Progressive epidural fibrosis leading to spinal cord compression has been reported in patients receiving long-term epidural morphine. Epidural fibrosis may result from a chronic reaction to the catheter or morphine.

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8  Neurological Complications of Anesthesia

Coma  Unintended subarachnoid injection may result in high spinal block, coma, or cardiopulmonary arrest. Patients are frequently undergoing simultaneous epidural and general anesthesia and cannot be monitored for high spinal block. Patients with complete spinal block usually regain consciousness within a few hours, but this may take longer.

It can be prevented by aspiration of the catheter for blood and injection of a test dose that includes epinephrine. Intravascular injection of epinephrine causes rapid onset of tachycardia. Despite these precautions, intravascular injection of high doses of anesthetic has been reported and can cause seizures, which may respond rapidly to diazepam.

Headache  A variety of intracranial abnormalities are associated with epidural anesthesia. Postdural puncture headache is an occasional complication. In a study, the frequency of headache following inadvertent dural puncture was 0.6% of epidural anesthesia procedures, and, of those, 16% developed headache. Patients with postdural puncture develop symptoms of a lowpressure postural headache like that of postlumbar puncture headache. Treatment includes hydration, caffeine, or epidural blood patch. Rarely, the process of injecting air after entering the epidural space can be complicated by inadvertent injection of air into the subarachnoid space, leading to pneumocephalus and headache.

Guillain-Barre syndrome  Guillain-Barre syndrome is a rare complication that may appear in patients 1–2 weeks after epidural anesthesia (Steiner et al. 1986). Patients may be at risk for Guillain-Barre syndrome because of interaction between the anesthetic and myelin or nerve trauma from the needle or catheter leading to immunological processes that result in the neuropathy (Steiner et al. 1986). Of the four reported patients, all had complete or near-complete recovery in 1–12 months.

Intracranial hypotension  Besides the more common complication of headache following inadvertent dural puncture, other complications of intracranial hypotension have been reported. Several patients have developed intracranial subdural hematomas from low CSF pressure. Sixth cranial nerve palsies have been reported to develop following dural puncture, presumably from intracranial hypotension, shifts in the brain, and subsequent stretching of the nerve. Prognoses for these disorders are generally good. Cranial nerve palsy as a complication of epidural anesthesia is rare. When it occurs, it is often due to unintended dural puncture, often unilateral, and because of its long intracranial course, sixth nerve palsy is most common. It can occur in as early as a day after epidural anesthesia or might take as long as 3 weeks. Spontaneous recovery is the rule. Seizure  Inadvertent intravascular injection of anesthetics during attempted epidural anesthesia is a known complication that can cause a seizure.

Postural hypotension  Epidural analgesia provides excellent pain relief in thoracic and abdominal surgery. Single-injection subcostal transversus abdominis plane (TAP) block is more effective than intravenous opioid analgesia, whereas continuous thoracic epidural analgesia is more effective than the single-injection subcostal TAP block (Wu et  al. 2013). But a well-known complication includes postural hypotension, which can delay mobilization in the postoperative period.

 afety of Epidural Anesthesia S in Special Populations  pidural Anesthesia in Pregnant E Patients Neurologic complications of epidural anesthesia have been reported in pregnant as well as nonpregnant patients, but they are less severe and long-lasting in the pregnant group. The more severe neurologic complications in the nonpregnant group may be due to inclusion of elderly patients who are more likely to have preexisting neurologic disorders that may make them more susceptible to severe complications. Moreover,

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 pidural Anesthesia in Myasthenia E Gravis The use of epidural anesthesia or combined anesthesia in this population is widely accepted and has been shown to decrease the need for mechanical ventilation in patients undergoing elective thymectomy (Chigurupati et al. 2018), decrease the postoperative time to extubation (Liu et  al. 2015), and decrease postoperative opioid consumption. Finally, pregnancy and labor are an important consideration in this population. Although many patients with optimal disease control will have no additional issues in the peripartum period, there is an increased incidence of caesarean section in myasthenic patients. This is thought to be due to maternal fatigue during labor, which can be ameliorated by lumbar epidural anesthesia (Farrugia and Goodfellow 2020; Tsurane et al. 2019).

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130 Hu X, Xu G. Does anesthesia cause postoperative cognitive decline? Med Princ Pract. 2016;25(5):497. Husnudinov RE, Ibrahim GM, Propst EJ, Wolter NE.  Iatrogenic neurological injury in children with trisomy 21. Int J Pediatr Otorhinolaryngol. 2018;114:36–43. Ing C, DiMaggio C, Whitehouse A, et  al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130(3):e476–85. Johans SJ, Garst JR, Burkett DJ, et  al. Identification of preoperative and intraoperative risk factors for complications in the elderly undergoing elective craniotomy. World Neurosurg. 2017;107:216–25. Kashyap A, Varshney R, Titiyal GS, Sinha AK. Comparison between ropivacaine and bupivacaine in deep topical fornix nerve block anesthesia in patients undergoing cataract surgery by phacoemulsification. Indian J Ophthalmol. 2018;66(9):1268–71. Keifer JC, Dentchev D, Little K, et  al. A retrospective analysis of a remifentanil/propofol general anesthetic for craniotomy before awake functional brain mapping. Anesth Analg. 2005;101(2):502–8. Ko IC, Park KS, Shin JM, Baik JS. Visual loss after intraoral local anesthesia for the removal of circumzygomatic and circum-mandibular wires: a case report. J Oral Maxillofac Surg. 2015;73(10):1918. Ko RR, Pinyavat T, Stylianos S, et al. Optimal timing of surgical procedures in pediatric patients. J Neurosurg Anesthesiol. 2016;28(4):395–9. Kolcun JPG, Chang KH, Wang MY.  Food and Drug Administration issues warning of neurodevelopmental risks with general anesthesia. Neurosurgery. 2017;81(1):N10. Landin JD, Gore-Langton JK, Varlinskaya EI, Spear LP, Werner DF. General anesthetic exposure during early adolescence persistently alters ethanol responses. Alcohol Clin Exp Res. 2020;44(3):611–9. Lee MH, Kim KY, Song JH, et  al. Minimal volume of local anesthetic required for an ultrasound-guided SGB. Pain Med. 2012;13(11):1381–8. Lei SY, Hache M, Loepke AW.  Clinical research into anesthetic neurotoxicity: does anesthesia cause ­neurological abnormalities in humans? J Neurosurg Anesthesiol. 2014;26(4):349–57. Li L, Zhang QG, Lai LY, et  al. Neuroprotective effect of ginkgolide B on bupivacaine-induced apoptosis in SH-SY5Y cells. Oxidative Med Cell Longev. 2013;2013:159864. Lin D, Liu J, Hu Z, Cottrell JE, Kass IS. Neonatal anesthesia exposure impacts brain microRNAs and their associated neurodevelopmental processes. Sci Rep. 2018;8(1):10656. Liu XZ, Wei CW, Wang HY, et  al. Effects of general-­ epidural anaesthesia on haemodynamics in patients with myasthenia gravis. West Indian Med J. 2015;64(2):99–103. Lonnqvist PA. Toxicity of local anesthetic drugs: a pediatric perspective. Paediatr Anaesth. 2012;22(1):39–43.

8  Neurological Complications of Anesthesia Lu F, Tian J, Dong J, Zhang K. Tonic-clonic seizure during the ultrasound-guided stellate ganglion block because of an injection into an unrecognized variant vertebral artery: a case report. Medicine (Baltimore). 2019;98(48):e18168. Mahajan A, Derian A. Local anesthetic toxicity. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019. Marcucci G, Siani A, Accrocca F, et  al. Preserved consciousness in general anesthesia during carotid endarterectomy: a six-year experience. Interact Cardiovasc Thorac Surg. 2011;13(6):601–5. McSwain JR, Doty JW, Wilson SH. Regional anesthesia in patients with pre-existing neurologic disease. Curr Opin Anaesthesiol. 2014;27(5):538–43. Mizutani K, Oda Y, Sato H.  Successful treatment of ropivacaine-induced central nervous system toxicity by use of lipid emulsion: effect on total and unbound plasma fractions. J Anesth. 2011;25(3):442–5. Neal JM, Barrington MJ, Brull R, et al. The second ASRA practice advisory on neurologic complications associated with regional anesthesia and pain medicine: executive summary 2015. Reg Anesth Pain Med. 2015;40(5):401–30. Pain L, Laalou FZ. Postanesthesia cognitive dysfunction. Presse Med. 2009;38(11):1597–606. Pavel MA, Petersen EN, Wang H, Lerner RA, Hansen SB. Studies on the mechanism of general anesthesia. Proc Natl Acad Sci U S A. 2020;117(24):13757–66. Rappaport B, Mellon RD, Simone A, Woodcock J. Defining safe use of anesthesia in children. N Engl J Med. 2011;364(15):1387–90. Rappaport BA, Suresh S, Hertz S, Evers AS, Orser BA.  Anesthetic neurotoxicity--clinical implications of animal models. N Engl J Med. 2015;372(9):796–7. Reiss W, Kurapati S, Shariat A, Hadzic A.  Nerve injury complicating ultrasound/electrostimulation-guided supraclavicular brachial plexus block. Reg Anesth Pain Med. 2010;35(4):400–1. Sargunam ED, Ganesan A, Chandrasekaran D, Siroraj PA.  Transient diplopia: a loco regional complication of inferior alveolar nerve block. Indian J Dent Res. 2019;30(4):639–42. Scarano A, Sinjari B, Lorusso F, Mortellaro C, D'Ovidio C, Carinci F.  Intense, instantaneous, and shooting pain during local anesthesia for implant surgery. J Craniofac Surg. 2018;29(8):2287–90. Schneemilch C, Schiltz K, Meinshausen E, Hachenberg T.  Sexual hallucinations and dreams under anesthesia and sedation: medicolegal aspects. [Article in German]. Anaesthesist. 2012;61(3):234–41. Seitz DP, Reimer CL, Siddiqui N. A review of epidemiological evidence for general anesthesia as a risk factor for Alzheimer's disease. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013;47:122–7. Shalbaf A, Saffar M, Sleigh JW, Shalbaf R.  Monitoring the depth of anesthesia using a new adaptive neurofuzzy system. IEEE J Biomed Health Inform. 2018;22(3):671–7.

References Steiner I, Wirguin I, Abramsky O. Appearance of GuillainBarre syndrome in patients during corticosteroid treatment. J Neurol. 1986;233:221–3. Sun Z, Liu H, Guo Q, Xu X, Zhang Z, Wang N. In vivo and in vitro evidence of the neurotoxic effects of ropivacaine: the role of the Akt signaling pathway. Mol Med Rep. 2012;6(6):1455–9. Swain A, Nag DS, Sahu S, Samaddar DP.  Adjuvants to local anesthetics: current understanding and future trends. World J Clin Cases. 2017;5(8):307–23. PMID 28868303. Ting HY, Tsui BC.  Reversal of high spinal anesthesia with cerebrospinal lavage after inadvertent intrathecal injection of local anesthetic in an obstetric patient. Can J Anaesth. 2014;61(11):1004–7. Townsend JA, Spiller H, Hammersmith K, Casamassimo PS.  Dental local anesthesia-related pediatric cases reported to U.S. Poison Control Centers. Pediatr Dent. 2020;42(2):116–22. Tseng WC, Wu ZF, Liaw WJ, Hwa SY, Hung NK.  A patient with postpolio syndrome developed cauda equina syndrome after neuraxial anesthesia: a case report. J Clin Anesth. 2017;37:49–51. Tsurane K, Tanabe S, Miyasaka N, et al. Management of labor and delivery in myasthenia gravis: a new protocol. J Obstet Gynaecol Res. 2019;45(5):974–80. Ulloa ML, Froyshteter AB, Kret LN, et  al. Anesthetic management of pediatric patients with Niemann-­ Pick disease type C for intrathecal 2-hydroxypropyl-­ β-cyclodextrin injection. Paediatr Anaesth. 2020;30(7):766–72. Vasques F, Behr AU, Weinberg G, Ori C, Di Gregorio G.  A review of local anesthetic systemic toxicity cases since publication of the American Society of Regional Anesthesia recommendations: to whom it may concern. Reg Anesth Pain Med. 2015;40(6):698–705. von Arx T, Lozanoff S, Zinkernagel M. Ophthalmologic complications after intraoral local anesthesia. Swiss Dent J. 2014;124(7–8):784–806. Wadlund DL. Local anesthetic systemic toxicity. AORN J. 2017;106(5):367–77.

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9

Neurological Complications of Cancer Therapies

Introduction Use of anticancer therapies is expanding and becoming increasingly more aggressive. Use of colony growth factor stimulating agents such as filgrastim counteracts hematological toxicity such as granulocytopenia; higher doses of anticancer agents can be used but have neurotoxic effect. Prolonged survival of patients and longer duration of anticancer therapy increase the exposure to neurotoxic effects that need to be distinguished from metastatic spread, recurrence of cancer, adverse effects of concomitant radiotherapy, and remote effects of cancer manifesting as neoplastic syndromes. In addition to conventional anticancer agents, novel therapies such as small molecule tyrosine kinase inhibitors, immunotherapy, CAR-T cell therapy, and various monoclonal antibodies (MAbs) are being used and have been associated with neurologic complications (Ly and Arrillaga-Romany 2018; Zukas and Schiff 2018). Moreover, some anticancer agents are used for the treatment of neurological disorders other than cancer.

Pathomechanism of Neurological Complications of Anticancer Drugs Neurological complications may be due to the direct toxic effects of the drug on the nervous system or secondary to metabolic derange-

ments, inflammatory responses, or cerebrovascular disorders induced by the drugs. Manifestations of toxic effects may be encephalopathy, seizures, cognitive impairment, cerebellar disorders, myelopathy, cranial neuropathies, and peripheral neuropathies. Anticancer therapies are also included in the chapters dealing with drug-­induced disorders with these manifestations.

Peripheral Neuropathies Anticancer drugs that can induce a peripheral neuropathy are listed in Table 9.1 A typical example of this neurologic complication is cisplatin ganglionopathy affecting predominantly large diameter sensory neurons, and symptoms result from injury to the dorsal root ganglion. There is marked individual susceptibility to the development of cisplatin-induced neuropathies. It is characterized by subacute development of nonpainful numbness and paresthesias in the extremities. Symptoms usually begin in the toes and then spread to the fingers and then, in ascending fashion, affect the proximal legs and arms. Proprioception is impaired and reflexes are lost, but pinprick sensation, temperature sensation, and power are often spared. Nerve conduction studies show decreased amplitude of sensory action potentials and prolonged sensory latencies consistent with a sensory

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_9

133

134 Table 9.1  Anticancer drugs that can induce a peripheral neuropathy 5-Azacytidine 5-FU Bortezomib Capecitabine Carboplatin Cetuximab Cisplatin Cytosine arabinoside Docetaxel Etoposide Gemcitabine Hexamethylmelamine Ifosfamide Interferon-alpha Ipilimumab Misonidazole Nelarabine Nivolumab Oprelvekin Oxaliplatin Paclitaxel Pembrolizumab Pemetrexed Procarbazine Purine analogs (fludarabine, cladribine, pentostatin) Sorafenib Sunitinib malate Suramin Taxanes Teniposide (VM-26) Thalidomide Tumor necrosis factor Vinca alkaloids Zarnestra © Jain PharmaBiotech

a­ xonopathy. Sural nerve biopsy may show both demyelination and axonal loss. The main differential diagnoses include paraneoplastic neuropathies and neuropathies associated with autoimmune disorders such as Sjögren syndrome. Paraneoplastic neuropathies tend to involve all sensory fibers and progress despite discontinuation of cisplatin. Some patients test positive for antineuronal antibodies (anti-Hu) in serum. Patients with autoimmune neuropathies often have clinical features of the underlying connective tissue disease, and autoimmune antibodies are usually present in the serum.

9  Neurological Complications of Cancer Therapies Table 9.2  Anticancer drugs that can induce a cranial neuropathy BCNU CAR-T cell therapy Cisplatin Cytosine arabinoside Ifosfamide Methotrexate Nelarabine Vincristine © Jain PharmaBiotech

Cranial Neuropathies Anticancer drugs that can induce a cranial neuropathy are listed in Table 9.2. Cisplatin may cause ototoxicity, leading to high-frequency sensorineural hearing loss as well as tinnitus due to peripheral receptor (hair) loss in the organ of Corti and is related to dose (see Chap. 25). Audiometric hearing loss is present in 74–88% of patients receiving cisplatin, and symptomatic hearing loss occurs in 16–20% of patients. Cranial irradiation probably increases the likelihood of significant hearing loss. The hearing loss tends to be worse in children, although they have a slightly greater ability to improve after the drug has been stopped. Cisplatin may also cause a vestibulopathy, resulting in ataxia and vertigo. It may or may not be associated with hearing loss. Previous use of aminoglycosides may exacerbate the vestibulopathy. Intra-arterial infusion of cisplatin for head and neck cancer produces cranial palsies in a small percentage of patients. Intracarotid infusion of cisplatin may also cause ocular toxicity, although these complications may also rarely occur after intravenous administration of the drug (see Chap. 26). They include retinopathy, papilledema, optic neuritis, and disturbed color perception due to dysfunction of retinal cones. Other complications of intra-arterial cisplatin include headaches, confusion, and seizures. CNS complications are rare with vincristine as it poorly penetrates the blood-brain barrier. However, cranial neuropathies may occasionally be seen with vincristine. The most common nerve to be involved is the oculomotor nerve, resulting

Pathomechanism of Neurological Complications of Anticancer Drugs

in ptosis and ophthalmoplegia. Other nerves that may be involved include the recurrent laryngeal nerve, optic nerve, facial nerve, and the auditory vestibular system. Vincristine may also cause retinal damage.

Myelotoxicity Myelotoxicity, characterized by paresthesias in the upper back and extremities with neck flexion (Lhermitte sign), is seen in 20–40% of patients receiving cisplatin. Patients tend to develop this symptom after several weeks or months of treatment with anticancer therapies listed in Table 9.3. Neurologic examination and MRI scans are usually normal, and the Lhermitte sign usually resolves spontaneously several months after the drug has been discontinued. It is due to transient demyelination of the posterior columns or from Wallerian degeneration of the central projections of the dorsal root ganglion (Jongen et al. 2015). A true myelopathy is very rare. For example, transverse myelopathy, a complication of intrathecal methotrexate, is characterized by back or leg pain followed by paraplegia, sensory loss, and sphincter dysfunction. The symptoms usually occur within an hour after treatment but may be characterized by a delayed onset up to several weeks after treatment. Most of cases show clinical improvement, but the extent of recovery is variable. This complication is more common in patients receiving concurrent radiotherapy or frequent treatments of intrathecal methotrexate.

Encephalopathy Anticancer therapies listed in Table  9.4 may induce encephalopathy, possibly associated with seizures and focal neurologic symptoms, including cortical blindness. Encephalopathy is associated with reversible abnormalities in the white matter of the occipital, parietal, and frontal lobes and clinically resembles the reversible posterior leukoencephalopathy syndrome. Encephalopathy is less serious Table 9.4  Anticancer encephalopathy

Cisplatin Cladaribine Corticosteroids Cytosine arabinoside Docetaxel Doxorubicin DFMO Fludarabine Interferon alpha Methotrexate Mitoxantrone Taxotere Thiotepa Vincristine

5-Azacytidine Asparaginase BCNU CAR T cell therapy Chlorambucil Cisplatin Corticosteroids Cyclophosphamide Cytosine arabinoside Dacarbazine Doxorubicin Etoposide Fludarabine 5-Fluorouracil Gemcitabine Hexamethylmelamine Hydroxyurea Ibritumomab Ifosfamide Imatinib Interferons Interleukins 1 and 2 Larotrectinib Mechlorethamine Methotrexate Misonidazole Mitomycin C Nelarabine Paclitaxel Pentostatin Procarbazine Sunitinib malate Suramin Tamoxifen Thalidomide Thiotepa Tumor necrosis factor Vinca alkaloids Zarnestra

© Jain PharmaBiotech

© Jain PharmaBiotech

Table 9.3  Anticancer myelotoxicity

therapies

associated

with

135

therapies

associated

with

9  Neurological Complications of Cancer Therapies

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than leukoencephalopathy with white matter lesions. It should be differentiated from a metabolic encephalopathy that may result from water intoxication caused by prehydration or from renal impairment, hypomagnesemia, hypocalcemia, and syndrome of inappropriate secretion of antidiuretic hormone that may follow treatment with cisplatin.

Leukoencephalopathy Anticancer therapies that cause leukoencephalopathy are listed in Table 9.5. Leukoencephalopathy is a major delayed complication of methotrexate therapy (Dietrich and Klein 2014). Although this syndrome may be produced by intrathecal or high-dose systemic methotrexate alone, it is exacerbated by radiotherapy, especially if radiotherapy is administered before or during methotrexate therapy. The clinical features are characterized by the gradual development of cognitive impairment months or years after treatment with methotrexate. The clinical picture ranges from mild learning disabilities to severe progressive dementia associated with somnolence, seizures, ataxia, and hemiparesis. CT and MRI scans show cerebral atrophy and diffuse white matter lesions. Pathologic lesions range from loss of oligodendrocytes and gliosis to a necrotizing leukoencephalopathy. The clinical course is variable. Many patients stabilize or improve after discontinuation of methotrexate, Table 9.5  Anticancer leukoencephalopathy 5-Fluorouracil Bevacizumab Capecitabine Cisplatin Cytosine arabinoside Cyclosporine-A G-CSF/GM-CSF Ipilimumab Methotrexate Nelarabine Oxaliplatin Sorafenib Sunitinib malate Vinca alkaloids © Jain PharmaBiotech

therapies

that

cause

but the course is progressive in some patients and may result in death. No effective treatment is available. The cause of leukoencephalopathy is poorly understood. Studies from mouse models suggest that methotrexate activates microglia and astrocytes in white matter, which ultimately depletes myelin-forming cells, resulting in a ­persistent deficit in myelination (Gibson et  al. 2019). Studies also suggest that genetic polymorphisms for methionine metabolism, which is required for myelination, may constitute a risk factor for methotrexate-associated neurotoxicity (Muller et al. 2008). It is likely that cranial irradiation either potentiates the toxic effects of methotrexate or disrupts the blood-brain barrier, allowing high concentrations of methotrexate to enter the brain parenchyma. It is also seen after high-dose intravenous methotrexate chemotherapy.

Cerebellar Neurotoxicity Anticancer therapies that cause acute cerebellar syndromes are listed in Table 9.6. The neurologic toxicity of 5-FU, the original fluoropyrimidine, including an ataxic cerebellar syndrome is well known. Capecitabine, an oral prodrug of 5-F, was designed to reduce toxicity by enabling selective activation in tumor tissues, but a few cases are still reported (Gounaris and Ahmad 2010). It is extensively used to treat many solid tumors, particularly breast and colorectal cancers. Neurotoxicity of capecitabine has been reported as peripheral neuropathy, cerebellar syndrome, and multifocal leukoencephalopathy. Table 9.6  Anticancer therapies that cause acute cerebellar syndromes Cytosine arabinoside 5-Fluorouracil (5-FU) Hexamethylmelamine Ifosfamide Interleukin-2 Methotrexate (intrathecal) Procarbazine Tamoxifen Thalidomide Vinca alkaloids Zarnestra © Jain PharmaBiotech

Neurological Complications of Biological Therapies for Cancer

Although very little is known about the pathogenetic mechanisms responsible for this toxicity, dihydropyrimidine dehydrogenase (DPD) deficiency has been found in few of these patients. Polymorphism of TYMS gene, which encodes for the human thymidylate synthase, plays a role in neurotoxicity and efficacy of 5-FU and capecitabine. A patient with metastatic colorectal cancer undergoing chemotherapy consisting of oxaliplatin and capecitabine was reported to develop acute cerebellar syndrome during cycle 5 (Saif 2019). MRI did not show any abnormalities. Pharmacogenetic studies related to capecitabine showed that DPD gene mutation analysis was negative for the IVS14+1G>A mutation in the DPD gene, which accounts for 50% of the DPD deficiency alleles. However, the patient was found to have 3RG/3RC genotype and Del/Del genotype of TYMS 3'-untranslated region. Withdrawal of capecitabine improved neurotoxicity within two weeks. Cerebellar toxicity is also a known potential adverse effect of high-dose cytarabine chemotherapy.

Cerebrovascular Disorders Anticancer therapies that produce cerebrovascular disorders are listed in Table 9.7. Table 9.7  Anticancer therapies associated with cerebrovascular disorders 5-Fluorouracil (5-FU) BCNU Bevacizumab Bleomycin Carboplatin Cisplatin Danazol Doxorubicin Erlotinib Erythropoietin Estramustine Imatinib mesylate Interleukin L-Asparaginase Methotrexate Mitomycin Nelarabine Sorafenib Tamoxifen © Jain PharmaBiotech

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Ischemic as well as hemorrhagic stroke is important complications of cancer or its treatment. No well-planned prospective studies about other causes of cerebral thrombosis in cancer are available, although various case reports related to chemotherapy have been published. L-Asparaginase, cisplatin, 5-FU, and methotrexate are anticancer agents which are more often reported to relate to stroke. The mechanisms by which antineoplastic agents may lead to stroke include endothelium toxicity and abnormalities of coagulation factors (Saynak et al. 2008). Reperfusion therapy is being given successfully to patients with stroke complicating cancer. Hemorrhagic stroke may occur with metastatic disease to the brain, coagulopathies from cancer, in particular leukemia, or as complications of chemotherapy. Ischemic stroke also may be a complication of metastatic disease with local invasion of vessels, a prothrombotic disorder such as nonbacterial thrombotic endocarditis or disseminated intravascular coagulation, or secondary to chemotherapy. Stroke also is a potential consequence of radiation therapy to the head and neck. Venous sinus thrombosis may develop with hematologic malignancies or chemotherapy. Although many patients will have a history of cancer at the time of stroke, a cerebrovascular event may be the initial manifestation of a malignancy (Adams Jr. 2019).

Neurological Complications of Biological Therapies for Cancer Neurological complications of biotechnology-­ based (biological) therapies are described in Chap. 10. Cancer is an important area of application of biological therapies, and their complications are described here.

Alpha Interferon This is less frequently used therapeutically for hairy cell leukemia, Kaposi sarcoma, melanoma, and myeloma. Systemic toxicities include flulike symptoms and myelosuppression. Neurotoxicity tends to be dose-related. It is generally mild when

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low doses of alpha-interferon are used as adjuvant therapy in patients with malignant melanoma. At higher doses, alpha-interferon can cause headaches, confusion, lethargy, hallucinations, and seizures. These are usually reversible, but occasionally a permanent dementia or a persistent vegetative state may result. Rarely, alpha interferon has been associated with oculomotor palsy, sensorimotor neuropathy, myasthenia gravis, brachial plexopathy, and polyradiculopathy. A high incidence of neuropsychiatric toxicity has been noted in patients treated with recombinant interferon alpha-2b for chronic myelogenous leukemia. All patients recovered on withdrawal of interferon alpha-2b. Patients with a psychiatric history were more likely to develop severe neuropsychiatric toxicity than patients without a psychiatric history.

9  Neurological Complications of Cancer Therapies

Erythropoietin  This is used to stimulate red cell production. Some patients may experience fatigue, dizziness, and paresthesias, but serious neurologic complications have not been described. With long-term administration, erythropoietin has rarely been associated with hypertensive encephalopathy and seizures. Oprelvekin  This is a recombinant platelet growth factor used to prevent severe chemotherapy-­ induced thrombocytopenia and for platelet transfusion following myelosuppressive chemotherapy. Neurologic complications are uncommon, but some patients complain of headaches, dizziness, insomnia, and paresthesias.

Monoclonal Antibodies Bevacizumab  This is a monoclonal antibody directed against vascular endothelial growth Interleukin-2 factor. It is used in combination with chemoIL-2 has been used alone and in combination therapy in patients with colorectal, breast, and with lymphokine-activated killer cells and tumor-­ non-small cell lung cancer. There have been infiltrating lymphocytes in the treatment of sev- reports of syncope, hypertension, cerebral eral cancers, especially renal cell carcinoma and thrombosis and hemorrhage, and reversible melanoma. Neuropsychiatric complications posterior leukoencephalopathy (Tlemsani occur in 30–50% of patients. These include cog- et  al. 2011). Rarely, severe optic neuropathy nitive changes, delusions, hallucinations, and has been reported in brain tumor patients after depression. In addition, there have been reports bevacizumab treatment. Patients with brain of transient focal neurologic deficits, acute leuko- metastases were often excluded from clinical encephalopathy, carpal tunnel syndrome, and trials of VEGF/VEGFR inhibitors due to the brachial neuritis. Administration of interleukin-2 concern for intratumoral hemorrhage. The directly into the tumor bed for the treatment of incidence of arterial thromboembolic events gliomas can cause significant cerebral edema. including strokes is slightly elevated in Severe neurotoxicity has been reported in patients patients treated with bevacizumab. treated with interleukin-2  in combination with Approximately 1.8–1.9% of patients with granulocyte-macrophage colony-stimulating glioblastoma treated with bevacizumab will factor. have an ischemic stroke (Seidel et al. 2013). Growth Factors Granulocyte colony-stimulating factor and granulocyte-­macrophage colony-stimulating factor are used to increase the granulocyte count and reduce the incidence of infections in patients with non-myeloid tumors receiving chemotherapy. Musculoskeletal symptoms such as cramps and bone pain occur commonly. Rarely, they cause fatigue and headaches. Other rare adverse reactions include confusion and reversible posterior leukoencephalopathy.

Blinatumomab  This is a bispecific CD19-­ directed CD3 T cell engager indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B cell precursor acute lymphoblastic leukemia and minimal residual ­ disease-­positive B cell precursor acute lymphoblastic leukemia. In a phase II clinical trial of 189 patients with Ph-ALL (Stein et al. 2019), 52% of patients experienced a neurologic adverse event, such as dizziness, tremor, confusional state, or encephalopathy. Most neurologic events occurred

Neurological Complications of Biological Therapies for Cancer

during the first cycle, are mild in severity, and resolve with treatment interruption and with dexamethasone. Brentuximab vedotin  This is an antibody-drug conjugate targeting CD30 and is used in the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma. Peripheral neuropathy (24% any grade, 6% grade 3 or 4) is the most common treatment-emergent, nonhematologic adverse event reported, sometimes requiring treatment discontinuation (Zinzani et al. 2015). Rarely, progressive multifocal leukoencephalopathy has been reported in patients who received brentuximab vendotin (Carson et al. 2014). Cetuximab  This chimeric mouse-human antibody targeted against epidermal growth factor is FDA approved for head and neck cancer as well as colorectal cancer. Cases of aseptic meningitis and chronic immune-mediated demyelinating polyneuropathy have been reported in association with cetuximab. Patients may also develop symptomatic magnesium, causing severe fatigue, cramps, and somnolence. Gemtuzumab ozogamicin  Gemtuzumab ozogamicin is an antibody targeted chemotherapeutic agent used in patients with CD33+ acute myelogenous leukemia. It can cause headaches and dizziness. Severe thrombocytopenia is common and may result in intracranial hemorrhage. Ipilimumab  Ipilimumab is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that inhibits the immune system, and is approved for use in unresectable or metastatic melanoma. The incidence of neurologic complications is low, less than 4% with ipilimumab alone and 12% with combination ipilimumab and anti-PD1 therapy (Puzanov et al. 2017). Common neurologic symptoms include headache, although most cases are mild. Immune-related neurologic complications have rarely been described, including inflammatory myopathy, aseptic meningitis, posterior reversible encephalopathy syndrome, Guillain-Barre syndrome, inflammatory enteric neuropathy, a myasthenia gravis-like syndrome,

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chronic inflammatory demyelinating polyneuropathy, transverse myelitis, and a meningo-­ radiculo-­neuritis. Autoimmune encephalitis has also been reported in patients treated with combined ipilimumab and nivolumab. Immunotherapy-related neurologic complications are a diagnosis of exclusion; therefore, diagnostic evaluation is often aimed at ruling out other causes such as hypophysitis, infectious etiologies, metastatic disease, strokes, seizures, paraneoplastic disorders, and toxic-metabolic derangements. Rituximab  Rituximab is a genetically engineered chimeric murine and human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. It is used for the treatment of low-­ grade or follicular B cell lymphoma. Neurologic complications are uncommon, but some patients complain of headaches, myalgia, dizziness, or paresthesias. There may be an increased risk for patients treated with rituximab to develop progressive multifocal leukoencephalopathy, with a reported incidence of 1 per 32,000 in HIV negative patients (Bohra et al. 2017). Ado-trastuzumab emtansine (T-DM1)  This is an antibody-drug conjugate containing trastuzumab and the microtubule inhibitor DM1 and is also used in the treatment of advanced HER/neu-­ overexpressing breast cancer. In a randomized clinical trial, 2% of patients in the T-DM1 group experienced grade 3 peripheral neuropathy compared to 0.2% in the lapatinib plus ­ capecitabine group (Dieras et al. 2017). Emerging data suggest that T-DM1 may increase the risk of clinically significant radiation necrosis and cerebral edema in brain metastases treated with stereotactic radiosurgery (Stumpf et  al. 2019), although further data are needed from ongoing clinical trials of T-DM1.

 argeted Molecular Agents T Bortezomib  This is a proteosome inhibitor used in the treatment of patients with multiple myeloma. It may cause a subacute sensory, and often painful, axonal neuropathy that requires dose reduction. Autonomic dysfunction may

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occur, but motor fibers are rarely affected (Jongen et  al. 2015). The risk of bortezomib-induced peripheral neuropathy is increased in patients with a preexisting neuropathy. Nerve conduction studies may be normal, as small fibers are preferentially affected. Treatment discontinuation or dose modification leads to improvement in most of the patients. A dose-adjusted algorithm is available from manufacturer for patients who develop bortezomib-related neuropathy (www. accessdata.fda.gov/drugsatfda_docs/ label/2008/021602s015lbl.pdf). Ibrutinib  Ibrutinib is a first-in-class oral irreversible inhibitor of Bruton tyrosine kinase used in the treatment of a variety of B cell malignancies including mantel cell lymphoma, chronic lymphocytic leukemia, and Waldenström macroglobulinemia. Although direct neurologic toxicities are uncommon, ibrutinib can increase the risk of invasive fungal infections including CNS aspergillosis (Chamilos et al. 2018). Imatinib mesylate  Imatinib is a protein tyrosine kinase inhibitor of the BCR-Abl oncogene and c-kit used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. Neurologic side effects are usually mild and may include headache and fatigue. Rarely, cerebral edema and encephalopathy may occur. Larotrectinib  This oral TRK inhibitor is used in the treatment of adult and pediatric solid tumors with neurotrophic receptor tyrosine kinase gene fusion, a rare driver of cancers. Among 176 patients treated with larotrectinib on trial, 53% experienced neurologic adverse reactions of any grade, including 6% grade 3 and 0.6% grade 4 (Lassen et  al. 2018). The most common neurologic toxicities included delirium, dysarthria, dizziness, gait disturbance, and paresthesias. Lorlatinib  Lorlatinib is an inhibitor of anaplastic lymphoma kinase (ALK) and ROS1 with blood-brain barrier penetration and is used in the treatment of ALK-positive metastatic non-small cell lung cancer. Peripheral neuropathy was reported in 47% of patients, but most cases were mild and reversible with dose modifications or

9  Neurological Complications of Cancer Therapies

standard medical therapy (Bauer et al. 2019). In clinical trials, a variety of CNS toxicities occurred in 54% of patients receiving lorlatinib, including changes in cognitive function, mood, and speech (Bauer et al. 2019). Of those patients who experienced such CNS side effects, 71.8% had CNS metastases at baseline. Most toxicities were mild, intermittent, and improved or resolved with dose modifications.

Cancer Immunotherapy Cancer immunotherapy, which aims to control the immune system to eradicate cancer cells and prevent their spread, includes pharmaceuticals such as immune checkpoint inhibitors and monoclonal antibodies (MAbs) as well as cell therapy, immunogene therapy, and vaccines. MAbs described in a preceding section are also immunotherapies (Jain 2021). Combination of programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) drugs with other immunotherapy drugs, for example, antibody-drug conjugates, as well as combination of PD-1/PD-L1 drugs with other therapies, for example, chemotherapy and radiation therapy, are being explored. Chimeric antigen receptor (CAR) T cell therapy  In CAR-T cell therapy, a patient’s own T lymphocytes are genetically modified ex vivo to attack specific proteins, expanded in a production facility, and infused back into the patient. Tisagenlecleucel is a CD19-directed genetically modified autologous T cell immunotherapy approved for the treatment of pediatric B cell precursor acute lymphoblastic leukemia (ALL), whereas axicabtagene ciloleucel is a CD19-­ directed genetically modified autologous T cell immunotherapy approved for use in relapsed or refractory diffuse large B cell lymphoma. Several other CAR-T cell therapies are in clinical trials. Neurologic toxicities have been reported with anti-CD19 CAR-T cells at high frequency in up to 80% of patients and with varying manifestations, including headache, confusion, somnolence, hallucinations, dysphasia, ataxia, apraxia, facial nerve palsy, tremor, dysmetria, and seizures (Gust et  al. 2017; Karschnia et  al. 2019; Santomasso et al. 2018). Deaths related to cere-

Management of Neurological Complications of Anticancer Drugs

bral edema have been reported in a small number of patients. These neurologic symptoms mostly occur in the setting of CRS but have also been reported in patients without CRS, suggesting a differential pathogenesis. The manifestations can be severe, sometimes necessitating intubation and ventilation for airway protection. Retrospective reviews suggest increased risk of neurotoxicity in young patients, patients with B-ALL, higher tumor burden, presence of CD19+ cells in the bone marrow, high CAR-T cell dose, pre-existing neurologic comorbidity, higher peak CAR-T cell expansion, and early and higher elevations of proinflammatory cytokines in blood (Gust et  al. 2017; Karschnia et  al. 2019; Santomasso et al. 2018). Immune checkpoint inhibitors (ICI)  These include PD-1 inhibitors (cemiplimab, nivolumab, and pembrolizumab) and PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab). Cemiplimab, nivolumab, and pembrolizumab are PD-1 immune checkpoint inhibitor antibodies, whereas atezolizumab, avelumab, and durvalumab are PD-L-1 antibodies. These agents are collectively approved for use in non-small cell lung cancer, head and neck cancer, colorectal cancer, urothelial cancer, hepatocellular carcinoma, and melanoma. ICIs produce durable antitumor responses but provoke autoimmune toxicities, including uncommon but potentially devastating neurologic toxicities. The incidence of neurologic complications is low, 6% with anti-­PD1 therapy alone and 12% with combination ipilimumab and anti-PD1 therapy (Puzanov et al. 2017). Neurologic complications like those from ipilimumab have been described with anti-PD1 therapy, including cases of Guillain-Barre syndrome, myasthenia gravis, facial and abducens nerve paresis, demyelination, and acute encephalitis. A disproportionality analysis is performed using VigiBase, the World Health Organization pharmacovigilance database, comparing neurologic adverse event (AE) reporting in patients receiving ICIs vs. the full database. Associations between ICIs and neurologic AEs were assessed using reporting odds ratios and information component (IC), and a higher association of the following AEs was found (Johnson et al. 2019):

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• ICIs were associated with higher incidence of myasthenia gravis, peripheral neuropathy, and meningitis. • Myasthenia gravis and encephalitis were associated with anti-PD-1, whereas other neurologic AEs were associated with anti-CTLA-4. Myasthenia gravis was characterized by high fatality rates, early onset, and frequent concurrent myocarditis and myositis, whereas other neurologic AEs had lower fatality rates and later onset and were non-overlapping.

Management of Neurological Complications of Anticancer Drugs Preventive Measures Use of a standardized neurologic assessment and documentation method can aid in early detection of adverse effects and minimizing patient harm during chemotherapy administration (Szoch and Snow 2015). It also provides an opportunity for discontinuation of anticancer therapy and use of limited neuroprotective measures. After cessation of chemotherapy, most patients with peripheral neuropathy eventually improve, although recovery is often incomplete. Neuropathy usually continues to deteriorate for several months in about one-third of patients. Many agents have been tested for the prevention or treatment of chemotherapy-induced peripheral neuropathy, including neuropathy caused by cisplatin (Albers et  al. 2014). The best available data support a moderate recommendation for treatment with duloxetine.

Treatment of Neurological Complications of Immune Therapies of Cancer Management of neurologic toxicities of ipilimumab involves prompt recognition and intervention. For moderate to severe toxicities, cessation of immunotherapy and corticosteroids may be indicated. The National Comprehensive Cancer Network in association with the American Society of Clinical Oncology provides guidelines

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for management of immunotherapy-related toxicities (National Comprehensive Cancer Network 2019). Like ipilimumab, management of neurologic toxicities of PD-1 and PD-L1 inhibitors may include diagnostic evaluation for other causes, cessation of immunotherapy, and/or corticosteroids. A cytokine release syndrome (CRS) is the most common toxicity associated with CAR-T cell therapies, which is characterized by a systemic inflammatory response and can lead to widespread reversible organ dysfunction. Treatment includes aggressive supportive care, including management of hypotension and any concurrent infections, as well as consideration of interleukin-6 receptor blockade with tocilizumab (Brudno and Kochenderfer 2019). Limited experience suggests that tocilizumab may not ameliorate neurologic toxicity. Instead, supportive care, symptomatic management (i.e., seizure medications for patients experiencing seizures), and corticosteroids are recommended for severe neurologic toxicities (Neelapu et al. 2018).

Neuroprotection Against Chemotherapy-Induced Brain Damage Several chemotherapeutic agents and other toxic substances used for the treatment of malignant brain tumors have adverse effects on the normal brain produced a drug-induced encephalopathy referred to as “chemo brain.” Neurotoxicity of anticancer agents has been reported with increasing frequency in cancer patients. These complications may result from the direct toxic effects of the drug on the nervous system or indirectly from metabolic derangements or cerebrovascular disorders induced by the drugs. The adverse effects are aggravated by concomitant radiotherapy. The normal brain tissue can be protected by targeted delivery of chemotherapy and radiotherapy to the tumor. A study found that 5-bromo-2-deoxyuridine labeling following chemotherapy given to C57BL/6 mice revealed that chemotherapeutic

9  Neurological Complications of Cancer Therapies

agents readily able to cross the BBB (cyclophosphamide and fluorouracil), as well as those not known to readily cross the barrier (paclitaxel and doxorubicin), and reduce neural cell proliferation following chemotherapy (Janelsins et  al. 2010). IGF-1, a molecule implicated in promoting neurogenesis, counteracted the effects of high doses of chemotherapy on neural cell proliferation. The research team plans to conduct additional studies which will allow them to further test the impact of IGF-1 and other related interventions on the molecular and behavioral consequences of chemotherapy. Neurogenesis can also be altered by stress, sleep deprivation, and depression, all of which are common among cancer patients. More thorough studies are needed to understand the interplay of these factors and the long-term effects of chemotherapy on the brain. Chemotherapy-induced cognitive impairment occurs in a substantial proportion of treated cancer patients, with no drug currently available for its therapy. A study has investigated whether PAN-811, a ribonucleotide reductase inhibitor, can reduce cognitive impairment and related suppression of neurogenesis following chemotherapy in an animal model (Jiang et  al. 2018). Results showed that the chemo group was impaired on the three cognitive tasks, but co-­ administration of PAN-811 significantly reduced all MTX/5-FU-induced cognitive impairments. Overall, PAN-811 protects cognitive functions and preserves neurogenesis from adverse effects of MTX/5-FU providing a basis for clinical translation to determine the effect of PAN-811 on chemotherapy-induced cognitive impairment in human patients.

References Adams HP Jr. Cancer and cerebrovascular disease. Curr Neurol Neurosci Rep. 2019;19:73. Albers JW, Chaudhry V, Cavaletti G, Donehower RC. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev. 2014;3:CD005228.

References Bauer TM, Felip E, Solomon BJ, et al. Clinical management of adverse events associated with lorlatinib. Oncologist. 2019;24(8):1103–10. Bohra C, Sokol L, Dalia S.  Progressive multifocal leukoencephalopathy and monoclonal antibodies: a review. Cancer Control. 2017;24(4):1073274817729901. Brudno JN, Kochenderfer JN.  Recent advances in CAR T-cell toxicity: mechanisms, manifestations and management. Blood Rev. 2019;34:45–55. Carson KR, Newsome SD, Kim EJ, et  al. Progressive multifocal leukoencephalopathy associated with brentuximab vedotin therapy: a report of 5 cases from the Southern Network on Adverse Reactions (SONAR) project. Cancer. 2014;120(16):2464–71. Chamilos G, Lionakis MS, Kontoyiannis DP.  Call for action: invasive fungal infections associated with ibrutinib and other small molecule kinase inhibitors targeting immune signaling pathways. Clin Infect Dis. 2018;66(1):140–8. Dieras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732–42. Dietrich J, Klein JP.  Imaging of cancer therapy-induced central nervous system toxicity. Neurol Clin. 2014;32(1):147–57. Gibson EM, Nagaraja S, Ocampo A, et al. Methotrexate chemotherapy induces persistent tri-glial dysregulation that underlies chemotherapy-related cognitive impairment. Cell. 2019;176(1–2):43–55.e13. Gounaris I, Ahmad A.  Capecitabine-induced cerebellar toxicity in a patient with metastatic colorectal cancer. J Oncol Pharm Pract. 2010;16:277–9. Gust J, Hay KA, Hanafi LA, Li D, et  al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 2017;7(12):1404–19. Jain KK. Personalized immuno-oncology. Med Princ Pract 2021;30(1):1–16. Janelsins MC, Roscoe JA, Berg MJ, et al. IGF-1 partially restores chemotherapy-induced reductions in neural cell proliferation in adult C57BL/6 mice. Cancer Investig. 2010;28:544–53. Jiang ZG, Winocur G, Wojtowicz JM, et  al. PAN-811 prevents chemotherapy-induced cognitive impairment and preserves neurogenesis in the hippocampus of adult rats. PLoS One. 2018;13:e0191866. Johnson DB, Manouchehri A, Haugh AM, et  al. Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study. J Immunother Cancer. 2019;7:134. Jongen JL, Broijl A, Sonneveld P. Chemotherapy-induced peripheral neuropathies in hematological malignancies. J Neuro-Oncol. 2015;121(2):229–37.

143 Karschnia P, Jordan JT, Forst DA, et al. Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells. Blood. 2019;133(20):2212–21. Lassen UN, Albert CM, Kummar S, et  al. Larotrectinib efficacy and safety in TRK fusion cancer: an expanded clinical dataset showing consistency in an age and tumor agnostic approach. Presented at: the ESMO 2018 Congress; Munich, Germany: October 19–23, 2018. Abstract 409O. Ly KI, Arrillaga-Romany IC.  Neurologic complications of systemic anticancer therapy. Neurol Clin. 2018;36(3):627–51. Muller J, Kralovanszky J, Adleff V, et al. Toxic encephalopathy and delayed MTX clearance after high-dose methotrexate therapy in a child homozygous for the MTHFR C677T polymorphism. Anticancer Res. 2008;28:3051–4. National Comprehensive Cancer Network. About the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Accessed April 12, 2019. https://www.nccn.org/professionals/default.aspx. Neelapu SS, Tummala S, Kebriaei P, et  al. Chimeric antigen receptor T-cell therapy  - assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47–62. Puzanov I, Diab A, Abdallah K, et  al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5(1):95. Saif MW.  Capecitabine-induced cerebellar toxicity and TYMS pharmacogenetics. Anti-Cancer Drugs. 2019;30:431–4. Santomasso BD, Park JH, Salloum D, et  al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 2018;8(8):958–71. Saynak M, Cosar-Alas R, Yurut-Caloglu V, et  al. Chemotherapy and cerebrovascular disease. J BUON. 2008;13:31–6. Seidel C, Hentschel B, Simon M, et al. A comprehensive analysis of vascular complications in 3,889 glioma patients from the German Glioma Network. J Neurol. 2013;260(3):847–55. Stein AS, Schiller G, Benjamin R, et  al. Neurologic adverse events in patients with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab: management and mitigating factors. Ann Hematol. 2019;98(1):159–67. Stumpf PK, Cittelly DM, Robin TP, et al. Combination of trastuzumab emtansine and stereotactic radiosurgery results in high rates of clinically significant radionecrosis and dysregulation of aquaporin-4. Clin Cancer Res. 2019;25(13):3946–53.

144 Szoch S, Snow KK. Implementation and evaluation of a high-dose cytarabine neurologic assessment tool. Clin J Oncol Nurs. 2015;19:270–2. Tlemsani C, Mir O, Boudou-Rouquette P, et al. Posterior reversible encephalopathy syndrome induced by anti-­ VEGF agents. Target Oncol. 2011;6(4):253–8. Zinzani PL, Sasse S, Radford J, Shonukan O, Bonthapally V.  Experience of brentuximab vedotin in relapsed/

9  Neurological Complications of Cancer Therapies refractory Hodgkin lymphoma and relapsed/refractory systemic anaplastic large-cell lymphoma in the Named Patient Program: review of the literature. Crit Rev Oncol Hematol. 2015;95(3):359–69. Zukas AM, Schiff D.  Neurological complications of new chemotherapy agents. Neuro-Oncology. 2018;20(1):24–36.

Adverse Effects of Biological Therapies on the Nervous System

Introduction During the past two decades, biotechnology has been playing an increasing role in pharmaceuticals. Most of the newly approved medicines are based on biotechnology including endocrine preparations, monoclonal antibodies, proteins/ peptides, interleukins, growth factors, etc. Throughout the book, such products are included among the various treatments listed as cauding adverse reactions on the nervous system. The term biotechnology also covers biological therapies. Biological therapy is defined as a type of treatment that uses substances made from living organisms to treat disease. These substances may occur naturally in the body or may be made in the laboratory. Monoclonal antibodies also fulfill this definition, but they are now being described along with other biopharmaceuticals. This chapter will discuss the adverse effects of the following biological therapies on the nervous system: • Cell therapy • Gene therapy including RNAi and antisense • Vaccines

 eurological Complications of Cell N Therapy Cell therapy is the term used to describe use of any type of body cell for treatment of disease

10

although most of the current interest is on stem cells. Cell therapy is described in detail in a special report on this topic (Jain 2021a). Body cells may be used for treatment of systemic disorders or specifically for CNS disorders as shown in Table 10.1.

 eurological Complications of CAR-T N Cell Therapy Chimeric antigen receptor (CAR)-T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR-T products have been approved in the United States and Europe for the treatment of patients up to age 25 years with relapsed or refractory B cell acute lymphoblastic leukemia (ALL) and/or adults with large B cell lymphoma. More CAR-T products, as well as other immunotherapies, including various immune cell- and bi-­ specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS). No unifying definition of cytokine storm exists, and there is much disagreement about what the definition should be and whether specific conditions such as COVID-19 should be included in the spectrum of cytokine storm disorders. A uni-

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_10

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Table 10.1  A practical classification of cell therapy

accuracy of clinical assessment of neurotoxicity in the future. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, to harmonize the definitions and grading systems for CRS and neurotoxicity, the American Society for Transplantation and Cellular Therapy (ASTCT) has made consensus recommendations and proposed new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities (Lee et al. 2019). fying definition for cytokine storm has been The goal is to provide a uniform consensus grad­proposed that is based on the following criteria: ing system for CRS and neurotoxicity associated elevated circulating cytokine levels, acute sys- with immune effector cell therapies, for use temic inflammatory symptoms, and secondary across clinical trials and in the postapproval clinorgan dysfunction beyond that which could be ical setting. attributed to a normal response to a pathogen A mouse model recapitulates key features of (Fajgenbaum and June 2020). CRS and neurotoxicity. In humanized mice with high leukemia burden, CAR-T cell-mediated Neurotoxicity of CAR-T Cell Therapy clearance of cancer triggered high fever and eleThese therapies are associated with neurologic vated IL-6 levels, which are hallmarks of toxicity. Manifestations of neurotoxicity include CRS. Human monocytes were the major source confusion, delirium, aphasia, and seizures. of IL-1 and IL-6 during CRS (Norelli et al. 2018). Neurologic toxicity associated with T cell immu- Accordingly, the syndrome was prevented by notherapy is referred to as immune effector cell-­ monocyte depletion or by blocking IL-6 receptor associated neurotoxicity syndrome or with tocilizumab. Nonetheless, tocilizumab CRS-associated encephalopathy. The neurologic failed to protect mice from delayed lethal neurotoxic effects are often delayed, developing sev- toxicity, characterized by meningeal inflammaeral days after the onset of the cytokine storm. tion. Instead, the IL-1 receptor antagonist The most commonly occurring neurological anakinra abolished both CRS and neurotoxicity, symptoms in a post-transfusion study on patients resulting in substantially extended leukemia-free who had undergone CAR-T cell therapy for lym- survival. These findings offer a therapeutic stratphoma, myeloma, leukemia, and sarcoma were egy to tackle neurotoxicity and open new avenues encephalopathy (57%), headache (42%), tremor to safer CAR-T cell therapies. (38%), aphasia (35%), and focal weakness (11%) (Rubin et al. 2019). Despite the common occurrence of neurologic symptoms, imaging studies Complications of Cell Therapy such as MRI were almost always normal. In con- of Neurological Disorders trast, diagnostic studies that more directly evaluated neuronal functioning, like EEG and PET In clinical trials using transplantation of hESCs scan, could reliably detect and predict neurologic into the brain, adverse effects including tumors or dysfunction. This finding could help improve the vigorous immune reactions have been reported. Cell therapy for diseases of various organs using somatic and stem cells Personalized cell therapy using induced pluripotent stem cells (iPSCs) Special cell therapies for hematological malignancies Hematological stem cells for treatment of leukemia Chimeric antigen receptor (CAR)-T cell therapy Cells as vehicles for drug delivery Cell transplantation for regeneration of damaged organs Cell therapy of neurological disorders CNS implants of live cells secreting therapeutic substances CNS implants of genetically engineered cells producing therapeutic substances Cells for facilitating crossing of the blood-brain barrier Cell transplantation for regeneration of the damaged brain, e.g., following cerebral infarction

Complications of Cell Therapy of Neurological Disorders

 umor Formation After CNS T Transplantation of Stem Cells  onor Stem Cell-Derived Brain Tumor D The first such report is that of a patient affected by the neurodegenerative hereditary disorder ataxia telangiectasia who was treated by repeated transplantations of fetal NSCs and who developed a multifocal brain tumor 4 years later (Amariglio et al. 2009). The biopsied tumor was diagnosed as a glioneuronal neoplasm. The tumor cells and the patient’s peripheral blood cells were compared by FISH using X and Y chromosome probes, by PCR for the amelogenin gene X- and Y-specific alleles, by MassArray for the ATM patient-specific mutation and for several SNPs, by PCR for polymorphic microsatellites, and by human leukocyte antigen (HLA) typing. Molecular and cytogenetic studies showed that the tumor was of nonhost origin suggesting it was derived from the transplanted NSCs. It is generally believed that induced pluripotent stem cells (iPSCs) are unlikely to have tumorigenic potential. However, comparisons of the in vitro neural differentiation of hiPSCs and hESCs showed that some hiPSC clones retained a significant number of undifferentiated cells, even after neural differentiation, and formed teratoma when transplanted into mouse brains (Koyanagi-­ Aoi et  al. 2013). These differentiation-defective hiPSC clones were marked by higher expression levels of several genes, including those expressed from long terminal repeats of specific human endogenous retroviruses. These need to be identified and eliminated before applications in regenerative medicine.  lioproliferative Lesion of Spinal Cord G as a Complication of Cell Therapy A patient developed low back pain, paraplegia, and urinary incontinence following intrathecal infusions of MSCs, ESCs, and fetal NSCs for the treatment of residual deficits from an ischemic stroke at commercial stem cell clinics in China, Argentina, and Mexico (Berkowitz et  al. 2016). MRI showed a lesion of the thoracic spinal cord and thecal sac. A biopsy specimen of the lesion revealed a densely cellular, highly proliferative, primitive tumor with glial differentiation. Short tandem repeat DNA fingerprinting analysis indi-

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cated that the lesion originated from the intrathecally introduced exogenous stem cells. The lesion had some features that overlapped with malignant gliomas (nuclear atypia, a high proliferation index, glial differentiation, and vascular proliferation) but did not show cancer-associated genetic aberrations on NGS and did not fit in any category of previously described human neoplasms. Radiation therapy led to partial relief of back pain, improved mobility of the right leg, and decrease of the size of the lesion on MRI.

Uncontrolled Differentiation of Implanted ESCs Although transplantation of undifferentiated pluripotent ESCs into the injured CNS may lead to targeted cell replacement of lost/damaged cells, sustained proliferative activity combined with uncontrolled differentiation of implanted cells presents a risk of tumor formation. Because tumorigenic potential is associated with pluripotency of ESCs, pre-differentiation may circumvent this problem. However, tumorigenesis occurs despite pre-differentiation if the neural precursor cells are implanted into the brain of a homologous animal (e.g., mouse to mouse), but xenotransplantation (e.g., mouse to rat) without pre-differentiation leads to the development of healthy neuronal cells, in absence of tumor formation, suggesting that tumor-suppressive effects of host tissue on engrafted ESCs may play a role in transplant tumorigenesis. Xenotransplantation of D-3 murine ESCs into uninjured adult rat brains lacking any preliminary inflammatory potential was found to lead to tumor formation in five out of eight of animals within 2 weeks postimplantation (Molcanyi et al. 2009). Tumor-suppressive effects could possibly be ascribed to immunomodulatory activity of macrophages scavenging the tumorigenic fraction of the implanted cells. The importance of number of engrafted cells, implantation site, and immunosuppressive effects are possible variables determining tumorigenic outcome after ESC transplantation. The stage of differentiation of the cells at the time of implantation and factors released by the host tissue may influence the formation of teratoma or tumors. A study has analyzed the relative

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effects of the stage of differentiation and the postischemic environment on the formation of tumors following transplanted hESC-derived neural progenitor cells into rats with middle cerebral artery occlusion lesions (Seminatore et  al. 2010). The effects of the ischemic environment on the formation of teratoma by transplanted hESC-derived neural progenitors are limited to early differentiation stages that will likely not be used clinically for stem cell therapy. In contrast, hyperproliferation observed at later stages of differentiation corresponds to an intrinsic activity that should be monitored to avoid tumorigenesis. The risk of tumorigenesis is reduced by use of iPSCs.

genetic material are called vectors, which are usually viral, but several nonviral techniques are being used as well. Gene therapy technologies are described in detail in a special report on the topic (Jain 2021b). A simplified classification of gene therapy techniques is shown in Table 10.2.

Adverse Effects of Gene Therapy

A large number of complicated technologies might lead one to suspect safety of gene therapy, but the procedures are now reasonably safe, and some gene therapies are approved by regulatory authorities. Gene therapy has been studied extenTumorigenicity of ESC-Derived Retinal sively in animal experiments and human clinical Progenitor Cells trials. The record of safety has been well mainA study has evaluated multiple kinds of ESC-­ tained. The following are some of the adverse derived retinal progenitor cells (ESC-RPCs) in a effects that have been observed. mouse model of retinal degeneration and conducted genome-wide gene expression profiling to Retroviral vectors  Although the viruses are find major extracellular signaling and intrinsic made replication-defective, the possibility of profactors controlling tumorigenicity as well as ther- duction of a replication-competent virus remains. apeutic functionality of transplanted ESC-RPCs Stable transformation of target cells makes it dif(Cui et al. 2013). The authors identified canonical ficult to reverse the treatment if appearance of WNT signaling as a critical determinant for the undesirable side effects requires that the treattumorigenicity and therapeutic function of ESC-­ ment be stopped. RPCs. The function of WNT signaling is primarily mediated by TCF7, which directly induces Herpes simplex virus vectors  The issue of neuexpression of Sox2 and Nestin. Inhibition of ronal cytotoxicity remains unsolved. Novel WNT signaling, overexpression of dominant-­ recombinant herpes simplex virus-1 vectors that negative Tcf7, and silencing Tcf7, Sox2, or Nestin appear to reduce the risk of neurovirulence and all resulted in drastically reduced tumor formation cytotoxicity also are less effective. Further studand substantially improved retinal integration and ies on the source of herpes simplex virus-1 cytovisual preservation in mice. These results demon- toxicity and improved vector development are strate that the WNT signaling cascade plays a required. critical role in modulating the tumorigenicity and functionality of ESC-derived progenitors. Adenoviral vectors  Most of the adverse effects of viral vectors are associated with adenoviruses, and some of these are the following:

 eurological Complications of Gene N Therapy

Gene therapy can be broadly defined as the transfer of defined genetic material to specific target cells of a patient for the ultimate purpose of preventing or altering a particular disease state. Carriers, or delivery vehicles, for therapeutic

Inflammatory effects  These have been observed mostly in the respiratory tract after local administration of adenoviral vectors. Induction of immune response  One major concern about using adenoviral vectors for repetitive gene delivery is the induction of immune response

Neurological Complications of Gene Therapy Table 10.2  A simplified classification of gene therapy techniques Gene transfer  Chemical: calcium phosphate transfection  Physical  Electroporation  Gene gun Recombinant virus vectors  Transduction Viral vectors  Retroviruses, e.g., Moloney murine leukemia virus  Adenoviruses  Adeno-associated virus  Herpes simplex viruses  Lentiviruses  Vaccinia virus  Other viruses Nonviral vectors for gene therapy  Liposomes  Ligand-polylysine-DNA complexes  Nanoparticles, e.g., dendrimers  Synthetic peptide complexes  Artificial viral vectors  Artificial chromosomes Use of genetically modified microorganisms as oncolytic agents  Genetically modified viruses  Genetically modified bacteria Cell/gene therapy  Administration of cells modified ex vivo to secrete therapeutic proteins in vivo  Implantation of genetically engineered cells to produce therapeutic substances  Genetic modification of stem cells—stem cell therapy Gene/DNA administration  Direct injection of naked DNA or genes: systemic or at target site  Receptor-mediated endocytosis  Use of refined methods of drug delivery: e.g., microspheres, nanoparticles Gene regulation  Regulation of expression of delivered genes in target cells by locus control region technology  Molecular switch to control expression of genes in vivo  Promoter element-triggered gene therapy Repair/editing of genes  Correction of the defective gene in situ  Transcription activator-like effector nucleases (TALENs): restriction enzymes that can be engineered to cut specific sequences of DNA for gene editing

149 Table 10.2 (continued)  Zinc finger nucleases (ZFNs): engineered DNA-­ binding proteins for targeted editing of the genome by creating double-strand breaks in DNA at user-specified locations  Gene editing, i.e., altering the genomes of living cells by adding or deleting genes  Clustered regularly interspaced short palindromic repeats (CRISPR) Gene replacement  Excision or replacement of the defective gene by a normal gene RNA gene therapy  RNA trans-splicing Inhibition of gene expression  Antisense oligodeoxynucleotides  RNA interference  Ribozymes © Jain PharmaBiotech

to the vector that impedes effective gene transduction. Alternate use of adenovirus vectors from different serotypes within the same subgroup can circumvent anti-adenovirus humoral immunity to permit effective gene transfer after repeat administration although the chronicity of the expression is limited by cellular immune processes directed both against the transgene and the viral gene products expressed by the vector. Animal experimental data show the potential of immunosuppression in the management of immune reactions triggered by adenoviral vectors by use of monoclonal antibodies. Undesirable effects of in vivo adenoviral vectors for arterial gene transfer  In patients with prior exposure to adenovirus, adenoviral vector-­ mediated arterial gene transfer might affect the success of arterial gene transfer and the duration of recombinant gene expression as well as the likelihood of a destructive immune response to the transduced cells.

Neurotoxicity of Gene Therapy Neurotoxicity of adenoviral vectors for brain tumor therapy  Adenoviral vector-mediated herpes simplex virus-thymidine kinase gene transfer

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combined with ganciclovir is being considered as a therapy for malignant brain tumors. The aim is to develop a more effective and less toxic vector for brain tumor therapy. The major concern is the toxicity of adenovirus, which has not yet been resolved by animal experiments. However, a phase 1 clinical trial on patients with glioblastoma is planned to determine if there is significant toxicity. E-1 deleted adenoviral vectors trigger a strong inflammatory response in the brain, but this immune response is not sufficient to eliminate complete expression of genes encoded by the adenoviral construct. Injection of adenoviral vector carrying a thymidine kinase gene produces viral meningitis (as seen on histopathological examination) when injected into the cerebrospinal fluid space in experimental animals including nonhuman primates. Toxicity of lipopolysaccharides  The presence of lipopolysaccharides as a contaminant in plasmid prepared from Escherichia coli is well documented. Lipopolysaccharides are internalized during adenovirus-mediated gene transfer and can generate toxicity in primary cell types. Other commonly used nonviral methods of gene transfer can also generate toxicity in some primary cell types. Toxicity has been found to be due to lipid A component of lipopolysaccharides. The lipopolysaccharide-chelating antibiotic polymyxin B can block this activity. Measures to improve safety and efficacy of gene therapy  Ability to direct gene transfer vectors to specific target cells is an important task to be tackled and will be important not only to achieve a therapeutic effect but also to limit potential adverse effects. Considerable efforts are being made to develop nonviral vectors to avoid some of the adverse effects of viral vectors.

 dverse Effects of Vaccines A on the Nervous System Introduction Vaccines have probably prevented more diseases than any other medical or public health intervention except sanitation. Measles, mumps, rubella

(MMR), and varicella (chickenpox) are serious diseases that can lead to serious complications, disability, and death. However, public debate over the safety of the trivalent MMR vaccine and the resultant drop in vaccination coverage in several countries persists, despite its almost universal use and accepted effectiveness. The Cochrane Central Register of Controlled Trials was searched to assess the effectiveness, safety, and long- and short-term adverse effects associated with the MMR trivalent vaccine or tetravalent vaccine containing MMR and varicella strains (MMRV), given to children aged up to 15 years. ADRs involving the nervous system were as follows (Di Pietrantonj et al. 2020): • There is evidence supporting an association between aseptic meningitis and MMR vaccines containing Urabe and Leningrad-Zagreb mumps strains, but no evidence supporting this association for MMR vaccines containing Jeryl Lynn mumps strains. • The analyses provide evidence supporting an association between MMR/MMR + V/MMRV vaccines (Jeryl Lynn strain) and febrile seizures. Febrile seizures normally occur in 2–4% of healthy children at least once before the age of 5. The attributable risk of febrile seizure vaccine induced is estimated to be from 1 per 1700 to 1 per 1150 administered doses. • There is no evidence of an association between MMR immunization and encephalitis or encephalopathy and autistic spectrum disorders. The traditional use of vaccines has been mostly limited to the prevention of disease. The trend changed in the 1990s when several clinical trials were underway for treatment of active infections with viruses such as HIV-1 and the herpes simplex virus. DNA vaccines, which are easy to produce and stable, were the most important development in this area in the last decade. RNA vaccine technology, the most recent technology, has been applied to create successful vaccines to combat COVID-19 pandemic. Apart from infectious diseases, therapeutic vaccines are in development for cancer, autoimmune disorders (e.g., multiple sclerosis), and

Adverse Effects of Vaccines on the Nervous System

degenerative disorders (e.g., Alzheimer disease). Alzheimer disease and stroke have important inflammatory and immune components and may be amenable to treatment by antiinflammatory and immunotherapeutic approaches including vaccines. Cancer vaccination involves attempts to activate immune responses against antigens to which the immune system has already been exposed. Vaccines are available in various forms and given by several routes of administration. Advances in genomics with sequencing of genomes of infectious organisms are providing opportunities for genetically engineered specific vaccines. This article is a brief overview of vaccines for neurologic disorders. Only active immunization is considered here. Active immunization should be distinguished from passive immunization, which results in immediate protection of short duration and may be achieved by the administration of antibodies themselves in the form of antisera (of animal origin) or immunoglobulins (of human origin). Two well-known approaches for vaccine construction are the following: 1. The use of a related immunogen to achieve cross-reactive immunity against the more pathogenic organism (e.g., the use of cowpox for smallpox immunization). 2. The use of attenuated or weaker version of an organism by passage of an organism in culture or animals with selection of a weaker version (e.g., the Bacille Calmette-Guerin vaccine). Bacterial vaccines were broadly of three types: (1) killed suspensions prepared from virulent organisms, (2) live preparations of strains selected for attenuation by manipulation of culture conditions, and (3) toxoids prepared by detoxification of crude bacterial toxins. Viral vaccines corresponded to the first two types of bacterial vaccines. Vaccination is used for both prophylaxis and treatment of neurologic disorders, which includes mainly infections but also diseases (e.g., malignant brain tumors and multiple sclerosis). Neurologic disorders where vaccines have either been used or are in development are shown in Table 10.3.

151 Table 10.3  Disorders affecting the nervous system for which vaccines are in development or have been used Prevention of infections to the central nervous system:  Encephalitis    Eastern equine encephalitis   Japanese encephalitis    Tick-borne encephalitis    Venezuelan equine encephalitis    Western equine encephalitis  Lyme disease  Malaria  Meningitis   Meningococcal meningitis   Lymphocytic choriomeningitis    Haemophilus influenzae  Poliomyelitis  Rabies  Tetanus  Herpes zoster infections Prevention of congenital and neonatal infection:  Congenital rubella  Congenital cytomegalovirus  Congenital HIV-1 infections  Neonatal meningitis Treatment of infections that can affect the nervous system:  HIV-1  Herpes simplex  Leprosy  Tuberculosis Treatment of degenerative neurologic disorders:  Alzheimer disease  Amyotrophic lateral sclerosis Treatment of demyelinating neurologic disorders  Multiple sclerosis Treatment of addiction  Cocaine addiction  Nicotine addiction  Opioid addiction  Methamphetamine addiction Therapeutic vaccines for primary malignancies of the nervous system  Glioblastoma Vaccines for neuroprotection in CNS trauma  Spinal cord injury  Traumatic brain injury © Jain PharmaBiotech

Administration of a vaccine by injection may be followed by local reaction, possibly with inflammation and lymphangitis. Fever, headache, and malaise may occur a few hours following vaccination and last for 1–2 days. Hypersensitivity reactions may occur, and anaphylaxis has rarely

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been reported. Further details of adverse effects of vaccines are listed in the product inserts of various preparations.

 dverse Effects of Vaccines A on the Nervous System Neurologic adverse effects of vaccines used for infections affecting the nervous system are sometimes difficult to distinguish from the manifestations of the disease. The most significant neurologic complication of vaccination is acute disseminated encephalomyelitis, a syndrome characterized by rapid development of multifocal neurologic dysfunction. Neurologic sequelae of smallpox vaccination in the 1920s led to an awareness that such complications can follow other vaccines. Acute disseminated encephalomyelitis has been reported in association with several vaccines. These include the rabies vaccine and the Japanese encephalitis vaccine. Meningococcal vaccine  Most reported adverse event following vaccination with Trumenba (bivalent rLP2086) was injection site pain (Fiorito et al. 2018). Other adverse effects such as fatigue, myalgia, fever, and chills were similar as those reported in clinical trials. Rabies vaccine  The incidence of encephalitis with original Pasteur vaccine, prepared in rabbit brain, was estimated to be from 1 to 3000 vaccinations to 1 to 35,000 vaccinations. Various other preparations involving neural tissues continue to be associated with encephalomyelitis. Introduction of nonneural tissue vaccines, particularly human diploid cell vaccine, has markedly reduced but not eliminated the neurologic complications. Cases of encephalitis, radiculitis, and acute inflammatory demyelinating polyradiculoneuropathy have been reported following rabies vaccination containing neural elements. Antitetanus vaccine  Antitetanus vaccination is generally safe but adverse effects such as neuropathy may occur. History of such vaccination

should be considered in the differential diagnosis of neuropathies. Japanese encephalitis vaccine  The Japanese encephalitis vaccine has been used for childhood immunization programs in Asia since the 1960s and is generally considered to be safe. Neurologic side effects reported in larger vaccine trials in Asia range from 1 to 2.3 per million vaccines. A few patients have been reported to develop severe encephalitis-like illness with MRI changes, indicating acute disseminated encephalomyelitis. Similar findings have been reported in naturally occurring Japanese B encephalitis. A review of the adverse event reports following Japanese encephalitis vaccination in the United States from 1999 to 2009 revealed no reports of encephalitis, meningitis, or Guillain-Barre syndrome (Lindsey et al. 2010). Oral poliomyelitis vaccine  Using a description of a child with acute flaccid paralysis possibly caused by a poliovirus vaccine, the authors reviewed the literature and stated that oral ­poliomyelitis vaccine and type 2 serotype poliomyelitis virus vaccine were the risk factors for vaccine-associated paralytic poliomyelitis (Tian et  al. 2020). Moreover, the combination of two vaccines was associated with an increased risk of acute disseminated encephalomyelitis and flaccid paralysis following immunization when compared with the administration of vaccines separately. The risk of paralytic poliomyelitis resulting from polio vaccine as presented by these authors is not convincing. Tick-borne encephalitis  Adverse neurologic reactions after tick-borne vaccination are rare and reversible. Most frequently reported adverse events are headache, neuropathy, and meningeal irritation. DNA vaccines  Even though the DNA is not injected with adjuvant, induction of antibodies to DNA is always a possibility and might depend on the sequences found in the injected plasmid. However, the results obtained to date have indicated that high levels of high affinity antibodies

Adverse Effects of Vaccines on the Nervous System

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are not induced. In addition, it has been shown that plasmid DNA can be reinjected at later times to boost the immune response. This suggests that any immune response to the DNA that might occur is not able to block the effect of subsequent injections of DNA.

verified by epidemiological studies, was reported with use of Pandemrix pandemic influenza vaccine in Sweden (Feltelius et  al. 2015). Genetic studies confirmed the association with the allele HLA-DQB1*06:02, which is known to be related to sporadic narcolepsy.

Miscellaneous neurologic complications  Various reported neurologic complications not listed above include Guillain-Barre syndrome following influenza vaccine and seizures following pertussis vaccination. In a study from China, a total of 89.6 million doses of influenza A (H1N1) vaccine were administered from 2009 to 2010, and only 11 cases of the Guillain-Barre syndrome were reported as adverse events, i.e., a rate of 0.1 per 1 million doses, which is lower than the background incidence of this syndrome in China (Liang et al. 2011). Rigorous scientific studies have not identified links between autism and the measles, mumps, and rubella vaccine as alleged previously in some publications (Miller and Reynolds 2009). Several case reports of the onset or exacerbation of multiple sclerosis or other demyelinating conditions shortly after vaccination have suggested that vaccines may increase the risk of demyelinating diseases. One report concerns an army officer who received 20 vaccinations and boosters (hypervaccination) during the period 2000–2006 in the Balkans and was subsequently diagnosed with multiple sclerosis in 2008 (Vacchiano and Vyshka 2012). However, case-­ control studies have not shown that vaccination against hepatitis B, influenza, tetanus, measles, or rubella is associated with an increased risk of multiple sclerosis. A strong association was found between the inactivated intranasal influenza vaccine used in Switzerland and Bell palsy. Therefore, this vaccine was withdrawn from clinical use. There is a suggestion that the inflammatory response of amyloid beta vaccination in Alzheimer disease is related to dose. A low dose of vaccine with a rather small peptide or low levels of antibodies would help to keep the inflammatory response as low as possible. A three- to fourfold increased risk of narcolepsy in vaccinated children and adolescents,

Vaccination during pregnancy  Live virus vaccines should not be administered during pregnancy because of the potential risk to the fetus. However, other immunizations are often avoided in pregnancy and the early postpartum period because of the mistaken belief that vaccines are harmful to the fetus or neonate. The protective effect of maternal antibody against many viral diseases has been recognized, and the use of maternal immunization has been considered for augmenting this protection in the young infant. Advantages of maternal immunization include the following: • Prevention of congenital neonatal infections. • IgG antibodies cross the placenta wall during the third trimester so that immunization of the pregnant women protects the infants who remain highly susceptible to infections but are the least responsive to vaccines given directly. Disadvantages of maternal vaccination are the following: • Potential inhibition of an infant’s response to active immunization or natural infection • Liability issues with pharmaceutical companies and physicians Immunization of pregnant women with viral vaccines for poliovirus, influenza viruses, and rubella has been found to be safe for both the mother and the fetus. The efficacy of the rubella vaccine has not been proven, and it is used only during pregnancy with rubella titers. The brain is an immune privileged organ based on differences between the innate and adaptive immune responses of the brain as compared to those of other organs. However, the brain parenchyma has a functional type I interferon (IFN) response that can limit spread of vesicular stomatitis virus (VSV) at the inoculation site as well as among synaptically connected neurons

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(Drokhlyansky et  al. 2017). Moreover, the infected microglia produce type I interferon, and uninfected microglia induce an innate immune response following virus injection, which can limit viral spread. This finding has implications for design of vaccines for viral diseases involving the brain.

References Amariglio N, Hirshberg A, Scheithauer BW, et al. Donor-­ derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med. 2009;6:e1000029. Berkowitz AL, Miller MB, Mir SA, et al. Glioproliferative lesion of the spinal cord as a complication of “stem-­ cell tourism”. N Engl J Med. 2016;375(2):196–8. Cui L, Guan Y, Qu Z, et  al. WNT signaling determines tumorigenicity and function of ESC-derived retinal progenitors. J Clin Invest. 2013;123:1647–61. Di Pietrantonj C, Rivetti A, Marchione P, Debalini MG, Demicheli V.  Vaccines for measles, mumps, rubella, and varicella in children. Cochrane Database Syst Rev. 2020;4(4):CD004407. Drokhlyansky E, Aytürk GD, Soh TK, et  al. The brain parenchyma has a type I interferon response that can limit virus spread. Proc Natl Acad Sci U S A. 2017;114(1):E95–E104. Fajgenbaum DC, June CH.  Cytokine Storm. N Engl J Med. 2020;383:2255–73. Feltelius N, Persson I, Ahlqvist-Rastad J, et al. A coordinated cross-disciplinary research initiative to address an increased incidence of narcolepsy following the 2009–2010 Pandemrix vaccination programme in Sweden. J Intern Med. 2015;278(4):335–53. Fiorito TM, Baird GL, Alexander-Scott N, et al. Adverse events following vaccination with bivalent rLP2086 (Trumenba®): an observational, longitudinal study during a college outbreak and a systematic review. Pediatr Infect Dis J. 2018;37(1):e13–9.

Jain KK.  Cell therapy. Basel: Jain PharmaBiotech Publications; 2021a. Jain KK.  Gene therapy. Basel: Jain PharmaBiotech Publications; 2021b. Koyanagi-Aoi M, Ohnuki M, Takahashi K, et  al. Differentiation-defective phenotypes revealed by large-scale analyses of human pluripotent stem cells. Proc Natl Acad Sci U S A. 2013;110(51):20569–74. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25:625–38. Liang XF, Li L, Liu DW, et  al. Safety of influenza A (H1N1) vaccine in postmarketing surveillance in China. N Engl J Med. 2011;364(7):638–47. Lindsey NP, Staples JE, Jones JF, et  al. Adverse event reports following Japanese encephalitis vaccination in the United States, 1999–2009. Vaccine. 2010;29(1):58–64. Miller L, Reynolds J. Autism and vaccination-the current evidence. J Spec Pediatr Nurs. 2009;14(3):166–72. Molcanyi M, Riess P, Haj-Yasein NN, et al. Developmental potential of the murine embryonic stem cells transplanted into the healthy rat brain–novel insights into tumorigenesis. Cell Physiol Biochem. 2009;24:87–94. Norelli M, Camisa B, Barbiera G, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-­ release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018;24:739–4. Rubin DB, Danish HH, Basil Ali A, et  al. Neurological toxicities associated with chimeric antigen receptor T-cell therapy. Brain. 2019;142:1334–48. Seminatore C, Polentes J, Ellman D, et al. The postischemic environment differentially impacts teratoma or tumor formation after transplantation of human embryonic stem cell-derived neural progenitors. Stroke. 2010;41:153–9. Tian M, Yang J, Li L, Li J, Lei W, Shu X.  Vaccine-­ associated neurological adverse events: a case report and literature review. Curr Pharm Des. 2020;25(43):4570–8. Vacchiano G, Vyshka G.  Balkans syndrome: a potential link between multiple sclerosis and hypervaccination. J R Army Med Corps. 2012;158(4):338–40.

Part III Drug-Induced Neurological Disorders

Drug-Induced Aseptic Meningitis

Introduction Drug-induced aseptic meningitis is a form of aseptic meningitis. Viral infection is the usual cause of aseptic meningitis, although chemical agents, such as drugs, may produce the same clinical syndrome. Postoperative aseptic meningitis was first described by Harvey Cushing in 1925 (Cushing and Bailey 1928). Wallgren first described the criteria for the diagnosis of aseptic meningitis in 1925, as follows (Wallgren 1925): • An acute onset of signs and symptoms of meningeal involvement such as headache, fever, and stiff neck. • Changes in CSF typical of meningitis (e.g., pleocytosis). • Absence of bacteria in CSF as demonstrated by culture. • Short and benign course of the illness; the patient recovers within a matter of days. • Absence of local parameningeal infection (e.g., otitis media). • Absence from the community of epidemic diseases of which meningitis is a feature. The etiology of Mollaret meningitis, a recurrent form of aseptic meningitis, is not clear (Mollaret 1944). The criteria for the diagnosis of this form of meningitis are like those of Wallgren meningitis, except that Mollaret meningitis is recurrent, and in the interval between the attacks,

11

the patient is free from symptoms and signs (Frederiks and Bruyn 1989). In a case of Mollaret meningitis, two of the five attacks were drug induced (Thilmann et al. 1991). It has been suggested that the term “Mollaret meningitis” should be restricted to idiopathic recurrent aseptic meningitis (Pearce 2008). Before the term “aseptic meningitis” was introduced, the term “hypersensitivity meningitis” was used in the literature to describe the meningeal reaction accompanying serum sickness and allergic reactions in a patient following the first dose of the second course of sulfathiazole (Longcope 1943). Some of these cases fulfill the present criteria of drug-induced aseptic meningitis. Two patients who experienced headache, stiff neck, and fever following administration of sulfanilamide, later developing encephalomyelitis, have been reported (Fisher and Sydney 1939). Barrett and Thier reported a case of aseptic meningitis in a patient receiving sulfamethoxazole (Barrett and Thier 1963). This episode recurred twice with rechallenge (i.e., readministration of the drug to see if it would reproduce the adverse manifestations after the patient had recovered from the initial exposure). With the increasing recognition of the term “drug-induced aseptic meningitis,” several reports and reviews have appeared in the literature. The term “aseptic meningitis” broadly covers some of the complications of devices used in the treatment of neurologic disorders.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_11

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Clinical Manifestations The classical signs of meningitis, headache, neck stiffness, and fever are the features of aseptic meningitis as well. Other symptoms include photophobia, myalgia, nausea, and vomiting. If aseptic meningitis is a part of a neurotoxic reaction to the drug, then there may be manifestations other than meningitis. In aseptic meningitis following vaccination, evidence exists of viral infection with associated signs, such as parotid swelling, as in the case of the measles-mumps-rubella vaccine. Convulsions may occur in some children and are probably associated with viral encephalitis. All drug-induced aseptic meningitis cases reported in the literature resolved without mention of specific neurologic complications. However, there is some concern regarding long-­ term neuropsychiatric sequelae. Some studies have reported decreased psychomotor speed and impaired executive as well as visuo-constructive functions following aseptic meningitis (Damsgaard et al. 2015). Controlled prospective studies are required to elucidate the neuropsychiatric complications of aseptic meningitis.

Pathomechanism A list of drugs and chemicals reported to be associated with aseptic meningitis is shown in Table 11.1. In a report from the French Pharmacovigilance Database, the most frequently involved drugs in drug-induced aseptic meningitis were intravenous polyvalent immunoglobulin, nonsteroidal anti-inflammatory drugs, vaccines, and antimicrobials, and it was not possible to differentiate them in terms of biological characteristics (Bihan et al. 2019).

11  Drug-Induced Aseptic Meningitis

was reported in lamotrigine-associated aseptic meningitis, and this should be considered in the differential diagnosis of culture-negative meningitis (Simms et al. 2012). Antineoplastics  The usual manifestations of systemic antineoplastic neurotoxicity are cerebellar syndromes, leukoencephalopathy, and peripheral neuropathy. Aseptic meningitis has been reported after systemic treatment with cytosine arabinoside. It may be difficult to sort out some reports of meningitis associated with antineoplastic therapy because of occurrence of neoplastic meningitis. Antibiotics  Systemic use of cephalosporins has been associated with cases of aseptic meningitis. Antibiotic-induced aseptic meningitis limits the direct application of antibiotics into the brain or subarachnoid space. An example is the use of colistin, an antibiotic that penetrates the brain poorly, for CNS infections due to multidrug-­ resistant Acinetobacter baumannii. Direct instillation of colistin into the CNS is an effective treatment in this situation but may cause chemical meningitis. Diagnosis of drug-induced aseptic meningitis was difficult in a patient with human immunodeficiency virus who was receiving moxifloxacin as a modified treatment for tuberculosis following severe hepatotoxicity (Rowley et  al. 2014). Abnormal finding on CSF examination did not normalize to confirm diagnosis until risk was taken to withhold moxifloxacin.

Cetuximab  Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor, which is used for the treatment of cancer. There are isolated case reports of aseptic meningitis induced by cetuximab (Emani and Zaiden Jr. 2013; Nagovskiy et al. 2010; Ulrich et al. 2015). The symptoms—headache, neck stiffness, and Antiepileptic Drugs  Several case reports have high fever—develop within a few hours of the linked antiepileptic drugs to aseptic meningitis. first cetuximab administration. Diagnosis is There are several case reports of carbamazepine-­ established by CSF analysis, and recovery ­usually associated aseptic meningitis. In nearly 40% of occurs within days to weeks after withdrawal of cases in one case series, a positive rechallenge the drug.

Pathomechanism Table 11.1  Drugs, chemicals, and devices associated with aseptic meningitis Antiepileptic drugs  Carbamazepine  Lamotrigine (Sethi 2012) Antimicrobial drugs  Sulfonamides    Trimethoprim    Trimethoprim/sulfamethoxazole   Sulfasalazine  Cephalosporin  Ciprofloxacin  Fluoroquinolones: moxifloxacin  Isoniazid  Metronidazole  Ornidazole  Penicillin and its analogs    Amoxicillin (Prieto-González et al. 2011)  Rifampicin (Tuleja et al. 2010)  Antimicrosporidial    Fumagillin (Audemard et al. 2012)  Antivirals    Valacyclovir Antineoplastics (systemic use)  Cytosine arabinoside Corticosteroids  Methylprednisolone acetate  Hydrocortisone sodium succinate Monoclonal antibodies  Adalimumab (Jazeron et al. 2010; Wang et al. 2017)  Cetuximab  Efalizumab  Infliximab  Muromonab CD-3a  Natalizumab (Foley et al. 2017) Nonsteroidal anti-inflammatory drugs  Celecoxib  Diclofenac  Ibuprofen  Naproxen  Sulindac  Tolmetin  Ketoprofen  Loxoprofen  Salicylates  Piroxicam  Rofecoxib (withdrawn from the USA and other markets due to adverse effects) Intraventricular drugs  Gentamicin  Antineoplastic drugs Spinal intrathecal drugs  Antineoplastics

159 Table 11.1 (continued)   Cytosine arabinoside   Methotrexate  Antimicrobials  Baclofen  Steroids  Spinal anesthesia: bupivacaine (Doghmi et al. 2017) Intrathecal diagnostic agents  Radiologic contrast media   Iophendylate   Metrizamide   Iohexol  Radiolabeled albumin Miscellaneous drugs  Allopurinol  Azathioprine  Famotidine  Intravenous immune globulina (Mullane et al. 2012)  Isotretinoin (Chalimou et al. 2019)  Pyrazinamide  Ranitidine  Vaccines   Polio    Measles, mumps, and rubella   Hepatitis B Devices used in the management of neurologic disorders  Coils used for the treatment of intracranial aneurysms  Devices implanted into the brain  Intraventricular catheters Denotes well documented. Others are based on isolated case reports

a

Intravenous Immunoglobulin  In recent years, intravenous immunoglobulin has been employed in the treatment of a variety of medical conditions such as idiopathic thrombocytopenic purpura, Guillain-Barré syndrome, dermatomyositis, and Kawasaki disease. Several cases of aseptic meningitis have been described. There are several published case reports of aseptic meningitis following intravenous immunoglobulin and these case reports can be easily retrieved from literature. A retrospective review of all cases of IVIG-­ associated adverse transfusion reactions from 2008 to 2013 at a large tertiary care center identified 8 cases of aseptic meningitis representing an overall incidence of 0.60% for all treated patients and 0.067% for all IVIG infusions (Bharath et al.

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11  Drug-Induced Aseptic Meningitis

Trimethoprim-Sulfamethoxazole   Aseptic meningitis is recognized as an adverse effect of administration of trimethoprim-­sulfamethoxazole or trimethoprim-containing drugs. Known factors include autoimmune diseases and HIV infection. Muromonoab-CD3  This monoclonal murine The pathomechanism is not well understood, IgG immunoglobulin is directed at the T3 recep- although interleukin-6 has been implicated and tors of the T-lymphocyte and is reportedly effec- the rise of the level of this inflammatory cytokine tive in the treatment of steroid-resistant kidney in the blood as well as CSF may be a biomarker of allograft rejection. Aseptic meningitis has been trimethoprim-induced meningitis. Trimethoprimreported in patients following use of muro- sulfamethoxazole-induced aseptic meningitis is monoab-­ CD3 (Orthoclone OKT3) in cardiac used to be the most common form of antimicrotransplantation programs. Patients on this drug bial therapy-induced meningitis. Trimethoprimshould be monitored for symptoms suggestive of sulfamethoxazole is not commonly used now and meningeal irritation, and therapy should be dis- is primarily limited to Pneumocystis carinii pneumonia prophylaxis in AIDS patients; cases of continued if such symptoms develop. drug-induced aseptic meningitis have been Nonsteroidal Anti-inflammatory Drugs reported in these patients. A predominance of (NSAIDs)  These drugs have anti-inflammatory, female patients and those with autoimmune disanalgesic, and antipyretic properties, but can also eases were reported in a review of 41 cases in the produce adverse effects of which gastric ulcer- literature up to 2014 (Bruner et al. 2014). Typical ation and renal insufficiency are well known. CSF findings included elevated white blood cell CNS effects, such as aseptic meningitis, are less count with neutrophil predominance, elevated well known. Nine nonsteroidal anti-inflammatory protein, and normal glucose. Full recovery was drugs have been implicated in causing drug-­ typical after discontinuation of the drug, but perinduced aseptic meningitis. This reaction appears sistent paraplegia was reported in one case. Two to be unrelated to the chemical class of nonsteroi- further cases of trimethoprim-­sulfamethoxazole-­ dal anti-inflammatory drugs or to nonsteroidal induced aseptic meningitis have been reported, anti-inflammatory drug-mediated effects of the and complete recovery occurred in both after disdrug. There does not appear to be cross-reactivity continuation of the drug (Jha et al. 2016). of the nonsteroidal anti-inflammatory drugs because, with a few exceptions, patients who Intrathecal Drugs and Diagnostics  Aseptic develop aseptic meningitis after exposure to one meningitis is well documented for this route of nonsteroidal anti-inflammatory drug have been administration. Some examples are as follows: previously and subsequently treated with other nonsteroidal anti-inflammatory drugs without Antineoplastics  Neurotoxic effects of antineoany reaction. Patients with systemic lupus erythe- plastic agents when administered systemically are matosus appear to be at greater risk for develop- well documented. The clinical manifestations of ing nonsteroidal anti-inflammatory drug-induced aseptic meningitis occur 2–4  h after intrathecal injection of methotrexate. Meningismus is rarely aseptic meningitis. Ibuprofen is the most frequently implicated seen after the first injection, but incidence increases drug in drug-induced aseptic meningitis. The with the number of intrathecal injections and is most common background disease among these dose related. The presence of chemical preservapatients is systemic lupus erythematosus. Aseptic tives in the solution for intrathecal injection may meningitis has been reported with other nonste- contribute to the meningeal reaction. roidal anti-inflammatory drugs including rofeIntrathecal administration of cytarabine. coxib, which is reported to act by selectively Intrathecal administration of cytarabine for meninhibiting cyclooxygenase-2. ingeal leukemia is associated with CNS toxicity, 2015). Symptoms manifested within 24–48 h of the infusion. The reactions were self-limited and resolved within 5–7  days, and treatment was supportive.

Pathomechanism

including aseptic meningitis. This usually occurs in cases where the tumor is resistant to methotrexate. The symptoms and signs are like those of aseptic meningitis induced by methotrexate, and because its use follows that of methotrexate, the incidence and predisposing factors are difficult to determine. Antibiotics  Intrathecal aminoglycosides have been given without significant local reactions, although reports exist of neurotoxicity involving loss of hearing and polyradiculitis. Aseptic meningitis is an extremely rare adverse reaction of systemic administration of amoxicillin, with only 16 cases reported in the literature. The pathophysiology is not well defined, but the consensus is that it is most probably the result of an immunologic hypersensitivity reaction (Sousa and Raimundo 2020). Corticosteroids  Intrathecal injections of methylprednisolone acetate are associated with aseptic meningitis. Epidural injections of steroids are considered safer, but cases of aseptic meningitis have been reported following this procedure as well. It is likely that in these cases, subarachnoid space was entered inadvertently. Spinal anesthesia. Aseptic meningitis may follow spinal anesthesia due to complications resulting in arachnoiditis: blood in the intrathecal space, introduction of neurotoxic and neuroirritant substances, and surgical interventions on the spine. Intrathecal Baclofen  Aseptic meningitis is a rare complication of intrathecal baclofen injections that must be recognized. It is a diagnosis of exclusion, and its pathophysiological mechanism remains unclear (Bensmail et al. 2006). Radiologic Contrast Media  Arachnoiditis was recognized as a residual effect of oil-based intrathecal contrast agents used more than two decades ago. Introduction of water-soluble contrast agents reduced the incidence of aseptic meningitis, but it was still reported as a complication of metrizamide myelography in 5% of cases. Introduction of less toxic water-soluble agents

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further reduced adverse effects, but rare cases of aseptic meningitis are still reported after intrathecal iohexol injection for CT myelography. Neurotoxicity of radiological contrast media includes transient encephalopathy, seizures, and meningeal reactions. Radiolabeled Albumin  Aseptic meningitis is also described following the use of intrathecal isotopes for diagnostic purposes and as a complication of scinticisternography utilizing 111indium-DTPA and intrathecal injection of radioiodinated serum albumin. Both iodine and albumin might be implicated as causing an “allergic” reaction when injected into the subarachnoid space. Intraventricular Drugs  Aseptic meningitis is the most frequent complication of intraventricular chemotherapy for leptomeningeal metastases. Devices Used for Treatment of Neurologic Disorders  Aseptic meningitis has been reported as a complication of hydrogel-coated coils used in the treatment of intracranial aneurysms. Vaccines  Measles-mumps-rubella vaccines containing the Urabe strain of mumps were withdrawn in the UK in 1992 following demonstration of an increased risk of aseptic meningitis 15–35 days after vaccination. In 1998, a replacement measles-mumps-rubella vaccine called Priorix was introduced and the number of cases of aseptic meningitis decreased significantly. A systematic review of literature including clinical trials and other studies as well as case reports provides evidence supporting an association between aseptic meningitis and MMR vaccines containing Urabe and Leningrad-Zagreb mumps strains but no evidence supporting this association for MMR vaccines containing Jeryl Lynn mumps strains (Di Pietrantonj et al. 2020). Pathomechanism of Drug-Induced Aseptic Meningitis  Although the exact pathomechanism of drug-induced aseptic meningitis is still unknown, the most implicated drugs act likely

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through immunological mechanisms. The proposed mechanisms of drug-induced aseptic meningitis fall into two categories: (1) hypersensitivity reactions and (2) direct irritation of the meninges. The latter usually involves direct instillation of an agent into the meninges. The circumstantial evidence in favor of a hypersensitivity reaction is the rapid development of symptoms following drug ingestion, the progressively shorter periods in recurrent cases, and the development of classic features (facial edema, conjunctivitis, pruritus) in some cases. Elevated levels of immune complexes in CSF of patients with drug-induced aseptic meningitis would support the hypersensitivity reaction theory. Some patients may be able to tolerate a drug initially but develop drug-­induced aseptic meningitis on subsequent administration. One explanation is that the drug may behave as a hapten that binds to intravascular proteins, prompting the immune system of the body to subsequently recognize those proteins as foreign antigens. Unlike the hypersensitivity reactions, drug-­ induced aseptic meningitis due to direct irritation may be delayed up to several weeks following the administration of the drug. The toxicity of the drug or the chemical in the CSF is related to the following criteria:

11  Drug-Induced Aseptic Meningitis

• Some patients with chronic migraine are prone to intravenous immunoglobulin-induced aseptic meningitis (Yelehe-Okouma et al. 2018). • Patients with AIDS. Immune abnormalities such as serum and CSF antiribonucleoprotein antibodies may play a role in the development of nonsteroidal anti-inflammatory drug-induced aseptic meningitis in patients with a history of connective tissue disorders. Antiribonucleoprotein antibodies were positive in serum and CSF of a patient who developed aseptic meningitis following the use of loxoprofen, a nonsteroidal anti-inflammatory drug (Matsui et al. 2018). A drug lymphocyte stimulation test was negative, and symptoms resolved after cessation of loxoprofen, confirming the diagnosis of nonsteroidal anti-­ inflammatory drug-induced aseptic meningitis. Pathomechanism of Aseptic Meningitis Induced by Intravenous Immunoglobulin  The mechanism is not well understood, but the following hypotheses have been proposed:

• Serum immunoglobulins, particularly IgG, can cross the blood-brain barrier. Breech of the blood-brain barrier in patients with autoimmune disorders of the CNS may allow entry of even the high molecular weight IgM into the CSF compartment. One of the cardinal • Concentration of the drug or the chemical features of Guillain-Barré syndrome is the • Lipid solubility high concentration of protein in the lumbar • Particle size CSF.  The endothelial barriers of the dorsal • Ability to ionize the CSF root ganglia and ventral roots, which already • Duration of contact with CSF leak more than under normal conditions, become severely damaged and permit the pasPredisposing Factors  The following risk facsage of plasma proteins, including intravenous tors can be identified from studying drug-induced immunoglobulin. aseptic meningitis case reports: • The infused IgG is derived from a pool of multiple donors and is allogeneic. Within the CSF, it may react with antigenic determinants • Patients suffering from autoimmune disorders on the endothelial cells of the meningeal vasmay be at greater risk for developing drug-­ culature, release cytokines, and lead to an induced aseptic meningitis. inflammatory reaction as evidenced by the • Systemic lupus erythematosus predisposes to pleocytosis in the CSF. drug-induced aseptic meningitis during NSAID therapy, especially ibuprofen-based • Intravenous immunoglobulin-associated aseptic meningitis is presumed to be an acute one (Yelehe-Okouma et al. 2018).

Differential Diagnosis

hypersensitivity reaction limited to the leptomeninges without systemic anaphylaxis. • Patients with a history of migraine are more likely to develop aseptic meningitis when receiving the intravenous immune globulin, and this may be due to increased cerebrovascular sensitivity in migraineurs.

Pathogenesis of Aseptic Meningitis Due to Muromonab-CD3  First-dose reaction to muromonab-­CD3 was originally considered to be idiosyncratic, but recurrence with subsequent administration is against this theory. Serum levels of various cytokines are elevated during this reaction. The pathomechanism remains uncertain. Drug-Induced Eosinophilic Meningitis  The pathomechanism is uncertain, but it is presumably an idiosyncratic reaction.

Epidemiology No figures are available for overall incidence of drug-induced aseptic meningitis. The incidence of aseptic meningitis (including viral meningitis and other systemic disorders) has been reported as 11 per 100,000 person-years, compared with a rate of 8.6 per 100,000 for bacterial meningitis. Some idea of the frequency of occurrence of drug-induced aseptic meningitis can be obtained from cases reported with drugs in specific therapeutic areas.

Prevention Prevention involves the avoidance of drugs suspected to produce aseptic meningitis in susceptible individuals. This is not always predictable because of the idiosyncratic nature of the adverse effects in some cases. The use of some drugs is unavoidable, even if there exists a risk of this complication. One example is the use of trimethoprim-­sulfamethoxazole therapy for pro-

163

phylaxis against Pneumocystis carinii in HIV-­ infected adults, even though AIDS is a risk factor for aseptic meningitis due to this drug.

Differential Diagnosis Differential diagnosis of drug-induced aseptic meningitis should be conducted according to the causes of aseptic meningitis (as shown in Table 11.2). The possibility that the patient may have recently taken an antibiotic and may have partially treated bacterial meningitis should also be considered. Drug-induced aseptic meningitis should be considered in the differential diagnosis of acute and recurrent aseptic meningitis. The diagnosis of drug-induced aseptic meningitis is difficult, and in some cases it has been confirmed by rechallenging the patient with the suspected agent.

Table 11.2  Differential diagnosis of drug-induced aseptic meningitis Aseptic meningitis of Mollaret Bacterial meningitis Cerebral vasculitis Fungal meningitis: e.g., Cryptococcus neoformans Leptomeningeal cancer Neurosyphilis: aseptic meningitis Parasitic infections of the brain: Toxoplasma gondii and cysticercosis Viral meningitis Systemic diseases  Adult-onset Still disease, a systemic inflammatory disease (Akkara Veetil et al. 2012)  Behçet disease  Fabry disease  Immunodeficiency states (e.g., AIDS)  Mixed connective tissue disease  Sarcoidosis  Vogt-Koyanagi-Harada syndrome  Wegener granulomatosis Defects at base of skull (e.g., post-traumatic CSF fistula iatrogenic)  Neurosurgical procedures  Intrathecal injections of drugs and diagnostic agents Spontaneous intracranial hypotension syndrome (Balkan et al. 2012) © Jain PharmaBiotech

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Informed written consent is necessary and rechallenge must be medically supervised. Drug-induced aseptic meningitis has an association with the following underlying disorders: • • • • • • • • • •

Crohn disease HIV infection Idiopathic thrombocytopenic purpura Rheumatoid arthritis Sjögren syndrome Systemic lupus erythematosus Bacterial meningitis Viral infections Neoplastic disease Systemic diseases

11  Drug-Induced Aseptic Meningitis

teristic of aseptic meningitis associated with intravenous immunoglobulin. • CSF proteins are usually elevated. CSF culture results are always negative. • CSF lactic acid levels differentiate aseptic from early purulent meningitis. Drug-induced aseptic meningitis should be suspected in patients who have a normal CSF lactic acid level and a predominance of polymorphonuclear cells.

Human enteroviruses are the most frequent cause of aseptic meningitis. Drug-induced meningitis needs to be differentiated from viral aseptic meningitis, which can be detected by polymerase chain reaction (PCR)-based tests. A Drug-induced aseptic meningitis cannot be real-time reverse transcriptase-quantitative PCR distinguished from meningitis caused by other (RT-qPCR) assay is a valuable tool for diagnosis agents, and diagnosis is, therefore, based on close of enterovirus infection from CSF samples as association between drug administration and shown in research studies (Volle et al. 2012). onset of symptoms, as well as negative microbiIt is important to differentiate between bacteology test results (Farr and Mogensen 2010). In a rial meningitis and aseptic meningitis to prevent patient with headache, fever, meningeal signs, unnecessary use of antibiotics and hospitalizaand CSF results consistent with meningitis, tions. A multicenter, retrospective cohort study infections should be ruled out as a cause. has shown that the Bacterial Meningitis Score Diagnosis of drug-induced aseptic meningitis is may be helpful in guiding clinical decision-­ also made by exclusion, unless clear-cut evidence making for the diagnosis of children presenting shows a relationship to the drug. to emergency departments with CSF pleocytosis (Nigrovic et  al. 2007). This method classifies patients at very low risk of bacterial meningitis if Laboratory Investigations they lack all the following criteria: positive CSF Gram stain, CSF absolute neutrophil count of at White blood count and lumbar puncture are rele- least 1000 cells/microL, CSF protein of at least vant tests. 80  mg/dL, peripheral blood absolute neutrophil count of at least 10,000 cells/microL, and a his• The peripheral white blood count may be nor- tory of seizure before or at the time of mal or elevated. A predominance of mononu- presentation. clear cells in the CSF is characteristic of In cases of nonsteroidal anti-inflammatory chronic recurrent meningitis. drugs, meningitis mostly occurred within weeks • Lumbar puncture usually reveals a high open- of the start of therapy, but cases have been ing pressure. CSF examination shows pleocy- reported as late as 2 years after initiation of thertosis ranging from a hundred to several apy. The CSF findings in these cases varied thousand cells. The predominant cells are greatly. In general, there were polymorphonupolymorphonuclears; however, rarely, lym- clear pleocytosis, an elevation in protein concenphocytic and eosinophilic forms of drug-­ tration, and normal glucose content. Staining and induced aseptic meningitis have also been culture of CSF for microorganisms were negative reported. Eosinophils in the CSF are charac- in all cases.

References

165

Meningitis Due to Intravenous Immunoglobulin  In the reported cases, aseptic meningitis appeared on the second or the third day of therapy, except in one case where the reaction appeared 2 days after the discontinuation of combined intravenous immunoglobulin and steroid therapy. A renal transplant recipient developed aseptic meningitis and diplopia due to abducent nerve palsy following intravenous immunoglobulin administration of antibody-­ mediated rejection (Wright et al. 2008). A patient with a history of systemic lupus erythematosus, a well-known predisposing factor for aseptic meningitis due to other drugs, presented with meningismus 36  h after first infusion of intravenous immunoglobulin (Graça et al. 2018). In most of the reported cases, intravenous immunoglobulin therapy was discontinued after onset of aseptic meningitis; however, in one case, intravenous Management immunoglobulin could not be discontinued Discontinuation of the offending drug is the main because of the low platelet count and risk of life-­ step in the management of drug-induced aseptic threatening hemorrhage. Despite continuation of meningitis. This depends on the drug involved therapy in this case, the symptoms of meningitis and the condition of the patient. If drug-induced cleared up on the fourth day of treatment with meningitis is suspected, the drug should be dis- intravenous immunoglobulin. The following continued, if possible. Recovery usually occurs three measures are helpful in preventing or reducfollowing discontinuation of the offending drug. ing the problems associated with high-dose intraSymptomatic treatment involves the use of anti- venous immune globulin: (1) the initial infusion emetics for nausea and analgesics for headache, should be diluted and given slowly, and if well taking care to avoid nonsteroidal anti-­tolerated, then the concentration can be increased; inflammatory drugs suspected of inducing this (2) patients should be well hydrated during the condition. Headache due to drug-induced aseptic treatment; and (3) antihistaminics and acetaminmeningitis is different from headache due to ophen may be used as premedication. overuse of analgesics as it may be relieved when the underlying cause is removed. Headache in Aseptic Meningitis Due to Myelography  This drug-induced aseptic meningitis may have is a hypersensitivity reaction to the contrast matemigrainous features, and there are single case rial, and patients usually recover after removal of reports of response to triptans (Holle and the residual iophendylate and the administration of large doses of corticosteroids. Obermann 2015). Ibuprofen should not be prescribed for patients with systemic lupus erythematosus because of the frequent occurrence of ibuprofen-induced References aseptic meningitis with the background of this Akkara Veetil BM, Yee AH, Warrington KJ, Aksamit AJ disease. Jr, Mason TG. Aseptic meningitis in adult onset Still’s A patient has reported to have developed drug-­ disease. Rheumatol Int. 2012;32(12):4031–4. induced liver injury as well as meningitis while Audemard A, Le Bellec ML, Carluer L, et al. Fumagillin-­ induced aseptic meningoencephalitis in a kidney using ibuprofen (Nayudu et  al. 2013). Both transplant recipient with microsporidiosis. Transpl cleared up when the drug was discontinued. In postmyelographic meningitis, serum procalcitonin might be able to discriminate between bacterial and chemical causes of meningitis. Serum levels of procalcitonin, a precursor of calcitonin, are raised in bacterial meningitis due to leakage through the impaired blood-brain barrier, whereas they are normal in viral infections and other types of meningitis such as aseptic meningitis (Velissaris et al. 2018). Pathologic meningeal enhancement has been reported in patients with bacterial and viral meningitis. MRI may show diffuse supratentorial white matter abnormalities that clear up after recovery from aseptic meningitis. MRI could be a valuable adjunct diagnostic procedure in drug-­ induced aseptic meningitis.

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166 Balkan II, Albayram S, Ozaras R, et  al. Spontaneous intracranial hypotension syndrome may mimic aseptic meningitis. Scand J Infect Dis. 2012;44(7):481–8. Barrett PV, Thier SO.  Meningitis and pancreatitis associated with sulfamethizole. N Engl J Med. 1963;268:36–7. Bensmail D, Peskine A, Denys P, Bernard L, Bussel B. Aseptic meningitis after intrathecal baclofen injection. Spinal Cord. 2006;44(5):330–3. Bharath V, Eckert K, Kang M, Chin-Yee IH, Hsia CC.  Incidence and natural history of intravenous immunoglobulin-induced aseptic meningitis: a retrospective review at a single tertiary care center. Transfusion. 2015;55(11):2597–605. Bihan K, Weiss N, Théophile H, Funck-Brentano C, Lebrun-Vignes B.  Drug-induced aseptic meningitis: 329 cases from the French pharmacovigilance database analysis. Br J Clin Pharmacol. 2019;85(11):2540–6. Bruner KE, Coop CA, White KM.  Trimethoprim-­ sulfamethoxazole-­induced aseptic meningitis-not just another sulfa allergy. Ann Allergy Asthma Immunol. 2014;113(5):520–6. Chalimou I, Krilis A, Anastopoulou GG, et  al. Acute aseptic meningitis during isotretinoin treatment for nodular acne solely presenting with headache: case report and brief review of the literature. Int J Neurosci. 2019;129(2):204–6. Cushing H, Bailey P.  Tumors arising from the blood-­ vessels of the brain: angiomatous malformations and hemangioblastomas. Charles C Thomas: Springfield; 1928. Damsgaard J, Hjerrild S, Andersen H, Leutscher PD.  Long-term neuropsychiatric consequences of aseptic meningitis in adult patients. Infect Dis (Lond). 2015;47(6):357–63. Di Pietrantonj C, Rivetti A, Marchione P, Debalini MG, Demicheli V.  Vaccines for measles, mumps, rubella, and varicella in children. Cochrane Database Syst Rev. 2020;4(4):CD004407. Doghmi N, Meskine A, Benakroute A, Bensghir M, Baite A, Haimeur C.  Aseptic meningitis following a bupivacaine spinal anesthesia. Pan Afr Med J. 2017;27:192. Emani MK, Zaiden RA Jr. Aseptic meningitis: a rare side effect of cetuximab therapy. J Oncol Pharm Pract. 2013;19(2):178–80. Farr KP, Mogensen CB. Drug-induced aseptic meningitis. [Article in Danish]. Ugeskr Laeger. 2010;172(4):298– 9. PMID 20105400 Fisher JH, Sydney MB.  Encephalomyelitis following administration of sulfanilamide. Lancet. 1939;1:301–5. Foley RW, Tagg NT, Schindler MK, et  al. Recurrent natalizumab-­ related aseptic meningitis in a patient with multiple sclerosis. Mult Scler. 2017;23(10):1424– 7. https://doi.org/10.1177/1352458517702533. Frederiks JA, Bruyn GW.  Mollaret’s meningitis. In: McKendall RR, editor. Handbook of clinical neurology, Vol 12, viral disease. Amsterdam: Elsevier Science Publishers; 1989. p. 627–35.

11  Drug-Induced Aseptic Meningitis Graça L, Alves J, Nuak J, Sarmento A. Immunoglobulin-­ induced aseptic meningitis: a case report. BMC Neurol. 2018;18(1):97. Holle D, Obermann M. Headache in drug-induced aseptic meningitis. Curr Pain Headache Rep. 2015;19(7):29. Jazeron A, Lallier JC, Rihn B, Thiercelin MC.  Aseptic meningitis possibly induced by adalimumab. Joint Bone Spine. 2010;77(6):618–9. Jha P, Stromich J, Cohen M, Wainaina JN.  A rare complication of trimethoprim-sulfamethoxazole: drug induced aseptic meningitis. Case Rep Infect Dis. 2016;2016:3879406. Longcope WT.  Serum sickness and analogous reactions from certain drugs particularly the sulfonamides. Medicine. 1943;22:251–86. Matsui T, Nakagawa K, Yamazaki K, Wada T, Kadoya M, Kaida K.  An anti-RNP antibody-positive case of aseptic meningitis induced by non-steroidal anti-­ inflammatory drugs in a young woman [Article in Japanese]. Rinsho Shinkeigaku. 2018;58(1):25–9. Mollaret MP. La meningite endothelio-leucocytaire multirecurrente benigne syndrome nouveau ou maladie nouvelle. Rev Neurol. 1944;76:57–76. Mullane D, Williams L, Merwick A, Tobin WO, McGuigan C. Drug induced aseptic meningitis caused by intravenous immunoglobulin therapy. Ir Med J. 2012;105(6):182–3. Nagovskiy N, Agarwal M, Allerton J. Cetuximab-induced aseptic meningitis. J Thorac Oncol. 2010;5(5):751. Nayudu SK, Kavuturu S, Niazi M, Daniel M, Dev A, Kumbum K. A rare coexistence: drug induced hepatitis and meningitis in association with Ibuprofen. J Clin Med Res. 2013;5(3):243–6. Nigrovic LE, Kuppermann N, Macias CG, et al. Clinical prediction rule for identifying children with cerebrospinal fluid pleocytosis at very low risk of bacterial meningitis. JAMA. 2007;297(1):52–60. Pearce JM.  Mollaret’s meningitis. Eur Neurol. 2008;60(6):316–7. Prieto-González S, Escoda R, Coloma E, Grau JM.  Amoxicillin-induced acute aseptic meningitis. J Clin Neurosci. 2011;18(3):443–4. PMID 21239175 Rowley D, Houlihan L, McFaul K, Clarke S, Lyons F. A diagnostic dilemma: drug-induced aseptic meningitis in a 45-year-old HIV-positive man. Int J STD AIDS. 2014;25(4):309–11. PMID 23999938 Sethi NK. Lamotrigine and aseptic meningitis. Neurology. 2012;79(8):833–4. Sousa D, Raimundo P. Amoxicillin-Induced Aseptic Meningitis. Eur J Case Rep Intern Med. 2020;7(6): 001543. Simms KM, Kortepeter C, Avigan M.  Lamotrigine and aseptic meningitis. Neurology. 2012;78(12):921–7. Thilmann AF, Mobius E, Thilmann RR, et  al. Rezidivierende aseptische Meningitis (Mollaret-­ Meningitis) spontanes und Medikamentos induziertes Auftreten. Fortschr Neurol Psychiat. 1991;59:493–7. Tuleja E, Bourgarit A, Abuaf N, Le Beller C, Séréni D.  Rifampin-induced severe aseptic meningitis. Rev Med Interne. 2010;31(9):e1–3. PMID 20674104

References Ulrich A, Weiler S, Weller M, Rordorf T, Tarnutzer AA.  Cetuximab induced aseptic meningitis. J Clin Neurosci. 2015;22(6):1061–3. PMID 25769257 Velissaris D, Pintea M, Pantzaris N, et al. The role of procalcitonin in the diagnosis of meningitis: a literature review. J Clin Med. 2018;7(6):148. Volle R, Nourrisson C, Mirand A, et al. Quantitative real-­ time RT-PCR assay for research studies on enterovirus infections in the central nervous system. J Virol Methods. 2012;185(1):142–8. Wallgren A. Une nouvelle maladie infectieuse du systeme nerveux central. Acta Pediatr Scand. 1925;4:158–82.

167 Wang DY, Chong WS, Pan JY, Heng YK. First case report of aseptic meningitis induced by adalimumab administered for treatment of chronic plaque psoriasis. J Investig Allergol Clin Immunol. 2017;27(3):183–5. Wright SE, Shaikh ZH, Castillo-Lugo JA, Tanriover B. Aseptic meningitis and abducens nerve palsy as a serious side effect of high dose intravenous immunoglobulin used in a patient with renal transplantation. Transpl Infect Dis. 2008;10(4):294–7. Yelehe-Okouma M, Czmil-Garon J, Pape E, et al. Drug-­ induced aseptic meningitis: a mini-review. Fundam Clin Pharmacol. 2018;32:252–60.

Drug-Induced Intracranial Hypertension

Introduction The clinical syndrome of raised intracranial pressure without a space-occupying lesion was first recognized in 1897 by Quincke who had already discovered lumbar puncture. Subsequently various terms have been used for this condition: • • • •

Otitic hydrocephalus Pseudotumor cerebri (Nonne 1904) Benign intracranial hypertension (Foley 1955) Idiopathic intracranial hypertension (Buchheit et al. 1969)

The term idiopathic intracranial hypertension (IIH) is the most frequently used of the above and defined as prolonged raised intracranial pressure without ventricular enlargement or focal neurological signs or disturbances of consciousness and intellect (Foley 1955). The term “benign” may be misleading as 5 of a series of 20 patients with IIH had persistent intellectual impairment (Sorensen et al. 1986). The most frequent symptoms are headaches and diplopia and impairment of visual acuity. Papilledema and bilateral abducent nerve palsies are the only signs. IIH may occur without headache and papilledema. Revised criteria in 2013 defined the diagnosis of pseudotumor idiopathic intracranial hypertension including criteria for those in whom papilledema is absent as follows (Friedman et al. 2013):

12

A. Papilledema. B. Normal neurologic examination, except for cranial nerve abnormalities. C. Neuroimaging. For obese women, normal brain parenchyma without evidence of hydrocephalus, mass, or structural lesion and no abnormal meningeal enhancement on magnetic resonance imaging (MRI) with and without gadolinium; for other patients, MRI criteria listed for obese women, together with magnetic resonance venography (MRV) to rule out dural venous sinus thrombosis. If MRI is unavailable or contraindicated, contrast-­ enhanced computed tomography may be substituted. D. Normal cerebrospinal fluid (CSF) composition. E. Elevated lumbar puncture opening pressure [≥250  mm of CSF fluid in adults and ≥280  mm of CSF in children (250  mm of CSF if the child is not sedated and not obese)] in a properly performed lumbar puncture (lateral decubitus position). The diagnosis is considered “definite” if the patient fulfills criteria A through E. Patients meeting criteria A through D whose CSF pressure is below the limit specified in criterion E have “probable” idiopathic intracranial hypertension. If papilledema is not present, the diagnosis of idiopathic intracranial hypertension should not

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_12

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be made unless criteria B through E are satisfied and the patient has a unilateral or bilateral sixth cranial nerve palsy. If papilledema and a sixth cranial nerve palsy are not present, idiopathic intracranial hypertension is “suggested” when criteria B through E are fulfilled and at least three of the following imaging findings are apparent: 1. Empty sella. 2. Distention of the perioptic subarachnoid space with or without a tortuous optic nerve. 3. Flattening of the posterior sclerae. 4. Transverse venous sinus stenosis.

Epidemiology The incidence of IIH is 1–2 per 100,000 per year in the general population. It is more common in the females than in the males by a factor of 3:1. In the high-risk group of obese females in the reproductive age group, the annual incidence rises to 19–21 per 100,000. There is evidence that the incidence of IIH in the USA has at least doubled over the past decade, parallel to the rising incidence of obesity.

Pathophysiology of Idiopathic Intracranial Hypertension Obese women in the childbearing period are at risk for developing IIH. Obesity is an important cause. Increased intraabdominal pressure associated with central obesity is the probable etiology of benign intracranial hypertension. This concept is the basis for gastric plication to reduce obesity in preference to the CSF-peritoneal shunting procedure. The syndrome may appear de novo in otherwise healthy persons. Several explanations have been considered for the pathophysiology of IIH. These include the following: • An increased rate of CSF formation • Sustained increase in intracranial venous pressure

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• A decreased rate of CSF absorption by arachnoid villi apart from venous occlusive disease • Increase in brain volume because of an increase in cerebral blood volume or interstitial fluid Histological evidence of cerebral edema in brain biopsy specimens taken at the time of surgical decompression for IIH was provided (Sahs and Joynt 1956). This is not a constant finding because it has been reported that two patients with IIH who died unexpectedly showed no evidence of cerebral edema at autopsy (Wall et al. 1995).

Secondary Intracranial Hypertension In contrast to IIH, secondary intracranial hypertension without ventricular enlargement is due to causes as listed in Table  12.1. Clinical features of idiopathic and secondary intracranial hypertension may be identical. However, because the treatment of secondary forms may be different, it is extremely important to investigate for secondary causes before concluding that the intracranial hypertension is idiopathic. Drugs are an important cause of secondary intracranial hypertension.

Drug-Induced Intracranial Hypertension (DIIH) DIIH is not always diagnosed as such in adverse drug reaction reports. Often the presenting symptom headache and the presenting sign papilledema are reported. Acute rise of intracranial pressure following drug therapy has been reported in situations listed in Table 12.2. The mechanism of rise of intracranial pressure in the above cases is not known. Some of the drugs used for lowering blood pressure by vasodilatation may have contributed to the rise of

Pathogenesis of Drug-Induced Intracranial Hypertension

intracranial pressure. Only one of the above, nalidixic acid, is associated with IH as well. Suxamethonium is contraindicated in neurosurgical anesthesia because of its potential to increase intracranial pressure. However, suxamethonium does not alter cerebral blood flow velocity, cortical activity, or intracranial pressure in patients with brain injury. Hoffmann-La Roche, Basel, and the Committee on Safety of Medicines in the UK reviewed the data of WHO and found 162 cases of DIIH reported during a period from 1972 to

Table 12.1  Causes hypertension

of

secondary

intracranial

Cranial venous outflow disturbances  Intracranial: lateral or superior sagittal sinus thrombosis, venous sinus obstruction due to meningiomas, arteriovenous fistula  Extracranial: head and neck surgery, ear infections  Venous hypertension: cardiac failure, respiratory disease Endocrine disorders  Adrenal insufficiency (Addison’s disease)  Corticosteroid excess (Cushing’s syndrome)  Pituitary disorders  Hypothyroidism Hematological disorders  Iron deficiency anemia  Pernicious anemia  Polycythemia rubra vera  Thrombocytopenia  Paroxysmal nocturnal hemoglobinuria  Myeloma Drugs Miscellaneous  Chronic respiratory disease  HIV infection  Renal failure  Systemic lupus erythematosus

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1987 (Askmark et  al. 1989; Griffin 1992). The ten most frequently reported drugs in these reviews were: 1. Minocycline 2. Isotretinoin 3. Nalidixic acid 4. Tetracycline 5. Trimethoprim-sulfamethoxazole 6. Cimetidine 7. Prednisolone 8. Methylprednisolone 9. Tamoxifen 10. Beclomethasone This list does not correspond with the results of the review of the literature on this subject as shown in Table 12.3. Table 12.3  Drugs reported to be associated with intracranial hypertension Amiodaronea Antibiotics/antimicrobial agents  Amphotericin  Ciprofloxacin  Minocyclinea  Nalidixic acida  Nitrofurantoin  Ofloxacin  Sulfonamides: sulfasalazine  Tetracyclinea, aspirin Chorionic gonadotropins Corticosteroidsa (withdrawal) Cyclosporine Cytosine arabinoside Danazola Growth hormonea Insulin-like growth factor-1 Lithiuma Nonsteroidal anti-inflammatory drugs (NSAIDs)a Oral contraceptives Perhexiline Phenytoin Quinagolide Retinoidsa Thyroid preparations Vaccination: DPT Vitamin A (excess as well as deficiency)a

© Jain PharmaBiotech Table 12.2  Drug-related acute intracranial hypertension Ketamine as an anesthetic Nalidixic acid for urinary infection Intravenous nitroglycerine for hypertension Suxamethonium in patients with brain tumors Sodium nitroprusside for hypertension Urapidil for hypertension in head injury © Jain PharmaBiotech

Well documented. Evidence for the other drugs consists of isolated case reports, and a causal relationship has not been established

a

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Pathogenesis of Drug-Induced Intracranial Hypertension In addition to the general factors in the etiology of IH, the following drug-related factors have been considered in DIIH: • Hypovitaminosis can reduce CSF absorption due to interstitial fibrosis of the meninges. • Hypervitaminosis A through increase of CSF production. • Lithium-induced inhibition of Na+, K+, and ATPase pump at arachnoid villi interferes with vitamin A transport leading to hypervitaminosis A. • Effect on cyclic AMP at arachnoid villi: lithium and tetracycline. • Intracranial infusion of arginine vasopressin leads to the rise of intracranial pressure and reduces CSF absorption and may be a factor in the etiology of DIIH. • Genetic susceptibility may predispose to development of DIIH. Amiodarone  Amiodarone has been reported to induce DIIH. Acute DIIH has also been reported during amiodarone infusion which may be explained by the vasodilator effect of the drug. Amphotericin  Intravenous amphotericin given for cryptococcal infection has been reported to induce DIIH in AIDS patients without any neuromeningeal involvement. DIIH regresses after withdrawal of the drug and treatment for cerebral edema. Androgens  Supporting the pathogenic role of androgens are some case reports detailing the development of IIH among patients undergoing gender reassignment from female to male with testosterone therapy (Hornby et al. 2017). IIH has been reported among hypogonadal males, particularly in men after androgen deprivation therapy for prostate cancer. There may be a “pathophysiological window” of testosterone levels in humans, with androgen excess in women and androgen deficiency in men that causes metabolic disturbances such as increased visceral fat deposition and insulin resistance, thus creating the possible neurometabolic syndrome of IIH.

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Aspirin  Cases of DIIH related to aspirin therapy have been reported in children with regression after discontinuation of the drug. The pathomechanism is not known. Chorionic Gonadotropin  Cases of DIIH have been reported following beta human chorionic gonadotropin (beta-hCG) therapy in children with undescended testes, but recovery is complete after treatment with acetazolamide. DIIH has also been reported in association with high serum levels of endogenous beta-hCC due to testicular tumors. DIIH develops after treatment of the tumor with chemotherapy, and return of beta-­ hCC levels to normal is followed by recovery from DIIH. These cases indicate that DIIH may be a withdrawal effect from beta-hCC. Ciprofloxacin  Winrow and Supramaniam (1990) have reported a case of DIIH after the use of ciprofloxacin in a teenager with cystic fibrosis. This patient improved after discontinuation of the drug and treatment with repeated lumbar punctures to lower the intracranial pressure. Corticosteroids  DIIH is associated with prolonged corticosteroid therapy. The syndrome is seen during the withdrawal phase of the steroids. Adrenal suppression from corticosteroids may be a factor in the pathogenesis of this syndrome although the cause is not known. DIIH has been reported in corticosteroid-deficient states and following removal of ACTH-secreting pituitary tumors. Corticosteroids are also used in the treatment of cerebral edema, and gradual tapering of the steroids reduces the chances of developing DIIH. Rarely DIIH develops with increase in corticosteroid dose. Little has been  added to our understanding of this problem and similar cases continue to occur. Cyclosporine  Asymptomatic optic disc edema and elevated intracranial pressure, resolving after discontinuation or lowering of the cyclosporine dose, have been reported in allogeneic bone marrow transplant patients. Pseudotumor cerebri develops during cyclosporine therapy after undergoing allogeneic bone marrow transplantation complicated by graft versus host disease. Improvement occurs after discontinuing cyclosporine.

Pathogenesis of Drug-Induced Intracranial Hypertension

Cytosine Arabinoside (ARA-C)  One case of DIIH has been reported following high-dose ARA-C therapy for promyelocytic leukemia (Evers et  al. 1992). The patient recovered after lumbar punctures to reduce the intracranial pressure. One theoretically possible mechanism in this case is the ARA-C-induced local phosphorus depletion and disruption of the ATPase-dependent choroidal secretion of CSF. Danazol  This is a synthetic ethisterone derivative, which inhibits the secretion and production of pituitary gonadotropin hormones. It has anabolic and androgenic effects and is used in the treatment of endometriosis, benign cystic breast disease, and some hematologic disorders. Several cases of DIIH have been reported in patients on danazol therapy. Cessation of danazol led to improvement in most of the cases. The mechanism is unknown, but it may be related to danazol-­ induced fluid retention and weight gain. One case has been reported after withdrawal of danazol therapy. One possible explanation is that some metabolites of danazol with a long half-life may continue to play a role in rising intracranial pressure after the drug is withdrawn. Growth hormone. Twenty-three cases of DIIH have been reported worldwide between 1986 and 1993 in association with the use of recombinant growth hormone (Malozowski et al. 1993). Three additional cases were reported after treatment with insulin growth factor I, the primary mediator of action of growth hormone. Some of these patients had other risk factors for IH such as obesity, renal failure, and endocrine disorders. A case of DIIH was reported in an 11-year-old girl where the diagnosis was delayed because the initial symptoms were only headaches which are reported commonly in children on growth hormone therapy and usually resolve spontaneously (Price et  al. 1995). DIIH has been reported in three children from Australia and one from New Zealand, who were being treated with recombinant human growth hormone (Crock et al. 1998). A 9-year-old girl developed DIIH 3 months after starting recombinant growth hormone treatment (Tornese et al. 2009). Recombinant growth hormone was discontinued, and acetazolamide was given without any clinical improvement, but

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intravenous dexamethasone led to a dramatic clinical improvement. The incidence of DIIH in children treated with growth hormone is small (1.2 per 1000 cases overall). The following measures are recommended for improved detection of DIIH: • Headaches in a patient on growth hormone therapy should be reported to the physician. • Fundoscopy should be done on these patients prior to the start of growth hormone therapy and during routine reviews. Insulin-Like Growth Factor (IGF)-1  Transient bilateral papilledema with DIIH has been reported in a 10-year-old boy treated with IDF-1 therapy for growth hormone receptor deficiency (Lordereau-Richard et  al. 1994). This occurred after increasing the dose. Recovery was complete after interruption of IGF-1 therapy, and the treatment was resumed 9 months later at a lower dose without recurrence of DIIH. Lithium  DIIH is known as a complication of long-term lithium therapy in patients with bipolar affective disorders, and several cases have been reported in the literature (Ames et  al. 1994; Chatillon et al. 1989; Lobo et al. 1978; Pesando et al. 1980). It has also been reported in patients on short-term lithium therapy (Alvarez-Cermeno et al. 1989). In most of the cases DIIH resolved on discontinuation of lithium therapy. In those patients where the lithium therapy could not be discontinued, DIIH did not resolve. Most of the cases are in adults, but a case of the onset of DIIH associated with lithium treatment in a child has been reported where sustained long-term optic atrophy and vision loss occurred required acetazolamide treatment for approximately 1 year after cessation of lithium (Kelly et al. 2009). The pathomechanism of lithium-induced DIIH is not known. Patients treated with lithium whose antidiuretic hormone-cyclic adenosine monophosphate mechanism is disturbed are most likely to develop pseudotumor cerebri via dysregulation of sodium balance, thyroid hormone production, and glucose metabolism. Lithium-­ induced inhibition of vitamin A transport in the choroid plexus can lead to hypervitaminosis A.

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Minocycline  This is a semisynthetic tetracycline with greater lipid solubility than tetracycline itself and permeates the BBB more readily (see also the section on tetracycline). Several cases of minocycline-induced DIIH have been reported (Ang et  al. 2002; Boyd 1995; Delaney et  al. 1990; Donnet et al. 1992; Oswald et al. 2001; Wandstrat and Phillips 1995; Weller and Klockgether 1998). Most of these patients had taken minocycline for treatment of acne, and some had taken retinoids concomitantly which are also known to be associated with DIIH.  The pathomechanism is not known. The treatment is discontinuation of minocycline. Some of the cases required other measures for lowering intracranial pressure. Nalidixic Acid  Nalidixic acid, the quinolone frequently used in the treatment of acute dysentery, is now emerging as an important cause of DIIH in infants and young children. Since Boreus and Sundström (Boreus and Sundström 1967) reported the first case of DIIH in a child on treatment with nalidixic acid, several other cases have been reported. Twelve cases of DIIH were reported following nalidixic acid overdose (Mukherjee et al. 1990). A study of 20 such cases from India showed that all the patients had received a higher than recommended dose of nalidixic acid and that 85% of them were given the drug unnecessarily, i. e., for acute watery diarrhea (Riyaz et al. 1998). A high concentration of the drug in the commercial preparations and the lack of awareness about this among physicians were possible contributory factors leading to this situation. Nitrofurantoin  Three case reports have been published of DIIH following nitrofurantoin therapy of urinary infections (Korzets et  al. 1988; Mushet 1977; Sharma and James 1974). The pathomechanism is not known. Nonsteroidal Anti-inflammatory Drugs (NSAIDs)  These have been reported to cause DIIH.  Twenty-four new cases of papilledema with or without DIIH associated with NSAID therapy were reported to the National Registry of Drug-induced Ocular effects in the USA (Fraunfelder et al. 1994). More than half of these

12  Drug-Induced Intracranial Hypertension

cases were related to the use of propionic acid derivatives (ibuprofen and naproxen), and no cases were seen with pyrazolone derivatives. There are reports of indomethacin (Konomi et al. 1978) and ketoprofen (Larizza et al. 1979) producing DIIH in patients with Bartter’s syndrome. DIIH subsided in both cases after discontinuation of the offending drugs. Inhibition of prostaglandins by these drugs may lead to the retention of sodium and fluids, thus precipitating DIIH. Oral contraceptives (OC). DIIH has been reported following the use of OCs (Arbenz and Wormser 1965; Cosnet 1969; Vespignani et  al. 1984). This appears to be related to the estrogen and progesterone content of these pills which leads to water retention and weight gain which are risk factors for DIIH.  DIIH has been reported after replacement therapy with mestranol and norethisterone (Sheehan 1982). The rare complication of cerebral venous thrombosis caused by oral contraceptives may lead to DIIH (Agostoni et al. 2009). Levonorgestrel Implants  Two cases of DIIH have been reported in young women with levonorgestrel implants (Alder et al. 1995). In one of these, the symptoms resolved, whereas in the other, there was recurrence of symptoms which was controlled by acetazolamide. Although the causal relation is not certain, the authors recommend periodic examination of ocular fundus in patients with such implants who complain of headaches and visual problems. Sunku et  al. (1993) have reported two patients who developed DIIH after levonorgestrel implants for contraception. The patients recovered after removal of implants and treatment with diuretics. Perhexiline  DIIH following perhexiline therapy has been reported (Mandelcorn et  al. 1982; Stephens et al. 1978; Vespignani et al. 1984). Its profile in this respect is like that of amiodarone— a drug in the same therapeutic category. Phenytoin  DIIH has been reported in a patient with seizure disorder treated with phenytoin (Kalanie et al. 1986). This was confirmed by positive rechallenge in this case.

Pathogenesis of Drug-Induced Intracranial Hypertension

Quinagolide. This is a novel non-ergot-derived dopamine agonist which is used for the treatment of hyperprolactinemia in patients intolerant of bromocriptine. Two cases have been reported where withdrawal of this drug has led to development of DIIH (Atkin et al. 1994). These patients had other risk factors: one had an empty sella secondary to an operation and the other patient was on oral contraceptives. Both patients had migraine headaches. The headaches improved in intensity during treatment and increased in intensity after withdrawal. The relationship to quinagolide is indicated by the appearance of DIIH in both patients 2 weeks after discontinuation of the drug and disappearance a month after restarting quinagolide therapy. Vascular basis of migraine as well as DIIH suggests that quinagolide has an effect on the cerebral vasculature.

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Effects, the WHO, the FDA, and medical journals between 1979 and 2003, revealed 21 cases of DIIH (Fraunfelder and Fraunfelder 2004). Sulfonamides  Trimethoprim-sulfamethoxazole has been reported to be associated with DIIH (Askmark et  al. 1989; Jain and Rosner 1992). Another case has been reported with the use of sulfenazone (Murgia et al. 1989). A young female patient developed DIIH under sulfasalazine treatment for ulcerative colitis, which subsided after the drug was discontinued and the patient was given acetazolamide to lower intracranial pressure (Sevgi et al. 2008). These drugs are also known to be associated with aseptic meningitis (see Chap. 11).

Tetracycline  Association between DIIH and tetracycline was first reported by in the 1950s. Since then, several case reports of DIIH associRetinoids  Isotretinoin and etretinate are used ated with tetracycline therapy have appeared for the treatment of acne and other skin condi- (Maroon and Mealy 1971; Meacock and Hewer tions. There are several published reports of asso- 1982; Minutello et al. 1988; Pearson et al. 1981; ciation of these retinoids with DIIH (Bonnetblanc Pierog et  al. 1986). Walters et  al. (1981) preet al. 1983; Fraunfelder et al. 1985; Lebowitz and sented five such cases. Over 60 cases have been Berson 1988; Roytman et  al. 1988; Smith-­ reported in the literature to date. Symptoms disWhitley and Lange 1993; Spector and Carlisle appeared in most of the cases after discontinua1984; Viraben et  al. 1985). Sixty-four unpub- tion of tetracycline although papilledema lished cases of DIIH associated with retinoids persisted for several months in two of the cases. manufactured by Hoffmann-La Roche, Basel, Combination with vitamin A in young women were reviewed (Griffin 1992). The pathomecha- was recognized to be a risk factor. nism of this adverse effect is not known. In some One retrospective study (Ireland et  al. 1990) cases, tetracycline and minocycline (both of and 1 prospective case-control study (Guiseffi which are known to cause DIIH) were used con- et al. 1991) involving a total of 90 patients found comitantly with retinoids. In other cases, there no statistical association between tetracycline-­ was no concomitant medication. induced and other types of DIIH.  Two fraternal twin sisters developed DIIH after beginning Tretinoin  This is a retinoid that induces matura- treatment with tetracycline (Gardner et al. 1995). tion and decreased proliferation of acute promy- The authors reviewed 19 familial cases of DIIH elocytic leukemia (APL) cells. Although DIIH is from the literature and suggested genetic suscepknown as a complication of APL, cases of tibility may be a factor in the development of tretinoin-­induced DIIH have been reported (Chen drug-induced DIIH. The effect of tetracycline on et al. 1998; Sano et al. 1998; Selleri et al. 1996). cyclic AMP (second messenger to ADH) has The symptoms usually resolve after discontinua- been proposed as a mechanism for tetracycline-­ induced DIIH (Walters and Gubbay 1981a, b). tion of therapy. Most of the previously reported cases are in A review of 331 case reports of ocular side effects associated with the 3 marketed retinoids: the adults. Six young patients with DIIH ranging tretinoin, acitretin, and etretinate, drawn from the in age from 12 to 17  years were reported who National Registry of Drug-Induced Ocular Side were being treated for acne vulgaris (Quinn et al.

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1999). All patients responded to treatment, with recovery in 1 day to 4 weeks. Thyroid Preparations  DIIH has been associated with initiation of levothyroxine therapy for hypothyroidism (McVie 1983; Rohn 1985; Van Dop et  al. 1983; Williams 1997). Huseman and Torkelson (1984) described the first case of DIIH following T4 replacement for hypothalamic hypothyroidism. The cause of increased intracranial pressure following T4 remains unclear. DIIH has been reported with different kinds of thyroid replacement therapies: T3, and combinations of T3 and T4. Careful and frequent neurologic and fundoscopic assessment is recommended during the initiation of thyroid replacement therapy in hypothyroid states. Vaccination  DIIH has been reported following DPT vaccination in 10 cases (Salinas et al. 1990). There are other reports of bulging anterior fontanelle in infants after vaccination when vitamin A supplementation is given (de Francisco et  al. 1993). Vitamin A  Taken in the form of retinol or retinyl esters, vitamin A appears to be safe at doses of 5000–10,000  IU/day. Beta-carotene has not reported to have any ocular toxicity (Gross and Helfgott 1992). Toxic reactions are common when vitamin A is taken in megadoses. Marie and See (1954) were the first to describe a case of benign hydrocephalus following hypervitaminosis A in a 17-month-old child. In a series of 17 cases of vitamin A toxicity, nearly half of patients have signs and symptoms of DIIH (Muenter et al. 1971). Headaches were reported after 10 weeks of daily intake of 50,000 IU of vitamin A. Several reports of DIIH due to hypervitaminosis A have been described in the literature since then and have been reviewed by Griffin (1992). There are other single case reports (Bhettay and Bakst 1988; Bousser 1998; Gangemi et al. 1985; Drouet and Valance 1998; Sharieff and Hanten 1996; Wettstein and O’Neill 1998). Mechanisms by which vitamin A alters CSF circulation are still controversial but it may involve the following:

12  Drug-Induced Intracranial Hypertension

• An obstruction in the CSF pathways • An increase in CSF secretion may occur via the following: –– Interaction with transthyretin –– Impaired vitamin A transport in the choroid plexus • It is also possible that alterations in vitamin A metabolism modify the functions of arachnoid villi and reduce the absorption of CSF. Management of DIIH due to hypervitaminosis A involves withdrawal of this vitamin under medical observation. The symptoms usually resolve spontaneously. DIIH has also been reported to be caused by vitamin A deficiency during infancy (Kasarskis and Bass 1982). This may lead to thickening of the meninges with interstitial fibrosis and reduced CSF absorption. Prevention of this would obviously be adequate vitamin A intake.

Management of DIIH Various methods for the management of DIIH are listed in Table 12.4. Recognition of association of DIIH with drugs is important. There is no specific diagnostic method for ascertaining the specific contributing factors. Improvement following discontinuation of the suspected drug is one piece of the evidence. If the elevated intracranial pressure is being Table 12.4  Management of drug-induced intracranial hypertension (DIIH) Recognition and treatment of contributing diseases, e.g., management of obesity Discontinuation of the offending drug Reduction of intracranial pressure by medical measures  Lumbar punctures  Dehydrating agents Reduction of intracranial pressure by surgical procedures  Ventriculoperitoneal shunt  Optic nerve fenestration  Dural venous sinus stenting © Jain PharmaBiotech

Management of DIIH

treated at the same time, the value of dechallenge in linking the drug to the adverse reaction is questionable. Various methods are used for lowering the intracranial pressure: lumbar punctures, dehydrating agents such as mannitol, loop diuretics such as furosemide, corticosteroids, etc. Such a decision is made by the physician treating the patient according to the severity of the situation. DIIH due to tetracycline has been treated successfully by using acetazolamide without discontinuing tetracycline therapy. Based on the metabolic pathogenesis of IIH, an 11β-hydroxysteroid dehydrogenase type 1 inhibitor is currently being investigated as a treatment through a phase II, double-blind, randomized, placebo-controlled trial (Markey et  al. 2017). The primary outcome will assess the effect of this novel medication on intracranial pressure over a 12-week time frame. Secondary outcomes will include symptoms, visual function, papilledema, and safety. Ventriculoperitoneal Shunts  These have been performed more frequently and afford good relief from headaches, but the small ventricles present a technical difficulty in inserting catheters into this space. Further visual loss may be precipitated by the late failure of shunt. Optic Nerve Sheath Fenestration  The main concern is preservation of vision and the preferred operation is optic nerve sheath fenestration. In this procedure a window is made through the dura and arachnoid which enclose the optic nerve and contain CSF.  Improvement of optic nerve head has been shown after optic nerve sheath fenestration in those patients who do not respond to oral medications to decrease intracranial pressure. The mechanism by which optic nerve sheath fenestration resolves papilledema and preserves visual function is not entirely elucidated. It is believed to serve as an additional pathway for CSF egress or cause subarachnoid scarring around the nerve, serving as a mechanical blockade to shift pressures away from the retrolaminar optic nerve. The success of optic nerve sheath fenestrations may also be related to a cyst-­ like structure that develops contiguous to the fen-

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estration site, diverting CSF away from the confines of the optic nerve sheath or by improving blood perfusion to the optic nerve head (Gilbert et al. 2018). Dural Venous Sinus Stenting  Venous sinus stenting has emerged as a possible minimally invasive treatment option for medically refractory IIH. Improved MR venographic technology has identified dural venous sinus stenoses. Whether this venous narrowing is pathogenic or the result of elevated intracranial pressure remains unresolved. Case reports and case series document normalization of CSF opening pressures after endovascular stenting of transverse sinus stenoses, whereas others have detailed resolution of venous sinus narrowing after CSF drainage by cervical/lumbar drainage or CSF diversion procedures. Patients with higher mean pressure gradients and higher changes in pressure gradients after stenting tend to achieve more favorable outcomes (McDougall et al. 2018).

References Agostoni E, Aliprandi A, Longoni M.  Cerebral venous thrombosis. Expert Rev Neurother. 2009;9:553–64. Alder JB, Fraunfelder FT, Edwards R.  Levonorgestrel implants and intracranial hypertension. N Engl J Med. 1995;332(25):1720–1. Alvarez-Cermeno JC, Fernandez JM, O’Neill A, et  al. Lithium-induced headache. Headache. 1989;29:245–6. Ames D, Wirshing WC, Cokey HT, et  al. The natural course of pseudotumor cerebri in lithium-treated patients. J Clin Psychopharmacol. 1994;14:286–7. Ang ER, Zimmerman JC, Malkin E.  Pseudotumor cerebri secondary to minocycline intake. J Am Board Fam Pract. 2002;15:229–33. Arbenz JP, Wormser P.  Pseudotumor cerebri durch Sexualhormone. Schweiz Med Wochenschr. 1965;95:1654. Askmark H, Lundberg PO, Olsson S. Drug-related headache. Headache. 1989;29:441–4. Atkin SL, Masson EA, Blumhardt LD, et al. Benign intracranial hypertension associated with the withdrawal of a non-ergot dopamine agonist. J Neurol Neurosurg Psychiatry. 1994;57:371–2. Bhettay EM, Bakst CM.  Hypervitaminosis A causing benign intracranial hypertension. S Afr Med J. 1988;74:584–5. Bonnetblanc JM, Hugon J, Dumas M. Intracranial hypertension with etretinate. Lancet. 1983;ii:974.

178 Boreus LO, Sundström B.  Intracranial hypertension in a child during treatment with nalidixic acid. BMJ. 1967;2:744–5. Bousser MG.  Benign intracranial hypertension and chronic hypervitaminosis A.  Rev Neurol (Paris). 1998;154(11):784–5. Boyd I.  Benign intracranial hypertension induced by minocycline. Curr Ther. 1995;36:70–1. Buchheit W, Burton C, Haag B, et  al. Papilledema and idiopathic intracranial hypertension: report of familial occurrence. N Engl J Med. 1969;280:938–42. Chatillon JD, Schaison M, Berche M, et  al. Deux complication neuro-ophthalmiques rares d’un traitement au long cours par les sels de lithium. L’encephale. 1989;15:415–7. Chen HY, Tsai RK, Huang SM. ATRA-induced pseudotumour cerebri--one case report. Kao Hsiung I Hsueh Ko Hsueh Tsa Chih. 1998;14(1):58–60. Cosnet JE. Stroke and the pill. BMJ. 1969;2:450. Crock PA, McKenzie JD, Nicoll AM, et al. Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand. Acta Paediatr. 1998;87(4):381–6. de Francisco A, Chakraborty J, Chowdhury HR, et  al. Acute toxicity of vitamin A given with vaccines in infancy. Lancet. 1993;342:526–7. Delaney RA, Wee D, Naraynaswamy TR.  Pseudotumor cerebri and acne. Mil Med. 1990;155:511. Donnet A, Dufour H, Graziani N, et  al. Minocycline and benign intracranial hypertension. Biomed Pharmacother. 1992;46:171–2. Drouet A, Valance J.  Benign intracranial hypertension and chronic hypervitaminosis A. Rev Neurol (Paris). 1998;154(3):253–6. Evers JP, Jacobson RJ, Pincus J, et al. Pseudotumor cerebri following high-dose cytosine arabinoside. Br J Hematol. 1992;80:559–60. Foley J.  Benign forms of intracranial hypertension –“Toxic” and “Otitic” hydrocephalus. Brain. 1955;78:1–41. Fraunfelder FW, Fraunfelder FT.  Adverse ocular drug reactions recently identified by the National Registry of Drug-Induced Ocular Side Effects. Ophthalmology. 2004;111:1275–9. Fraunfelder FT, LaBraico JM, Meyer SM. Adverse ocular reactions possibly associated with isotretinoin. Am J Ophthalmol. 1985;100:534–7. Fraunfelder FT, Samples JR, Fraunfelder FW.  Possible optic nerve side effects associated with nonsteroidal anti-inflammatory drugs. J Toxicol Cut & Ocular Toxicol. 1994;13:311–6. Friedman DI, Liu G, Digre KB. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2013;81(13):1159–65. Gangemi M, Maiuri F, Di Martino L, et  al. Intracranial hypertension due to acute vitamin A intoxication. Acta Neurol (Napoli). 1985;7:27–31. Gardner K, Cox T, Digre KB.  Idiopathic intracranial hypertension associated with tetracycline use in fraternal twins. Neurology. 1995;45:6–10.

12  Drug-Induced Intracranial Hypertension Gilbert AL, Chwalisz B, Mallery R.  Complications of optic nerve sheath fenestration as a treatment for idiopathic intracranial hypertension. Sem Ophthalmol. 2018;33:36–41. Griffin JP. A review of the literature on benign intracranial hypertension associated with medication. Adv Drug React Toxicol Rev. 1992;11:41–58. Gross EG, Helfgott MA. Retinoids and the eye. Dermatol Clin. 1992;10:521–31. Guiseffi V, Wall M, Siegel PZ, et al. Symptoms and disease association in idiopathic intracranial hypertension (pseudotumor cerebri): a case control study. Neurology. 1991;41:239–44. Hornby C, Mollan SP, Mitchell J, et  al. What do transgender patients teach us about idiopathic intracranial hypertension? Neuroophthalmology. 2017;41:326–9. Huseman CA, Torkelson RD.  Pseudotumor cerebri following treatment of hypothalamic and primary hypothyroidism. AJDC. 1984;138:927–31. Ireland B, Corbett J, Wallace R.  The search for causes of idiopathic intracranial hypertension. Arch Neurol. 1990;47:315–20. Jain N, Rosner F.  Idiopathic intracranial hypertension: report of seven cases. Am J Med. 1992;93:391–5. Kalanie H, Niakan E, Harati Y, et al. Phenytoin-induced benign intracranial hypertension. Neurology. 1986;36:443. Kasarskis EJ, Bass NH. Benign intracranial hypertension induced by deficiency of vitamin A during infancy. Neurology. 1982;32:1292–5. Kelly SJ, O’Donnell T, Fleming JC, Einhaus S. Pseudotumor cerebri associated with lithium use in an 11-year-old boy. J AAPOS. 2009;13:204–6. Konomi H, Imai M, Nihei K, et al. Indomethacin causing pseudotumor cerebri in Bartter’s syndrome. N Engl J Med. 1978;298:855. Korzets A, Rathaus M, Chen B, et  al. Pseudotumor cerebri and nitrofurantoin. Drug Intell Clin Pharm. 1988;22:345. Larizza D, Colombo A, Lorini R, et al. Ketoprofen causing pseudotumor cerebri in Bartter’s syndrome. N Engl J Med. 1979;300:976. Lebowitz MA, Berson DS.  Ocular effects of oral retinoids. J Am Acad Dermatol. 1988;19:209–11. Lobo A, Pilek E, Stokes PE. Papilledema following therapeutic dosages of lithium carbonate. J Nerv Ment Dis. 1978;166:526–9. Lordereau-Richard I, Roger M, Chaussain JL.  Transient bilateral papilloedema in a 10-year old boy treated with recombinant insulin-like growth factor 1 for growth hormone receptor deficiency. Acta Paediatr Suppl. 1994;399:152. Malozowski S, Tanner LA, Wysowski D, et  al. Growth hormone, insulin-like growth factor I, and benign intracranial hypertension. N Engl J Med. 1993;329:665–6. Mandelcorn M, Murphy J, Coleman J. Papilledema without peripheral neuropathy in a patient taking perhexiline maleate. Can J Ophthalmol. 1982;17:173.

References Marie J, See G. Acute hypervitaminosis A of the infant. Am J Dis Child. 1954;87:731. Markey KA, Ottridge R, Mitchell JL, et al. Assessing the efficacy and safety of an 11β-hydroxysteroid dehydrogenase type 1 inhibitor (AXD4017) in the idiopathic intracranial hypertension drug trial, IIH:DT: clinical methods and design for a phase II randomized controlled trial. JMIR Res Protoc. 2017;6:e181. Maroon JC, Mealy J.  Benign intracranial hypertension: sequel to tetracycline therapy in a child. JAMA. 1971;216:1479–80. McDougall CM, Ban VS, Beecher J, et al. Fifty shades of gradients: does the pressure gradient in venous sinus stenting for idiopathic intracranial hypertension matter? A systematic review. J Neurosurg. 2018;130(3):999–1005. McVie R.  Pseudotumor cerebri and thyroid replacement therapy. N Engl J Med. 1983;309:731732. Meacock DJ, Hewer RL.  Tetracycline and benign intracranial hypertension. BMJ. 1982;282:1240. Minutello JS, Dimayuga RG, Carter J.  Pseudotumor cerebri, a rare reaction to tetracycline therapy. J Periodontol. 1988;59:848–51. Muenter MD, Perry HO, Judwig J.  Chronic vitamin A intoxication in adults. Am J Med. 1971;50:129–36. Mukherjee A, Dutta P, Lahiri M, et al. Benign intracranial hypertension after nalidixic acid overdose in infants. Lancet. 1990;335:1602. Murgia S, Del Curto E, Zecca G.  Benign intracranial hypertension caused by sulfenazone. Pediatr Med Chir. 1989;11:541–2. Mushet GR.  Pseudotumor and nitrofurantoin therapy. Arch Neurol. 1977;34:257. Nonne M. Über Fälle von Symptomenkomplex "Tumor cerebri" mit Ausgang in Heilung (Pseudotumor cerebri). Z Nervenheilkunde. 1904;27:169–216. Oswald J, Meier K, Reinhart WH, Kuhn M. Pseudotumor cerebri in minocyline treatment. Praxis (Bern 1994). 2001;90:1691–3. Pearson MG, Littlewood SM, Bowdon AN. Tetracycline and benign intracranial hypertension. BMJ. 1981;282:568–9. Pesando P, Nuzzi G, Maraini G. Bilateral papilledema in long term therapy with lithium carbonate. Pharmakopsychiatr Neuropsychopharmakol. 1980;13:235–9. Pierog SH, Al Salihi FL, Cinotti D. Pseudotumor c­ erebri – a complication of tetracycline treatment of acne. J Adolesc Health Care. 1986;7:139–40. Price DA, Clayton PC, Lloyd IC.  Benign intracranial hypertension induced by growth hormone treatment. Lancet. 1995;345:458–9. Quinn AG, Singer SB, Buncic JR. Pediatric tetracycline-­ induced pseudotumor cerebri. J AAPOS. 1999;3(1):53–7. Riyaz A, Aboobacker CM, Sreelatha PR.  Nalidixic acid induced pseudotumour cerebri in children. J Indian Med Assoc. 1998;96(10):308–14. Rohn R.  Pseudotumor cerebri following treatment of hypothyroidism. AJDC. 1985;139:752.

179 Roytman M, Frumkin A, Bohn TG. Pseudotumor cerebri caused by isotretinoin. Cutis. 1988;42:399–400. Sahs AL, Joynt RJ.  Brain swelling of unknown cause. Neurology. 1956;6:791–802. Salinas EC, Mir ES, Comalat AF, et  al. Hipertension endocraneal benigna tras immunizacion con DTP y polio. Ann Esp Pediatr. 1990;32:466–7. Sano F, Tsuji K, Kunika N, et  al. Pseudotumor cerebri in a patient with acute promyelocytic leukemia during treatment with all-trans retinoic acid. Intern Med. 1998;37:546–9. Selleri C, Pane F, Notaro R, et al. All-trans-retinoic acid (ATRA) responsive skin relapses of acute promyelocytic leukemia followed by ATRA-induced pseudotumor cerebri. Br J Haematol. 1996;92:937–40. Sevgi E, Yalcin G, Kansu T, Varli K. Drug induced intracranial hypertension associated with sulphasalazine treatment. Headache. 2008;48:296–8. Sharieff GC, Hanten K. Pseudotumor cerebri and hypercalcemia resulting from vitamin A toxicity. Ann Emerg Med. 1996;27:518–21. Sharma DB, James A.  Benign intracranial hypertension associated with nitrofurantoin therapy. BMJ. 1974;4:771. Sheehan JP.  Hormone replacement treatment and benign  intracranial hypertension. BMJ. 1982;284:1675–6. Smith-Whitley K, Lange B.  Fatal all-trans retinoic acid pneumonitis. Ann Intern Med. 1993;118:472–3. Sorensen PS, Thomsen AM, Gjerris F.  Persistent disturbances of cognitive functions in patients with pseudotumor cerebri. Acta Neurol Scand. 1986;73:264–8. Spector RH, Carlisle J.  Pseudotumor cerebri caused by a synthetic vitamin A preparation. Neurology. 1984;34:1509–11. Stephens WP, et  al. Raised intracranial pressure due to perhexiline maleate. BMJ. 1978;1:21. Sunku AJ, O’Duffy AE, Swanson JW. Benign intracranial hypertension associated with levonorgestrel (abstract). Ann Neurol. 1993;34:299. Tornese G, Tonini G, Patarino F, et  al. Double adverse drug reaction: recombinant human growth hormone and idiopathic intracranial hypertension  - acetazolamide and metabolic acidosis: a case report. Cases J. 2009;2:6534. Van Dop C, Conte FA, Koch TK, et  al. Pseudotumor cerebri associated with initiation of levothyroxine therapy for juvenile hypothyroidism. N Engl J Med. 1983;308:1076–80. Vespignani H, Lepori JC, Gehin P, et al. L’hypertension intracranienne bènigne: a propos de 4 observations d’étiologie médicamenteuse. Rev Otoneuroophtalmol. 1984;56:277–86. Viraben R, Mahieu C, Fontan B.  Benign intracranial hypertension during etretinate therapy for mycosis fungoides. J Am Acad Dermatol. 1985;13:515–7. Wall M, Dollar JD, Sadun AA, et al. Idiopathic intracranial hypertension. Arch Neurol. 1995;52:141–5.

180 Walters BNJ, Gubbay SS. Tetracycline and benign intracranial hypertension: report of five cases. BMJ. 1981;282:19–20. Walters B, Gubbay S. Reply to enquiries (letter). Br Med J. 1981a;282:1240. Walters BNJ, Gubbay SS.  Tetracycline and benign intracranial hypertension: report of five cases. BMJ. 1981b;282:19–20. Wandstrat TJ, Phillips J. Pseudotumor cerebri responds to acetazolamide. Ann Pharmacother. 1995;29:318.

12  Drug-Induced Intracranial Hypertension Weller M, Klockgether T.  Minocycline-induced benign intracranial hypertension. J Neurol. 1998;245:55. Wettstein A, O’Neill J.  Benign intracranial hypertension associated with hypervitaminosis A.  Aust Fam Physician. 1998;27(suppl 1):55–6. Williams JB. Adverse effects of thyroid hormones. Drugs Aging. 1997;11:460–9. Winrow AP, Supramaniam G. Benign intracranial hypertension after ciprofloxacin administration. Arch Dis Child. 1990;65:1165–6.

Drug-Induced Encephalopathies

Introduction The term “encephalopathy” has been used in the literature to characterize a constellation of symptoms and signs reflecting a generalized disturbance of brain function. Here the term is restricted to non-inflammatory organic disturbances of the brain. Encephalopathy may be acute or chronic. Encephalopathy and seizures may occur either together or separately but seizures are usually an acute manifestation. The manifestations vary according to the involvement of brain structures. Nonpharmacological causes of encephalopathy include the following: • Infectious encephalopathies, e.g., viral infections • Chronic traumatic encephalopathy following repeated brain injuries • Hypoxic/ischemic encephalopathy • Hypoglycemic encephalopathy • Toxic/metabolic encephalopathy • Hashimoto’s encephalopathy: autoimmune thyroid disease • Hepatic encephalopathy • Hypertensive encephalopathy • Uremic encephalopathy Toxic and metabolic encephalopathies are usually reversible. Periodic triphasic waves are seen on EEG examination in patients with metabolic and some drug-induced encephalopathies.

13

EEG may be normal or show only nonspecific disturbances. A classification of drug-induced encephalopathies is shown in Table 13.1. The term “leukoencephalopathy” is a special type of encephalopathy which indicates lesions of the white matter which may be viral or toxic or ischemic or immunologic in origin. The evidence for this pathology should ideally be based on brain imaging (ideally MRI) or neuropathological examination. The former is not always carried out in practice and the latter is usually limited to brain biopsy or autopsy. In case of uncertainty or lack of evidence, it may be preferable to refer to leave these cases under the broader category of encephalopathy. Leukoencephalopathy may be reversible or irreversible depending upon the nature of brain lesions and progression of the disease. The disease process may be localized as in the case of posterior leukoencephalopathy with involvement of the parieto-occipital region. The terms “encephalitis” and “encephalomyelitis” indicate widespread inflammatory disease of the CNS. Among therapeutic substances, only vaccines for viral diseases can be linked to encephalomyelitis. Some of the clinical manifestations of encephalopathies are covered in other chapters; disturbances of consciousness (Chap. 15), neuropsychiatric disorders (Chap. 16), seizures (Chap. 19), movement disorders (Chap. 20), and cerebellar disorders (Chap. 33). This chapter is an overview of CNS adverse effects referred to as

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_13

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13  Drug-Induced Encephalopathies

182 Table 13.1  Classification encephalopathies

of

drug-induced

Table 13.2  Drugs and other therapeutics reported to be associated with encephalopathy

Encephalopathy: nonspecific drug-induced disturbance of brain function Encephalopathies secondary to drug-induced metabolic disorders:  Hepatic encephalopathy and hyperammonemia  Hypoglycemic encephalopathy  Hyponatremic encephalopathy  Uremic encephalopathy  Wernicke’s encephalopathy Leukoencephalopathy: encephalopathy with white matter lesions  Secondary leukoencephalopathy: drug-induced hypertension  Natalizumab-associated multifocal leukoencephalopathy in multiple sclerosis Syndromes associated with drug-induced encephalopathy:  Reye’s syndrome  Toxic encephalopathy of the newborn Encephalitis or encephalomyelitis: inflammatory or infectious lesions of the CNS

Acyclovir a Alum Antibiotics: cephalosporins, isoniazid, mefloquine, metronidazolea, penicillin, sulfonamides Antiepileptic drugs Antineoplastic/anticancer drugs Baclofen a Bismuth a Bromides Digoxin Dimethylsulfoxide (DMSO) Fat emulsion therapy Filgrastim Histamine H2-receptor antagonists HOPA Intrathecal contrast agents: methotrexate, iohexol Intravenous immunoglobulin Levodopa a Lithium OKT3 Podophyllin PSC833 Stem cell transplantation Theophylline

© Jain PharmaBiotech

encephalopathies and which involve disturbance of more than one CNS function. Encephalopathies are common with overdosage of drugs and environmental toxins. The coverage in this chapter is restricted mainly to encephalopathies associated with the therapeutic use of drugs. Encephalopathy may be secondary to other drug-induced disorders such as hepatic encephalopathy, hypertensive encephalopathy, uremic encephalopathy, hyponatremia, and hypoglycemia. In Reye’s syndrome there is multi-­ organ involvement including the brain.

Drugs Associated with Encephalopathy Drugs which have been reported to be associated with encephalopathy are shown in Table 13.2.

Acyclovir Acyclovir is used for the treatment of herpes simplex virus encephalitis. Neuropsychiatric symptoms have been reported during acyclovir

Frequently reported

a

therapy as a manifestation of acyclovir neurotoxicity. Acyclovir encephalopathy is distinguishable from viral encephalitis by sudden onset, absence of fever or headache, and lack of focal neurologic findings and normal CSF findings. Symptoms usually appear within 2 days of start of acyclovir and resolve within several days after discontinuation of the drug. The most common risk factors are the concomitant use of other potentially neurotoxic medications and chronic renal failure. Encephalopathy with coma has been reported in patients with renal disease and herpes simplex or zoster after treatment with oral acyclovir. These patients recover after discontinuation of acyclovir and hemodialysis. Encephalopathy can also occur as an idiosyncratic reaction with normal blood levels of acyclovir in patients with renal disease. It has also been reported in patients with renal disease on peritoneal dialysis after start of acyclovir therapy because acyclovir peritoneal clearance is negligible.

Drugs Associated with Encephalopathy

Management  Dose of acyclovir should be lowered in patients with risk factors such as renal disease. A loading dose of 400 mg and a maintenance dose of 200  mg are recommended. Hemodialysis has been recommended as a diagnostic as well as therapeutic measure in such patients if acyclovir assay is not easily available. Due to its slow protein binding, low steady state volume of distribution, and high water solubility, acyclovir is an ideal drug for hemodialysis to enhance its elimination.

Aluminum Aluminum encephalopathy associated with hemodialysis, also called dialysis encephalopathy, is well known. Its manifestations include dysarthria, myoclonus, dementia, and seizures. Aluminum toxicity has been described in infants and children with abnormal renal function who are treated with oral or intravenous solutions containing aluminum. Alum bladder irrigation (aluminum ammonium sulfate or aluminum potassium sulfate) is used for hematuria, and several cases of acute encephalopathy have been reported following this procedure. The risk factors for this complication are renal failure and concomitant high-dose chemotherapy. Normally alum is an astringent and when applied locally, it prevents its own absorption. However, in patients with damage to bladder epithelium resulting from chemotherapy, alum cannot serve the astringent function and may be absorbed. Several cases of aluminum encephalopathy have been reported following the use of bone cement Ionocem (IONOS, D-8031 Seefeld/ Obb, Germany), a biomaterial that is widely used in Europe. Neuropathology  Experimental aluminum encephalopathy has been produced in the rabbit as an evidence for aluminum-induced neurodegeneration, and unless definitive evidence is available, aluminum remains a strong suspect in neurotoxicology. Examination of the brain of an elderly patient who died as a sequel of aluminum encephalopathy showed characteristic argyro-

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philic, aluminum-induced lysosomal intracytoplasmic inclusions in the choroid plexus epithelium, cortical glia, and numerous neuron populations. Laser microprobe mass analysis (LAMMA) has confirmed manifold increase in subcellular aluminum content, especially in the neuronal cytoplasm, which has also been demonstrated by atom absorption spectrometry. Management  Dialysis-associated encephalopathy must be considered as a possible cause of uncertain neuropsychiatric symptoms in patients on chronic hemodialysis. The diagnosis of aluminum-­ induced neurotoxicity is established by observing characteristic EEG changes which may precede clinical abnormalities by several months. Aluminum concentration in the plasma gives a reasonably accurate measure of the aluminum burden of the body. Values above 100 mg/L indicate that neurotoxicity can occur, and 200  mg/L is associated with overt signs of neurotoxicity. Preventive measures include avoidance of excessive use of aluminum-­ containing drugs and monitoring of serum aluminum levels in patients undergoing dialysis. Aluminum toxicity can be treated and reversed by using the chelator desferrioxamine as a therapeutic agent.

Antibiotics Antibiotics are among the most widely used medications in clinical settings. Seizures, encephalopathy, optic neuropathy, peripheral neuropathy, and exacerbation of myasthenia gravis are important examples of neurotoxic adverse events associated with the use of antibiotics (Rezaei et al. 2018).

Cephalosporins Like penicillin, cephalosporins can produce encephalopathy and seizures (see Chap. 19). Cefazolin encephalopathy has been reported mainly in patients with renal failure. Neurotoxicity of cephalosporins is due to low serum protein concentration in renal failure patients. Cefazolin is highly protein-bound and

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decreased protein binding in renal failure may be responsible for neurotoxicity. Ceftazidime, a third-generation cephalosporin, is structurally like penicillin. Absence status and toxic hallucinations have been reported following its use. Most of the neurotoxicity has been reported after intravenous use of this drug. Intraperitoneal ceftazidime is the recommended drug for treatment of peritonitis in general. Encephalopathy has been reported in an elderly patient after resolution of peritonitis by intraperitoneal ceftazidime. The manifestations are impaired consciousness, bilateral slow waves on EEG, and myoclonus. The patient had a recurrence of encephalopathy after repetition of ceftazidime for recurrence of peritonitis. Encephalopathy has been reported with another third-generation cephalosporin—cefuroxime. Patients usually recover within 48 h after discontinuation of the drug. Quinolone antibiotics are usually not associated with encephalopathy. There are rare cases of ciprofloxacin-induced encephalopathy in patients with renal failure and recovery followed by discontinuation of the drug.

Mefloquine Mefloquine is an effective prophylaxis and therapy for falciparum malaria. Neuropsychiatric adverse reactions are well documented (see Chap. 16). An acute brain syndrome (encephalopathy) has been reported as an adverse effect of the therapy. Metronidazole The neurotoxicity associated with metronidazole may manifest clinically as headache, dizziness, confusion, encephalopathy cerebellar toxicity (ataxia and dysarthria with cerebellar lesions seen on MRI), optic neuropathy, and peripheral neuropathy. These adverse effects usually develop with the long-term use of the medication and resolve after its discontinuation. A case of metronidazoleinduced encephalopathy has been described due to systemic absorption following topical/transdermal application (Mathew et al. 2020). The underlying mechanism is unknown, but axonal swelling secondary to metronidazole-­induced vasogenic edema has been proposed as an explanation.

13  Drug-Induced Encephalopathies

Penicillins Various penicillins may cause neurotoxic complications, such as confusion, disorientation, myoclonus, seizure, encephalopathy, and nonconvulsive status epilepticus. Intravenous penicillin G has been reported to produce encephalopathy. Penicillin encephalopathy has been produced experimentally and can be reversed by the use of intravenous penicillamine. Risk factors that may be associated with penicillin-­ induced neurotoxicity are previous CNS diseases, renal insufficiency, and an increased permeability of the BBB.  The major cause of penicillin-induced neurotoxicity is the inhibitory effect on gamma-aminobutyric acid (GABA) transmission because of the structural resemblance of the beta-lactam ring with GABA. Enzymatic cleavage of this ring results in the loss of epileptogenic activity. In addition, the thiazolidine ring and side-chain length may also contribute to the epileptogenic potential of penicillin. A study on rats has suggested that penicillins can reduce the number of benzodiazepine receptors and thus lower inhibition and alter neuronal excitability. Sulfonamides Sulfonamide-induced toxic encephalopathy is rare. Patients with AIDS are more susceptible to adverse drug reactions including sulfonamides. Cases of encephalopathy associated with sulfadiazine therapy in AIDS patients have been reported. Trimethoprim-sulfamethoxazole is associated with psychosis, encephalopathy, and aseptic meningitis (see Chap. 11). Cases of encephalopathy as a part of general hypersensitivity reaction to the drug have been reported. These neurotoxic effects are transient and resolve immediately after drug discontinuation. The predisposing factors have been shown to be old age and an immunocompromised status. The exact mechanism of neurotoxicity is not known, but trimethoprim-­ sulfamethoxazole easily penetrates the CNS. Sulfasalazine can produce encephalopathy by a hypersensitivity reaction causing cerebral microangiitis.

Drugs Associated with Encephalopathy

Antiepileptic Drugs Valproic acid, vigabatrin, lamotrigine, phenytoin, and carbamazepine have been reported to be associated with encephalopathy. Valproic Acid (VPA)  VPA-induced encephalopathy is characterized by somnolence, reduced motor activity, and severe deterioration of cognitive and behavioral abilities. It should be distinguished from VPA intoxication, which is associated with increased VPA blood levels. Most reports of VPA-associated encephalopathy are about children where VPA was used in combination with other AEDs and serum ammonia concentration was elevated. Other cases have been described in adults where encephalopathy occurred after the initiation of VPA therapy and resolved after discontinuation of therapy. Several cases of valproic acid-induced encephalopathy have been reported with increased seizure frequency and with or without hyperammonemia. Pathomechanism  Mechanisms of encephalopathy may include interactions of the hepatic enzymes, a direct toxic effect on the cerebral receptors, as well as drug interactions. Possible explanations of VPA-associated encephalopathy are: • Toxic effect of VPA on the brain, particularly interaction with GABA receptors. • VPA-induced hepatic failure leading to hepatic encephalopathy. • VPA-induced hyperammonemia. Various causes of hyperammonemia during treatment with VPA are not clear but it may be due to depletion of mitochondrial acetylCoA.  VPA or its metabolites may act by inhibiting the activity of ornithine transcarbamylase (OTC) and carbomoyl-phosphate synthetase (CPS). Patients with partial deficiency of OTC and CPS appear to be more susceptible to VPA-­induced hyperammonemia. Hyperammonemia during VPA treatment may be asymptomatic and is not an indication for reducing or eliminating VPA therapy.

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• MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) has been reported after start of VPA therapy. A nucleotide 3243 A(R)G mutation, which predisposes the patient to the detrimental effects of valproate on oxidative phosphorylation, was detected in the mitochondrial DNA. • Mechanism of anticonvulsant effect of VPA is believed to involve elevation of GABA by inhibition of degradation enzymes of GABA shunt. Experiments on mice have shown that higher doses of VPA significantly increase the brain levels of glutamate which opposes the action of GABA. This may be an explanation of VPA-associated encephalopathy. • VPA encephalopathy may be a manifestation of VPA-induced aggravation of epileptic activity which may cause progression of focal epilepsy to grand mal seizures. Management  Diagnostic tests for the detection of ornithine transcarbamylase deficiency must be performed before prescribing valproate for patients with a history of encephalopathy. VPA should not be given to patients suspected of having mitochondrial diseases. VPA-induced encephalopathy is usually reversible after discontinuation of VPA. General management requires correction of hyperammonemia if present. L-carnitine or citrulline supplementation has been used but the rationale is unclear. Phenytoin  Most of the reports of neurotoxicity of phenytoin concern cerebellar disorders (see Chap. 33). Encephalopathy has been reported as a toxic effect of chronic use of phenytoin. Carbamazepine (CBZ)  Encephalopathy with brainstem dysfunction has been reported as an effect of CBZ overdose. Encephalopathy has also been reported as an idiosyncratic reaction to CBZ. Vigabatrin  Encephalopathy has been reported in patients on vigabatrin monotherapy. Although microvacuolation has been shown in the brains of

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animals exposed to vigabatrin, no white matter vacuolation has been reported on neuropathologic examination of the brains of patients who had been on long-term vigabatrin therapy. Vigabatrin is associated with transient, asymptomatic MRI abnormalities in infants treated for infantile spasms, but most of these resolve, even in subjects who remain on vigabatrin therapy (Wheless et al. 2009). Two children with early myoclonic encephalopathy owing to nonketotic hyperglycinemia who were treated with vigabatrin deteriorated, likely due to enhancement of the encephalopathy by elevated GABA concentration together with the elevated levels of glycine (Tekgul et al. 2006). Caution should be exercised in using vigabatrin in children with elevated glycine levels. Baclofen  This is a GABA derivative and is used for the treatment of spasticity. Spinal effects predominate when it is given within the therapeutic range, but acute encephalopathy, manifested by impairment of consciousness, seizures, respiratory depression, and hypotonia, has been reported with increasing toxic doses. Patients with chronic baclofen intoxication present with hallucinations, impairment of memory, catatonia, or acute mania. Periodic bursts of triphasic waves are seen on EEG of patients with baclofen intoxication, and these changes resolve on discontinuation of baclofen and clinical recovery. A case was reportedof acute transient encephalopathy with confusion, drowsiness, myoclonic jerks, periodic triphasic sharp wave EEG patterns induced by low doses of baclofen (Lazzarino et al. 1991). Baclofen encephalopathy is likely to develop in patients with renal failure particularly in the presence of preexisting cerebral damage. Intrathecal use of baclofen for spasticity is expanding now, and overdosage by this route leads to coma and respiratory depression and is treated by physostigmine even though it is not a specific antidote. Anticancer Drugs  Anticancer drugs are known to produce a nonspecific encephalopathy. They are also known to produce leukoencephalopathy, but the evidence for this is not

13  Drug-Induced Encephalopathies

always provided in the adverse drug reaction reports. Most of CNS effects are described in a subsequent section on leukoencephalopathy and in Chap. 9. Bismuth  Bismuth subsalicylate is a component of widely used over-the-counter remedies. Reversible myoclonic encephalopathy due to intoxication by bismuth salts was first described in 1974 (Burns et al. 1974). Since then, over 1200 cases have been reported worldwide, mostly in France. Encephalopathy has been reported to result from abuse of Pepto-Bismol. Special presentation of bismuth-induced encephalopathy includes the following: • Encephalopathy with dementia • Encephalopathy resembling Creutzfeldt-­ Jakob disease • Encephalopathy with myoclonus Three phases of bismuth encephalopathy are: 1. A prodromal phase lasting from 2 to 6 weeks and characterized by gait disturbances and cognitive decline. 2. Clinical phase characterized by myoclonus, confusion, and dysarthria. 3. Recovery phase lasting 4–6 weeks. Symptoms usually clear spontaneously in the reverse order of their appearance after discontinuation of bismuth therapy. Diagnosis  The diagnosis of bismuth poisoning is supported by increased concentration of bismuth in the blood. Frontotemporal 4–6 Hz activity is seen in the frontotemporal region on EEG and increased density of the cerebral cortex has been noted on CT scanning. A radio-opaque substance can be seen on abdominal films in the large intestine of patients with barium intoxication. Management  The following therapeutic measures should be considered in bismuth encephalopathy: • Recovery usually occurs after discontinuation of bismuth intake.

Drugs Associated with Encephalopathy

• Evacuation of the bismuth from the intestine by gastrointestinal lavage. • Dimercaprol has been found to be effective in the treatment of bismuth encephalopathy. Bromides  Bromism is known as an effect of chronic ingestion of bromide salts which are often used as hypnotics. The clinical picture is variable with confusion, drowsiness, hallucinations, extrapyramidal signs, etc. It is forgotten in modern medicine but not gone and cases are still reported (Lugassy and Nelson 2009). Bromism is reported in dogs with idiopathic epilepsy treated with potassium or sodium bromide. Regular serial monitoring of serum bromide concentrations is recommended to optimize anticonvulsant treatment in dogs with idiopathic epilepsy (Rossmeisl and Inzana 2009). Calcium Hopantenate (HOPA)  It is a complex of GABA and pantoic acid used in Japan for the treatment of mental retardation in children and dementia in the elderly. There are several reports from Japan of encephalopathy with acidosis during HOPA treatment. Reye’s syndrome with encephalopathy has also been reported as a result of HOPA treatment (Kuzuhara et al. 2005). It has been presumed that HOPA induces defects of coenzyme A because its structure is common between HOPA and pantothenic acid. Dogs given increasing doses of HOPA over 8  weeks become comatose (Noda et  al. 1991). One group of dogs who received concomitant pantothenic acid did not develop any significant abnormality. The authors concluded that HOPA produces an acute encephalopathy in dogs by inducing a deficiency of pantothenic acid. Digoxin  Extreme fatigue or drowsiness is common in patients receiving digitalis and may be attributed to cardiac failure. Such a manifestation may also be due to digitalis encephalopathy associated with high serum digoxin concentrations. Recovery follows discontinuation of digitalis with fall of digoxin levels. Other causes of cerebral dysfunction should be ruled out in these patients. It is recommended that serum digoxin levels should be checked in patients who present with abnormal cerebral dysfunction.

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Dimethylsulfoxide (DMSO)  It is approved for use as a bladder irrigant for interstitial cystitis. It is commonly used for the cryopreservation of autologous peripheral blood stem cells. Its unapproved use extends to other indications. Encephalopathy has been reported in cancer patients receiving several courses of intravenous DMSO. Reduction of DMSO level with plasmapheresis results in marked improvement in encephalopathy. Encephalopathy has been reported in patients receiving infusion of hematopoietic progenitor cells preserved in DMSO (Júnior et al. 2008). Filgrastim  This is a granulocyte colony-­ stimulating factor, which is used for treating the neutropenia associated with cancer chemotherapy. Several neurological adverse events have been reported in patients receiving this therapy in clinical trials, but it is difficult to evaluate these because of advanced malignancy and multiple medications that these patients receive including chemotherapy. The first published case of encephalopathy associated with filgrastim presented with cortical blindness and seizures in patient with ovarian cancer who had anticancer therapy with cyclophosphamide and cisplatin (Kastrup and Diener 1997). She had similar adverse events on a previous treatment with molgramostim, another colony-stimulating factor used for the same indication. This resolved after discontinuation of molgramostim. EEG showed a left occipitotemporal focus with continuous spike-wave complexes. Filgrastim was discontinued and the patient was treated with phenytoin and valproic acid. Her symptoms resolved and there was no recurrence of seizures. Histamine-2 (H2)-Receptor Antagonists  H2-receptor antagonists, particularly, cimetidine, are known to cause CNS toxicity manifested by confusion, agitation, hallucinations, and seizures. The underlying mechanism is blockage of CNS H2 receptors. Ancillary mechanisms are cimetidine-induced release of norepinephrine in the hypothalamus, blocking of cholinergic receptors, inhibition of mitochondrial respiration, and interaction with GABA receptors. Mental confusion and seizures have been observed in neurosurgical patients

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treated with intravenous famotidine, and this has been associated with renal failure and raised CSF concentrations of famotidine. Intrathecal Contrast Agents  Methotrexate and iohexol, contrast materials used for lumbar myelography, have been reported to be associated with encephalopathy. Metrizamide  Myelography with this contrast agent can be associated with encephalopathy. In children with hydrocephalus, metrizamide shunt-­ gram may be followed by disturbance of consciousness and extrapyramidal symptoms. This is due to periventricular penetration of contrast material into the medial part of thalamus and caudate nucleus, with resulting deficiency of the ascending noradrenergic reticular activating system and the nigrostriatal dopaminergic system. Iohexol  This is considered to have less neurotoxicity than metrizamide. However, cases of encephalopathy have been reported following its use. Usual manifestations are coma and generalized slowing of EEG activity. Recovery is mostly spontaneous and dexamethasone administration is beneficial. Intravenous Immune Globulin (IVIG)  This modulator of the immune system is being used for the treatment of immune thrombocytopenic purpura and Guillain-Barré syndrome. There are several spontaneous reports of ADRs involving CNS but only a few cases have been published. Reported manifestations include visual loss, confusion, seizures, and hemiplegia. Acute hypertension, leukoencephalopathy, and reversible cerebral arterial vasoconstriction developed shortly after initiating intravenous immune globulin therapy in a patient with Guillain-Barré syndrome (Doss-Esper et  al. 2005). The signs and symptoms of the encephalopathy usually resolve after discontinuation of the treatment. There is a clinical similarity between IVIG-related encephalopathy and the “reversible posterior leukoencephalopathy syndrome,” described in the section on hypertensive encephalopathy.

13  Drug-Induced Encephalopathies

The pathomechanism is not known but one possible explanation is transient hyperviscosity syndrome associated with rapid infusion of large doses of IVIG.  Vasospasm is another explanation. Encephalopathy may be an immunoallergic reaction, caused by the entry of the exogenous IgG into the CSF compartment. CSF examinations usually show a neutrophilic or a mixed pleocytosis and aseptic meningitis has also been reported with IVIG (see Chap. 11). Levodopa  Levodopa is a precursor for dopamine and is actively transported across the intestinal wall and the BBB by a branched chain amino acid carrier. This is important because dopamine itself cannot cross the BBB. It is taken up by the dopaminergic neurons and decarboxylated in the presynaptic terminal to form dopamine; this then replaces the dopamine lost in the degeneration of substantia nigra. This is the basis for its use in the treatment of Parkinson’s disease. Several cases have been reported of patients with Parkinson’s disease who developed a subacute encephalopathy and periodic triphasic EEG activity following an increase in dose of levodopa. These changes reverse following levodopa reduction or discontinuation. There is a suspicion that long-term use of levodopa may accelerate neurodegeneration in Parkinson’s disease. There is no conclusive evidence for neurotoxicity of levodopa. It is generally accepted that deterioration in Parkinson’s disease patients is due to natural progression of the disease, and not due to levodopa. This deterioration correlates with degeneration in nonlevodopa circuits in the brain. Lithium  Toxic neuropathy has been described in patients receiving a combination of lithium and neuroleptics. Approximately 25% of the patients on a combination of lithium and neuroleptics develop neurotoxicity. Various clinical features reported include delirium, cerebellar dysfunction, and extrapyramidal signs. Lithium neurotoxicity syndrome is poorly defined, lacks diagnostic criteria, and is based mostly on anecdotal reports. Acute lithium toxicity can be graded as follows:

Drugs Associated with Encephalopathy

Grade I.  Drowsiness, hypertonia, and muscle rigidity Grade II. Impaired consciousness progressing to lethargy Grade III. Seizures, stupor, and coma. A reversible Creutzfeldt-Jakob-like syndrome with triphasic EEG waves has been described following the use of lithium. Interactions with other drugs result in a higher incidence of lithium encephalopathy. Some drugs decrease the renal clearance of lithium and lead to toxic lithium blood levels. Lithium may have additive effects with psychopharmacologically active drugs. Some of the important interactions are with the following drugs: • • • •

Antipsychotics such as haloperidol Antidepressants Carbamazepine Diuretics

There is no specific antidote for lithium toxicity. Long-term neurotoxic effects can be prevented in most of the cases. Even though high serum lithium levels are neurotoxic, a rapid decrease in high serum lithium concentrations may be even more toxic. OKT3 (Muromonab CD3)  OKT3, a monoclonal antibody, is used as an immunosuppressive agent in patients receiving organ transplantation. Aseptic meningitis as a complication of this drug has been described in Chap. 11. Encephalopathy associated with OKT3 has also been reported. Various clinical manifestations apart from aseptic meningitis are convulsions, hallucinations, deterioration of mental function, and motor incoordination. The pathomechanism of encephalopathy is not known. It is believed that OKT3 induces a release of cytokines from lymphocytes or monocytes and these may mediate these symptoms. This has been described as “the cytokine release syndrome” or cytokine encephalopathy. Delayed graft function is a significant risk factor for cytokine encephalopathy especially in diabetics. Delayed graft function might allow the retention of uremic toxins, which, in combination with

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cytokines, might mediate cytokine syndrome or it might cause the retention of released cytokines which, by themselves, mediate the syndrome. Brain swelling may be due to leakage from abnormal capillaries as an effect of cytokines. Podophyllin  Podophyllin poisoning is uncommon and most reported cases result from accidental ingestion of podophyllin resin. Neurological manifestations of poisoning include encephalopathy, autonomic peripheral neuropathy, and cerebral involvement resulting in acute alterations of sensorium varying from mental confusion to coma. Podophyllin is a constituent of Chinese medicines, and cases of encephalopathy with peripheral neuropathy have been described after ingestion of such a substance. These patients developed cerebral atrophy documented by CT scan. The toxic agent responsible for podophyllin poisoning is podophyllotoxin, a lipid-soluble compound that crosses cell membrane with ease. Neurotoxicity may be related to its in vitro ability to bind microtubular protein and inhibit axoplasmic flow. Colchicine and podophyllin toxins are structurally related and have similar clinical effects. Stem Cell Transplantation  Autologous bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) are increasingly used to treat hematological malignancies and solid tumors. The incidence of encephalopathy with PBSCT is lower than in the case of allogeneic BMT where there are added complications due to immunosuppressive therapy. The higher reported incidence in some of the earlier studies (10–40%) is likely due to inclusion of cases which has suffered only confusion or somnolence or decrease in alertness. Some of the complications can also be attributed to the primary disease (malignancy) and other medications used. Theophylline  Seizures due to theophylline are well known (see Chap. 19). Asthmatic children have been reported to develop a semicomatose

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condition following status epilepticus due to theophylline treatment, and CT scan showed cortical edema characteristic of theophylline encephalopathy.

Encephalopathies Secondary to Drug-Induced Metabolic Disorders Several encephalopathies are secondary to metabolic disorders associated with drug-induced hepatic encephalopathy, hyperammonemia, Wernicke’s encephalopathy, hypoglycemia, and hyponatremia.

Hepatic Encephalopathy Hepatic encephalopathy is characterized by disturbances of consciousness, personality changes, fluctuating neurological signs, asterixis (flapping tremor), and distinctive electroencephalographic changes. It may be acute and reversible or chronic and progressive (Jain 2021). Coma and death may occur. Drugs associated with hepatic encephalopathy are shown in Table 13.3. There is a long list of other drugs which are hepatotoxic or produce fulminating hepatic failure which may be accompanied by hepatic encephalopathy. Valproate-induced hyperammonemic encephalopathy is a rare but serious complication in patients after craniotomy and is diagnosed by mental state changes and elevated blood ammonia. A patient who developed hyperammonemic encephalopathy following perioperative administration of valproic acid recovered completely following discontinuation of the drug (Guo et al. 2017). Pathogenesis  The most important factor in the pathogenesis is severe hepatocellular function. The pathomechanism of drug-induced hepatic encephalopathy is not clear but various hypotheses are: • Ammonia neurotoxicity. • Action of multiple neurotoxins.

• Imbalance of excitatory and inhibitory amino acids. • GABA hypothesis. Activation of brain receptors for benzodiazepines which is closely related to GABA receptor. This may facilitate GABA neurotransmission (inhibitory). The role is uncertain because of the inconsistent effect of flumazenil in hepatic encephalopathy. • In patients with cirrhosis, the existence of hyponatremia is a major risk factor for the development of overt hepatic encephalopathy. • Modestly elevated concentrations of ammonia, which commonly occur in liver failure, may contribute to the manifestations of hepatic encephalopathy by enhancing GABAergic inhibitory neurotransmission. This concept appears to unify the ammonia and GABAergic neurotransmission hypotheses. Hyperammonemia can occur as an adverse reaction to drugs without clinical evidence of liver disease. Examples of this are valproic acid Table 13.3  Drugs which are associated with hepatic encephalopathy Drugs associated with encephalopathy because of hepatotoxic effect Acetaminophen, overdose Acetylsalicylic acid, high dose Anesthetic agents: halothane as idiosyncratic reaction COX 2 inhibitors Docetaxel Lanreotide, a somatostatin analog Omeprazole Propylthiouracil Sorafenib (Sidhu et al. 2017) Terbinafine Tuberculostatic agents Valproic acida Drugs that can precipitate hepatic encephalopathy in cirrhosis Antiepileptic drugs: valproic acid Benzodiazepines: midazolam, a sedative for gastrointestinal endoscopy Diuretics, by causing electrolyte imbalance Narcotics Propranolol Proton pump inhibitors The exact mechanism is not known, but various explanations include direct hepatotoxicity, direct cerebral neurotoxicity, and hyperammonemia © Jain PharmaBiotech

a

Encephalopathies Secondary to Drug-Induced Metabolic Disorders

(see under antiepileptic medications), cimetidine, and anticancer therapy. High-dose 5-fluorouracil infusion therapy is associated with hyperammonemia, lactic acidosis, and encephalopathy. A substantial amount of clinical and experimental evidence suggests that ammonia toxicity is a major factor in the pathogenesis of hepatic encephalopathy. Ammonia has been proven to be neurotoxic in animal experiments. Arterial blood ammonia concentrations are frequently elevated in all forms of hepatic encephalopathy. Altered mitochondrial metabolism appears to be an important mechanism responsible for the cerebral abnormalities associated with hepatic encephalopathy and other hyperammonemic states. However, hyperammonemia does not fully explain hepatic encephalopathy because 10% of affected patients have normal blood ammonia levels. Although cerebral metabolic rates for both glucose and oxygen are reduced in hepatic encephalopathy, the rate at which ammonia is taken up and metabolized by the brain is increased. Brain ammonia concentrations are difficult to determine accurately in humans, but they are elevated up to more than 20-fold as determined in animal models. Ammonia has an adverse effect on the brain. The exact mechanism of ammonia toxicity is not properly understood, but the following explanations should be considered: • A direct blocking effect of ammonia on the glutamate transmitter system could contribute to cerebral depression caused by hyperammonemia. • Hyperammonemia disturbs the electrophysiological function of the neurons (e.g., interference with inhibitory postsynaptic potentials). • Hyperammonemia interferes with brain energy metabolism, possibly by inhibiting discrete steps of the tricarboxylic acid cycle, and, in part, by interfering with malate aspartate shuttle. • Hyperammonemia is a major factor responsible for cerebral edema due to astrocyte swelling, and aquaporin-4, a water channel protein that is abundantly expressed in astrocytes, is implicated in this process.

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Supporting evidence for the role of ammonia in hepatic encephalopathy is as follows: • Administration of ammonia to experimental animals reproduces the Alzheimer type 2 astrocyte change. • High cerebrospinal fluid ammonia is found in hepatic encephalopathy as well as in other disorders with disturbances of mental function such as Reye’s syndrome and valproic acid toxicity. • Measures to reduce blood ammonia levels improve hepatic encephalopathy. Management  Early recognition of hyperammonemia (before the ammonia level reaches 350  mmol/L) and institution of ammonia-­ lowering agents are important to avoid further complications. Specific measures for treatment of hepatic encephalopathy are: • Discontinuation of the offending drug. • Lowering of blood ammonia. Sodium benzoate and sodium phenylacetate have been used for anticancer drug-induced hyperammonemia. • Exclusion of protein from diet and of amino acids from parenteral nutrition. • Hemodialysis to remove toxic substances. Management of encephalopathy from acute hepatic failure is aimed at control and reduction of intracranial hypertension. Intracranial pressure monitoring should be started, and mannitol (1 g/ kg) should be administered as an intravenous bolus. Two other measures for management of cerebral edema, hypothermia, and hyperbaric oxygen have been used in open studies with good results, but these have not been proven by controlled studies. Chronic encephalopathy is effectively controlled by administration of lactulose. Management of chronic hepatic encephalopathy is focused on the identification and correction of precipitating factors. These include the correction of diuretic-induced hypokalemia and the removal of nitrogenous load from the intestine. The latter is accomplished by agents that increase the fre-

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quency of stools to remove blood from the intestine, by the reduction of protein content in the diet, and by nonabsorbable carbohydrates or antibiotics to reduce the activity of intestinal flora.

Hypoglycemic Encephalopathy Hypoglycemia induced or exacerbated by medications can result in convulsions, coma, and brain damage. In one study, drug-induced hypoglycemia represented 23% of all hospital admissions attributed to adverse drug events, which in turn represented 4.4% of all admissions (Kilbridge et al. 2006). Most cases are associated with the use of glucose-lowering treatments, particularly sulfonylureas and insulin, but non-diabetic drugs can also produce hypoglycemia. A review of the literature on drug-induced hypoglycemia found 448 studies that described 2696 cases of hypoglycemia associated with 164 different drugs (Murad et al. 2009). The quality of evidence supporting associations between drugs and hypoglycemia was mostly very low due to methodological limitations and imprecision. The most reported offending drugs were quinolones, pentamidine, quinine, beta-blockers, angiotensin-converting enzyme agents, and insulin-like growth factor. Some of the drugs that produce hypoglycemia are listed in Table 13.4.

Hyponatremic Encephalopathy Hyponatremia occurs in several systemic disease states and is also frequently drug induced. Various pharmaceutical agents include those that interfere with the ability of the kidneys to excrete free water. They include sedatives, antidepressants, antiepileptics, analgesics, oral hypoglycemic agents, tranquilizers, narcotics, anticancer agents, and diuretics. Symptomatic hyponatremia leads to brain swelling, seizures, and rise of intracranial pressure. Hypoxia is the major factor contributing to brain damage in patients with hyponatremia. Hypoxia leads to a failure of homeostatic brain ion transport, which allows the brain to adapt to increases in cell water.

In some drug-induced encephalopathies, it is important to differentiate between direct neurotoxicity and that via hyponatremia as the management depends on the mechanism involved. For example, encephalopathy due to hyponatremia resulting from ifosfamide infusion (also known to be directly neurotoxic) is reversed by correction of hyponatremia. Encephalopathy with hyponatremia as an ADR of the antiepileptic drug oxcarbazepine may be an explanation for seizures occurring in an epileptic patient on this drug rather than lack of efficacy of the drug. Central Pontine Myelinolysis  Hyponatremia can cause central pontine myelinolysis, an uncommon non-inflammatory disease of the white matter tracts traversing the pons, which has commonly been reported in patients with chronic alcoholism, cirrhosis, malnutrition, and severe burns, who experienced rapid correction of slowly progressive hyponatremia. A patient with history of hypertension and on treatment with a diuretic was admitted with confusion and was given slow saline infusion to correct hyponatremia (Grémain et  al. 2016). There was improvement in confusion with correction of hyponatremia but 2 weeks later, the patient was readmitted for recurrence of confusion, fever, dysarthria, ataxia, and brisk deep tendon reflexes. T2-weighted Table 13.4 Drugs hypoglycemia

and

circumstances

producing

Angiotensin-converting enzyme agents, e.g., captopril in diabetic patients a Beta-blockers, by enhancing the action of insulin in diabetic patients Disopyramide, in patients with hepatic and renal disease Ethanol, by potentiating hypoglycemia by other drugs a Insulin overdose a Insulin-like growth factor Lithium, long-term treatment in diabetics a Pentamidine, by inducing hemorrhagic pancreatitis a Quinine, during treatment of severe falciparum malaria a Quinolones Salicylate poisoning Streptozotocin, by cytolytic effect on beta cells of the pancreas Sulfamethoxazole, in patients with renal failure a

Most frequently reported

a

Encephalopathies Secondary to Drug-Induced Metabolic Disorders

axial MRI of the brain showed changes consistent with central pontine myelinolysis and characteristic “owl’s eye” pattern on. Management  This is determined largely by symptomatology. If the patient is asymptomatic, hyponatremia can be corrected by discontinuation of the drug and water restriction. If the patient is symptomatic, active therapy to increase the plasma sodium with hypertonic saline is indicated. This should be done carefully as rapid correction may rarely lead to central pontine myelinolysis. Use of intermittent intravenous bolus therapy with 3% sodium chloride (2 cc/kg with a maximum of 100 cc) can rapidly reverse CNS symptoms and at the same time avoid the possibility of overcorrection of hyponatremia (Moritz and Ayus 2010).

Wernicke’s Encephalopathy This is also referred to as Wernicke’s syndrome or Wernicke’s disease or cerebral beri-beri and is an encephalopathy resulting from thiamine deficiency. It is usually associated with alcoholism and is by no means confined to alcoholics. It occurs in anorexia nervosa, gastric plication, hyperemesis gravidarum, and prolonged fasting, which are all associated with poor intake of vitamins. The clinical features are memory impairment, dysarthria, ataxia, and ophthalmoplegia. The neuropathological lesions in fatal Wernicke’s cases are in the paraventricular region of the thalamus and hypothalamus, mammillary bodies, the periaqueductal region, and the floor of the fourth ventricle. Causes of drug-induced Wernicke’s encephalopathy are shown in Table 13.5. Table 13.5  Drug-induced Wernicke’s encephalopathy Amiloride-furosemide Anticancer agents, e.g., erbulozole and ifosfamide Glucose intravenous infusions in “at risk” patients High-dose nitroglycerin Lithium-induced diarrhea Nitroglycerine (high-dose infusion) Tolazamide © Jain PharmaBiotech

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Anticancer agents like erbulozole and ifosfamide may interfere with conversion of thiamine to thiamine pyrophosphate. This syndrome can develop after long-term treatment with amiloride-­ furosemide for congestive heart failure. Furosemide is known to impede magnesium absorption in the kidneys by as much as 400%. Since magnesium is an essential factor in the conversion of thiamine into its active diphosphate and triphosphate esters, magnesium depletion may aggravate thiamine deficiency. Wernicke’s encephalopathy has been reported after high-­ dose nitroglycerin infusion and is possibly a consequence of the effect of the diluents ethyl alcohol and propylene glycol on thiamine metabolism. Tolazamide can cause Wernicke’s encephalopathy by lowering thiamine levels in individuals with marginal stores. Management  Intravenous infusions of glucose without thiamine supplementation should be avoided in patients at risk of developing Wernicke’s encephalopathy. Treatment is discontinuation of the offending medication and administration of intravenous thiamine. Intravenous thiamine can result in effective reversal of ifosfamide-­ induced encephalopathy. Recovery takes place and severe neurological disability can be avoided if treatment is instituted early.

Drug-Induced Leukoencephalopathy Drugs which have been reported to be associated with leukoencephalopathy are shown in Table 13.6.

Amphotericin B Intravenous amphotericin B (A mpB) is the drug of choice in the treatment of severe fungal infections although its systemic and renal toxicity is well known. Neurotoxicity, however, is less well recognized. A syndrome of progressive dementia, akinesia, mutism, and sphincter dysfunction has been reported as an ADR of the treatment of a variety of mycoses with intrave-

194 Table 13.6  Drugs and other therapies associated with leukoencephalopathy Amphotericin B Anticancer agentsa (see Table 13.7) Arsenicals Corticosteroids Heroin Immunosuppressive therapy with organ transplantation  Cyclosporinea  Tacrolimusa (FK506) Interferons Interleukin-2a a Intravenous immunoglobulina Monoclonal antibodies: natalizumaba, rituximab, tocilizumab Vaccines Frequently reported

a

nous amphotericin B-methyl ester. Leukoencephalopathy with parkinsonian features has been described in children following bone marrow transplantation and high-dose AmpB. Although the course has been progressive and fatal in more than half of the reported cases, some recovered with residual neurological deficits. In other cases, it was shown to be reversible in early stages after discontinuation of the infusion. The following clinical and pathological features were mostly observed in the cases reported in the literature: • The pathology and clinical course is less severe in patients with infections alone as compared to those with malignant disease where there is concomitant CNS adverse effect of chemotherapy. • Most patients with malignant disease were immunosuppressed and received standard intravenous doses of AmpB for pulmonary aspergillosis, a complication of chemotherapy. None of the patients had clinical evidence of infection or a neoplastic process involving the CNS. • Most patients with malignant disease had cranial radiation as well as treatment with a variety of anticancer and antimicrobial agents. • Onset is either acute or a subacutely evolving neurologic disorder. It is characterized

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by a progressive dose-dependent course and  is reversible if AmpB is discontinued early. • Brain imaging studies showed abnormal findings. CT demonstrated hypodensity of the white matter of the cerebral hemispheres, particularly in the frontal regions. MRI showed increased signals from cerebral white matter on T2-weighted images from the frontal regions and basal ganglia. • Neuropathologic findings are a diffuse non-­ inflammatory leukoencephalopathy characterized by florid astrogliosis, myelin loss, and infiltration of rarefied white matter by numerous macrophages containing phagocytized myelin debris. Pathomechanism  Normally AmpB does not penetrate the BBB, but in some of the cases described in literature, BBB may have been damaged by cranial radiation. There may also be an element of an idiosyncratic reaction in the development of this syndrome. The biologic effects of polyene macrolide antibiotics such as AmpB are chiefly mediated through their binding to cell membrane sterols including cholesterol. This results in a structural alteration which increases membrane permeability and permits leakage of intracellular constituents from susceptible cells. Cholesterol-rich myelin may be a target for binding of AmpB.  AmpB-associated leukoencephalopathy has been reproduced in experimental animals. Management  Patients receiving amphotericin should be monitored carefully for early signs of neurotoxicity. Early discontinuation of amphotericin may lead to recovery before irreversible lesions develop.

Anticancer Agents Neurotoxicity has been reported with increasing frequency in cancer patients due to aggressive anticancer therapy with neurotoxic agents and prolonged patient survival. These

Encephalopathies Secondary to Drug-Induced Metabolic Disorders Table 13.7  Anticancer agents associated with encephalopathy and leukoencephalopathy Drugs associated with encephalopathy  Asparaginase  5-Azacytidine  5-Fluorouracil  BCNU  Chlorambucil  Cisplatina  Corticosteroids  Cyclophosphamide  Cytosine arabinoside  Dacarbazine  Doxorubicin  Etoposide  Fludarabine  Gemcitabine  Hexamethylmelamine  Hydroxyurea  Ibritumomab  Ifosfamidea  Imatinib  Interferons  Interleukins 1 and 2  Mechlorethamine  Methotrexate  Misonidazole  Mitomycin C  Nelarabine  Paclitaxel  Pentostatin  Procarbazine  Suramin  Tamoxifen  Thalidomide  Thiotepa  Tumor necrosis factor  Vinca alkaloids  Zarnestra Drugs associated with leukoencephalopathy  5-Fluorouracil  Bevacizumab  Capecitabine  Cisplatin  Cytosine arabinoside  Cyclosporine A  G-CSF/GM-CSF  Methotrexate  Nelarabine  Oxaliplatin  Sorafenib  Sunitinib malate  Vinca alkaloids Frequently reported © Jain PharmaBiotech

a

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c­ omplications may result from the direct toxic effects of the drug on the nervous system or indirectly from metabolic derangements or cerebrovascular disorders induced by the drugs. Anticancer agents associated with encephalopathy and leukoencephalopathy are listed in Table 13.7. There is a duplication as some anticancer agents can cause encephalopathy as well as leukoencephalopathy. Mechanisms of neurotoxicity of individual compounds have been postulated but they do not necessarily correlate with the anticancer effect. Some of the explanations for the variations in neurotoxicity of various anticancer agents are: • Individual characteristics and metabolites. Interactions with various enzymes • Dose • Ability of various agents to cross the blood-­ brain barrier which normally has a protective function against neurotoxicity • Adjuvants used to increase penetration of blood-brain barrier • Combination with radiotherapy Factors related to the patients which influence neurotoxicity include the following: • Type of malignancy. • Presence of other systemic diseases. • Cerebral involvement with cancers of other organs: metastases, paraneoplastic syndromes. • Patients with brain tumors have damage to the blood-brain barrier with increased permeability. Cisplatin  Cisplatin is a metal coordination compound that was approved for use in 1979 for management of testicular cancer. The “cis” form exerts its biological effect by binding directly to DNA and formation of inter- and intra-strand links. Its effect is enhanced by other anticancer drugs and radiotherapy. The encephalopathy is associated with reversible abnormalities in the white matter of the occipital, parietal, and frontal lobes and clinically resembles the reversible posterior leukoencephalopathy syndrome. The encephalopathy tends to be more common after intra-arterial administration of the drug. It should

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be distinguished from metabolic encephalopathy that may result from water intoxication caused by prehydration, or from renal impairment, hypomagnesemia, hypocalcemia, and syndrome of inappropriate secretion of antidiuretic hormone that may follow treatment with cisplatin. Cisplatin can also cause vascular toxicity, resulting in strokes. There is unusual accumulation of cisplatin in the brains of patients who manifest encephalopathy perhaps via an altered BBB. Cytosine Arabinoside (ARA-C)  Neurologic toxicity of intravenous ARA-C is usually dose related and predominantly cerebellar (see Chap. 33). Cerebral toxicity is reported to be less severe and may manifest as somnolence and confusion. Subacute encephalopathy with prominent cerebellar dysfunction has been reported in several patients treated with high-dose ARA-C. The clinical features of intrathecal ARA-C neurotoxicity include meningeal irritation, arachnoiditis, myelopathy, and encephalopathy, manifested by seizures. Encephalopathy has also been reported following chemotherapy with a combination of ARA-C and fludarabine, both of which are structurally similar. The pathomechanism of ARA-C neurotoxicity is not known but CNS injury may be the result of ARA-C triphosphate (ARA-CTP), a cytotoxic substance or a metabolite such as uracil arabinoside. The primary determinants of cytotoxicity by ARA-CTP include the competitive inhibition of DNA polymerase alpha and direct incorporation into DNA. The concentration of ARA-CTP in the brain after intrathecal administration is sufficient to inhibit DNA synthesis, and this may interfere with repair process in the CNS and replication of glial cells. Other mechanisms such as formation of arabinosylcytidine-choline may inhibit the synthesis of membrane glycolipids and glycoproteins in the CNS and contribute to neurotoxicity. However, it is difficult to establish a correlation between ARA-C metabolites in the CSF and clinical neurotoxicity to design a schedule of intrathecal ARA-C which may be effective but minimally neurotoxic. An interval of 2–3  days between intrathecal ARA-C treatments may reduce the risk of neurotoxicity.

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5-Fluorouracil (5-FU)  5-FU is a derivative of the pyrimidine base uracil in which fluorine is substituted for the 5-position hydrogen. Manifestations of neurotoxicity are cerebellar disorders (see Chap. 33) and leukoencephalopathy. Several cases of multifocal inflammatory leukoencephalopathy have been reported with combined use of 5-FU and levamisole for adenocarcinoma of colon. Clinical manifestations vary from decline of mental function, ataxia, diplopia, and dysarthria to loss of consciousness. MRI shows multifocal periventricular enhancing white matter lesions. Cerebral biopsy in some cases shows active demyelinating disease. Most of the patients improve after cessation of therapy and treatment with corticosteroids although there are some residual neurological deficits. Pathomechanism  Leukoencephalopathy in these cases is a toxic effect of 5-FU but a direct relationship has not been proven. Patients with decreased dihydropyrimidine dehydrogenase (DPD) activity are at increased risk for experiencing leukoencephalopathy following 5-FU therapy because more than 80% of the administered 5-FU is catabolized by DPD.  A case is reported of encephalopathy developing in a patient with DPD deficiency following 5-FU therapy where recovery occurred in 1 week with cessation of 5-FU and fluid supplementation with a lactulose enema and intravenous thiamine supplementation (Kwon et al. 2010). Administration of 5-FU with other drugs may increase the incidence of neurotoxicity. For example, the coadministration of 5-FU with allopurinol, N-phosphonoacetyl-L-aspartate, doxifluridine, carmofur, or tegafur has been reported to cause increased incidences of encephalopathies. The comedication levamisole has also been reported to be associated with encephalopathy. Experimental studies have shed further light on the cell-biological basis of 5-FU-related short-­ term and long-term toxicity. 5-FU appears to be particularly harmful to oligodendrocyte precursor cells, and long-term adverse effects may be explained by a disruption of the integrity of myelinated fiber tracts in the mammalian nervous system (Han et al. 2008). A rare tumor lysis syndrome may occur along with fluorouracil-induced

Encephalopathies Secondary to Drug-Induced Metabolic Disorders

leukoencephalopathy. A fatal case due to this combination of adverse effects has been reported after fluorouracil monotherapy for colorectal cancer with hepatic metastases (Stephan et  al. 1995). The patient developed a generalized seizure, coma, and uric acid nephropathy. This patient was considered to have experienced a chemotherapy-induced tumor lysis (confirmed by hepatic CT scan) rather than spontaneous tumor necrosis. 5-FU derivative hexylcarbonyl-5-FU (HCFU) passes readily through the BBB to provide 5-FU and its derivatives of which alpha-fluoro-beta-­alanine is thought to be the culprit, which produces leukoencephalopathy. Several cases of leukoencephalopathy resulting from use of HCFU (Carmofur) have been reported in the Japanese literature. Another 5-FU derivative Tegafur which is used in Japan has also been reported to produce leukoencephalopathy. Fludarabine  High doses of fludarabine are used for the treatment of acute leukemia and have been reported to induce leukoencephalopathy. Lower doses are used in the treatment of chronic lymphocytic leukemia (CLL) and are generally considered to be safe. A case of fatal progressive multifocal leukoencephalopathy (confirmed by brain biopsy and neuroimaging) has been reported to develop 6 months after completion of a course with low-dose (25 mg/m2/day) fludarabine monotherapy for B-CLL (Zabernigg et  al. 1994). Lymphoma involving the brain was excluded at autopsy. Ifosfamide/Mesna  Ifosfamide (IFX), a structural isomer of cyclophosphamide, is active against several tumors. Unlike cyclophosphamide it has significant neurotoxicity. Combination with mesna (sodium 2-mercaptoethanesulfonate) permits higher doses of ifosfamide by detoxifying its urotoxic metabolite. IFX encephalopathy is characterized by confusion, stupor, and mutism. Several cases of ifosfamide encephalopathy have been reported. Reported incidence of encephalopathy in patients receiving IFX is 20% (Ajithkumar et al. 2007; Brunello et al. 2007). The encepha-

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lopathy begins hours or days after administration of the drug and usually resolves completely after several days. Risk factors are low serum albumin indicative of hepatic dysfunction, high serum creatinine suggesting renal compromise, presence of neoplastic disease in the pelvis, and previous exposure to cisplatin and radiotherapy. Neurotoxic effects may range from subclinical EEG changes to severe irreversible encephalopathy and death. One recommendation to prevent neurotoxicity is that ifosfamide/mesna should not be given to patients with less than 20% probability of remaining free of CNS toxicity. Pathomechanism  IFX is a prodrug which requires biotransformation to become cytotoxic. Neurotoxicity of IFX may be related to the high serum concentrations of chloroacetaldehyde, which is one of its major metabolites. Chloroacetaldehyde depletes intracellular glutathione concentration. Patients who develop encephalopathy on IFX therapy are poor metabolizers of phenotype of carbocysteine, so that endogenous cysteine is not available in sufficient amounts to produce the carbocysteine metabolite, which is carboxymethyl thiocysteine. This predisposes to toxic effects of aldehydes. High serum creatinine concentration, presence of pelvic disease, fast infusion of IFX, and low serum albumin concentration are the risk factors for IFX encephalopathy. Stereoselective study of urinary excretion of IFS metabolites shows that high R-3 dechloroacetaldehyde concentration is linked with neurotoxicity in a subset of patients with overexpression of enzyme P450 (Wainer et al. 1994). Management  IFX neurotoxicity is dose dependent and can be reversed by methylene blue as an antidote, which acts by inhibiting monoamine oxidases (Patel 2006).Prophylactic use of methylene blue can prevent the onset of IFX neurotoxicity. Intravenous diazepam has been reported to improve mental function and EEG in patients with IFX encephalopathy. Methotrexate (MTX)  MTX is a structural analog of folic acid and is widely used as an antime-

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tabolite in cancer chemotherapy. Its primary mechanism of action is inhibition of dihydrofolate with consequent depletion of intracellular folate pool. MTX also inhibits RNA, protein synthesis, glucose transport, and metabolism. Clinical expression of neurotoxicity of MTX depends on the route of administration and the combined effect of drug concentration and dose. Neurological complications of intrathecal MTX include arachnoiditis, myelopathy, and encephalopathy. The major risk factors are cumulative MTX dose and prior cranial radiation. CT scan and MRI are used for detection of leukoencephalopathy. Serial EEG may also be used for this purpose. MRI is more sensitive than CT scan. Early recognition is important as discontinuation of therapy leads to reversal of leukoencephalopathy. High-dose intravenous MTX has been reported to be associated with transient subacute leukoencephalopathy in some patients with acute lymphatic leukemia. Even low-dose intravenous MTX has been reported to produce a delayed leukoencephalopathy. Acute and subacute neurotoxicity and leukoencephalopathy with stroke-like focal deficits may be associated with abnormal MRI findings, such as diffusion-weighted imaging (DWI) hyperintensities that may not be confined to typical vascular territories (Baehring and Fulbright 2008). DWI abnormalities can be seen in subcortical or deep periventricular white matter, corpus callosum, cortex, cerebellum, and thalamus (Balin et al. 2008; Brugnoletti et al. 2009). These changes represent reversible cerebral dysfunction with associated cytotoxic edema and metabolic derangement rather than ischemic structural injury. Pathomechanism  The pathomechanism of MTX-induced leukoencephalopathy is not well understood but the following hypotheses have been considered: • • • •

Cytotoxic effect on glial elements. Disruption of myelin metabolism. Depletion of reduced folate in the brain. Inhibition of cerebral protein and glucose metabolism.

• Injury to cerebral vascular endothelium resulting in increased BBB permeability. • Reduction of catecholamine neurotransmitter synthesis through direct inhibition of synthesis of tetrahydrobiopterin. This hypothesis is supported by the observation of increase of CSF biopterins in patients with MTX-induced encephalopathy. • Release of adenine due to inhibition of purine synthesis (responsible for anti-inflammatory effect in patients with arthritis). This has been implicated in CNS neurotoxicity as increased concentrations of adenosine have been demonstrated in patients on MTX therapy. • Genetic polymorphisms for methionine metabolism, which is required for myelination, may constitute a risk factor for methotrexate-­associated neurotoxicity (Muller et al. 2008). Treatment  In the absence of a clear-cut pathophysiological basis for MTX neurotoxicity, there is no definite treatment but the following drugs have been used: • Intravenous leucovorin has been reported to reverse MTX-leukoencephalopathy. • Intravenous aminophylline has been used to reverse MTX neurotoxicity as it displaces adenosine (implicated in neurotoxicity) from its receptor. Vincristine  Vincristine is a vinca alkaloid used to treat many cancers, including leukemia, lymphomas, sarcomas, and brain tumors. CNS complications are rare, as vincristine poorly penetrates the blood-brain barrier. Rare cases of reversible leucoencephalopathy have been reported.

Arsenicals For thousands of years, arsenic and its compounds have been used for therapeutic purposes although the substance acquired its bad reputation due to its use for homicidal purposes. Neurological symptoms of acute arsenic poisoning include seizures, and peripheral neuropathy is

Encephalopathies Secondary to Drug-Induced Metabolic Disorders

a more common sequel of chronic poisoning (see Chap. 28). Organic arsenicals such as melarsoprol, which are used for the treatment of trypanosomiasis, can cause severe encephalopathy. Convulsions and coma are frequent manifestations. It occurs in 7–13% of all cases treated with various schedules of this drug and may be fatal in up to 10% of cases. At autopsy the brain appears to be congested and swollen. Histological examination shows petechial hemorrhages and perivascular cuffing comprised of lymphocytes and macrophages. The pathologic changes in the brain are those of acute hemorrhagic leukoencephalopathy. A single toxic dose of phenylarsine oxide as well as its triazine analog produces hemorrhagic and at times non-hemorrhagic necrosis at several sites in the brains of experimental animals. Some animals develop white matter gliosis. However, none of the lesions of CNS are characteristic of arsenicals. Melarsoprol-induced encephalopathy is probably an immune phenomenon rather than the result of dose-related arsenical toxicity. Trypanosomal antigens released after exposure to melarsoprol, presumably from the trypanosomes present in the brain (rather than the bloodstream), bind to brain cells which eventually become the targets of antibodies and/or T lymphocytes. Sub-­ curative chemotherapy may underlie the fatal post-treatment reactions seen in. Oral prednisolone has been shown to reduce the incidence of encephalopathy induced by melarsoprol treatment of T. gambiense sleeping sickness. Azathioprine, a NSAID immunosuppressant, ameliorates the post-treatment encephalopathy in the murine trypanosomiasis model (Hunter et al. 1992).

Corticosteroids Glucocorticoids are frequently employed as immunosuppressive agents, and there are reports of occurrence and exacerbation of neurological immune-mediated conditions in patients receiving steroids. Cases of progressive multifocal leukoencephalopathy have been reported in patients with multiple connective tissue diseases who

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were treated with immunosuppressive therapy using corticosteroids for several years. Methylprednisolone is also used for the treatment of leukoencephalopathies. In experimental allergic encephalitis (EAE) in rats, methylprednisolone given prior to and during EAE significantly increases disease duration. In contrast, treatment with methylprednisolone after onset of the disease is markedly beneficial.

Heroin Spongiform leukoencephalopathy is a complication of heroin addiction. Numerous cases have been reported in the literature. Autopsy usually shows extensive white matter spongiosis and vacuolization affecting the cerebrum and the cerebellum on microscopic examination. MRI findings in heroin encephalopathy such as demyelination and vacuole formation in the white matter resulting in sponge-like appearance are characteristic and consistent with histopathological diagnosis (Zhang et  al. 2007). Leukoencephalopathy has been reported in the USA following inhalation of heroin vapor (Kriegelstein and Armitage 1997). MRI findings in these cases were symmetric lesions of high signal intensity in the occipital white matter, the posterior limb of the internal capsule, and the splenium of the corpus callosum. These are characteristic of heroin-induced leukoencephalopathy. Both these patients survived with neurological deficits. The pathomechanism remains unknown. None of the contaminants found in the heroin sample are known to produce leukoencephalopathy.

Immunosuppressive Therapy with Organ Transplantation Cyclosporine (CSP)  CSP is a widely used immunosuppressant to reduce the severity of graft versus host disease (GVHD) in organ transplantation. It is known to have toxic effects of the nervous system manifested by psychiatric disturbances, lethargy, tremor, visual disturbances, cerebellar ataxia, and seizures. A rare complication is cortical blindness. Some of these have been ­discussed

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individually in other chapters. Altogether, these manifestations are, sometimes, referred to as encephalopathy. However, because of the white matter changes shown on MRI scan, the more appropriate term is leukoencephalopathy. Use of CSP in organ transplantation. CSP-­ leukoencephalopathy has been reported with the following organ transplantations: liver, kidney, heart, and bone marrow. Only those associated with liver transplantation will be described here. Neurological complications occur frequently in recipients of orthotopic liver transplantation. These complications include changes in mental status, seizures, severe headache, and peripheral neuropathy. Neurological complications can occur from a multiplicity of factors which include the following: • • • • • •

Cerebrovascular accidents CNS infections Drug toxicity Electrolyte disturbances Metabolic factors Preoperative hepatic encephalopathy

The role of drugs is difficult to determine because there are no controls in the studies of liver transplantation where no immunosuppressant is used. In one study encephalopathy occurred in 46.1% of the patients, but the percentage of those who developed leukoencephalopathy is not given (Menegaux et al. 1994). In 27 of the 47 patients who developed neurological complications in this study, drug toxicity was the primary cause and the symptoms reversed with reduction of dosage or discontinuation of the drug. Cyclosporine and FK506, primarily during intravenous administration for the induction of immunosuppression, accounted for 25 of the 27 neurological complications. In a comparison of CSP and FK506, the incidence of neurotoxicity was higher among patients treated with FK506 (21.3% vs. 11.7%) than those treated with CSP (Mueller et  al. 1994). In another study 25% of patients developed CSP leukoencephalopathy after liver transplantation (Aksamit and de Groen 1995). In a study of 340 liver transplants, neuro-

13  Drug-Induced Encephalopathies

toxicity was reported in only 12% of the cases, and it was reverse in some of these by replacement of CSP by FK506 (Wijdicks and Wieser 1995). CSP neurotoxicity can occur unrelated to organ transplantation. Leukoencephalopathy has been reported during CSP therapy of Wegener’s granulomatosis, idiopathic uveitis, and nephrotic syndrome, and rheumatoid arthritis. In most of these cases, encephalopathy was diagnosed on MRI and resolved after discontinuation of CSP. Risk Factors. Risk factors for CSP-­ leukoencephalopathy are: • Low serum cholesterol levels after liver transplantation, which may interfere with the transport of cholesterol and other lipids into the brain. Low concentration of LDL cholesterol may also lead to increased CSP delivery to astrocytes and thus increase neurotoxicity. • Intravenous lipid solutions of CSP cause earlier and more severe symptoms than oral CSP. Fat embolism leading to encephalopathy has also been reported to be induced by the drug’s solvent. • Children are more susceptible to neurotoxicity of CSP. • Impaired renal function. Nephrotoxicity may be due to CSP. • Impaired liver function. Hepatoxicity may be due to CSP. • Hypomagnesemia has been reported in recipients of allogeneic bone marrow transplants who experience neurotoxicity of CSP. Hypomagnesemia is known to lower seizure threshold. • Concomitant use of doxorubicin. Leukoencephalopathy has been reported after addition of doxorubicin to CSP therapy. One explanation is that BBB changes induced by CSP therapy may allow diffusion of doxorubicin (also a neurotoxin) into the brain. High brain levels of doxorubicin in the brain can inhibit P-glycoprotein in the brain capillary endothelial cells. • Methylprednisolone combined with CSP for prophylaxis of GVHD in bone marrow transplant patients.

Encephalopathies Secondary to Drug-Induced Metabolic Disorders

• Etoposide administration as a part of conditioning the patients for bone marrow transplantation. • Microangiopathy developing as a part of GVHD. • Aluminum overload. • Hypertension. Pathomechanism  The risk factors are well recognized but the mechanism of neurotoxicity of CSP is unknown. Concentration of CSP in the plasma of patients who develop leukoencephalopathy is usually within the therapeutic range. However, concentration of metabolites of CSP has been reported to be increased in these patients. These metabolites may accumulate in more vulnerable regions of the brain, particularly in the white matter, which has a high lipid content. Endothelin (ET), a vasoconstrictor neuropeptide that has been implicated in cerebral vasospasm, may potentiate CSP-induced damage to the endothelium and promote CSP neurotoxicity. Normally the integrity of BBB restricts the movements of both CSP and ET.  However, in many patients on CSP, conditions exist that disrupt the BBB and permit access of both ET and CSP to otherwise protected areas of the brain. Management  CSP leukoencephalopathy is reversible after discontinuation of the drug, and later institution of the drug at a lower dose appears to be a safe approach. In patients undergoing treatment with CSP, risk factors for leukoencephalopathy should be corrected if possible, e.g., magnesium supplementation for hypomagnesemia. Tacrolimus (FK506)  FK506 is a biologically active macrolide antibiotic that was found to have a powerful immunosuppressant action. It is now approved for use in liver transplantation. Since its initial application to orthotopic liver transplantation, the use of FK506 has been associated with the development of a variety of major neurological complications including progressive multifocal leukoencephalopathy. Posterior reversible encephalopathy syndrome is known to occur after solid organ transplantation and is caused by

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immunosuppressive agents such as tacrolimus. It usually occurs within the first 2 months after liver transplantation. Clinical findings include seizures, headache, focal neurological deficits, visual disturbances, and altered mental status. These are associated with characteristic imaging features of subcortical white matter lesions on brain MRI. Seizures may persist in spite of resolution of MRI lesions and EEG is a prognostic factor (Baldini et al. 2010). Some of the neurological complications after orthotopic liver transplantation are multifactorial and cannot be ascribed solely to FK506 toxicity. Tacrolimus-related encephalopathy has similar radiographic and pathologic appearances to those that occur in patients taking cyclosporine. Tacrolimus (like cyclosporine) binds to specific intracellular protein-protein ligands which play a vital role in maintaining the stability of intracellular structures. The exact mechanism of demyelination has not been determined, but it involves particularly the parieto-occipital region and the centrum semiovale. Although the syndrome is not associated with any particular (absolute) serum level of tacrolimus, it resolves spontaneously after decreasing the dose or discontinuing tacrolimus.

Interferons The body’s interferon system is well known as an antiviral and antitumor mechanism. Various interferons (alpha, beta, gamma) have been undergoing clinical trials in the treatment of viral and malignant diseases. It has even been used in the treatment of AIDS-related progressive multifocal leukoencephalopathy. Although there was no improvement, it was not reported to cause any deterioration of the neurological status. Manifestations of neurotoxicity of interferon are termed as an “interferon syndrome.”

Monoclonal Antibodies Monoclonal antibodies (MAbs) have been used for the treatment of several autoimmune and

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inflammatory diseases in addition to cancer. Leucoencephalopathy has been reported as a complication of several MAbs and some examples are presented here.

13  Drug-Induced Encephalopathies

sclerosis patients’ anti-JCV antibody status and is the first blood test to be approved by the FDA for the qualitative detection of antibodies to the JC virus. Quantification of T and B lymphocytes can be used to monitor natalizumab therapy Natalizumab safety because new lymphocyte production indiNatalizumab, a selective adhesion molecule cates the integrity of immune surveillance. inhibitor, blocks the ability of alpha4 beta1 integPlasma exchange and immunoadsorption have rin to bind to its receptor, the vascular cell adhe- been used to accelerate clearance of natalizumab sion molecule. This interaction is needed for the successfully, with improvement of symptoms in lymphocytes to enter the CNS, a process that is patients who developed progressive multifocal implicated in the pathogenesis of acute inflam- leukoencephalopathy after natalizumab monomatory lesions and the breakdown of blood-brain therapy (Linda et al. 2009; Wenning et al. 2009). barrier in patients with multiple sclerosis. In Although rapid withdrawal of the drug and 2004, the FDA approved it for the treatment of administration of plasma exchange has enabled multiple sclerosis. survival in some of the patients with progressive In 2005, the manufacturer of natalizumab multifocal leukoencephalopathy, a new problem, reported one confirmed fatal case and one possi- immune reconstitution inflammatory syndrome, ble case of progressive multifocal leukoencepha- occurs after drug withdrawal, which requires lopathy in patients receiving natalizumab for treatment with corticosteroids. multiple sclerosis. JC viral DNA was detected in Currently, more than 110,000 multiple sclerocerebrospinal fluid and was confirmed at autopsy. sis patients worldwide have been treated with No new cases of multifocal leukoencephalopathy natalizumab, and the risk of developing progreshave been observed since the initial three cases. sive multifocal leukoencephalopathy is approxiRisk of progressive multifocal leukoencephalop- mately 2.7 per 1000 cases. Planned dosage athy in patients treated with natalizumab was interruptions of natalizumab have been recomestimated to be 1 in 1000 patients based on more mended for decreasing the cumulative risk of than 3000 patients treated in clinical trials. multifocal leukoencephalopathy, but it is associApproval of the drug was restored in 2006 after ated with clinical flares and recurrence of radiotemporary suspension in 2005. A risk-benefit graphic lesions. Some of these flares can be analysis concluded that more than sevenfold clinically severe, with a high number of contrast-­ increase in actual risk of progressive multifocal enhanced lesions, suggesting a possible rebound leukoencephalopathy was required to decrease of multiple sclerosis activity. Postmortem study natalizumab’s health gain below that of inter- in a patient with multiple sclerosis who died folferon beta-1a (Thompson et  al. 2008). In 2012, lowing natalizumab-associated progressive multhe FDA approved a product label change for tifocal leukoencephalopathy showed coexistence natalizumab that helped enable individual and lack of interplay between lesions of chronic benefit-­risk assessment for patients with multiple multiple sclerosis and progressive multifocal leusclerosis. The new label identifies positive anti-­ koencephalopathy (Wuthrich et al. 2013). JCV antibody status as a risk factor for developProgressive multifocal leukoencephalopathy ing progressive multifocal leukoencephalopathy, associated with natalizumab has better prognosis whereas negative anti-JCV antibody status indi- than that due to other causes. Early diagnosis, cates that exposure to the JC virus has not been localized disease on MRI, and aggressive mandetected. Irrespective of treatment, approxi- agement may improve outcomes. Because of the mately 55% of multiple sclerosis patients are effect of natalizumab treatment on JCV seroconanti-JCV positive. The Stratify JCV antibody version, monitoring of patients’ JCV serology as ELISA Testing Service (Quest Diagnostics) well as incorporation of additional risk factors enables neurologists to determine their multiple into the progressive multifocal leukoencephalop-

Encephalopathies Secondary to Drug-Induced Metabolic Disorders

athy risk stratification is recommended (Schwab et al. 2016).

Tocilizumab Tocilizumab is an anti-interleukin (IL)-6 receptor antibody for the treatment of rheumatoid arthritis and other autoimmune diseases and cytokine storms. A patient with well-controlled rheumatoid arthritis presented with cognitive impairment after 34  months of tocilizumab administration (Sasaki et al. 2020). Brain MRI showed leukoencephalopathy with a lactic acid peak in magnetic resonance spectroscopy (MRS), a decreased blood flow in single-photon emission computed tomography (SPECT), and a decreased accumulation in fluorodeoxyglucose positron emission tomography (FDG-PET). Discontinuation of tocilizumab improved the cognitive function and MRI findings at 3 months after drug cessation.

Leukoencephalopathy Secondary to Drug-Induced Hypertension Drug-induced hypertension may produce hypertensive encephalopathy which is a well-known acute syndrome precipitated by sudden, severe hypertension. There is a disturbance of autoregulation that leads to severe vasospasm, petechial hemorrhages, microinfarcts, and cerebral edema. Several drugs can induce hypertension. Hypertension may be associated with white matter changes and hypertensive encephalopathy could be termed leukoencephalopathy. Dialysis-dependent chronic renal failure patients who developed hypertension, headache, and seizures while on erythropoietin therapy have shown posterior white matter changes on neuroimaging. The patients recovered after discontinuation of erythropoietin and management with antihypertensives and anticonvulsants. A similar reversible posterior leukoencephalopathy has been described following blood transfusion in a patient who was not receiving any medications (Ito et al. 1997). The patient developed seizures, hypertension, and lethargy. MRI showed high signal areas in parieto-occipital lobes, and cerebral angiography showed vasospasm which

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was associated with vascular endothelial damage and cerebral edema. Recovery was complete within 4  weeks of treatment with antihypertensive and anticonvulsant medications. Although leukoencephalopathy was not induced by a pharmaceutical preparation, it was caused by a therapeutic substance—blood transfusion—and the effects were like erythropoietin administration. Hypertension is a well-recognized, common side effect of vascular endothelial growth factor (VEGF) blocking agents. Reversible posterior leukoencephalopathy syndrome (RPLS) with hypertensive crisis has been described as a rare but serious consequence of administration of bevacizumab, a monoclonal antibody targeting VEGF, to a child with refractory hepatoblastoma (Levy et al. 2009). MRI changes were consistent with diagnosis of RPLS.  Findings completely resolved without neurologic sequelae with stringent blood-pressure control. Reversible posterior leukoencephalopathy has been described in patients who developed hypertension while on immunosuppressant therapy (Hinchey et al. 1996). The findings on neuroimaging were characteristic of subcortical edema without infarction. Clinical finding included headaches, confusion, seizures, and visual abnormalities. These resolved within 2 weeks after start of antihypertensive therapy and reduction or withdrawal of immunosuppressants. The pathomechanism is a brain capillary leak syndrome related to hypertension, fluid retention, and cytotoxic effect of immunosuppressant agents on the vascular endothelium.

Syndromes with Encephalopathy in Which Drugs Are Implicated Two syndromes will be considered in this section: Reye’s syndrome and toxic encephalopathy of the newborn.

Reye’s Syndrome It is a rare sporadic disorder of childhood of unknown origin characterized by hepatic dysfunction and metabolic encephalopathy. The syndrome is named after Reye who described 21 children between the ages of 5  months and

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9 years (Reye et al. 1963). The outstanding clinical features were profound disturbances of consciousness, vomiting, disturbances of respiratory rhythm, convulsions, and coma. There were abnormalities of liver function tests. Seventeen of these patients died, and the main autopsy findings were brain swelling and fatty accumulation in the liver and the kidneys. The prodrome is viral infection. Viruses most often associated with the syndrome are influenza B and varicella. In the 1980s this syndrome received prominent attention because of its link to salicylate intoxication. Pathogenesis  Genetic predisposition is recognized, and several metabolic abnormalities have been identified. Both experimental and epidemiologic studies suggest that Reye’s syndrome is a stereotypic reversible reaction in mitochondria arising from an interaction of viral, toxic, and genetic factors. Transient mitochondrial dysfunction possibly limited to the hepatocytes and increased tissue metabolism account for most of the biochemical changes reported in Reye’s syndrome. Aspirin, particularly in subjects deficient in L-carnitine, may compromise detoxification and lead to accumulation of toxic products and precipitate the onset of symptoms. Aspirin is the drug most often associated with Reye’s syndrome. The evidence for this along with criticisms is as follows. Epidemiological Studies  Various studies have shown that patients with Reye’s syndrome had taken aspirin more frequently, prior to, or early in the illness than had controls with prodromal illnesses that were similar. These studies were criticized because of bias in case-control selection and data collection. Histopathological Evidence  Apparent similarities between liver changes in Reye’s syndrome and those associated with salicylate poisoning have not been confirmed. Elevated serum levels of salicylates. The report of these findings in Reye’s syndrome was

13  Drug-Induced Encephalopathies

based on nonspecific technology and has not been confirmed. Long-Term Salicylate Therapy  The syndrome was reported among children on long-term salicylate therapy for connective tissue disorders, and the reported reduction in incidence now is attributed to decrease in use of salicylates in the USA. However, studies from Japan failed to confirm any such association. A retrospective study has examined Reye’s syndrome with different degrees of encephalopathy, hyperammonemia, and hypoglycemia, associated to acetyl salicylic acid (ASA) ingestion (Lemberg et  al. 2009). All the cases presented with moderate hyperbilirubinemia as well as elevated alanine aminotransferase and aspartate aminotransferase. The study reached the following conclusions: (i) hyperammonemia and perhaps the increase of glutamate are the leading factors in the mechanism of brain damage and encephalopathy in Reye’s syndrome; (ii) the presence of ASA could cause the onset of the mitochondrial permeability transition and the mitochondrial swelling in the astrocyte, leading to hyperammonemia; and (iii) ASA should be carefully administrated under the supervision of professionals, while parents are informed about the risks in the use of this drug in children. In conclusion, Reye’s syndrome is still an enigma and challenge for further research. It indicates the range of metabolic responses to exogenous agents, some of which will modify the body’s response to viral infection.

 oxic Encephalopathy in the Newborn T Most cases of neonatal encephalopathy are secondary to hypoxia, ischemia, major malformations, and infection. Toxic encephalopathy refers to disorders of cerebral function due to extraneous toxins including drugs. Exposure to drugs is usually via the mother through the placenta in the prenatal period and through breast milk in the postnatal period. A discussion of congenital malformations induced by drugs is beyond the scope

Encephalopathies Secondary to Drug-Induced Metabolic Disorders Table 13.8  Drugs involved in the toxic encephalopathies of the newborn Drug abuse by the mother  Opiates  Cocaine  Amphetamines  Phencyclidine  Marijuana  Alcohol Prescription drugs used during pregnancy  Anticonvulsants  Antidepressants  Barbiturates  Benzodiazepines  Codeine  Propoxyphene Drug exposure through breast milk © Jain PharmaBiotech

of this work. Drugs involved in toxic encephalopathies of the newborn are shown in Table 13.8. Most of the neurological manifestations in the newborn of a mother exposed to these drugs during pregnancy are those of withdrawal or abstinence except non-barbiturate anticonvulsants. Chronically drug effects are mostly manifested by a static encephalopathy, probably secondary to teratogenic effects of the drugs on the developing nervous system. Such infants may be obviously retarded or may have developmental retardation which may not be diagnosed till a few years later. During breastfeeding drugs which are excreted in the milk are ingested by the infant and may produce direct neurotoxicity. Drugs such as diazepam and chlorpromazine taken by the nursing mother can produce drowsiness of the infant. Exposure to drugs via the mother is an important factor to be considered in the evaluation of an infant with encephalopathy (see Chap. 5).

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Aksamit AJ Jr, de Groen PC. Cyclosporine-related leukoencephalopathy and PML in a liver transplant recipient. Transplantation 1995;60:874–6. Baehring JM, Fulbright RK.  Delayed leukoencephalopathy with stroke-like presentation in chemotherapy recipients. J Neurol Neurosurg Psychiatry. 2008;79:535–9. Baldini M, Bartolini E, Gori S, et  al. Epilepsy after neuroimaging normalization in a woman with tacrolimus-­ ­ related posterior reversible encephalopathy syndrome. Epilepsy Behav. 2010;17:558–60. Balin J, Parmar H, Kujawski L.  Conventional and diffusion-weighted MRI findings of methotrexate related sub-acute neurotoxicity. J Neurol Sci. 2008;269:169–71. Brugnoletti F, Morris EB, Laningham FH, et al. Recurrent intrathecal methotrexate induced neurotoxicity in an adolescent with acute lymphoblastic leukemia: serial clinical and radiologic findings. Pediatr Blood Cancer. 2009;52:293–5. Brunello A, Basso U, Rossi E, et  al. Ifosfamide-related encephalopathy in elderly patients : report of five cases and review of the literature. Drugs Aging. 2007;24:967–73. Burns R, Thomas DW, Barron VJ.  Reversible encephalopathy possibly associated with bismuth subgallate ingestion. BMJ. 1974;1(5901):220–3. Doss-Esper CE, Singhal AB, Smith MS, Henderson GV.  Reversible posterior leukoencephalopathy, cerebral vasoconstriction, and strokes after intravenous immune globulin therapy in Guillain-Barré syndrome. J Neuroimaging. 2005;15:188–92. Grémain V, Richard L, Langlois V, Marie I.  Imaging in central pontine myelonolysis: animals in the brain. QJM. 2016;109:431–2. Guo X, Wei J, Gao L, Xing B, Xu Z. Hyperammonemic coma after craniotomy: hepatic encephalopathy from upper gastrointestinal hemorrhage or valproate side effect?: case report and literature review. Medicine (Baltimore). 2017;96:e6588. Han R, Yang YM, Dietrich J, Luebke A, Mayer-Proschel M, Noble M. Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system. J Biol. 2008;7:12. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med. 1996;334:494–500. Hunter CA, Jennings FW, Kennedy PGE, et al. The use of azathioprine to ameliorate post-treatment encephalopathy associated with African trypanosomiasis. Neuropathol Appl Neurobiol. 1992;18:619–25. Ito Y, Niwa H, Iida T, et  al. Post-transfusion reversible posterior leukoencephalopathy syndrome with cerebral vasoconstriction. Neurology. 1997;49:1174–5.

206 Jain KK.  Hepatic encephalopathy. In: Roos RP, editor. MedLink neurology. San Diego: MedLink Corporation (http://www.medlink.com); 2021. Júnior AM, Arrais CA, Saboya R, et  al. Neurotoxicity associated with dimethylsulfoxide-preserved hematopoietic progenitor cell infusion. Bone Marrow Transplant. 2008;41:95–6. Kastrup O, Diener HC.  Granulocyte-stimulating factor filgrastim and molgramostim induced recurring encephalopathy and focal status epilepticus. J Neurol. 1997;244:274–5. Kilbridge PM, Campbell UC, Cozart HB, Mojarrad MG. Automated surveillance for adverse drug events at a community hospital and an academic medical center. J Am Med Inform Assoc. 2006;13:372–7. Kriegelstein AR, Armitage BA. Kim PY: heroin inhalation and progressive spongiform leukoencephalopathy. N Engl J Med. 1997;336:589–90. Kuzuhara S. Itrogenic neurological disorders in old people: a review. Nihon Ronen Igakkai Zasshi. 2005;42: 21–24. Kwon KA, Kwon HC, Kim MC, et  al. A case of 5-Fluorouracil induced encephalopathy. Cancer Res Treat. 2010;42:118–20. Lazzarino LG, Nicolai A, Valassi F. Acute transient cerebral intoxication induced by low doses of baclofen. Ital J Neurol Sci. 1991;12(3):323–5. Lemberg A, Fernández MA, Coll C, et  al. Reyes’s syndrome, encephalopathy, hyperammonemia and acetyl salicylic acid ingestion in a city hospital of Buenos Aires, Argentina. Curr Drug Saf. 2009;4:17–21. Levy CF, Oo KZ, Fireman F, et  al. Reversible posterior leukoencephalopathy syndrome in a child treated with bevacizumab. Pediatr Blood Cancer. 2009;52:669–71. Linda H, von Heijne A, Major EO, et al. Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N Engl J Med. 2009;361(11):1081–7. Lugassy D, Nelson L. Case files of the medical toxicology fellowship at the New York City poison control: bromism: forgotten, but not gone. J Med Toxicol. 2009;5:151–7. Mathew RP, Kunhimohammed SP, Joseph M.  A case of topical metronidazole-induced encephalopathy. JAMA Neurol. 2020; https://doi.org/10.1001/ jamaneurol.2020.2596. Menegaux F, Keeffe EB, Andrews BT, et al. Neurologic complications of liver transplantation in adult versus pediatric patients. Transplantation. 1994;58:447–50. Moritz ML, Ayus JC. New aspects in the pathogenesis, prevention, and treatment of hyponatremic encephalopathy in children. Pediatr Nephrol. 2010;25:1225–38.

13  Drug-Induced Encephalopathies Mueller AR, Platz KP, Bechstein WO, et al. Neurotoxicity after orthotopic liver transplantation. Transplantation. 1994;58:155–69. Muller J, Kralovanszky J, Adleff V, et al. Toxic encephalopathy and delayed MTX clearance after high-dose methotrexate therapy in a child homozygous for the MTHFR C677T polymorphism. Anticancer Res. 2008;28:3051–4. Murad MH, Coto-Yglesias F, Wang AT, et  al. Clinical review: drug-induced hypoglycemia: a systematic review. J Clin Endocrinol Metab. 2009;94:741–5. Noda S, Hartake J, Sasaki A, et  al. Acute encephalopathy with hepatic steatosis induced by pantothenic acid antagonist calcium hopantenate, in dogs. Liver. 1991;11:134–42. Patel PN. Methylene blue for management of Ifosfamideinduced encephalopathy. Ann Pharmacother. 2006;40:299–303. Reye RDK, Morgan G, Baral J. Encephalopathy and fatty degeneration of the viscera: a disease entity in childhood. Lancet. 1963;2:749–52. Rezaei NJ, Bazzazi AM, Naseri Alavi SA. Neurotoxicity of the antibiotics: a comprehensive study. Neurol India. 2018;66(6):1732–40. Rossmeisl JH, Inzana KD.  Clinical signs, risk factors, and outcomes associated with bromide toxicosis (bromism) in dogs with idiopathic epilepsy. J Am Vet Med Assoc. 2009;234:1425–31. Sasaki R, Hishikawa N, Nomura E, et  al. Tocilizumab-­ induced leukoencephalopathy with a reversible clinical course. Intern Med. 2020;59:2927–30. Schwab N, Schneider-Hohendorf T, Pignolet B, et al. PML risk stratification using anti-JCV antibody index and L-selectin. Mult Scler 2016;22:1048–60. Sidhu SS, Agarwal S, Goyal O, et al. Sorafenib induced hepatic encephalopathy. Acta Gastroenterol Belg. 2017;80:537–8. Stephan F, Etienne MC, Wallays C, et al. Fatal encephalopathy and tumor lysis syndrome: case report. Am J Med. 1995;99:685–8. Tekgul H, Serdaroglu G, Karapinar B, et  al. Vigabatrin caused rapidly progressive deterioration in two cases with early myoclonic encephalopathy associated with nonketotic hyperglycinemia. J Child Neurol. 2006;21:82–4. Thompson JP, Noyes K, Dorsey ER, Schwid SR, Holloway RG. Quantitative risk-benefit analysis of natalizumab. Neurology. 2008;71:357–64. Wainer V, Ducharme J, Granvil CP, et al. Ifosfamide stereoselective dichloroethylation and neurotoxicity (letter). Lancet. 1994;343:982–3.

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Drug-Induced Disorders of Memory and Dementia

Introduction to Drug-Induced Memory Impairment Drug-induced memory and cognitive impairment and drug-induced dementia are discussed in chapter as a continuum in severity under the broad term “cerebral insufficiency.” Some of the manifestations may overlap those described in Chap. 16 on drug-induced neuropsychiatric disorders.

Definitions and Historical Note Several commonly used therapeutic drugs and medications, and some recreational drugs, are known to produce memory disturbances, as is exposure to industrial chemicals. The focus of this article is on medication-induced memory disturbances, but studies of drugs of abuse, both experimental and clinical, also shed light on the pathomechanisms of drug-induced memory loss. The first mention of a therapeutic drug-­ induced dementia was after the introduction of synthetic drugs for the treatment of Parkinson disease (Porteus and Ross 1956). The frequently used term “cognitive impairment” refers to disturbances of information processing, which covers the acquisition, storage, retrieval, and use of information. According to the “working memory” model, the allocation of limited resources available for information pro-

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cessing is under the control of the central executive. Working memory corresponds to the set of things we are attending to at any given moment. Thus, attention and memory are processes that operate together, and drugs affecting attention would be expected to impair memory as well. Cognitive disturbances include delirium and disturbances of memory, intellect, and behavior. Various terms referring to memory disorders in this chapter are: Amnesia  This usually refers to a pathological loss of memory. Memory is disturbed in several conditions often secondary to disorders of attention. Isolated memory loss, also referred to as an amnestic syndrome, is also seen as an adverse reaction to drugs. Retrograde Amnesia  This refers to difficulty in recalling events that have occurred in the premorbid period. It is usually present in amnestic state or syndrome and affects individuals for a limited period. Anterograde Amnesia  This implies difficulty in registering new information (learning ability). Transient Global Amnesia  This is a clinical syndrome characterized by abrupt onset of severe anterograde amnesia from which the patient usually recovers within hours except for the memory gap for the duration of the attack.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_14

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Loss of episodic memory, i.e., a person’s unique memory of a specific event, can be affected by neurologic disorders such as a traumatic brain injury, hydrocephalus, brain tumors, and metabolic conditions such as vitamin B1 deficiency.

Table 14.1 Drugs and other substances reported to impair memory

Fugue  It is an episode during which a person assumes a new identity and has no memory of his or her real identity. Fugue-like states are associated with retrograde amnesia. Accelerated Long-Term Forgetting  It occurs when newly learned information decays faster than normal over extended periods. It occurs most frequently in temporal lobe epilepsy, where it is referred to as “transient epileptic amnesia,” but it can also be drug-induced.

 rugs Associated with Memory D Impairment Table 14.1 shows categories of drugs that are reported to be associated with memory impairment. Alcohol  Neurocognitive deficits, including memory impairment, resulting from chronic alcoholism are well known. This may be due to direct toxic effect of alcohol on the brain as well as other predisposing factors associated with chronic alcoholism. Episodic memory is severely affected in Korsakoff syndrome. Analgesics  Various forms of cognitive dysfunction, e.g., memory deficit and an inability to concentrate, have been associated with nonsteroidal anti-inflammatory drug use in retrospective studies involving ibuprofen and naproxen. Both pain and opioid analgesics affect the central nervous system, and there is contradictory evidence concerning the effects of opioid analgesics on cognitive performance including memory. Studies of long-term opioid use in patients with chronic noncancer pain have found such treatment to improve cognitive function, whereas others have found that it is impaired. A pilot study

Alcohol Analgesics  Dexmedetomidine infusions (alpha-2 agonist)  Nonsteroidal anti-inflammatory drugs: ibuprofen, naproxen  Opioids Anesthesia  Halothane  Ketamine Antineoplastic agents  Cytokines  Intrathecal chemotherapy Anticholinergic drugs Antidepressants Antiepileptic drugs Gabapentinoids  Gabapentin (used for treatment of neuropathic pain)  Pregabalin (used for treatment of neuropathic pain) Antiparkinsonian drugs Benzodiazepines  Alprazolam  Clorazepate  Diazepam  Lorazepam  Triazolam Beta-blockers and similar drugs  Atenolol  Propafenone Corticosteroids Drug abuse  Amphetamine dependence  Marijuana smoking  MDMA (ecstasy)  Phencyclidine Ergot compounds Dopaminergic drugs Gap junction blockers Gonadotropin-releasing hormone agonist Hypnotics  Barbiturates  Zolpidem Immunosuppressive drugs  Sirolimus  Tacrolimus Contrast media  Iohexol for cerebral angiography  Cardiac and peripheral arteriography with nonionic contrast medium Mefloquine Oxytocin Statins (continued)

Introduction to Drug-Induced Memory Impairment Table 14.1 (continued) Sildenafil Sibutramine Sodium oxybate Industrial chemicals  Toluene © Jain PharmaBiotech

that has controlled for the use of long-term opioids while measuring cognitive performance in patients with chronic low back pain found that patients receiving long-term opioid analgesics have minor differences from those not taking opioids (Richards et al. 2018). A systematic review and meta-analysis of studies of neuropsychological effects of long-term use of opioids in patients with chronic noncancer pain concluded that opioids reduce attention when compared with treatments not targeted to the central nervous system and that this effect increases if opioids are used in combination with antidepressants, or anticonvulsants, or both (Allegri et al. 2019). Anesthetics  Most anesthetic agents impair memory. Although inhalational anesthetic agents are among the most potent drugs that cause temporary amnesia, their effect on human emotional memory processing is not clear and is being studied. A study using glucose PET has shown that 0.25% sevoflurane blocks emotional memory by suppressing amygdala-to-hippocampal effective connectivity (Alkire et al. 2008). Diazepam-induced amnesia has been used therapeutically in combination with analgesic medications to reduce painful memories of endoscopic procedures. Intravenous ketamine is used for relief of pain and is associated with cognitive impairment, which may vary according to the isomer of the drug. A controlled study in volunteers showed that immediate recall, retention in primary memory, and short-term storage capacity were less reduced after the isomers than after equianalgesic small-dose racemic ketamine. Antineoplastic Agents  Various drugs used for the treatment of cancer can directly affect the central nervous system and cause acute as well as

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chronic cognitive disturbances. Examples of these treatments are cytokines and chemotherapy. Cancer patients often complain of difficulties with memory and concentration, popularly referred to as “chemobrain” or “chemofog,” but some studies suggest that chemotherapy may not be the cause of cognitive impairment as some patients might already have cognitive problems before the treatment is started (Zachariae and Mehlsen 2011). Experimental studies in rats have provided an explanation for chemotherapy-­ induced memory disturbances. Prolonged administration of temozolomide, which is used for the treatment of malignant brain tumors, is associated with a decrease in hippocampal adult neurogenesis that may explain the selective deficits in processes of learning, whereas memory for previously learned associations is not disrupted (Nokia et al. 2012). Immunotherapy of cancer with cytokines can produce cognitive impairment including memory disturbances. Duration of therapy is an important determinant of the cognitive effects of interferon-alpha. Memory impairment is recognized as an adverse effect of chemotherapy and has been reported in several studies of breast cancer patients treated with various chemotherapeutic agents. Memory impairment is more severe in those who receive adjuvant tamoxifen, a hormonal agent, compared with women who received chemotherapy alone. Aromatase inhibitors such as anastrozole have been used instead of tamoxifen for the adjuvant treatment of breast cancer, but a study has shown that women who received anastrozole had poorer verbal and visual learning and memory than women who received tamoxifen (Bender et al. 2007). Anticholinergic Drugs  Several drugs with anticholinergic properties, listed in Table  14.2, are used in medical practice. Cognitive adverse effects of anticholinergic drugs include confusion, impaired memory, delirium, hallucinations, and psychosis. Anticholinergics impair memory retrieval, especially free recall. Even over-the-counter H1 antihistaminics, which have anticholinergic effects, can impair cognitive performance.

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Table 14.2  Drugs with anticholinergic properties

In a 4-year follow-up study, a patient with baclofen-induced accelerated long-term forgetting was retested 18  months after discontinuing baclofen and showed evidence of recovery by improvements in autobiographical memory for recent but not remote events (Savage et al. 2019).

Antiarrhythmics, e.g., propafenone Antiemetics, e.g., meclizine Antihistaminics, e.g., brompheniramine Antiparkinsonian, e.g., benztropine, trihexyphenidyl, amantadine, profenamine Antispasmodics, e.g., atropine Antiasthmatics, e.g., ipratropium bromide Muscle relaxants, e.g., baclofen Antipsychotics, e.g., clozapine, chlorpromazine Tricyclic antidepressants, e.g., amitriptyline © Jain PharmaBiotech

Drugs with anticholinergic activity are the major pharmacological agents that contribute to the verbal memory deficit observed in patients with schizophrenia. These drugs appear to act by impeding semantic organization at encoding. Cumulative anticholinergic exposure across multiple medications over 1 year may negatively affect verbal memory and executive function in older men (Han et al. 2008). A longitudinal study of cognitively normal older adults found that use of anticholinergic medications was associated with increased brain atrophy as shown by brain imaging and cognitive decline, including lower mean scores on Wechsler Memory Scale-Revised Logical Memory Immediate Recall over a mean follow-up period of 32 months (Risacher et al. 2016). Functional connectivity MRI (fcMRI) has been used as an experimental tool to examine the systems pharmacology of psychoactive drugs and reveals disrupted connectivity within and between default and salience networks in scopolamine-­induced amnesia (Chhatwal et  al. 2019). A cross-sectional study has shown that anticholinergic burden, as measured by the Anticholinergic Drug Scale and various other tools, in patients with subjective cognitive decline or neurocognitive disorders is associated with lower functional score (Dauphinot et  al. 2017). Therefore, caution should be exercised in prescribing anticholinergic drugs to patients with memory complaints. In a retrospective review of case histories of the patients who presented with the complaint of cognitive impairment, one third were found to be taking anticholinergic drugs (López-Matons et al. 2018).

Dopaminergic Drugs  Paradoxical effects have been reported by which the same drug causes cognitive enhancement as well as adverse effects. Individual differences in impulsive personality account for the contrasting effects of dopaminergic drugs on working memory and associated frontostriatal activity. Antidepressants  Depression is a cause of cognitive impairment, and antidepressants generally reduce cognitive deficits. However, the central cholinergic effects of tricyclic antidepressants are the primary cause of the cognitive effects in these agents. Amitriptyline can disrupt verbal recall and produce noticeable and significant impairment of cognition and psychomotor function, whereas moclobemide, a selective monoamine oxidase inhibitor, is relatively free from these adverse effects. Selective serotonin reuptake inhibitors usually do not impair memory. Antiepileptic Drugs  Because antiepileptic drugs reduce neuronal irritability, it is suspected that they may reduce neuronal excitability and impair cognitive function. Most of the cognitive effects of antiepileptic drugs are dose-related. Assessment of the effects of antiepileptic drugs on cognitive function, however, is a controversial issue because of subject selection, genetic factors, statistical difficulties, choice of cognitive tests, and the impact of seizures on psychological performance. Declarative memory functions show characteristic patterns of impairment in epilepsy when mediotemporal and associated neocortical structures are affected by lesions, ongoing epileptic activity, or the undesired effects of conservative or operative treatment. Evaluation of memory function in most studies is limited, and when effects are recorded, they are possibly secondary to changes in the level of attention or speed of mental processing. Long-term pheno-

Introduction to Drug-Induced Memory Impairment

barbital therapy induces a significant impairment in learning ability. Few cognitive side effects have been reported in studies of newer antiepileptic drugs. Memory deficit is a concomitant disorder in patients suffering from neuropathic pain and is also a side effect of gabapentinoids, gabapentin and pregabalin, which are used for the treatment of neuropathic pain. Experimental studies in rats have shown that 5-HT6 receptor antagonist attenuates the cognitive deficits associated with neuropathic pain treated with gabapentinoids, enabling reduction in the dosage and frequency of administration (Jayarajan et al. 2015). Antiparkinsonian Drugs  Several new antiparkinsonian drugs have minimal neuropsychiatric side effects. Among the older medications, anticholinergic drugs are still in use. Chronic administration of trihexyphenidyl to patients with Parkinson disease can cause a decrease in performance on recent memory tests, but not on immediate memory tests. Antipsychotics  Although some atypical antipsychotics may improve cognitive impairment due to schizophrenia, antipsychotic drugs have anticholinergic properties that can impair cognitive function. In a study of institutionalized older adults with dementia, specific impairment of cognitive function such as executive or attentional impairments was associated with antipsychotic medication use (Eggermont et al. 2009). A study found significant association between antipsychotic-­ induced parkinsonism and working memory performance, which are clinically significant because working memory deficits are known to impair patients’ social and occupational functions (Potvin et al. 2015). Benzodiazepines  Clinical features of memory disturbances produced by various benzodiazepines (triazolam, lorazepam, and diazepam) were described in the clinical manifestations section. Benzodiazepines are used for several indications besides their hypnotic action. For example, alprazolam has been used as an anxiolytic in minor surgical procedures, but it produces memory

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impairment at the dosages necessary to be clinically effective during oral surgery. Although, as a class, benzodiazepines act rapidly and are well tolerated, their use continues to be associated with issues such as dependence and memory impairment. As examples, some amnesic states associated with the benzodiazepines are: Triazolam. Most reported amnesic states concern the use of triazolam. Travelers’ amnesia is a transient global amnesia secondary to triazolam. In addition to anterograde amnesia, there is amnesic complex automatism, during which the subjects can perform complicated tasks without errors but have no recollection of having done so afterward. Some individuals have negotiated and signed complicated agreements after the use of triazolam and had no recollection of the events afterward. Triazolam syndrome in the elderly is characterized by reversible delirium, anterograde amnesia, and automatic movements that are causally associated with triazolam used as a hypnotic. An application of triazolam-induced amnesia is its use as a premedication for surgical patients who wish to have no memory of the operating room (Iida et al. 2011). Lorazepam. This is an intermediate-acting benzodiazepine used intravenously to induce preoperative anterograde amnesia. Studies in human volunteers have shown that lorazepam produces dose-related deficits in verbal secondary memory as well as impairment of information acquisition and recall. Memory impairment with lorazepam is independent of increased sedation. In contrast to deficits in episodic memory with sedatives, no lorazepam-induced impairments on tests of semantic memory have been reported. Midazolam. Midazolam is a benzodiazepine with antianxiety and sedative effects. Because of rapid onset and short duration of action, it is commonly used in diagnostic and therapeutic procedures to create anterograde amnesia, which prevents undesirable memory of the procedure that is painful for the patient. An experimental study has shown that midazolam-induced amnesia reduces memory for details and affects the event-related potentials as correlates of recollection and familiarity (Nyhus and Curran 2012). An

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oral dose of midazolam 0.5–0.6 mg/kg or intranasal dose of 0.2 mg/kg is acceptable for use in children undergoing voiding cystourethrography for diagnosis and grading of vesicoureteral reflux, which is a very painful and distressing experience (Alizadeh et al. 2017). Diazepam. This is an anxiolytic benzodiazepine. Acute administration of diazepam can produce anterograde amnesia of both verbal and visual information. Intravenous diazepam impairs free recall significantly in a dose-dependent manner. Bromazepam. A randomized double-blind study with bromazepam showed that it can contribute to a reduced working memory load in areas related to attention processes although it produces higher cortical activation in areas associated with motor learning (Cunha et al. 2008).

glucocorticoids modulate body homeostasis and coordinate adaptive responses to stress, synthetic glucocorticoids can produce neuropsychiatric disturbances, including memory impairment, with structural changes in brain target areas with long-term use (Fietta et al. 2009). Pulsed methylprednisolone has been shown to induce reversible impairment of memory in patients with relapsing-­ remitting multiple sclerosis. Drug Abuse  Abuse of recreational drugs is associated with memory impairment. Some examples are: Amphetamines  Drugs in this category are associated with cerebral vasculitis and intracerebral as well as subarachnoid hemorrhage. Cognitive function impairment in illicit amphetamine users has been tested by a neuropsychological test battery (Revised Wechsler Memory Scale), and the severity of amphetamine dependence was found to be associated with poor performance on memory, attention, and concentration indices.

Beta-Blockers and Similar Drugs  Lipophilic beta-blockers such as propranolol cause cognitive impairment. Hydrophilic beta-blockers such as atenolol can also cause neuropsychiatric side effects. Drugs with structural similarities to beta-­ blocker agents can also produce adverse neuro- 3,4-Methylenedioxymethamphetamine logic effects. (MDMA or Ecstasy)  This amphetamine derivative has become increasingly popular as a recreAtenolol  There is a case report of a hypertensive ational drug. There are several reports of man who developed memory impairment after neuropsychiatric disturbances as well as cerebral 14-year therapy with atenolol (Ramanathan infarctions following MDMA use. Memory dis1996). Other causes of memory impairment were turbances have also been reported. MDMA is ruled out, and atenolol was replaced with a com- also neurotoxic with significant deleterious bination of amiloride and hydrochlorothiazide. effects on serotonergic neurons, memory, and One month later, the patient showed 75% recov- mood (El-Mallakh and Abraham 2007). ery, thus confirming atenolol as the cause of MDMA is known to damage brain presynaptic memory impairment. 5-HT neurons. Because loss of 5-HT neurons has been implicated in memory loss, it is possible Propafenone  This antiarrhythmic drug has that MDMA use may produce changes in poststructural similarities to beta-blocker agents. synaptic 5-HT receptors and memory function in Reported central nervous system effects include humans. Altered 5-HT neuronal function has seizures, psychoses, confusion, dizziness, ataxia, been correlated with memory impairment in headaches, tremor, and depression. Several cases abstinent MDMA users. of memory disturbances have been reported. Marijuana  Several studies have examined the Corticosteroids  Chronic treatment with corti- residual effects of cannabis on neuropsychologicosteroids can produce neuropsychiatric and cal performance. Subjects with a more prolonged memory disturbances in patients with systemic history of cannabis use have a greater deficit in diseases without brain lesions. Whereas natural short-term memory and better conserved long-­

Introduction to Drug-Induced Memory Impairment

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term memory (Coullaut-Valera et  al. 2011). Gap Junction Blockers  Gap junctions can be Heavy users display significantly greater impair- involved in the regulation of arousal and memory ment than light users on attentional and executive among other functions. Gap junction blockers function as evidenced by reduced learning and can disrupt neuronal activity, block seizure activrecall of visual and visuospatial information. The ity, and impair cognitive functions including question as to whether this impairment is due to a memory (Juszczak and Swiergiel 2009). residue of the drug in the brain, withdrawal effect Examples of gap junction blockers are quinine, from the drug, or a direct neurotoxic effect of the quinidine, mefloquine, carbenoxolone, retinoic drug remains unanswered. Functional brain acid, and several anesthetics. Some of these drugs imaging can show altered brain function after have been considered under other categories as marijuana, but the regions showing these abnor- well. malities have not been localized. Data from the “Coronary Artery Risk Development in Young Hypnotics  Zolpidem is a nonbenzodiazepine Adults” study were followed up for 25  years hypnotic of the imidazopyridine class. It acts by from 1986 to 2011 to estimate cumulative years modulation of a subunit of GABA receptor chloof exposure to marijuana and showed that past ride channel macromolecular complex. Reported exposure to marijuana is associated with deterio- central nervous system adverse effects include ration of verbal memory, but other domains of cognitive impairment, confusion, psychoses, and cognitive function appear to be unaffected (Auer vertigo. Amnesic events have also been reported et al. 2016). following ingestion of normal doses of the drug A double-blind, randomized, placebo-­as a hypnotic. Benzodiazepines are called controlled trial showed the acute and delayed “acquisition-­impairing” molecules because they effects of delta-9-tetrahydrocannabinol intoxica- are generally considered to affect anterograde tion on susceptibility to false memory in healthy memory processes. However, they have an impact volunteers (Kloft et al. 2020). Cannabis seems to on retrograde memory as well and more particuincrease false-memory proneness, with decreas- larly on retrieval processes. ing strength of association between an event and A randomized, double-blind, crossover study a test item, as assessed by different false-memory compared the effect of single nighttime therapeuparadigms. These findings have implications for tic doses of zaleplon, zolpidem, and triazolam how and when the police should interview sus- and found no impairment of memory with pects and witnesses who have been smoking mar- zaleplon (a nonbenzodiazepine hypnotic), ijuana. A cannabinoid has been approved as an whereas the other two drugs produced psychoantiepileptic drug. Other cannabinoids are now motor and memory impairment. under clinical investigation for therapeutic use in conditions such as chronic pain. Behavioral stud- Oxytocin  The neuropeptide oxytocin is essenies suggest that a disruption of normal hippocam- tial for parturition and lactation. A single dose of pal function contributes to impairment of memory intranasal oxytocin in healthy volunteers signifiand learning in marijuana smokers. cantly impaired recall performance as compared Phencyclidine, a noncompetitive NMDA with placebo treatment irrespective of the meanreceptor antagonist, can induce schizophrenia-­ ing of words in the cued recall test (Heinrichs like symptoms. It is known that schizophrenic et al. 2004). patients have deficits in memory processes. Statins  Statins are used widely for the treatment Ergot Compounds  Transient global amnesia of hypercholesterolemia. Experimental studies has been reported in two patients with a history support links between cholesterol intake and of migraines after taking ergotamine and dihy- amyloid synthesis. Statins are of prophylactic droergotamine to treat an attack of migraine (Gil-­ value in preventing the progression of Alzheimer Martinez and Galiano 2004). disease. However, several reports have attributed

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memory loss to statins. It is possible that, in rare • The basal forebrain cholinergic system plays cases, statins may be associated with memory an important role in memory. Patients with impairment, although no causal relation has been Alzheimer disease often show degeneration of established. A case of rosuvastatin-related short-­ the central cholinergic system. Anticholinergic term memory loss was reported in a man with drugs are known to impair memory. hypercholesterolemia but resolved gradually fol- • Drug-induced seizures may be followed by an lowing discontinuation of the drug (Galatti et al. amnesic syndrome. Status epilepticus is fol2006). lowed by amnesia in patients with theophylline-­induced seizures. Sibutramine  Sibutramine, a serotonin and nor- • The hippocampi, essential for episodic memadrenaline reuptake inhibitor, is widely used in ory function, are targets of MDMA neurotoxthe management of obesity. The World Health icity in experimental animals. Organization’s international database contains • Two drugs that produce amnesia, midazolam several reports of amnesia associated with and atropine, alter theta oscillations in the sibutramine, but they are rarely published. A case hippocampal CA1 region. Computational ­ of transient global amnesia has been reported in a modeling has shown that these effects can be patient on sibutramine treatment (Fu et al. 2010). produced by simultaneous changes in the The possible mechanism is the increase in synapactive somatic and distal dendritic inputs, tic serotonin concentrations by sibutramine. which indicates a common basis for impaired Discontinuation of sibutramine led to improvememory encoding although they target difment of memory in most of the cases. ferent receptors (Balakrishnan and Pearce 2014). Sodium Oxybate  This medical formulation of • Glucocorticoids, whether administered or genergamma-hydroxybutyrate is used for the treatment ated in response to stress, have been shown to of cataplexy in patients with narcolepsy, and have an adverse effect on the rodent brain, parillicit use is alleged to cause amnesia. A comparaticularly in the hippocampus, a structure vital to tive double-blind study in healthy volunteers learning and memory and a location of a high showed that sodium oxybate significantly concentration of receptors for glucocorticoids. impaired working memory and the encoding of Several days of exposure to cortisol at doses and episodic memory during the period of drug effect, plasma concentrations associated with physical but episodic memory tasks were impaired to a and psychological stress in humans can reverslesser extent after sodium oxybate than after triibly decrease specific elements of memory in azolam at doses that produce equivalent subjecotherwise healthy individuals. Hippocampal tive effects (Carter et al. 2009). atrophy has been attributed to glucocorticoid overproduction in patients with Cushing synIndustrial Chemicals  High levels of toluene, drome and post-­traumatic stress disorder. These over 50 ppm, are known to produce neurotoxicobservations imply that high-dose corticosteroid ity. Lower concentrations, 2–27 ppm in a printing therapy can produce hippocampal atrophy in plant, were associated with decreased perforhumans and explain the memory impairment. mance on tests of memory function (Chouaniere • Dopaminergic mechanisms are possibly et al. 2002). involved in morphine-induced memory impairment. • Memory storage is believed to be initiated by Pathomechanisms of Drug-Induced neuronal transmission increasing Ca2+ influx Memory Disturbances via NMDA receptors. • GABA is a major inhibitory neurotransmitter Pathomechanisms of drug-induced memory disin the brain. The classical benzodiazepines turbances are as follows: potentiate GABA-stimulated chloride flux.

Introduction to Drug-Induced Memory Impairment

Amnesia and Sedation  Drug-induced amnesia is often assumed to be related to the sedating effects of drugs. Electrophysiological evidence indicates that sedation and amnesia may not correlate. Midazolam and propofol affect memory differentially from their sedative effects, as revealed by a study of specific components of the auditory event-related potential. Benzodiazepine-Induced Amnesia  Drugs of this category affect the encoding stage of memory by disturbing attention and impair the transference of material from short-term storage to long-term memory. Another possible mechanism is that long-term memory deficit could be the result of failure of memory consolidation during rapid sleep onset. Neuroanatomically, the subcortical structures appear to play an important role in the consolidation of newly learned information. Results of various PET studies are consistent with behavioral evidence that benzodiazepines impair prefrontal control processes as well as contextual memory and episodic binding processes. Pharmacologically, benzodiazepines potentiate the effect of GABA, a major inhibitory neurotransmitter. GABA facilitation is likely to impair the function of these structures in the consolidation process. At a neurophysiological level, the disruption of consolidation that occurs in these structures may be mediated through the effect of GABA on long-term potentiation, a phenomenon in which relatively short periods of electrical stimulation result in enduring changes in the synaptic efficiency. Thus, benzodiazepines, as GABA agonists, may impair long-term potentiation and cause deficits both in the acquisition and retention of information through their immediate and long-term effects on consolidation. In long-term administration of benzodiazepines, the acquisition phase of memory may be affected, and delayed recall may be impaired for the material learned during the intoxication period. Benzodiazepine dependence in the elderly can cause memory impairment that can persist into the early drug-free period. Amnestic effects of benzodiazepines are mediated by the benzodiazepine receptor and can be blocked by

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specific benzodiazepine receptor antagonists in animal models. The frequency and severity of cognitive impairment resulting from the use of benzodiazepines have been correlated with pharmacokinetic and pharmacodynamic factors. The elimination half-life, receptor-binding affinity, effects on the locus coeruleus-norepinephrine and hypothalamic-pituitary-adrenal axis, and interaction of these factors appear to be the major determinants of the frequency and severity of these adverse reactions. Drug-Induced Amnesia as a Tool for Memory Research  Drug-induced amnesia has implications for cognitive neuropsychological investigations of memory. Cholinergic drugs have been used as tools to manipulate the functional state of the cerebral cortex based on the theory that the cholinergic system controls the functional state of the cortex. Cholinergic blockage by scopolamine impairs performance on tasks involving sustained and selective attention. It also reduces the working memory capacity and argues for a cholinergic modulation of a common, resource-­ limited, information processing system.

Epidemiology Attempts to design studies for determining the incidence of memory disturbance are problematic because memory disturbance is not a unitary phenomenon and tests of neuropsychologic function may vary as a function of sensitivity and selectivity among tests. Various clinical variables affecting results are drug dosage, blood levels, underlying disease, comedications, clinical response, and age of the patient. Drugs have been reported to be the primary cause contributing to cognitive impairment in approximately 10% of patients evaluated for dementia (Larson et  al. 1987). Polypharmacy increases the risks, with relative odds increasing from 2.7 with two or three drugs, to 9.3 with four or five drugs, to 13.7 with more than six drugs. Among the 188,284 adverse drug reactions recorded by the French PharmacoVigilance

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Database during a decade, there were 519 cases of memory loss (Chavant et  al. 2011). Using a case (reports in database)/noncase (literature) method, the study confirmed an association between memory disorders and some drugs, such as benzodiazepines and anticonvulsants. Significant association with memory disorders was found for other drugs, such as benzodiazepine-­ like hypnotics, newer anticonvulsants, serotonin reuptake inhibitor antidepressants, isotretinoin, and ciclosporin, which were poorly documented in the literature.

Diagnostic Workup

 rognosis of Drug-Induced Memory P Disturbances Drug-induced memory disturbances are usually benign and clear up after discontinuation of the offending medication. Patients recover from anterograde amnesia induced by drugs for relieving pain and anxiety of various procedures, and the memory loss is limited to that of the painful procedure. Permanent memory impairment may occur in patients with structural damage to the brain, particularly in the hippocampus region. Prognosis depends on the accompanying cognitive disturbances.

Prevention The following are general measures for prevention of drug-induced memory problems: • Avoidance of drugs known to cause memory disturbances (if possible) • Avoidance of polypharmacy • Careful use of psychotropic drugs in elderly subjects

Differential Diagnosis Table 14.3 lists conditions associated with amnesia in which drug-induced memory disturbance should be considered in the differential diagnosis.

The history of intake of drugs known to be associated with memory disorders is important. Blood levels of these drugs may be determined by appropriate laboratory tests. Neuropsychological tests with emphasis on tests of memory should be routine. Other diagnostic procedures should be done according to suspected or known concomitant illnesses.

 anagement of Drug-Induced M Memory Impairment Discontinuation of the medication causing memory disturbance is usually sufficient, and the patient may recover spontaneously. Memory training exercises may accelerate the recovery, but no controlled studies on patients with drug-­ induced memory disturbances exist.

Table 14.3  Differential diagnosis of drug-induced memory disturbance Alcoholism  Korsakoff syndrome Benign forgetfulness of aging Cerebral hypoxia  Carbon monoxide poisoning  Cardiac arrest and resuscitation Cerebrovascular diseases: transient ischemic attacks Epilepsy Excessive daytime sleepiness due to sleep apnea General medical disorders (e.g., hypoglycemia) Head injuries  Cerebral concussion  Post-traumatic brain syndrome  Boxer dementia Hypoglycemia Hypnotic amnesia Malingering and hysteria Neuropsychiatric paraneoplastic syndromes in cancer patients Normal pressure hydrocephalus Psychiatric disorders  Depression, anxiety, and stress  Schizophrenia  Electroconvulsive therapy © Jain PharmaBiotech

Drug-Induced Dementia

Use of a nonsedating dose of diazepam (5 mg in an adult) can relieve anxiety by effects on attentional vigilance and startle responsivity— the underlying mechanism of anxiolytic effect— without impairing memory (Murphy et al. 2008). Overdose of benzodiazepine, on the other hand, can produce severe amnesia due to sedative and hypnotic effects. Flumazenil, a competitive benzodiazepine antagonist, is indicated in the management, but its role in the routine reversal of endoscopic conscious sedation has not been defined. Uses of antidotes in anticholinergic-induced memory deficits are somewhat tricky because they are neurotransmitter-specific. Amphetamine can reduce the sedative effect of scopolamine but makes the memory deficits worse. Scopolamine-­ induced memory deficits can be ameliorated by anticholinesterase physostigmine, but not by a benzodiazepine antagonist. Switching from lipophilic to hydrophilic statins may resolve cognitive impairment. However, due to rarity of this event, discontinuation of statins is not recommended as the vascular benefits and putative cognitive benefits outweigh the risk of cognitive impairment associated with statin use (Rojas-Fernandez and Cameron 2012). Drug-induced memory impairment has been suggested as a mechanism that aggravates the loss of control over drug use. According to this concept, histaminergic compounds such as H3 receptor antagonists may improve the treatment of addiction by reversing drug-induced memory deficits and, thus, the reinforcing properties of addictive drugs (Alleva et al. 2013).

Drug-Induced Dementia Definitions and Historical Note Dementia is defined as a global impairment of higher cortical functions including memory, the capacity to solve problems of everyday living, the performance of learned perceptual motor skills, the correct use of social skills, and the control of emotional reactions in the absence of gross clouding of consciousness.

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Mental deterioration due to alcohol has been recognized for at least a century. The term “alcohol dementia” lacks a distinct defined pathology (Victor 1992). The first mention of a therapeutic drug-induced dementia was after the introduction of synthetic anticholinergic drugs for the treatment of Parkinson disease (Porteous and Ross 1956). The pathophysiology of memory loss associated with anticholinergic drugs was strengthened by the emergence of the cholinergic hypothesis of memory and by the demonstration that memory is adversely affected by the injection of scopolamine but that these adverse effects are reversible by an injection of physostigmine (Drachman and Leavitt 1974). In the early days of levodopa therapy, its use was deemed responsible for dementia in Parkinson disease patients (Barbeau 1971; Wolf and Davis 1973). Dementia is now considered part of the natural progression of the disease rather than an effect of levodopa. Various terms are used to describe dementia associated with drugs. Patients on long-term phenytoin therapy have been reported to deteriorate intellectually in the absence of any signs of oversedation, a condition termed “Dilantin dementia.” Drug-induced dementias fall under the broad category of pseudodementias, which differentiates them from dementias associated with degenerative neurologic disorders, as well as under the category of reversible dementias, which implies that the manifestations improve following discontinuation of the offending drug. Dementia is the most severe form of cognitive deficit and is sometimes referred to as brain failure. Cerebral insufficiency is a general term indicating a decline of mental function. It does not specify the cause but instead the clinical effects, which may be mild, moderate, or severe (dementia). The frequently used term cognitive impairment refers to disturbances of information processing. It covers the acquisition, storage, retrieval, and use of information. Cognitive processes involved in the acquisition of information are linked to consciousness and cognitive disturbances including delirium. Cognitive disorders also include disturbances of memory and intellect as well as behavioral disturbances.

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Clinical Manifestations

Table 14.4  Drugs associated with dementia

Drug-induced dementia has no characteristic features, except in the situations where it is accompanied by other drug-induced symptoms. Anticholinergic drugs used to treat parkinsonism may mimic or exacerbate the clinical signs of Alzheimer disease. Dementia may be a part of the neurotoxic manifestations of a drug, e.g., interferon dementia in “interferon syndrome.” Drug-induced dementia is usually reversible with the discontinuation of the offending drug. In situations where structural changes are present in the brain, cognitive deficits may persist. The complications would be no different from those that occur in patients with dementias due to other causes. Creutzfeldt-Jakob disease is an exception as some cases occur due to contamination of the therapeutic material and not due to pharmacological effect of any substance.

Drugs Associated with Dementia Adverse drug reactions are commonly associated with dementia in elderly persons on polypharmacy. Drugs reported to be associated with dementia are shown in Table  14.4. The causal effect is not proven in all cases, but the association, even though in single case reports, is sufficient to consider these drugs when investigating drug-induced dementia. Improvement after discontinuation of a suspected drug is strongly suggestive of the drug causing the dementia. Anesthetics  Most general anesthetics produce cognitive impairment for several hours after the medical or surgical procedure has ended. Whether long-term cognitive impairment occurs with various general anesthetics remains a question. The mechanism is not certain, but it is possible that inhibition of central nicotinic acetylcholine receptors contributes to secondary effects attributed to anesthesia such as impairment in memory and cognitive performance. The type of procedure performed, rather than the anesthetic agent used, appears to be a more important factor. Severe brain damage is more likely to develop

Anticholinergic drugs Antiepileptics Antihypertensives Antineoplastic drugs Antipsychotic drugs Benzodiazepines Corticosteroids Cyclosporine Cytokines: interferons and interleukins Deferoxamine Drugs of abuse Neuroleptics Sedative-hypnotics: diphenhydramine Opioids Tricyclic antidepressants Z-hypnotics: zolpidem, zaleplon, and eszopiclone (stereoisomer of zopiclone) Drug combinations, e.g., benzodiazepines and z-hypnotics © Jain PharmaBiotech

following cardiac surgical procedures rather than following noncardiac surgery. The most common anesthetic techniques for cardiac surgery include the use of high-dose opioids with adjuvant inhalational agents and benzodiazepines or a low-­ dose opioid combined with standard doses of inhalational agents (isoflurane, enflurane, and halothane). Anticholinergic Drugs  A nested case-control study showed that among drugs with anticholinergic action used in CNS disorders, there are significant increases in risk associated with use of antidepressants, antiparkinsonian drugs, antipsychotics, antiepileptic drugs, bladder antimuscarinics, and antivertigo/antiemetic drugs (Coupland et al. 2019). This observational study has shown associations, but causality cannot be evaluated. However, if this association is causal, approximately 10% of dementia diagnoses are attributable to anticholinergic drug exposure. There were no significant increases in risk associated with antihistamines, skeletal muscle relaxants, gastrointestinal antispasmodics, antiarrhythmics, and antimuscarinic bronchodilators. Anticholinergic drugs are common causes of both acute and chronic cognitive impairment (Shinohara and Yamada 2016). Patients with

Drug-Induced Dementia

Alzheimer disease show deterioration at serum levels of anticholinergic drugs, which cause no impairment in psychogeriatric patients without dementia. Cognitive impairment at 3 h following administration of a low dose of scopolamine with full cognitive recovery within 5 h can be used as a test to identify individuals who are likely to develop preclinical Alzheimer disease (Snyder et al. 2014). A study has used neuroimaging biomarkers of brain metabolism and atrophy to investigate the underlying biology of the clinical effects of anticholinergic medications in cognitively normal older adults from the Alzheimer’s Disease Neuroimaging Initiative and the Indiana Memory and Aging Study (Risacher et al. 2016). Results showed that the use of anticholinergic medications was associated with increased brain atrophy and dysfunction as well as clinical decline. This forms the basis of recommendation that use of anticholinergics in older adults should be discouraged if alternative therapies are available. A further study showed that cognitively normal older adults taking at least one anticholinergic drug were 47% more likely to develop mild cognitive impairment over the next decade than people who were not taking such drugs (Weigand et  al. 2020). The study also found that persons with biomarkers for Alzheimer disease in their cerebrospinal fluid who were taking anticholinergic drugs were four times more likely to later develop mild cognitive impairment than people who were not taking the drugs and did not have the biomarkers. Similarly, persons who had genetic risk factors for Alzheimer disease and took anticholinergic drugs were about 2.5 times as likely to develop mild cognitive impairment than those without the genetic risk factors and who were not taking the drugs. A population-based study has shown that elderly patients on anticholinergic drugs are at increased risk for dementia, and discontinuation of drugs was associated with a decreased risk (Carrière et al. 2009). Oxybutynin, an anticholinergic agent used for treatment of overactive bladder, is associated with cognitive impairment. A population-based retrospective analysis of oxybutynin versus other anticholinergics in older

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adults showed that the proportion of patients with cognitive impairment initiated on oral oxybutynin increased from 24.1% in 2008 to 41.1% in 2011; it was replaced by other more expensive anticholinergic agents that were less likely to cause impairment in only 5% of cases because of cost restrictions (Vouri et al. 2018). Patients with Parkinson disease show deterioration of mental function when treated with anticholinergics, whether alone or in combination with levodopa, whereas those treated with levodopa alone do not show any decline of mental function. Cases of chronic dementia have been reported in patients with Parkinson disease who had been treated for over 6 months with anticholinergic drugs and had no other adverse reactions. All these patients improved after discontinuation of the anticholinergics, and the improvement was documented by neuropsychological testing as well as by SPECT and PET scans. Antihypertensive Drugs  Older antihypertensive agents (reserpine and clonidine) have negative effects on cognition; however, large clinical trials in the elderly indicate that commonly used agents, such as thiazide diuretics, calcium antagonists (amlodipine, diltiazem), angiotensin-­ converting enzyme inhibitors (captopril, enalapril), and beta-blockers (atenolol), have minimal effects on cognition. Antineoplastic Drugs  Antineoplastic drugs are known to be associated with leukoencephalopathy. 5-Fluorouracil-induced leukoencephalopathy can manifest by impairment of cognitive function and ataxic gait. Symptoms of leukoencephalopathy due to carmofur, a drug widely used in Japan for carcinomas of the gastrointestinal tract, are gait disturbance followed by dysarthria and dementia in that order of frequency (Mizutani 2008). However, findings from a study on a large population-based cohort found no relation between chemotherapy use and cognitive impairments in older women with breast cancer (Du et al. 2010). Significant association between chemotherapy and the risk of developing drug-­ induced dementia was demonstrated in a large series of patients with colorectal cancer without

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mood disorder, whereas risk of developing other dementias was decreased (Du et al. 2013). Results of several clinical studies suggest that the most frequent neurotoxic adverse effects of chemotherapy are impairment of memory and learning, attention, concentration, processing speeds, and executive function. According to one hypothesis, inflammatory cytokines disrupt blood-brain barrier permeability and increase direct access of chemotherapeutic agents into the CNS to cause neurotoxicity (Wardill et al. 2016). Results of a cohort study indicate that androgen deprivation therapy in the treatment of prostate cancer may be associated with an increased risk of dementia, but this finding should be further evaluated in prospective studies (Nead et al. 2017).

Benzodiazepines  Benzodiazepine use by elderly patients is associated with cognitive impairment. A prospective population-based study showed that new use of benzodiazepines in subjects who were free from cognitive impairment at the start of therapy was associated with increased risk of dementia (Billioti de Gage et  al. 2012). A casecontrol study has shown that benzodiazepine use is associated with an increased risk of Alzheimer disease (Billioti de Gage et al. 2014).

Antiepileptic Drugs  Valproic acid-induced dementia is well known. Reversible cerebral atrophy has been documented by CT scan in valproate-­ induced parkinsonism-dementia syndrome. Several cases of dementia associated with extrapyramidal disorders have been reported in elderly patients, and all improved after discontinuation of valproic acid. Rapid cognitive decline and extrapyramidal manifestations can be considered drug-induced in patients who are being treated with valproate, as they can improve after discontinuation of the drug. Phenytoin intoxication with cerebellar dysfunction and dementia may occur in nonepileptic patients who receive phenytoin for cardiac arrhythmias. Withdrawal of phenytoin leads to slow improvement of neurologic status. Topiramate can cause cognitive impairment as an adverse effect. A double-blind, randomized, placebo-controlled, crossover study of topiramate’s impact on cognition on healthy volunteers showed that it led to a decline in behavioral performance through impairment of the primary task network by reducing its efficiency (Babu Henry Samuel et al. 2018). This triggers compensatory recruitment of additional resources to maintain task performance as revealed by an increase in event-related potential responses to high load, the magnitude of which was positively correlated with task performance.

Corticosteroids  Steroid-induced psychosis is well recognized, but steroid-induced impairment of cognitive function is rare. Steroid dementia syndrome describes the signs and symptoms of hippocampal and prefrontal cortical dysfunction, such as deficits in memory, attention, and executive function, induced by glucocorticoids. Reversible dementia-like cognitive changes are included in a review of corticosteroid-induced neuropsychiatric disorders (Bhangle et al. 2013). An increased risk of these disorders was observed in most cases when daily prednisone-equivalent dose was greater than or equal to 40 mg and in those suffering from systemic lupus erythematosus where they may mimic symptoms that may occur in the natural course of the disease. Corticosteroid-induced dementia usually recovers after discontinuation of the corticosteroids. High-dose steroid therapy can cause persisting cognitive disorders. Cytokines  Cytokines, particularly interleukin-2 and interferon-alpha, have been associated with neuropsychiatric disturbances when given systemically. Disorders of cerebral function associated with interferons are shown in Table 14.5. Recombinant interferon-alpha-induced frontal-­ subcortical dementia was first described in 2002 (Moulignier et  al. 2002). Other cases have been reported since then. Dementia after several months of interferon-alpha therapy may persist for 3 years despite cessation of interferon treatment. Sedative-Hypnotics  Diphenhydramine, an over-the-counter hypnotic sedative, is associated with cognitive impairment in elderly persons without preexisting dementia.

Drug-Induced Dementia Table 14.5  Disorders of cerebral function associated with interferons Neuropsychiatric  Confusion  Thought blockage  Memory disturbance  Hallucinations  Visuospatial disorientation Leukoencephalopathy  Lethargy  Anorexia  Somnolence  Confusion

Drug Combinations  A cohort study found that compared with nonusers, older people who used benzodiazepines or z-hypnotics for more than 28  days during each quarter of the year had a greater risk of dementia during the follow-up period, and the risk was even more pronounced in patients who took both types of drugs at the same time (Tseng et al. 2020). Short-acting benzodiazepines were associated with a greater risk of dementia than long-acting benzodiazepines. Persons who used a combination of short-acting and long-acting benzodiazepines as well as a z-hypnotic were nearly five times more likely to be diagnosed with dementia than people who did not use any of the drugs. Therapeutic Substances Involved in the Transmission of Creutzfeldt-Jakob Disease  Creutzfeldt-Jakob disease is a transmissible spongiform encephalopathy characterized by a long incubation period that precedes clinical symptoms related to the degeneration of the CNS, resulting in dementia. Various therapeutic procedures are reported to be associated with the transmission of Creutzfeldt-Jakob disease, shown in Table 14.6. These include corneal transplants, dural grafts, neurosurgical instrumentation, stereotactic placement of EEG electrodes, blood transfusion, drugs containing bovine-derived tissues, and administration of cadaver pituitary-­ derived human growth hormone.

223 Table 14.6 Therapeutic substances associated with Creutzfeldt-Jakob disease Human growth hormone from cadaver pituitary Dural grafts (human) Corneal grafts (human) Bovine somatotropin (equivalent of human growth hormone used in France)a Pharmaceutical preparations containing bovine material Blood for transfusion and blood products obtained from patients with Creutzfeldt-Jakob disease This drug was banned in 1992

a

pituitary-­derived growth hormone. Seven neuropathologically confirmed cases of Creutzfeldt-­ Jakob disease were detected during epidemiological follow-up of 6284 recipients of human growth factor in 1991 (Fradkin et  al. 1991). All 7 cases occurred among a group of 700 recipients who received human growth hormone before 1970. Contaminated human growth hormone-­ induced Creutzfeldt-Jakob disease is like the iatrogenic transmission-induced Creutzfeldt-Jakob disease that occurred during neurosurgical procedures in the 1970s. The brains of Creutzfeldt-Jakob disease-infected cadavers contain particles of an abnormal form of prion protein that is highly resistant to most common sterilization procedures. A preparation of one batch of hormone requires several thousand pituitary glands, and it is likely that a batch could become contaminated. This problem has been eliminated by the current use of recombinant human growth hormone, but cases of Creutzfeldt-­ Jakob disease may still show up years after treatment with contaminated growth hormone. The United States and the United Kingdom banned the use of cadaver-derived pituitary growth hormone in 1985, but France continued its use until 1993, only if it had been treated with urea, a procedure known to deactivate the prion; however, there were cases of Creutzfeldt-Jakob disease in France due to the distribution of potentially contaminated hormone after it was prohibited.

Cases of iatrogenic Creutzfeldt-Jakob disease are rare when considering a large number of subHuman Growth Hormone  Numerous studies jects treated with human growth hormone. have reported the emergence of Creutzfeldt-­ Genetic susceptibility to prion infection has been Jakob disease following the use of human considered as a predisposing factor. Iatrogenic

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Creutzfeldt-Jakob disease has been reported to manifest up to 24 years after human growth hormone administration. As of 2012, 77 cases of Creutzfeldt-Jakob disease were likely to have resulted in the United Kingdom from iatrogenic transmission among recipients of therapeutic products: 64 cases from human-derived growth hormone, 8 cases from dura mater grafts, 4 cases from blood transfusions, and 1 case that received a plasma product (Hall et al. 2014). Strategies to reduce iatrogenic transmission of Creutzfeldt-Jakob disease included recall of suspected products, improvements in decontaminating surgical instruments, and instructing approximately 6000 asymptomatic individuals who were at increased risk of Creutzfeldt-Jakob disease to follow public health precautions. In a study on human growth hormone (hGH) recipients in the United Kingdom, amyloid beta, which can accumulate in the pituitary gland, was present in the inoculated hGH preparations and had a seeding effect in the brains of around 50% of all hGH recipients, producing an Alzheimer disease-like neuropathology and cerebral amyloid angiopathy regardless of whether Creutzfeldt-­ Jakob disease neuropathology had occurred (Ritchie et al. 2017).

tia. Newer antidepressants, such as selective serotonin reuptake inhibitors and reversible inhibitors of monoamine oxidase A, have not been shown to have negative effects on cognition.

Antipsychotic Drugs  Use of antipsychotic drugs has been observed to be associated with acceleration of cognitive decline in patients with Alzheimer disease and multi-infarct dementia and those who had a previous leucotomy. In institutionalized older adults with dementia, impairment of cognitive function is associated with antipsychotic medication use (Eggermont et  al. 2009). This has not been a problem with modern atypical antipsychotic agents, which are used to manage the behavioral disorders in patients with dementia. However, other studies show that patients taking antipsychotic drugs in ­combination with sedatives have a significantly higher risk of cognitive deterioration than those who are taking none. Tricyclic Antidepressants  Tricyclic antidepressants are among the offenders for causing demen-

Gabapentin Toxicity  Creutzfeldt-Jakob-like syndrome with characteristic EEG changes has been reported in an elderly man who received gabapentin for treatment of trigeminal neuralgia and was predisposed to toxic effects of the drug because of renal insufficiency (Chau et al. 2010). The symptoms and signs resolved after discontinuation of gabapentin.

 athomechanism of Drug-Induced P Dementia Drugs may induce dementia by several different mechanisms, of which only a few are understood. Pathomechanisms of some of the drug-induced dementias are the following: Anticholinergic-induced dementia. Data from the German Study on Aging, Cognition, and Dementia in Primary Care Patients showed an increase in risk of dementia resulting from anticholinergic drug use and recommended strict avoidance of centrally acting anticholinergic drugs (Jessen et al. 2010). Anticholinergic drugs block the cholinergic neurotransmission and produce a condition like the dementia of Alzheimer disease. Long-term anticholinergic therapy in patients with Parkinson disease causes intellectual impairment that is correlated with bilateral diffuse glucose hypometabolism demonstrated by PET. Acetylcholinesterase inhibitors should theoretically benefit dementia, and most therapeutic agents that are currently available for the treatment of Alzheimer disease are based on this hypothesis (a condition in which cholinergic pathways are damaged). Acetylcholinesterase inhibitors may decrease the cholinergic tone as a delayed effect. This can be exacerbated by stress and may disrupt cognition. Both stress and acetylcholinesterase inhibitors increase the postsynaptic concentration of calcium in the cytosol.

Drug-Induced Dementia

This causes a rapid induction of the transcription factor c-Fos. This has been offered as an explanation of the neuropsychological features seen in “Gulf War syndrome,” a syndrome seen in soldiers who were given acetylcholinesterase inhibitors as a prophylactic against some of the poisonous war gases. Antihypertensive Drugs  Control of hypertension is expected to reduce the development of dementia or stroke in these patients. Prospective observational studies have shown that antihypertensive drug use is associated with 8% dementia risk reduction per year of use for persons over 75 years of age (Haag et al. 2009). Two important categories of drugs for this purpose are calcium channel blockers and adrenergic antagonists. Noradrenergic transmission is important for cognitive function. Antihypertensive drugs adversely affect cognitive function through the central noradrenergic system. Calcium channel blockers can have an inhibitory influence on neurotransmission by impairment of calcium and intracellular messenger systems as neurotransmitter release is calcium-dependent. Benzodiazepines  The sedative action of benzodiazepines is related to omega 1 receptors, whereas omega 2 receptors are responsible for their effects on memory and cognitive functioning. Nonbenzodiazepine sedatives such as zolpidem act on omega 1 receptors, whereas benzodiazepines also interact with omega 2 receptors with adverse effects on cognitive performance and memory. Pathomechanism of Valproate-Induced Dementia  Valproic acid-induced dementia in patients with epilepsy can be explained by the following: 1. A direct toxic effect of valproic acid on the CNS 2. An indirect CNS toxic effect mediated by valproic acid-induced hyperammonemia 3. A paradoxical epileptogenic effect secondary to valproic acid

225

The relation between valproate, brain atrophy, and dementia is likely to be exceedingly complex. These side effects may be related to a disturbance in the GABAergic pathways in the basal ganglia system. A placebo-controlled study of patients treated with valproic acid showed accelerated brain volume loss over 1 year as measured by MRI, which is likely associated with greater cognitive impairment (Fleisher et al. 2011). Pathomechanism of Cytokine-Induced Dementia  Cytokines are involved in the neuroinflammatory process, which has been reported in numerous neurodegenerative disorders. Interleukins and interferons are considered to have neurotoxic effects. Possible mechanisms include competition on the membrane receptors with neurotropic hormones. The pathomechanism of CNS toxicity of cytokines may involve direct interaction of these proteins at the level of the circumventricular organs (area postrema, hypothalamic neurosecretory centers, vascular organ of the lamina terminalis), but it appears unlikely to be on cortical neurons. Adeno-­associated virusmediated expression of interleukin-­ 10  in the brains of transgenic mouse models of Alzheimer disease was shown to result in increased Aβ accumulation by inhibition of its clearance by microglia and impaired memory (Chakrabarty et  al. 2015). Interleukin-2 has an adverse effect on cognition. It may act by the following mechanisms: • By increasing blood-brain barrier permeability • By activation of inappropriate central neuropeptidergic systems that impair memory • By direct neurotoxic effect Characteristics of interferon neurotoxicity are: • Usually, no structural alterations are present in the brain. • Neurotoxicity is dose-related and is not due to any impurities in the drug. • It is reversible. • Areas of the brain with opiate receptors are the most susceptible.

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The pathomechanism of interferon neurotoxicity is not well understood. Factors that predispose to this neurotoxicity are:

Cognitive Dysfunction in Drug-Induced Parkinsonism  The results of a clinical study suggest that cognitive impairment in patients with drug-induced parkinsonism reflects the toxic/metabolic symptoms associated with the offending drug in addition to being a risk factor for druginduced parkinsonism (Kim et al. 2011). Results of a retrospective study suggest that cognitive dysfunction in drug-induced parkinsonism caused by prokinetics/antiemetics is associated with structural changes in the brain, including cortical atrophy and reduction in hippocampal volume demonstrated by 3D MRI (Ahn et al. 2015).

• High dosage • A route of administration with slow absorption • Intrathecal use of interferon • Use by elderly patients with cerebral atrophy • Use by HIV-positive patients • Acute viral infection with increased production of endogenous interferon Pathomechanism of Desferrioxamine-Induced Dementia  Desferrioxamine is a chelating agent that is useful for the treatment of aluminum intoxication as a complication of renal failure but has been reported to precipitate dialysis dementia in patients with chronic renal failure. The pathomechanism is not known, but patients are at high risk for development of this complication if they demonstrate high levels of aluminum either before or after the standard desferrioxamine infusion test. Direct desferrioxamine CNS toxicity is unlikely, but desferrioxamine-aluminum complex has a relatively low molecular weight and may cross the blood-brain barrier more readily than the naturally occurring serum aluminum that is bound to serum albumin.

Drug-Induced Cognitive Disorders in AIDS Patients  Drugs of abuse consumed by AIDS patients may be important cofactors in the development of HIV-associated neurocognitive disorders (HAND) syndrome. Increases in CNS dopamine induced by drugs of abuse may aggravate HIV infection in monocytes, macrophages, and T cells of the brain by dysregulating their functions (Gaskill et al. 2013).

 pidemiology of Drug-Induced E Dementia

Medication toxicity accounts for 2% to 12% of dementia in several older studies. In a review of Pathomechanism of Neuroleptic-Induced 516 cases in the literature, toxic effect of medicaAcceleration of Dementia  Elderly patients with tions accounted for 2.7% of the dementia cases, Alzheimer disease are more susceptible to this whereas cerebral atrophies (including Alzheimer adverse effect because drug metabolism and disease and unknown causes) constituted 52.1% clearance slow down with aging, and target cells of the cases (Mummenthaler 1987). Among in the CNS may become more sensitive and vul- 263,962 adverse effects of drugs recorded nerable to drugs due to altered metabolism or cel- between 1985 and 2005  in the French lular loss. Repetitive sharp EEG discharges, PharmacoVigilance Database, 79 (0.03%) are reversible on withdrawal of neuroleptic drugs, dementia (Favreliere et al. 2007). Drug-induced, are seen in multi-infarct dementia. The EEG dementia-associated, and non-dementia, non-­ changes have been correlated with dysfunction of drug delirium hospitalizations in the United the adrenergic transmission. States have been analyzed from the years 1998 to 2005 (Lin et al. 2010). The presence of dementia Drugs that Increase Permeability of the Blood-­ and adverse drug effects had the strongest assoBrain Barrier  Cyclosporine, by increasing ciations with dementia-associated and drug-­ blood-brain barrier permeability, may explain the induced delirium. Age had significant associations aluminum-induced dementia in renal transplant with drug-induced and dementia-associated delirium as well. In a study on community-­ patients.

Drug-Induced Dementia

dwelling persons between 2005 and 2011  in Finland, use of antipsychotic drugs was found to be almost eight times more common among patients with clinically verified Alzheimer disease 5  years before their diagnosis than other groups (Orsel et  al. 2018). Four years after the diagnosis, psychotropic drug use was three times more common in Alzheimer disease sufferers than other comparable groups. Use of at least two psychotropics at the same time was three times more common among patients with Alzheimer disease 4  years after their diagnosis. The most common combination included an antidepressant plus either an antipsychotic or a benzodiazepine.

 actors that Predispose to Drug-­ F Induced Dementia Elderly persons are more susceptible than younger persons to develop cognitive impairments associated with medication use, and one of the reasons for this is the frequent impairment of renal and liver functions in the elderly, leading to impaired excretion and detoxification of drugs. Use of anticholinergic medication in this age group is linked to cognitive impairment and an increased risk of dementia. Disorders that predispose to drug-induced dementia include the following: • Aging patients with cognitive impairment • Persons at risk for development of Alzheimer disease including those with genetic links • Use of combinations of hypnotics with other CNS drugs with risk of synergic effect or interactions

 revention of Drug-Induced P Dementia Drugs known to produce dementia such as anticholinergics should be avoided in persons who have risk factors predisposing them to dementia. Anticholinergic drugs must be avoided in Parkinson disease patients with some cognitive

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decline and those who have incipient Alzheimer disease or vascular dementia. Patients with dementia who are on cholinesterase inhibitor therapy for dementia may receive anticholinergic medication for urge incontinence. This combination would seem to be inappropriate as anticholinergic medications are notorious for worsening cognitive function in susceptible patients. However, this combination can be clinically effective without risk of aggravation of dementia. Avoiding human-derived tissue extracts or cells can prevent iatrogenic Creutzfeldt-Jakob disease. Bovine products used for medicinal purposes require strict control to eliminate the possibility of transmission of bovine spongy encephalopathy. Exposure to drugs such as phenobarbital during pregnancy should be avoided as it can produce intellectual impairment in the offspring. Exposure in the third trimester is the most deleterious. Exposure of pregnant women to medications that can impair cognitive function should be avoided.

 ifferential Diagnosis of Drug-­ D Induced Dementia It is important to differentiate drug-induced dementia from other disorders of the brain associated with dementia. Drug-induced cognitive disturbance is a broad term that refers mostly to delirium. Delirium is characterized by a reduction of the level of consciousness, and this is manifested clinically by disorientation. In patients with dementia, the risk of delirium is enhanced due to diminished “cognitive reserve.” Most of the drug-induced dementias are reversible after discontinuation of the causal drug. Elderly people taking anticholinergic drugs have significant deficits in cognitive functioning and are likely to be misdiagnosed as having “mild cognitive impairment” that might be an early stage of Alzheimer disease. Use of anticholinergic drugs in elderly persons with mild cognitive impairment should be determined before considering administration of acetylcholinesterase inhibitors.

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Drug-induced dementia may mimic glucose metabolism and clinical symptoms of Alzheimer disease. In an elderly subject on polypharmacy, including lithium and primidone, imaging and clinical findings reversed to normal on discontinuation of drugs (Riepe et  al. 2015). In this case, amyloid PET was a helpful tool to rule out underlying Alzheimer disease. It is important to recognize the adverse effects of lithium-induced Creutzfeldt-Jakob disease-­like syndrome and to avoid the costly and unnecessary investigative procedures for Creutzfeldt-Jakob disease. This syndrome clears up after discontinuation of lithium. The clinical picture of an elderly man who presented with subacute onset of severe cognitive impairment, ataxia, tremor, and stimulus-sensitive myoclonus following treatment with a combination of tricyclic mimicked CreutzfeldtJakob disease, which could be excluded by CSF analysis that showed normal level of tau protein and Aβ1-42 as well as being negative for CSF 14-3-3 protein (Paolini Paoletti et al. 2018).

Table 14.7  DSM-IV diagnostic criteria for substance-­ induced persisting dementia

Diagnostic Workup The DSM-IV diagnostic criteria for substance-­ induced persisting dementia are shown in Table 14.7. The central nervous system in the elderly is particularly sensitive to drugs, and an iatrogenic cause must be sought for all recent or sudden alterations in memory functions. The diagnostic workup of a patient with suspected drug-induced dementia includes the following investigations: • • • • •

Serum levels of suspected drugs. Cognitive functioning tests. CT scan to detect cerebral atrophy. MRI to detect leukoencephalopathy. EEG from patients showing neurotoxic effects of interferon (interferon syndrome) who reveal a diffuse slowing of the alpha rhythm and an appearance of theta and delta waves, prominent in the frontal lobes and consistent with a diffuse encephalopathy. EEG in patients with lithium-induced Creutzfeldt-Jakob disease-­ like syndrome shows slow activity with synchronic periodic complexes.

A. The development of multiple cognitive deficits manifested by both of the following:  1. Memory impairment (impaired ability to learn new information or to recall previously learned information)  2. One or more of the following cognitive disturbances:    a. Aphasia (language disturbance)    b. Apraxia (impaired ability to carry out motor activities despite intact motor function)    c. Agnosia (failure to recognize or identify objects despite intact sensory function)    d. Disturbances in executive functioning (e.g., planning, organization, sequencing, etc.) B. The cognitive deficits in criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning C. The deficits do not occur exclusively during the course of a delirium and persist beyond the usual duration of substance intoxication or withdrawal D. Evidence acquired from the history, physical examination, or laboratory findings suggests that the deficits are etiologically related to the persisting effects of substance intoxication or withdrawal

 anagement of Drug-Induced M Dementia Management is supportive, and there should be a withdrawal of the offending medication. Anticholinergic medications should be withdrawn in patients with Parkinson disease if they develop dementia. These patients may also improve after reduction of anticholinergic therapy, and cholinesterase inhibitors might partially improve cognitive deficits. In the case of recent alterations in memory of elderly patients, all nonessential drugs, especially psychotropic agents, should be withdrawn or reduced. Caution should be exercised in the prescription of anticholinergic agents for patients at risk of cognitive decline. Possible pharmacologic interventions to decrease neurotoxicity associated with interferon-­ alpha therapy include the use of antidepressants, psychostimulants, and opioid antagonists. Identification of drug-induced cognitive impairment is important, as early detection and discontinuation of the offending medications

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Drug-Induced Disturbances of Consciousness

15

Introduction

Drug-Induced Syncope

Neurotoxicity of drugs can lead to various degrees of loss of consciousness. This can vary from syncope to coma as defined here.

“Presyncope” is a term that can be characterized as near fainting, light-headedness, or extreme dizziness; it may be a part of a continuum that leads to syncope or may occur as an isolated event. The “common faint” or neurocardiogenic syncope, also called vasovagal syncope or reflex syncope, is the most common type of syncope. Neurocardiogenic syncope is defined as a syndrome in which “triggering of a neural reflex” results in a usually self-limited episode of systemic hypotension characterized by both bradycardia and peripheral vasodilation (Chen-Scarabelli and Scarabelli 2004). Carotid sinus syncope and situational syncope are types of reflex syncope. Although syncope has been well documented in the medical literature since the nineteenth century, there is little mention of the drug-induced form. This chapter will focus on drug-induced syncope.

Syncope: sudden, transient loss of consciousness with a loss of postural tone usually lasting no more than 15 seconds. Delirium: a state of waxing and waning consciousness, with prominent disorientation, fear, and hallucinations, as well as an altered sleep/wake cycle. Drowsiness (obtundation): a mild to moderate reduction in alertness, with increasing time spent in the sleep state. Stupor: a state of deep sleep, from which the patient can be aroused only with repeated and vigorous stimulation. Coma: a state of complete unawareness of the environment; patients do not show any signs of awareness of themselves or of their environment; brainstem reflexes and posturing movements of the extremities are permissible, but eye opening should not occur in response to an external stimulus, and the patient should not move in a purposeful fashion. Three of these conditions—syncope, delirium, and coma—will be discussed in this chapter.

Clinical Manifestations Syncope may present as three types, which can all be caused by drugs: (1) reflex (neurally mediated) syncope, (2) cardiac syncope, and (3) syncope due to postural hypotension (Shen et  al.

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2017). Clinical manifestations of drug-induced syncope vary according to the mechanism involved. It may be a simple vasovagal faint from which the patient recovers promptly without any residual signs or symptoms. Syncope secondary to drug-induced cardiac arrhythmia may be less benign, and other signs and symptoms of cardiovascular disturbances may complicate the clinical state of the patient. A patient may faint during injection of a medication as a vasovagal reaction and not due to any adverse effect of the medication. Syncope is a manifestation of postural hypotension associated with some drugs such as antihypertensive medications. Dizziness is a frequent accompaniment of postural hypotension. Other symptoms of cerebral hypoperfusion are light-headedness, general weakness, and visual disturbances. Tonic or clonic movements may occur during syncopal episodes.

Prognosis and Complications The prognosis of patients with syncope due to a drug is excellent if the offending drug is discontinued. However, in patients with druginduced cardiotoxicity leading to rhythm or conduction disorders or with a preexisting cardiac disease, the mortality rate is higher than in patients with noncardiac causes and in patients where no cause is found. Development of torsades de pointes due to QT interval prolongation is life-threatening. In a multicenter, 2-year longitudinal, observational study of elderly patients hospitalized due to syncope, the total mortality was 17.2%, and syncope recurrence was 32.5% (Ungar et  al. 2011). Cardiac syncope was more frequent in those who died as compared to survivors. Drug-induced Brugada syndrome has a good prognosis if asymptomatic; however, sudden cardiac death is possible (Sieira et al. 2017). A review of patients with cardiovascular syncope revealed that drug-induced syncope was an independent risk factor for rehospitalization, and careful follow-up of these patients for at least 1 year is recommended (Onuki et al. 2017).

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Pathomechanism of Syncope Most episodes of syncope are single. It is recurrent syncope that is usually investigated as to the cause. A simple classification of syncope according to etiology is shown in Table 15.1. Vasovagal (reflex) syncope is the most common form of syncope, occurring in approximately 60% of syncope presentations; orthostatic hypotension presents in around 15%, with arrhythmic syncope in 10%, and structural heart disease as the cause of syncope in 5% (Sutton 2013). Besides the frankly identified drug-­induced causes, orthostatic hypotension, cardiac arrhythmias, and cerebrovascular ischemia may also be drug-induced. Drugs reported to be associated with syncope are shown in Table 15.2. Drugs most significantly associated with an excess risk of syncope in the elderly are (1) fluoxetine, (2) aceprometazine, (3) haloperidol, and (4) L-dopa. Two main mechanisms of drug-induced syncope are postural hypotension and cardiac arrhythmias. Syncope may occur in the absence of hypotension by drug-induced vasoconstriction of cerebral vessels. Drugs that produce postural hypotension are shown in Table 15.3.

Table 15.1 Classification of syncope according to etiology Cardiovascular  Organic cardiac disease  Cardiac arrhythmias  Orthostatic hypotension Neurogenic  Vasovagal (neurocardiogenic) overlaps with cardiovascular form  Situational syncope (micturition, cough, etc.)  Psychogenic syncope (anxiety and panic disorders)  Glossopharyngeal and trigeminal neuralgias  Cerebrovascular ischemia (transient ischemic attacks)  Carotid sinus syncope Drug-induced syncope  Syncope as a manifestation of drug-induced anaphylaxis Syncope of unknown etiology

Drug-Induced Syncope Table 15.2  Drugs associated with syncope Analgesics  Opioid analgesics  Nonsteroidal anti-inflammatory drugs Antineoplastic drugs: vincristine Cytokines: interferon-alpha Cholinesterase inhibitors in elderly patients with dementia Digitalis Drugs that produce postural hypotension (see Table 15.3) Drugs and combinations that prolong QT interval/ torsades de pointes (see Table 15.4) Hypnotic sedative drugs (depressants of the CNS)  Barbiturates  Benzodiazepines Other sedative-hypnotic drugs: niaprazine Hypoglycemic drugs  Insulin  Oral hypoglycemics Selective serotonin reuptake inhibitors  Fluoxetine  Citalopram Miscellaneous therapeutics  Apheresis: plasma, white cells, or red cell exchange  CNS stimulants  Gamma-hydroxybutyrate  Local anesthetics  Loperamide  Meglumine antimoniate (anti-leishmaniasis antimony compound) Topical ophthalmic preparations  Levobunolol ointment  Betaxolol ophthalmic solution  Vaccines Table 15.3  Drugs that produce postural hypotension Drugs used to treat hypertension  Angiotensin-converting enzyme inhibitors  Beta-blockers  Calcium antagonists  Diuretics Drugs that have hypotension as an adverse effect  Antidepressants  Antiparkinsonian drugs   Levodopa   Bromocriptine   Selegiline (deprenyl)    Anticholinergics  Antipsychotics   Phenothiazines   Butyrophenones  Vasodilators    Nitrates, e.g., nitroglycerine  Sildenafil

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Drug-Induced Hypotension Significant hypotension is a drop in systolic pressure of at least 20  mmHg or 10  mmHg in diastolic pressure on standing up. An alternative definition is used because a low blood pressure is not tolerated on standing. Any systolic blood pressure in the upright position of less than 95  mmHg, regardless of the change of posture, indicates orthostatic hypotension. Evidence from experimental animal studies suggests that the site for induction of postural hypotension by passive upright tilt may lie in the forebrain region, whereas the primary center for the induction of postural hypotension lies in the brainstem. Orthostatic hypotension and decreased cerebral blood flow are interrelated. The critical lower limit of cerebral perfusion lies at, or close to, 50% below baseline supine (horizontal) mean cerebral blood flow velocity. At this level of cerebral hypoperfusion, unconsciousness ensues in 80% of subjects. This indicates impaired autoregulation, and there may be an unknown clinical predisposition to this condition. There was enhanced susceptibility to vasovagal reaction during upright tilt testing on patients with syncope and a positive response to tilt testing. This demonstrates that chronic vasodilator therapy predisposes to syncope. Hypotension in the elderly is significantly associated with the use of potassium-sparing diuretics, dopaminergic antiparkinsonian drugs, and butyrophenone antipsychotics. Orthostatic hypotension is often associated with hyponatremia and is found in one fifth of the elderly who take diuretics. A slight decrease in sodium levels induced by diuretics results in marked orthostatic hypotension in healthy elderly persons, but it does not affect younger adults. Nitrates dilate arterial and venous smooth muscle and reduce cardiac output by pooling blood in the periphery. This leads to a fall in blood pressure, and the risk of this is higher in the elderly. Levodopa produces orthostatic hypotension in patients with late-onset Parkinson disease who are prone to it because of autonomic dysfunction. Oral formulation of the selective M1 agonist xanomeline, used for the treatment of Alzheimer disease, is associated with an increased incidence of syncope. Alzheimer patients, who presumably

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lack M1 receptor activity, usually have a reduced risk of tilt-induced syncope compared with normal subjects. Both groups, however, have enhanced susceptibility to hypotension and syncope when M1 receptor activity is pharmacologically increased such as by xanomeline administration. Ability of bromocriptine to induce syncope in head-up tilt test is utilized in investigation of neurally mediated syncope of unknown etiology. A positive test indicates that dopaminergic supersensitivity may play a role in the pathogenesis of syncopal episodes. An isoproterenol-mediated increase in cardiomotor tone and a decrease in afterload contribute to the induction of vasovagal syncope. Contrary to conventional belief, a significant decrease in preload is not observed immediately before isoproterenol-­induced syncope. Syncope after the use of an antihypertensive drug is not always due to postural hypotension. Beta-blockers may produce bradycardia in addition to hypotension. Paradoxically, beta-blockers are also used in the treatment of syncope. Paradoxical hypotension due to suppression of vasomotor outflow may occur after amphetamine intoxication. High-dose nitroglycerin infusion, used for treatment of “sympathetic crashing acute pulmonary edema,” can produce drug-induced hypotension and syncope (Paone et al. 2018).

 rug-Induced Cardiac Arrhythmias D and Conduction Disturbances An important cause of syncope is drug-induced prolongation of QT interval (torsades de pointes). Long QT syndrome and Brugada syndrome are arrhythmia syndromes characterized by presyncope, syncope, cardiac arrest, and seizures. Besides occurrence as a side effect of drugs, there is a genetic predisposition. A mutation in SCN5A gene, which encodes the cardiac sodium channel Nav1.5, is the most identified mutation in both conditions. Female gender is recognized as an independent risk factor for drug-induced long QT syndrome, which is influenced by other factors, including age, menstrual cycle, and hormone replacement therapy (Li et  al. 2013). A clinical

15  Drug-Induced Disturbances of Consciousness

pharmacology study during a drug’s development process can assess its propensity to induce torsades de pointes using prolongation of the QT interval as seen on the ECG as a biomarker (Klotzbaugh et al. 2020). The most common cause of sudden death of a young athlete on the competitive field is cardiac illness, usually that of congenital etiology. However, the use of anabolic steroids, peptide hormones, and stimulants that can cause dangerous arrhythmias has led to initial manifestation as drug-induced syncope, which, in some instances, can present as a sudden, unexpected death (Farzam et al. 2020). Andersen-Tawil syndrome is characterized by a triad of episodic periodic paralysis, ventricular arrhythmias, syncope, and weakness that occurs spontaneously following prolonged rest or prolonged QT interval, and congenital anomalies. Affected individuals present in the first or second decade with either cardiac symptoms (palpitations and/or syncope) or muscle weakness that occurs spontaneously at rest (Statland et  al. 2016). Clinical and ECG findings are characteristic, but the pathogenic variant in KCNJ2 gene confirms the diagnosis. Medications known to prolong QT intervals and potassium-wasting diuretics that provoke drug-induced hypokalemia, which aggravate the QT interval, could precipitate syncopal attacks. Drugs that produce cardiac arrhythmias and conduction disturbances are shown in Table 15.4. Torsades de pointes  Torsades de pointes may cause syncopal episodes and dizziness. It is characterized by polymorphic QRS complexes that change in amplitude and cycle length and may be preceded by QT prolongation. Torsades de pointes may result from acquired medical and genetic disorders, but it is often induced by drugs shown in Table 15.4. Quinolone antibiotics have potentially serious proarrhythmic effects. Ciprofloxacin may be used because the agent is believed to be safer than other drugs in its class, although a few cases of unexplained cardiac arrest temporally related to ciprofloxacin have been reported.

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Table 15.4  Drugs reported to cause syncope by inducing arrhythmias and conduction disturbances including torsades de pointes Single drugs  Antiarrhythmic drugs    Ajmaline    Amiodarone   Disopyramide   Procainamide   Quinidine   Sotalol  Antihistaminic drugs    Astemizole    Terfenadine    Fexofenadine, a nonsedating histamine H1 receptor antagonist  Antimalarial or antiprotozoal   Chloroquine/hydroxychloroquine   Halofantrine   Mefloquine   Pentamidine   Quinine  Antimicrobials    Combination antiretroviral therapy for HIV-1   Erythromycin    HIV protease inhibitors    Trimethoprim-sulfamethoxazole   Gatifloxacin    Antifungal agent isavuconazonium  Antineoplastic drugs    Anthracycline cardiotoxicity  Atropine (paradoxical effect)  Cisapride (cytochrome P450 3A4 substrate), for the treatment of gastrointestinal motility disorders  Drug abuse   Cocaine-induced bradyarrhythmia    Methadone for management of heroin dependence  Encainide  Flecainide  Psychoactive drugs Amphetamines    Atypical antipsychotics   Haloperidol   Phenothiazines   Pimozide  Miscellaneous drugs    Amantadine   Bromocriptine misuse   Carbamazepine   Carbimazole   Guanfacine   Probucol   Synthetic opioids (continued)

Table 15.4 (continued)    Tacrolimus    Trimethaphan    Vasopressin Combination of drugs    Cisapride and diltiazem    Cisapride and ranitidine    Clozapine and cocaine    Clozapine and diazepam    Clozapine and enalapril    Fluconazole and amitriptyline    Fluoxetine and ranitidine    Loratadine and amiodarone    Terfenadine and itraconazole    Terfenadine and erythromycin    Terfenadine and astemizole

Syncope in drug addicts using methadone and cocaine may not be due to effects on the central nervous system but rather on cardiac conduction. Cocaine and methadone may induce syncope by prolonging the QT interval (Krantz et al. 2005). Atropine is widely used as a parasympatholytic agent during diagnostic and therapeutic procedures. Syncope has been observed as an unexpected paradoxical response to atropine after cardiac transplantation. Various degrees of atrioventricular block have been documented in these patients. Although the underlying mechanism is not clear, these findings suggest that atropine may paradoxically cause high-degree atrioventricular block in patients after transplantation. Syncope may occur as a side effect of guanfacine, an alpha-2 adrenergic receptor agonist, and is probably due to drug-induced hypotension or bradycardia (King et al. 2006). Prolongation of the QT interval caused by antipsychotics (particularly, pimozide, thioridazine, ziprasidone, and sertindole) may produce dizziness, syncope, ventricular fibrillation, and sudden death (Sawicke and Sturla 2008). Antipsychotics are associated with ventricular tachycardia because of their inhibition of the cardiac delayed potassium rectifier channel, which extends the repolarization process of the ventricles of the heart, manifested as a prolongation of the QT interval (Nielsen et al. 2011).

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A case of syncopal attack, misdiagnosed as ing 2002 through 2004 and found that reports of epilepsy, was found to be related to oral cisapride postvaccination syncope had increased since use for dyspepsia (Attanasio et  al. 2007). 2005, primarily among females aged 11 to Discontinuation of cisapride and normalization 18  years (Centers for Disease Control and of serum potassium level led to disappearance of Prevention (CDC) 2008). both ECG abnormalities and loss-of-­ consciousness episodes. Methadone is associated with QT prolonga- Prevention of Drug-Induced Syncope tion and higher reporting of syncope in a population of heroin addicts (Fanoe et al. 2007). The use of multiple drugs in the elderly, particuUse of cholinesterase inhibitors is associated larly antihypertensives and central nervous syswith increased rates of syncope, bradycardia, and tem depressants, should be avoided. Other drugs pacemaker insertion in older adults with demen- with known effects on cardiac rhythm and contia (Gill et al. 2009). duction should be avoided in those susceptible to Drug-induced anaphylaxis. Syncope and syncope. The use of short-acting calcium antagohypotension are more common in drug-induced nists, such as oral or sublingual nifedipine, is no anaphylaxis, which is severe in 54.2% of cases of longer recommended to be used in hypertensive anaphylaxis due to all causes (Kim et al. 2018). patients because it can cause syncope and even Urticaria and other skin symptoms are signifi- more serious cardiovascular adverse effects. cantly more common in food-induced However, low doses of the long-acting formulaanaphylaxis. tions seem to be safer. Because syncope is a common adverse effect of vaccination, it is recommended that patients be Epidemiology of Drug-Induced observed for 15  minutes following vaccination. Syncope Those exhibiting presyncopal signs and symptoms around the time of immunization should be Syncope occurs in approximately 20% to 50% of evaluated carefully and may need to be assisted the population. In a certain study, using a stan- to sit or lie down until free of symptoms. dardized adverse drug reaction algorithm, 9 of 70 However, a survey has revealed that few physipatients (13%) with syncope were rated as having cians are aware of recommendations for postvacprobable drug-related syncope or presyncope cination observation for syncope, and strategies (Hanlon et al. 1990). Epidemiology of hypoten- to improve this need to be developed and implesion is also relevant to syncope. Hypotension is mented (Huang et al. 2011). common in the elderly, and in 10% of the individuals over 71 years, blood pressure values were found to be less than or equal to 122 mmHg sys- Differential Diagnosis of Syncope tolic and less than or equal to 68 mmHg diastolic (Busby et  al. 1994). An association between Although cardiovascular factors are involved in hypotension and drugs was found in this study. neurally mediated syncope, drug-induced synIn a study of clinically important adverse drug cope is more likely to be cardiovascular in origin. reactions on 393 newly introduced medicines in The following nondrug-induced disorders should Japan, 101 (25.7%) showed syncope/loss of con- be considered in the differential diagnosis of sciousness (Nagayama 2015). drug-induced syncope: Centers for Disease Control and Prevention and the FDA have analyzed data from the • Cardiac arrhythmias Vaccine Adverse Event Reporting System for • Drop attacks due to brainstem ischemia January 1, 2005, through July 31, 2007, and • Falls compared the results with reports received dur- • Neurally mediated syncope

Drug-Induced Syncope

• • • • •

Petit mal or absence epilepsy Tonic-clonic seizures Postural hypotension Psychogenic disorders Situational syncope

Syncope and falls are two common concomitant adverse drug effects reported in elderly patients. An overlap between syncope and falls is becoming increasingly acknowledged. In the elderly, determining the cause of a fall can be difficult. A patient may be unable to recall documented falls some months later, and a witness account for syncopal events is often unavailable. Drug-induced hypotension differs from neurogenic orthostatic hypotension due to failure of the sympathetic nervous system that occurs severe in multiple system atrophy with dysautonomia (Shy-Drager syndrome) and is also commonly seen in patients with Lewy body dementia and in patients with Parkinson disease. In contrast, the sympathetic nervous system function is preserved in secondary orthostatic hypotension associated with antihypertensive or psychotropic drugs (Monsuez et al. 2012). A study has shown that 35% of patients monitored with Brugada ECG showed vasovagal responses during the head-up tilt test, suggesting that some of these patients have impaired balance of the autonomic nervous system, which may relate to their syncopal episodes (Yokokawa et al. 2010). There are case reports of patients with primary autonomic neuropathy suffering from both severe orthostatic hypotension and arrhythmic syncope (Di Stefano et al. 2014).

Diagnostic Workup After defining the episode of syncope, the most important first step is to determine the history of drugs taken prior to the episode, particularly those with known association with syncope. Blood pressure should be evaluated carefully to detect postural hypotension. ECG is the most important laboratory test for detecting arrhythmias and conduction disturbances.

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Head-up tilt testing is widely used in the clinical assessment of patients with unexplained syncope. Drug provocation can be used in conjunction with tilting. Sublingual isosorbide dinitrate and tilting are sensitive and specific in inducing a vasovagal reflex in patients with syncope of uncertain origin. Patients with spontaneous vasovagal syncope have lower blood pressure, higher frequency of reflex asystole, and pronounced increases in epinephrine, as well as vasopressin during early phase of the head-up tilt test, than those with drug-potentiated positive head-up tilt test, but both groups share similar supine neuroendocrine profiles (Nilsson et al. 2016). In syncope patients with suspected cardiac channelopathies, DNA sequencing is now commercially available for patient diagnosis. The following three diagnostic scores for syncope have been shown to be useful in practice (Sheldon 2013): 1. Calgary Syncope Seizures Score discriminates between epileptic convulsions and syncope with a sensitivity and specificity of about 94%. 2. Calgary Syncope Score for Normal Hearts discriminates between vasovagal syncope and other causes of syncope with a sensitivity and specificity of about 90%. 3. Calgary Syncope Score for Structural Heart Disease diagnoses ventricular tachycardia with 98% sensitivity and 71% specificity.

 anagement of Drug-Induced M Syncope In a patient with suspected drug-induced syncope, the drug in question should be discontinued. When assessing orthostatic hypotension in the elderly, drug treatment should always be reviewed. Whenever possible, antihypertensive drugs should be discontinued, and the dosages of essential drugs should be reduced. Wearing elastic stockings sometimes corrects orthostatic hypotension. If non-pharmacological measures are inadequate, drug treatment may be c­ onsidered. Fludrocortisone (0.1 to 0.4 mg/day) is recommended. Also, a pros-

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taglandin inhibitor such as indomethacin may be useful at a dose of 25 to 150 mg/day. Ephedrine is recommended for syncope occurring after local or regional anesthesia, particularly in obstetrical procedures. Epinephrine is used for syncope due to drug-induced anaphylaxis. L-DOPS (L-threo-dihydroxyphenylserine) is in phase III clinical trials for the treatment of levodopa-induced neurogenic orthostatic hypotension. L-DOPS is a prodrug to the neurotransmitters—norepinephrine and epinephrine—with the difference that it can cross the blood-brain barrier. Patients with cardiac rhythm and conduction disturbances require care in a cardiology unit. Drug management is complicated by the fact that several of the drugs used for the treatment of cardiac arrhythmias also have syncope as a side effect. Several drugs are used for the treatment of syncope, but if syncope is drug-induced, there may be complications and interactions if the offending drug therapy is maintained. While the patient is monitored, adjustment or discontinuation of cardiovascular medications can help in the management of falls and syncope and may obviate the need for other treatment. Patients with Alzheimer disease have been reported to present with cardiac syncope soon after initiation treatment with donepezil, a cholinesterase inhibitor. In these cases, pacemaker implantation is recommended rather than cessation of donepezil.

Drug-Induced Delirium History Delirium was one of the first mental disorders to be described and has been recognized for over 2000  years. The essential features of delirium were described by Hippocrates as phrenitis, referring to the transient mental disorder associated with physical illness and characterized by restlessness, insomnia, and disturbance of mood, perception, and “wit” (Lipowski 1980). Celsius distinguished delirium from mania and depression. Galen differentiated between primary (idio-

15  Drug-Induced Disturbances of Consciousness

pathic) and secondary symptomatic forms of the disorder. There was much speculation about the relationship of delirium to sleep and dreams from the seventeenth to the nineteenth centuries. Benjamin Rush thought that dream was a transient paroxysm of delirium and that delirium was a permanent dream (Rush 1812). John Hunter described delirium as a diseased dream resulting from abnormally reduced awareness of the external world (Hunter 1835). Delirium was also considered as a point on the continuum between wakefulness and coma and described as “clouding of consciousness” (Greiner 1817). Delirium as a disorder of impaired consciousness was discussed by Hughlings Jackson in terms of his hierarchical model of organization of the nervous system (Jackson 1932). The term “confusion” was introduced by the French and the German authors in the nineteenth century to describe inability to think with one’s customary clarity and coherence, and the French psychiatric term delirie refers primarily to disordered thinking (Berrios 1981).

Terminology Historically, “acute encephalopathy” was the term used to describe unexpected change in mental status of a patient, but “delirium” is now defined by the Oxford English Dictionary as “an acutely disturbed state of mind characterized by restlessness, illusions, and incoherence that are occurring in intoxication, fever, and other disorders,” which was based on resemblance to delirium tremens (Bleck 2018). Delirium is now the accepted term for an acute, transient, global organic disorder of higher nervous system function involving impaired consciousness and attention. Delirium is further categorized as hypoactive or hyperactive. Hypoactive delirium is also referred to as “acute apathy syndrome” (Schieveld and Strik 2018). There are more than 30 synonyms for delirium, which include the following terms: acute brain failure, toxic confusional state, psychosis associated with organic brain ­syndrome, postoperative encephalopathy, exogenous psychoses, reversible toxic confusional

Drug-Induced Delirium

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state, toxic delirious reaction, toxic encephalopathy, and toxic psychosis. Substance-induced delirium can be due to exposure to a medication, toxin, or drug of abuse as well as to withdrawal from any of these. Delirium is a disturbance of consciousness as well as a cognitive disorder. This chapter deals with drug-induced delirium.

deal from time to time. Other features include insomnia, difficulty in concentration, restlessness, irritability, hypersensitivity to lights and sounds, and nightmares. Physical signs of delirium may include autonomic system activation, but these are blunted in elderly patients.

Table 15.5  Diagnostic and Statistical Manual of Mental Disorders IV-TR criteria for substance intoxication delirium

DSM-V recognizes substance-related disorders resulting from the use of ten separate classes of drugs: alcohol; caffeine; cannabis; hallucinogens (phencyclidine or similarly acting arylcyclohexylamines) and other hallucinogens such as LSD; inhalants; opioids; sedatives, hypnotics, or anxiolytics; stimulants (including amphetamine-type substances, cocaine, and other stimulants); tobacco; and other or unknown substances. Drugs reported to be associated with delirium are listed in Table  15.6. Most of the information about drugs causing delirium is based on anecdotal information; sometimes this information is based on single case reports. Because of the complicating background factors, association of delirium with drugs is difficult to investigate by controlled studies. In some cases, the drug’s relationship

 rognosis and Complications of P Delirium The definition of delirium no longer requires Clinical Manifestations reversibility as a criterion. Drug-induced delirium usually clears up on removal of the offending Table 15.5 lists five criteria in the Diagnostic and medication, but it may be slow to resolve, and Statistical Manual of Mental Disorders V for the recovery may be only partial or may never occur diagnosis of delirium. Criterion E includes drug-­ at all. In the elderly, symptoms of delirium may related causes. persist even after the underlying condition is There are many specifiers for delirium that addressed and the patient is discharged from the clarify the cause. Those relevant to drugs are hospital; about one fifth of patients may have (American Psychiatric Association 2013): residual symptoms of the delirium present even 6 months after discharge. Cognitive impairment 1. Substance intoxication delirium may outlast the acute syndrome. 2. Substance withdrawal delirium Overall mortality rates reported in the litera 3. Medication-induced delirium ture vary between 10% and 70%. The higher mortality reflects advanced age and severe underlying Manifestations of delirium include short-term disease. Delirium is an important marker of risk memory deficits, misinterpretation of surround- for dementia and death in older people, even withings, and language difficulties. In addition to out prior cognitive or functional impairment. fluctuations of consciousness and cognition, the affective and psychotic features may vary a great Drugs Associated with Delirium

(A) There is a disturbance in attention and awareness (B) Delirium develops over a short period of time, typically hours to days. There is a change in baseline attention and awareness. It fluctuates throughout the day (C) There is also another disturbance in cognition, such as in memory, orientation, language, and perception (D) The disturbances in (A) and (C) are not better explained by another preexisting, established, or evolving neurocognitive disorder. (Having a neurocognitive disorder, however, increases the risk of the development of delirium) (E) There must also be evidence that the delirium is due to a direct physiological consequence of another medical condition, substance intoxication or withdrawal, or exposure to a toxin, or it is due to multiple etiologies

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242 Table 15.6  Drugs associated with delirium

Table 15.6 (continued)

Analgesics  Nonsteroidal anti-inflammatory drugsa  Opioid analgesicsa  Intrathecal ziconotidea Anticancer drugs  Chemotherapeutics  Cytokines: interferon-alpha, interleukin-2a Anticholinergic agentsa  Antimuscarinic agents, e.g., atropine, tricyclic antidepressants  Antinicotinic agents, e.g., bupropion Anticonvulsants  Levetiracetam (Hwang et al. 2014) Antidepressants  Tricyclic antidepressants  Selective serotonin reuptake inhibitors: fluoxetine  Noradrenergic and specific serotonergic antidepressants: mirtazapine  Serotonin and norepinephrine reuptake inhibitors: venlafaxine Antimalarials: chloroquine, mefloquine Antimicrobials  Acyclovir  Amphotericin  Azithromycin  Clarithromycin  Ertapenem (Veillette and Van Epps 2016)  Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin)  Gentamicin  Itraconazole  Nalidixic acid  Sulfonamides  Tobramycin Antiparkinsonian drugs  Levodopa  Dopamine agonists  Amantadine  Benztropine  Trimethobenzamide Antipsychotics  Chlorpromazine  Clozapine  Olanzapine  Lithium  Perphenazine  Risperidone  Thioridazine  Trifluoperazine (continued)

 Benzodiazepinesa Cardiovascular drugs  Antihypertensives  Beta-blockers  Clonidine Antiarrhythmics: amiodarone Diuretics  Digitalis  Quinidine CNS stimulants Drug abuse Drug interactions  Clozapine and lorazepam  Fluoxetine and clarithromycin  Ibuprofen and tacrine  Lithium and risperidone  Paroxetine and zolpidem  Tranylcypromine and disulfiram Drug combinations  Valproic acid and lamotrigine  Diphenhydramine and linezolid Corticosteroids Antihistaminics  Histamine H2-receptor antagonistsa Hypnotic sedatives  Zolpidem Miscellaneous drugs  Atropine  Baclofen  Bromides  Cyclobenzaprine  Disulfiram  Ergotamine-caffeine combination  Fentanyl transdermal  Metrizamide  Methazolamide  Niridazole  Omeprazole  Podophyllin  Procaine derivatives  Sodium nitroprusside  Theophylline Drug withdrawal  Abrupt discontinuation of serotonin reuptake inhibitors (Blum et al. 2008)  Sudden discontinuation of sedative drugsa  Withdrawal from narcotic drugsa  Withdrawal from gamma-hydroxybutyrate  Abrupt cessation of baclofen and tizanidine Denotes established and frequent association

a

Drug-Induced Delirium

with delirium has been established by “dechallenge,” i.e., clearing up of the adverse reaction after discontinuation of the suspected medication, and “rechallenge,” i.e., recurrence of the adverse effect after resumption of the suspected medication.

 nderlying Disorders and Risk U Factors for Delirium Underlying disorders and risk factors for delirium are shown in Table 15.7.

Anticholinergic Agents Anticholinergic agents, drugs that block the action of the neurotransmitter acetylcholine in the brain, are the leading cause of drug-induced delirium. Anticholinergics, together with several different drugs, may significantly contribute to the delirium onset, especially in elderly, demented persons. Side effects such as delirium, induced by anticholinergic drugs, are particularly severe in aging brain. Table 15.7  Underlying disorders and risk factors for stroke (A) Drug withdrawal  Withdrawal of therapeutic drugs  Withdrawal of drugs of abuse  Alcohol withdrawal: delirium tremens (B) Acute neurologic disorders that may present with delirium  Stroke  Meningitis  Traumatic brain injury  Epilepsy (C) Other conditions that are also risk factors for the development of delirium  Hypoglycemia  Hypoxia  Hepatic or renal insufficiency  Endocrinopathies, e.g., hyperthyroidism (D) Psychiatric disorders  Dementia  Confusion in elderly patients  Depressive stupor  Psychoses: schizophrenia, mania (E) The intensive care unit syndrome, which is an altered emotional state, occurs in a highly stressful environment and may manifest itself as delirium

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These agents are also an important cause of drug-induced memory disorders. Anticholinergic agents include antidepressants, antipsychotics, antihistamines, antispasmodics, antiemetics, and antiparkinsonian agents. However, the relationship of anticholinergic drugs to delirium is difficult to establish in prospective clinical studies. Anticholinergic syndrome used to be common after general anesthesia because of the premedication with anticholinergic agents atropine and scopolamine. Because these agents are used infrequently, this syndrome occurs infrequently but may still occur due to anticholinergic effect of some general anesthetics. Therefore, this syndrome should still be considered in the differential diagnosis of delirium after anesthesia. It can be reversed by administration of physostigmine.

Antidepressants Tricyclic antidepressants have a high affinity for antagonizing the histamine receptors, as well as the muscarinic acetylcholine receptors, which can induce delirium. SSRIs are associated with delirium as a side effect. Tianeptine, an atypical antidepressant that enhances serotonin reuptake, has been reported to induce delirium (Tobe and Rybakowski 2013). Antimicrobials A retrospective study in a veteran population has shown that fluoroquinolones were associated with delirium when used in patients on typical antipsychotics and those of advanced age (Sellick et  al. 2018). Delirium occurred in 3.6% of patients treated with ciprofloxacin and 4.5% of those treated with moxifloxacin. Delirium associated with fluoroquinolones is rarely reported, e.g., there are only eight published cases of levofloxacin-­induced delirium (Odeh et al. 2019). This potentially fatal adverse effect of levofloxacin is more common in practice than reported. Antiparkinsonian Drugs Several neuropsychiatric disturbances (e.g., psychoses, hallucinations, delirium) occur as a complication of the drug treatment of Parkinson disease. All drug categories including anticholinergic drugs, levodopa, and dopaminergic agonists have the

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potential to produce delirium. Older patients with dementia are particularly at risk when on anticholinergic drugs. Amantadine, originally discovered as an antiviral agent before it became an antiparkinsonian drug, is also used for the treatment of acute influenza. An elderly patient developed delirium with psychotic features 48 h after initiation of standard dose of amantadine for influenza (Neagoe 2013). Parkinson disease patients who tolerate amantadine well as long-term therapy can develop delirium when the drug is suddenly withdrawn due to therapeutic regimen change (Fryml et al. 2017; Marxreiter et  al. 2017). Gradual withdrawal can prevent this adverse effect.

15  Drug-Induced Disturbances of Consciousness

Interferons Neuropsychiatric symptoms are a prominent feature of interferon syndrome, including an acute confusional state that develops rapidly after initiation of high-dose interferon-alpha. Strategies for managing delirium should be employed, including treatment of contributing medical conditions, use of either typical or atypical antipsychotic agents, and avoidance of medications likely to worsen mental status.

Cocaine Abuse Cocaine-related delirium is now common and is likely due to disruption of dopaminergic function from chronic use of the drug, which, when couAntipsychotics pled with recent cocaine use, may precipitate agiAntipsychotics can induce delirium. Clozapine-­ tation, delirium, aberrant thermoregulation, induced delirium has been reported (Benckhuijsen rhabdomyolysis, and sudden death. Gamma-­ and Keet 2007; Shankar 2008). Delirium is hydroxybutyrate withdrawal syndrome may known with acute lithium intoxication but is rare progress to delirium (van Noorden et al. 2009). with therapeutic doses of the drug. A case has been reported of a patient with schizophrenia Histamine H2-Receptor Antagonists who developed severe delirium shortly after ini- All drugs of this class have the potential to cause tiation of a lithium-quetiapine combination ther- delirium. Cimetidine has the largest number of apy, although therapeutic doses of both drugs reported cases because it was the first drug of this were used, which resolved after discontinuation class to enter the market. CNS toxicity generally of lithium (Miodownik et al. 2008). occurs during the first 2 weeks of therapy and is seen mostly in intensive care patients, particuBenzodiazepines larly in those patients with renal and hepatic failRisk of delirium is increased in older hospital- ure. The reaction usually resolves within a few ized patients receiving benzodiazepines. Delirium days of drug withdrawal. may also occur in long-term users of benzodiazepines because of withdrawal. Short-acting Nonsteroidal Anti-inflammatory Drugs agents such as alprazolam are more likely to pro- There are several reports of the association of duce withdrawal reactions. nonsteroidal anti-inflammatory drugs with delirium. Because these are the most used drugs, the Corticosteroids cognitive impact is considerable. Toxicity from Psychological, cognitive, and behavioral distur- aspirin frequently manifests as delirium. bances are well-recognized side effects of glucocorticosteroids. Delirium, confusion, and Opioid Analgesics disorientation have been reported to occur in 15.7 Of the opioid analgesics, meperidine (pethidine) per 100 person-years at risk for all glucocorticoid poses the greatest risk for delirium because of the courses of treatment and 22.2 per 100 person-­ accumulation of its metabolite, norpethidine, years at risk for first courses (Judd et al. 2014). which has anticholinergic properties. Because the Tapered withdrawal of the offending drug usually clearance is by the kidney, the metabolite is more resolves the situation, but if symptoms persist, likely to accumulate in elderly subjects with treatment with antipsychotic drugs and benzodi- impaired renal function. In a comparative study of azepines may be needed. the use of opioids as analgesics in cancer patients,

Drug-Induced Delirium

fentanyl was associated with a much lower risk of delirium than morphine (Tanaka et al. 2017).

Delirium Due to Drug Withdrawal Delirium due to withdrawal of narcotics and sedatives is well known, but it may also occur due to cessation of other drugs such as muscle relaxants. A case of delirium was reported due to abrupt cessation of baclofen and tizanidine and resolved in 24  hours after reintroduction of baclofen (Karol et al. 2011). One case has been reported of delirium following withdrawal from gamma-­hydroxybutyrate, a recreational drug, but the patient recovered in 11 days (Kashyap and Patel 2011).

Pathomechanism of Delirium Little is known about pathophysiological mechanisms in delirium. Reduced severe oxidative metabolism may cause brain dysfunction due to abnormalities in various neurotransmitter systems. There is probably no final common pathway to delirium, but it is the final common symptom of multiple neurotransmitter abnormalities. One hypothesis of a final common pathway is based on neuroanatomical data derived from neuroimaging and lesion reports in the prefrontal cortex, thalamus, posterior parietal cortex, and basal ganglia. Among the neurotransmitters implicated in delirium, acetylcholine deficiency and dopamine excess (as well as their interaction with each other) appear to be critical in the final common pathway of delirium. Cerebrospinal fluid levels of somatostatin and beta-endorphin are low in patients with delirium, indicating disturbances in the chemistry of the brain. Another abnormality in delirium is cortisol excess, which seems to be an abnormal “shut-­ off” of the hypothalamic-pituitary-adrenal axis as tested by the dexamethasone suppression test. Measurement of serum levels of anticholinergic activity in delirious states shows that these levels are raised and correlate it with delirium induced by drugs with cholinergic effect.

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Pathogenesis of delirium is often multifactorial and may involve the interaction of precipitating factors with underlying patient vulnerability. A review of drug-induced delirium has shown that among hospitalized patients, the leading drug-induced causes in descending order are as follows: • • • • •

Opioid analgesics Benzodiazepines Anticholinergics Nonsteroidal anti-inflammatory drugs Sedative withdrawal

Drugs can induce delirium in several ways such as: • Toxic concentrations of drugs due to overdose or impaired clearance. • Pharmacodynamic changes may result in increased sensitivity to normal concentrations of centrally acting drugs. • Drug-disease interaction such as in patients with dementia where the risk of delirium is enhanced due to diminished “cognitive reserve.” • Drug-drug interactions in the case of polypharmacy. The actual mechanisms by which drugs cause delirium are poorly understood because the pathophysiology of delirium itself is not well understood. Delirium is a diffuse brain disturbance that involves both cortical and subcortical structures. Although multiple neurotransmitters are involved, most of the current evidence points to cholinergic failure. Anticholinergic medications produce classic delirium that can be reversed with cholinesterase inhibitors. Clinical conditions that cause delirium, such as thiamine deficiency and hypoglycemia, also impair acetylcholine synthesis. Radioreceptor assays, which measure muscarinic binding, enable a more precise determination of the mechanism of drug-induced delirium. Acute confusion can correlate with increased serum anticholinergic activity. Several drugs that are not traditional anticholinergics but cause delirium show measur-

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able cholinergic receptor binding by this assay. Among the drugs currently in use, well over 600 have some anticholinergic effects. In addition to cholinergic deficiency, there may be an imbalance between acetylcholine and dopamine. Two types of delirium have been described: a hyporeactive delirium due to tramadol (an opiate with anticholinergic effect) and a hyperreactive delirium after administration of L-dopa (Lauretani et al. 2010). Cases of delirium have been reported as side effects of selective serotonin reuptake inhibitors (SSRIs) used as antidepressants (Kogoj 2014). There is a case report of lidocaine-induced delirium (Afacan et al. 2015). The pathomechanism is not clear in these cases. A study on patients has shown that delirium following fentanyl and midazolam is unrelated to midazolam and may be linked to inflammatory status, suggesting that iatrogenic coma and delirium are not mechanistically linked (Skrobik et al. 2013). Fluctuations in sedation levels may contribute to development of delirium, but this can be reduced by maintaining a stable sedation level (Svenningsen et al. 2013). An example of delirium due to drug-drug interaction is the addition of bupropion to duloxetine in an elderly patient with major depressive disorder that resulted in a high level of hydroxybupropion, as both drugs are cytochrome P450 2D6 inhibitors (Ma et  al. 2017). An increase in the level of hydroxybupropion further raises dopamine level, which is a risk factor for delirium, and this patient improved after discontinuation of bupropion and drop in the blood level of hydroxybupropion.

 pidemiology of Drug-Induced E Delirium Accurate data on incidence of, prevalence of, and mortality due to delirium are difficult to obtain and evaluate because of differences in definitions and methodology. Most information is based on hospitalized patients, but a community study, the Eastern Baltimore Mental Survey, found a point prevalence rate of 0.4% in the adult population,

15  Drug-Induced Disturbances of Consciousness

rising to 1.1% in those aged 55  years or over (Folstein et al. 1991). In contrast to the low prevalence rate in the community, 10% to 30% of all hospitalized patients meet criteria for delirium at some point during their stay (Lipowski 1980). Delirium occurs in up to 50% of patients after major surgery. This would make delirium the mental disorder with the highest incidence. Prevalence in nursing homes is even higher. In a study combining old patients at home, in nursing homes, and in hospitals, delirium was diagnosed in 43.9% of the patients, and 42.9% of the delirious patients had dementia as well (Sandberg et al. 1999). This high figure of prevalence of delirium is due to the coincident prevalence of dementia in the elderly population. Approximately one third of all cases of delirium are drug-induced. Postoperative delirium occurs in 7% to 52% of patients undergoing surgery, depending on patient population and clinical setting (Bucht et al. 1999). Delirium develops in 44% to 55% of hip surgery patients versus 10% to 14% of general surgery patients (Parikh and Chung 1995). Delirium occurs in 25% to 40% of all patients with cancer and in up to 85% of patients who are in the terminal phase of the disease (Weinrich and Sarna 1994). This alteration in mental status may be attributable both to the underlying condition and to the cancer treatment utilized. Delirium develops in 43% of the patients undergoing hematopoietic stem cell transplantation (Beglinger et  al. 2006). Delirium is associated with higher mortality in these patients. In a prospective study of 1500 hospital neurologic consultations, delirium accounted for 7% of all cases and 19% of all iatrogenic neurologic disorders (Moses and Kadan 1986). Delirium was drug-induced in 17% of these cases, and drugs were suspected to have contributed to delirium in 47% of the cases in which no single cause was identified. A survey of hospitalized patients in the United States from 1998 to 2005 recorded delirium in 0.54% of nonpsychiatric adult hospitalizations (Lin et al. 2010). Whereas the overall prevalence of dementia-associated delirium and nondrug, non-dementia delirium decreased over time,

Drug-Induced Delirium

drug-induced delirium prevalence increased. The presence of dementia and adverse drug effects had the strongest associations with dementia-­ associated and drug-induced delirium, respectively, in the cohort hospitalizations. The findings suggest that interventions focusing on adverse drug effects have the greatest potential for preventing delirium.

Prevention of Drug-Induced Delirium Close monitoring of the patient’s medications is the most important prevention against drug-­ induced delirium. Multidisciplinary interventions to prevent delirium include the following: adjustment of medications, early detection and management of cognitive impairment, treatment of sleep disorders, mobilization of patients, aids for visual and hearing impairment, and correction of dehydration. To reduce the morbidity and mortality associated with drug-induced delirium, and to prevent it, patients’ medications should be closely monitored (Meyer et  al. 2010). Preventive measures against drug-induced delirium are: • Anticholinergic, sedative-hypnotic, and opioid medications should be used sparingly in the elderly. • Avoidance of combinations of drugs suspected to cause delirium. The combination of benzodiazepines and clozapine should be avoided if possible. • Clinicians caring for intensive care unit patients should carefully evaluate the need for benzodiazepines, opioids, and haloperidol, which are known risk factors for precipitating delirium. There is an association between cumulative dose of haloperidol and next-day delirium in older medical intensive care unit patients (Pisani et  al. 2015). Each additional cumulative milligram of haloperidol was associated with 5% higher odds and intubation with a fivefold increase of next-day delirium. Haloperidol use to control delirium has been associated with development of neuroleptic malignant syndrome (Dixit et al. 2013).

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Differential Diagnosis of Delirium Various conditions that have similar presentation and should be considered in the differential diagnosis of delirium are: • Anticholinergic syndrome: delirium, hallucinations, dilated pupils, etc. • Serotonin syndrome: agitation, confusion, hyperreflexia, tremor, fever, diarrhea, etc. • Neuroleptic malignant syndrome: confusion, disorientation, muscle rigidity, fever, etc. After drug-induced disorders, the next most important differential diagnosis is dementia. Delirium has an acute onset, whereas dementia develops slowly over a longer period. In uncomplicated dementia, consciousness remains essentially intact, whereas its impairment is an important feature of delirium. One of the features of dementia is short-term memory deficit in the absence of an attentional deficit before the disease progresses to impair long-term memory as well. In delirium, short-term memory deficit does not occur in the absence of attentional deficits, and there is no clearcut progression to long-term memory deficits. A higher-level term cognitive impairment that includes both dementia and delirium may be used if it is not possible to delineate delirium from dementia, which may coexist in a particular patient. Clinical features common to delirium and schizophrenia are incoherent speech, disturbances of affect, delusions, and hallucinations. Delusions form a part of abnormal beliefs in schizophrenic patients, and hallucinations are usually auditory. Hallucinations in delirium are usually visual. Consciousness, memory, and attention are relatively unimpaired in schizophrenia as compared to delirium. There may be a difficulty in differentiating between delirium and an acute psychotic state where the patient may be confused and show signs of altered consciousness.

Diagnostic Workup The most important step in the diagnosis of delirium is a careful drug history, noting in particular

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the temporal relationship to any new medication at the onset of delirium. Delirium is often overlooked on initial examination. Various rating scales are available. The Delirium Rating Scale is the most widely used instrument in research studies for rating the severity of delirium with validity, high interrater reliability, and substantial sensitivity and specificity. The Delirium Rating Scale has been translated from English into many other languages, and the ten items of the scale are: 1. Temporal onset 2. Perceptual disturbances 3. Hallucinations 4. Delusions 5. Psychomotor behavior 6. Cognitive status 7. Physical disorder 8. Sleep-wake cycle disturbances 9. Lability of mood 10. Validity of symptoms The Delirium Rating Scale has been revised to include separate items for each cognitive function and items for rating the severity of impairment of thought and language. The Memorial Delirium Assessment Scale (MDAS) is a ten-item severity rating instrument for delirium in patients with advanced cancer. A study has compared the revised Delirium Rating Scale (DRS-R98) and MDAS and found that the derived conversion rules demonstrated promising accuracy in this palliative care population (O'Sullivan et al. 2015). General investigations include basic laboratory studies: complete blood count, urine analysis, electrolytes, creatinine, blood urea nitrogen, arterial blood gases, liver enzymes, and calcium levels. Further tests are based on the results of the basic evaluation. In some cases, physical examination may give important clues to the nature of the drugs involved. Toxic screens and serum estimations of drugs are useful, but these may be within therapeutic range in elderly patients and still be the causative agent. Neurologic diagnostic procedures may include EEG, lumbar puncture, and brain imaging.

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 anagement of Drug-Induced M Delirium General principles of the clinical management of delirium are shown in Table 15.8. The causative role of newly initiated drugs, increased doses, interactions, over-the-counter drugs, and alcohol should be considered, especially the role of high-risk drugs, and measures should be to lower the dose, discontinue the drug, or substitute a less psychoactive medication (Marcantonio 2017).

Anticholinergic Delirium Anticholinergic delirium is the only form of delirium for which specific pharmacotherapy is available. Anticholinergic delirium is best managed by physostigmine, a cholinesterase inhibitor. It can reverse delirium due to anticholinergic toxicity for up to 1  hour following a 1 to 2  mg intravenous dose. Adverse effects of intravenous infusion are cardiotoxicity and signs of cholinergic excess such as seizures, nausea, and vomiting. The short duration of action and potential for Table 15.8  Principles of the clinical management of delirium (1) Early recognition of the condition (2) Identification and treatment of the underlying cause (a) Discontinuation of the offending medication (b) Treatment of the primary disease process  1. Correction of the electrolyte abnormalities and anemia  2. Correction of the hypoxemia  3. Treatment of heart failure  4. Pain relief in case of cancer and surgery (3) Management of agitation (a) Behavioral control  1. Reassuring communication  2. Provide orientation, e.g., time, window view (b) Social restraint (try to avoid physical restraints) (c) Pharmacotherapy (only if other measures fail) (4) General supportive care (a) Remove indwelling urinary catheter as soon as possible (b) Mobilize the patient as soon as possible (5) Maintenance of adequate nutrition (6) In postoperative patients, judicious use of oxygen can treat delirium effectively (7) Pharmacotherapy (a) Limited use of drugs with caution

Drug-Induced Delirium

serious cholinergic side effects, which requires close monitoring, are major limitations to its use. It can potentiate toxicity of tricyclic antidepressant overdose. Cholinesterase inhibitor donepezil is an effective choice in the management of anticholinergic drug-induced delirium.

Nonspecific Pharmacotherapy Few controlled studies of the pharmacological management of delirium have been performed. The major reported methods of treatment are antipsychotics or benzodiazepines. If the patient is aggressive or dangerous, intravenous diazepam may be used until the patient is fully sedated. Parenteral antipsychotics that have been used in this situation include haloperidol, trifluoperazine, and thiothixene. The major advantage of haloperidol is its lack of anticholinergic activity. Risperidone may prove to be an effective alternative to haloperidol in delirious patients, especially the elderly and the severely medically ill who are more prone to adverse effects.

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tics (haloperidol or chlorpromazine). Lorazepam alone appears to be ineffective and associated with treatment-limiting adverse effects. Cancer  Delirium precipitated by opioids and other psychoactive medications is frequently reversible with change of opioid or dose reduction and discontinuation of unnecessary psychoactive medication. Terminal cancer patients may experience acute delirium when treated with morphine but improve when the opioid is changed to oxycodone or fentanyl. This treatment allows patients to remain more comfortable and lucid in their final days. In cancer patients, opioid-­ induced delirium can improve with intravenous injection of the acetylcholinesterase inhibitor physostigmine.

Parkinson Disease  Drugs used to treat Parkinson disease, such as levodopa, often have neuropsychiatric adverse effects, most prominently psychosis and delirium. Elderly patients and those with dementia are particularly vulnerable to these adverse effects. The treatment of drug-induced delirium begins with the manipulaDelirium in Critically Ill Patients A large, double-blind, randomized, placebo-­ tion of the antiparkinsonian drug regimen, but controlled trial found no evidence that use of the this frequently worsens patient motor function. dopamine antagonists haloperidol or ziprasidone Anticholinergics should be tapered first, as they significantly altered the duration of delirium in are most likely to cause delirium. Levodopa the intensive care unit (Girard et al. 2018). The should be tapered slowly and not abruptly as it dose of haloperidol in the trial was less than may precipitate a neuroleptic-like syndrome. 20 mg/day, as a dose higher than 25 mg per day Atypical antipsychotics such as clozapine have can induce delirium. Patients in the intensive care been successfully employed to treat psychosis unit often suffer sleep disturbances and abnormal without worsening motor disability. circadian rhythms, which may increase delirium and lengthen stay. Non-pharmacological strate- Management of Delirium After Drug gies are usually tried first, but a multimodal Withdrawal approach to care including pharmacotherapy is There are no specific guidelines for the managerequired. Despite the limited available data sup- ment of delirium after drug withdrawal. porting their use, nonbenzodiazepine medica- Sometimes the withdrawn drug needs to be tions such as melatonin, ramelteon, suvorexant, resumed for the control of delirium. and dexmedetomidine may promote sleep and Delirium after withdrawal of clozapine improve a variety of patient-centric outcomes resolves rapidly with the resumption of low doses such as delirium (Fontaine et al. 2020). of clozapine. Severe withdrawal symptoms can probably be avoided by slowly tapering ­clozapine AIDS  Symptoms of delirium in medically hospi- or simultaneously substituting another psychotalized AIDS patients may be treated efficaciously tropic with high anticholinergic activity, such as with few side effects by using low-dose neurolep- thioridazine.

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Intravenous benzodiazepines are the recommended treatment when delirium is associated with withdrawal from alcohol or delirium tremens. Intravenous or intramuscular lorazepam may be given up to once every 4 hours. There is a risk associated with the use of drugs in this situation as it may aggravate delirium. Benzodiazepines are also causally associated with delirium. Excessive sedation or respiratory depression from benzodiazepines is reversible with flumazenil. Flumazenil can also reverse lorazepam-­ induced acute delirium if it should occur.

 anagement of Delirium Associated M with Anesthesia Delirium may result from some anesthetics, particularly during recovery from short-acting anesthetics. Preoperative benzodiazepines, breast and abdominal surgery, and surgery of long duration are risk factors for emergence of delirium in the postanesthetic period. In a randomized, double-­ blind, placebo-controlled trial in children, intravenous administration of 0.03 mg/ kg of midazolam just before the end of surgery reduces emergence of agitation without delaying the emergence time in children having surgery with sevoflurane anesthesia (Cho et  al. 2014). Limiting intraoperative sedation depth during spinal anesthesia for surgery in elderly patients can decrease the prevalence of postoperative delirium. The use of light propofol sedation decreased the prevalence of postoperative delirium by 50% compared with deep sedation (Sieber et  al. 2010). In a randomized clinical trial on older adults undergoing major surgery, EEG-guided anesthetic administration compared with usual care did not decrease the incidence of postoperative delirium (Wildes et  al. 2019). Because of the limited treatment options available for treatment of delirium, risk assessment and perioperative risk reduction may be the most effective approaches in managing postoperative delirium (Jin et al. 2020). The American Society for Enhanced Recovery and Perioperative Quality Initiative joint consensus statement on postoperative delirium prevention includes the following strategies (Hughes et al. 2020):

15  Drug-Induced Disturbances of Consciousness

• Use of multicomponent non-pharmacologic interventions for the prevention of postoperative delirium in older high-risk patients. • Minimization of medications known to be associated with an increased risk of postoperative delirium in older high-risk surgical patients. • Optimization of postoperative pain control to reduce the risk of postoperative delirium. • There is insufficient evidence to recommend administration of prophylactic medications to reduce the risk of postoperative delirium. • Intensive care units’ protocol should include sedation with dexmedetomidine to reduce the risk of postoperative delirium in patients requiring postoperative mechanical ventilation.

 anagement of Delirium in Special M Groups Geriatric Age Group  Elderly persons are more likely than younger adults to develop drug-­ induced cognitive impairments, as their renal and liver functions are often impaired (Shinohara and Yamada 2016). Antipsychotics, although not approved for drug-induced delirium, are effective in treating delirium of the elderly in a hospital setting. Pediatric Age Group  Intravenous physostigmine, despite a concern for toxicity, has been used successfully as intermittent intravenous injections for control of delirium in a 6-year-old boy who had accidently ingested olanzapine (Hail et al. 2013).

Coma Due to Drug Intoxication Coma is at the most severe end of the spectrum of disorders of consciousness, which include the following (in order of increasing severity): (1) delirium, a state of waxing and waning consciousness with prominent disorientation, fear, and hallucinations, as well as an altered s­leep/ wake cycle; (2) obtundation, which implies a mild to moderate reduction in alertness, with increasing time spent in the sleep state; (3) stu-

Coma Due to Drug Intoxication

por, a state of deep sleep, from which the patient can be aroused only with repeated and vigorous stimulation; and (4) coma. The term coma, as defined in the classic work of Plum and Posner, is reserved for patients who are in a state of “unarousable psychologic unresponsiveness” (Plum and Posner 1982). Comatose patients do not show any signs of awareness of themselves or of their environment; brainstem reflexes and posturing movements of the extremities are permissible, but eye opening should not occur in response to an external stimulus, and the patient should not move in a purposeful fashion. Many drugs can cause a comatose state, either as an anticipated and desired effect of their administration (e.g., anesthetic medications) or due to inappropriate administration, overdose, toxic side effects, or idiopathic reaction. Coma can result from therapeutic drugs as well as recreational drugs and drug abuse. The term “drug-­ induced coma” often refers to coma induced for therapeutic purposes, e.g., barbiturate-induced coma as a neuroprotective measure against hypoxia/ischemia. Therefore, the term “coma due to drug intoxication” is preferred when it is due to drug overdose and inappropriate use or as an adverse reaction. The term “encephalopathy” refers to generalized dysfunction of the brain with manifestations varying according to the involvement of brain structures, and coma may occur in severe cases. The causes are varied and may be toxic, metabolic, degenerative, inflammatory, vascular, or post-traumatic. The term “drug-induced encephalopathy” is used when the cause is use or abuse of therapeutic drugs as well as illicit or recreational drugs, but it may be secondary to other drug-induced disorders, such as hepatic encephalopathy, hypertensive encephalopathy, uremic encephalopathy, hyponatremia, and hypoglycemia (see Chap. 13). Encephalopathy may be associated with other neurologic manifestations and does not necessarily lead to coma. Because the focus of this article is on coma due to drug intoxication and not lesser degrees of disturbances of consciousness, reference to encephalopathy will be given only where it is relevant.

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Clinical Manifestations Drug intoxication leading to coma should be suspected in any patient presenting in an altered mental state without another overt etiology for his/her clinical condition. A careful history, often obtained from the caregivers of the patient, may help to elucidate predisposing conditions, such as depression or a seizure disorder or drug abuse, as well as prescription medications taken by the individual. Any recent history of erratic or unusual behavior or overt depression should alert the clinician of the possibility of medication overdose. In the absence of ancillary history, a toxicology screen should be performed, including serum and urine. Toxicodynetics aims at defining the time course of major clinical events in drug overdose. The physical examination may also give clues to the possibility of drug use or intoxication. The presentation of patients with encephalopathy or coma from drug intoxication is most often acute and rapidly progressive, but in some situations, the patient may have a more subacute course, e.g., in acetaminophen overdose leading to hepatic failure. Patients may have adequate treatment of the underlying intoxication but may have further clinical deterioration due to the systemic effects of the offending drug, e.g., with lithium-­induced renal failure, hypoglycemia due to liver failure, or antiglycemic drugs. The general physical exam may point to drug abuse as the cause of coma. A careful skin exam may reveal signs of venipuncture, suggesting self-injection of drugs, including heroin. The skin may look jaundiced and the sclera icteric, suggesting hepatic insufficiency. There may be evidence of epistaxis, common with nasal ingestion of cocaine. External signs of trauma, particularly to the head (“battle sign,” “raccoon eyes”), should alert the physician to the possibility of concomitant head injury. The vital signs of the patient may also reflect drug intoxication. For example, benzodiazepines and opiates commonly cause respiratory suppression; amphetamines and cocaine cause hypertension, tachydysrhythmias, and myocar-

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dial infarction; and tricyclic antidepressants (TCAs) may cause conduction block. Drugs that affect the autonomic nervous system can also cause temperature disturbances, vasoconstriction or vasodilation, and cardiac rhythm disturbances. The neurologic examination likewise may provide clues to drug intoxication. The pupillary exam may be abnormal; for example, opiates often cause profound miosis, whereas sympathomimetics cause mydriasis. The muscle tone in the extremities may be increased with certain agents, such as psychotropic medications (antipsychotics, selective serotonin reuptake inhibitors), even leading to neuroleptic malignant syndrome. Any focal neurologic signs should alert the clinician to a structural lesion, such as a stroke, which can occur as a complication of drug intoxication (e.g., cocaineinduced vasculitis, heroin injection associated with bacterial endocarditis). The prognosis with most drug intoxications may be good, even for those causing coma, provided that the patient can be carefully supported during the time of intoxication with adequate critical care and management of medical complications. Most often, the effect of the offending medication is relatively short-lived, and a full recovery may be expected within several days. Exceptions include drugs with direct CNS toxic effects, such as cyanide or carbon monoxide, which impair the ability to adequately oxygenate the brain. Other variables affecting outcome include secondary injuries caused to the brain, such as cerebral infarction from a cocaine-­ induced vasculitis, global anoxic injury from prolonged impaired ventilation with hypotension as may be seen with opiate overdose, or hepatic encephalopathy with hyperammonemia seen in fulminant liver failure caused by acetaminophen overdose.

Drugs that Can Cause Coma Several drugs can cause coma. An etiological classification of drug-induced coma is shown in Table 15.9.

15  Drug-Induced Disturbances of Consciousness Table 15.9  Etiological classification of coma due to drug intoxication Alcohol: combination with sedative-hypnotics Anesthetics: e.g., propofol Direct effect from prolonged use or overdose of the following drugs:  Anticholinergic drugs  Antipsychotics  Barbiturates  Benzodiazepines in combination with other CNS depressants  Cephalosporins  Cholinergic drugs  Lithium overdose  Metronidazole  Opioids  Sympatholytic drugs  Tricyclic antidepressants  Valproic acid  Vigabatrin Secondary effect of other drug-induced adverse effects  Drug-induced hypoglycemia, e.g., insulin  Drug-induced serotonin syndrome  Drug-induced diabetes insipidus with hyperosmolar coma  Drug-induced hyperosmolar nonketotic diabetic coma: e.g., prednisone  Drug-induced hepatic encephalopathy, e.g., 5-fluorouracil  Drug-induced cerebrovascular disorders: cerebral vasculitis, cerebral hemorrhage  Drug-induced cardiovascular disorders  Drug-induced hyponatremia  Drug-induced renal disorders: uremic encephalopathy  Neuroleptic malignant syndrome Poisons: e.g., cyanide Recreational drugs and drug abuse  MDMA (ecstasy)  Gamma-hydroxybutyric acid  Methaqualone  Psychedelics, e.g., LSD  Synthetic cannabinoids

 athomechanism of Drug-Induced P Coma Coma may be due to direct toxic effect of drugs on the brain or indirect effect due to disturbances of other systems. • Direct effect of drugs on the brain. This is usually due to drugs that act mainly on the ner-

Coma Due to Drug Intoxication

•

•

•

•

vous system such as sedative-hypnotics. However, overdose of drugs not normally acting on the CNS (e.g., propranolol) may also induce coma. Coma may be reversible or irreversible if there is significant structural damage to the brain such as in leukoencephalopathy. Indirect effect on the brain by drug-induced disorders of other systems. Examples of this are hepatic and renal failure and drug-induced hypoglycemia. A case has been reported of hepatic coma due to hepatotoxicity of abiraterone acetate, a drug used for the treatment of castration-resistant prostate cancer (Yumiba et al. 2017). Hyperammonemic encephalopathy may occur due to Krebs cycle inhibition or urea cycle deficiency following 5-fluorouracil infusion, but recovery of consciousness usually follows with proper management of hyperammonemia (Boilève et al. 2018). Drug-induced respiratory or circulatory failure can also depress the reticular activating system, leading to coma.

Coma is associated with several drug-induced encephalopathies. Normal doses of some drugs may produce overdose effect in some circumstances, such as drug interactions and renal failure, impairing excretion of the drug. Generally, older patients metabolize medications more slowly, and, thus, the elderly population may be at risk of side effects from psychoactive medications, and the duration of effect may be more prolonged. Furthermore, the effect of medications is influenced by concomitant organ system disease, particularly those affecting clearance (hepatic, renal).

Opiates Overdose of various opiates can cause coma, and this may occur in the hospital setting, such as with unintended overdose of morphine sulfate or with recreational drug use, such as with heroin use. Overdose of opioids causes the triad of coma, respiratory depression, and pinpoint pupils. Systemic manifestations of opiate overdose include hypothermia, hypoventilation, bradycar-

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dia, hypotension, and cool, clammy skin. Needle marks should be sought in suspected intravenous drug use, although heroin may also be sniffed, and even first-time users can present in severe states. Respiratory decompensation occurs either because of CNS suppression or secondary to pulmonary edema. The pupils are typically small but reactive and dilate widely in response to a narcotic antagonist (e.g., naloxone). Methadoneinduced hypoglycemia has been reported in cancer patients receiving long-acting methadone for pain. The case of an infant who developed hypoketotic, hyperinsulinemic hypoglycemia after an acute, unintentional methadone exposure indicates that hypoglycemia is due to methadoneinduced insulin secretion (Toce et al. 2018).

Benzodiazepines Distribution of benzodiazepines in the brain and their enhancement of GABA activity at specific sites account for the clinical features of benzodiazepine-­induced coma to a large extent. Toxicodynetic studies show that nordiazepam is not a cause of coma even in large overdose, whereas oxazepam causes coma only at a very high dose. Deep coma in overdose of nordiazepam and oxazepam involving therapeutic index of less than 20 results from an unrecognized drug-drug interaction (Sacre et al. 2017). Benzodiazepines can cause a decrease in cerebral blood flow and cerebral metabolism, the distribution of which correlates with the density of benzodiazepine binding sites. Endozepines, the ligands for benzodiazepine recognition sites on GABAA receptors in the CNS, are elevated. The major site of action of the benzodiazepines is the reticular activating system; however, in high doses, generalized cortical depression may occur, which contributes to stupor. Benzodiazepines potentiate the effects of other CNS depressants. With concomitant ethanol ingestion, respiratory depression becomes much more dramatic, and patients may become comatose and require ventilatory support. Barbiturates At high concentrations, barbiturates dissolve in lipid membranes and interfere with ionic transfer

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and calcium uptake by nerve cell membrane. They cause a dose-dependent decrease in cerebral blood flow and glucose utilization. Barbiturates act mainly at GABA synapses where they enhance inhibition and suppress excitation. Hypnotic and sedative effects of barbiturates may depress other brain structures in addition to the reticular activating system. Depression of the cerebral cortex can lead to confusion and intellectual impairment. A state of anesthesia supervenes as dosage increases above the hypnotic range. The clinical manifestations include hypotension, hypoventilation, hypothermia, and cool and dry skin. Patients are often hyporeflexive, and, with larger doses, brainstem or cranial nerve dysfunction can occur. Pupillary responses, however, are still preserved, except in cases of extreme doses.

15  Drug-Induced Disturbances of Consciousness

tions. Pop singer Michael Jackson died from a combination of propofol and lorazepam administered at home. Propofol infusion syndrome is a life-threatening syndrome, which includes cardiac failure, severe metabolic acidosis, renal failure, and rhabdomyolysis.

Valproic Acid Several cases of coma due to therapeutic use of valproic acid in epilepsy as well as to its overdose have been reported in literature. Various explanations have been given for valproic acid-induced coma, and some of these are:

• Overdose is more likely to occur in bipolar disorder where higher doses are used. • Increased permeability of blood-brain barrier due to intracranial lesions such as glioblastoma multiforme may allow excessive amount Cephalosporins of valproic acid to enter the brain. Cephalosporins are an important cause of drug-­ • Polytherapy with antiepileptic drugs where induced adverse effects on the central nervous coma may result from drug interaction after system. An analysis of reports of serious adverse addition of valproic acid. reactions of cephalosporins in the French • Carnitine deficiency. Low serum carnitine levPharmacoVigilance Database from 1987 to 2017 els may predispose patients to impairment of revealed that 30.3% of these were encephalopaconsciousness when treated with valproic thies (Lacroix et al. 2019). acid. • Hyperammonemia has been reported in valPropofol proic acid-induced coma. This is an agent that may be used to purposefully induce coma as a sedating agent or for control of status epilepticus. Anesthesia is a reversible drug-­ Antipsychotic Medications induced coma and not a state of deep sleep. The These are commonly used to control agitation mechanisms underlying anesthesia-induced loss and psychosis, but significant side effects can of consciousness are not clearly defined. Loss of occur with high doses. Hypotension and proconsciousness is marked simultaneously by an longed QT syndrome are the most common carincrease in low-frequency EEG power ( motor, predominantly axo- are particularly likely to develop in older nal, large-fiber > small-fiber polyneuropathy. A patients who are cachectic and in patients who more severe demyelinating polyneuropathy may have received prior radiation to the peripheral develop in a subset of patients. nerves or concomitant hematopoietic colonystimulating factors. Patients with hereditary Vinca Alkaloids neuropathies may be at increased risk of develVincristine  This is a vinca alkaloid and is used oping peripheral ­ neuropathy on exposure to mainly as a chemotherapeutic agent for Hodgkin’s vincristine, and this has been demonstrated in disease. Vincristine neuropathy has been reported Charcot-Marie-Tooth disease type 1A.  Rarely, following its use. This neuropathy is painful and vincristine can cause a fulminant neuropathy is usually of mixed sensory and motor type, with with severe quadriparesis that mimics Guillainmarked depression of tendon reflexes but with Barré syndrome (Gonzalez Perez et  al. 2007). little objective sensory loss. However, motor Vincristine may also cause focal neuropathies. weakness is the most serious manifestation of Autonomic neuropathy is also common in this neuropathy. The manifestations are mostly patients receiving vincristine. reversible after discontinuation of vincristine and do not recur if the dose is reduced. Neurotoxicity Management  Patients with mild neuropathies has been found to be not troublesome in patients can receive full doses of vincristine, but when maintained on long-term vincristine neuropathy the neuropathies increase in severity and interwith dose not exceeding 12  mg in 18–24-week fere with neurological function, reduction in periods. Vincristine toxicity may be precipitated dose or discontinuation of the drug may be necby interaction with itraconazole used concomi- essary. The neurotoxicity is dose related and tantly as an antifungal prophylaxis. cumulative with repeated dosage such that the drug therapy has to be stopped after a cumulaClinical, electrophysiological, and tive dose of 30–50  mg. The neurotoxicity is pathological studies all indicate that the domi- usually reversible on interruption of the thernant neuromuscular lesion caused by vincristine apy, but the recovery is slow and takes several in humans is peripheral neuropathy. Predominant months. There are no specific antidotes which lesion seen on sural nerve biopsy of human have established usefulness against neurotoxicpatients is axonal degeneration, but in guinea ity. The following therapies are either used or in pigs, myopathic changes are more prominent development:

Pathomechanisms of Drug-Induced Neuropathies

• Glutamine: There are anecdotal reports that glutamine may help some patients with vincristine neuropathy. • Org 2766: In a randomized, double-blind, placebo-­controlled pilot study on patients with lymphoma who were treated with combination chemotherapy containing vincristine and vinblastine, sensory disturbances occurred more often in the placebo group than in the Org 2766-treated group (van Kooten et al. 1992). • IGF-1: This has been shown to prevent vincristine neuropathy in mice and has been tested in clinical trials for chemotherapy-­ induced peripheral neuropathy. Vinorelbine  The related vinca alkaloids vindesine, vinblastine, and vinorelbine tend to have less neurotoxicity. This may be related to differences in lipid solubility, plasma clearance, terminal half-life, and sensitivities of axoplasmic transport. Vinorelbine is a semisynthetic vinca alkaloid. There is a high incidence of dose-­ dependent vinorelbine neurotoxicity in patients who receive an intensified regimen of the agent for the treatment of advanced breast cancer. In one study, all patients who received intravenous vinorelbine 25 mg/week for 24 weeks developed a sensorimotor distal symmetrical axonal neuropathy which was moderate in most patients but severe in 33.3% (Pace et al. 1996). The drug was not discontinued in any patient because of neuropathy, and followup data after 6 months showed that neuropathy was partially reversible. Combination of vinorelbine with paclitaxel is not recommended as it produces severe neurotoxicity.

Monoclonal Antibodies Monoclonal antibodies (MAbs) are important biological therapies for cancer. The following are in clinical use or trials: • • • • • • •

Ado-trastuzumab emtansine Brentuximab vedotin Cetuximab Enfortumab vedotin Isatuximab Pertuzumab Polatuzumab vedotin

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Cetuximab  This MAb is an epidermal growth factor receptor inhibitor and is the first-line treatment of certain head and neck cancers and for colorectal cancers that display certain genetic biomarkers. Most treated patients also received conventional chemotherapy that included oxaliplatin or other platins; however, a slightly higher but not significant rate of sensory neuropathy was observed in cetuximab-treated patients. A neurotoxic link with this agent is not established, and neuropathy is not cited as a common form of toxicity. One phase III trial showed that less than 1% of patients treated with cetuximab (along with bevacizumab, leucovorin, and 5-FU) developed grade 3 neuropathy but did not address lesser grades (Saltz et al. 2012). Another study did demonstrate that advanced non-small cell lung cancer patients treated with paclitaxel and carboplatin concurrently with cetuximab had a higher rate of sensory neuropathy than those treated sequentially (Herbst et al. 2010). There are case reports of cetuximab leading to a chemotherapy-induced peripheral neuropathy-like illness responsive to IVIG (Beydoun and Shatzmiller 2010). Immune checkpoint inhibitors  Immune checkpoint inhibitors are successful examples of MAbs that enhance immune function designed to target cytotoxic lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) for various cancers, notably melanoma and small cell lung cancers. Ipilimumab, nivolumab, and pembrolizumab are examples that are associated with presumed inflammatory reactions including focal or generalized neuropathy; examples include focal phrenic, facial, optic, other cranial, and generalized acute or subacute neuropathy (Gu et al. 2017; Hottinger 2016). Peripheral and neuromuscular conditions appear to be more common than central nervous system toxicity. Most examples are individual case reports or retrospective series. A search of 3763 treated patients in a global pharmacovigilance database found 35 had induced neurological conditions including 22 neuropathy cases (Larkin et al. 2017). The cases of acute neuropathy mimicking Guillain-Barré syndrome show

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more common lymphocytes in spinal fluid and over half show axonal neuropathy (Gu et  al. 2017). One melanoma case report found difficulty distinguishing ipilimumab-induced chronic inflammatory demyelinating polyneuropathy (CIDP) from leptomeningeal tumor extension (Cafuir et al. 2018). A 65-year-old woman with unresectable metastatic melanoma developed a subacute Guillain-Barré-like neuropathy after two doses of pembrolizumab that repeatedly recurred in a CIDP-like pattern. Her melanoma initially responded but the treatment was interrupted. Her prolonged recovery led to melanoma progression while off therapy. A switch to ipilimumab produced melanoma regression but no neuropathy exacerbation (Muralikrishnan et  al. 2020). Another case initially starting acutely to suggest Acute Inflammatory Demyelinating Polyneuropathy but relapsing after 8 weeks supported a CIDP diagnosis triggered by ­ nivolumab (Tanaka et al. 2016). A retrospective review of 347 Mayo Clinic patients treated with PD-1 inhibitors found 10 (2.9%) developed some subacute neurological process after a median of 5.5 treatment cycles (range 1 to 20) (Kao et  al. 2017). Of the ten identified, four developed neuropathies.

28  Drug-Induced Peripheral Neuropathies

Hodgkin’s lymphoma patients, all of whom received initial brentuximab but not vincristine, found roughly one-third developed neuropathy, mostly grades I and II—all but 1 more severe grade III case is reported to resolve (Eichenauer et al. 2017). A case of severe motor neuropathy is reported (Pastorelli et al. 2013). Polatuzumab vedotin, a similar antibody drug conjugate that delivers the suspected neuropathic agent monomethyl auristatin E, is also associated with neuropathy. Rates are likely 55–72% of non-Hodgkin’s lymphoma patients (Lu et  al. 2017). A B-cell lymphoma trial found neuropathy is about 40% of patients as part of initial therapy (Tilly et al. 2019). However, the treatment in combination with bendamustine and rituximab appears to be superior to conventional chemotherapy (Amaya et al. 2020). Enfortumab vedotin, another antibody-drug conjugate approved for the treatment of metastatic urothelial cancer, delivers the microtubule-­ disrupting agent monomethyl auristatin E to cells that express nectin-4. A study of 125 patients previously treated with platinum chemotherapy and PD-1 inhibitors found about half developed additional neuropathy but the agent delivered a clinically meaningful response (Rosenberg et  al. 2020).

Other monoclonal antibodies  Numerous MAb-­ based chemotherapy drugs are approved or under study. Some may cause chemotherapy-induced A  ntimicrobial Agents peripheral neuropathy, but most patients had received prior chemotherapy, and it is difficult to A  ntiviral Nucleoside Analogs assess the role of MAbs. A number of these compounds inhibit viral reverse transcriptase activity and are used as anti-­ Brentuximab vedotin is approved for refrac- HIV-­1 drugs. Dideoxycytidine (ddC, zalcitabine), tory Hodgkin’s lymphoma. Neuropathy is a rec- dideoxyinosine (ddI), stavudine, and lamivudine ognized side effect, although many patients are accompanied by varying degrees of neurotoxreceived prior platin or vincristine treatments. A icity. Peripheral neuropathies caused by these study of T-cell leukemia patients found neuropa- drugs are like those of HIV-associated distal senthy in two-thirds of treated patients and only 4% sory neuropathy. This condition, which presents of cases on either methotrexate or bexarotene; with pain, numbness, burning, and/or dysesthesia however, the leukemia response was markedly initially in the feet, is often multifactorial in its better in the brentuximab group (Prince et  al. origin. In contrast to HIV-associated neuropathy 2017). Axonal neuropathy is attributed to a toxic which evolves over months, drug-induced neueffect of monomethyl auristatin E on axonal ropathy progresses over weeks. Approximately microtubules (Mariotto et  al. 2018). An open-­ 10% of patients receiving stavudine or zalcitabine label German study of 104 newly diagnosed and 1–2% of didanosine recipients may have to

Pathomechanisms of Drug-Induced Neuropathies

discontinue therapy with these agents due to neuropathy (Moyle and Sadler 1998). Drug withdrawal eventually leads to recovery, although it may be incomplete and peripheral neuropathy may continue to improve for several weeks after cessation of the offending drug. Zidovudine (formerly AZT) causes myopathy but not neuropathy, and neither ddC nor ddI causes myopathy. Long-term treatment with all antiviral nucleoside analogs produces mitochondrial toxicity. ddC and ddI decrease mitochondrial DNA (mtDNA), cause destruction of mitochondria, and increase lactate production in neuronal cell lines. Rabbits treated with ddC develop an axonopathy with abnormal Schwann cell mitochondria and decreased myelin mRNA in vivo. Risk factors for the development of peripheral neuropathy with antiviral nucleoside analogs are: • AIDS patients with preexisting neuropathy are at risk of exacerbation of neuropathic symptoms when treated with these agents which inhibit mitochondrial DNA polymerase in  vitro and cause mitochondrial changes in the peripheral nerves in animals. • Patients in the advanced stages of AIDS low CD4+ cell count ( activity has been proposed. Recovery usually follows discontinuation of therapy. Preventive measures are periodic visual acuity screening and questioning the patients regarding paresthesias during chloramphenicol treatment. The value of prophylactic vitamin B complex therapy is not proven.

Chloroquine It is an antimalarial agent which is also used in the treatment of some connective tissue and dermatological conditions such as lupus erythematosus. The main adverse effect is myopathy, but peripheral neuropathy has also been described. Sural nerve biopsies of these patients have shown segmental demyelination and involvement of Schwann cells. Estes et  al. (Estes et  al. 1987) reported both axonal neuropathy and segmental demyelination in a patient with chloroquine neuromyotoxicity. Curvilinear bodies noted in pericytes on electron microscopy were diagnostic of chloroquine neuropathy. Neuropathy improves after discontinuation of treatment in most of the cases. Dapsone This is used mainly in the treatment of leprosy and various other dermatological conditions. Motor neuropathy has been reported in patients taking high doses for conditions other than leprosy and in patients with leprosy where involvement of the peripheral nerves by the disease had been ruled out. The clinical picture of neuropathy caused by dapsone is usually that of progressive muscle weakness and wasting involving the distal muscles of the extremities. It typically occurs many years after drug use and new cases continue to be reported (Nguyen et al. 2016). Dapsone has a primary, if not exclusive, effect on soma and axons of motor neurons rather than on the Schwann cells and myelin. The drug has been detected autoradiographically in nerves of patients with leprosy. The pathomechanism of this phenomenon may be dose-related toxicity or an idiosyncratic reaction. Dapsone metabolism, like that of isoniazid, involves acetylation. Slow acetylators are more liable to develop this com-

28  Drug-Induced Peripheral Neuropathies

plication. Therefore, pretreatment screening of patients for slow acetylation may be helpful in determining those patients who are at increased risk for the development of neurotoxicity. Recovery from neuropathy is good but may take months to years.

Ethambutol This is used for the treatment of tuberculosis. Peripheral neuropathy has been reported in 3.8% of patients on this therapy. Sensory disturbances are more frequent in lower than upper limbs, muscular weakness is noted in about one-third, and visual changes (optic neuritis) are recognized in nearly one-half of the patients. The major pathological change is axonal degeneration, although occasionally segmental demyelination and some evidence of remyelination may be present. Accelerated ethambutol toxic peripheral neuropathy is reported in a patient with a mitofusin 2 mutation, the most common cause of axonal Charcot-Marie-Tooth disease. This patient developed accelerated weakness, vocal cord paralysis, and optic atrophy after receiving ethambutol (Fonkem et al. 2013). The neurotoxic effects are reversible in most patients after discontinuation of ethambutol. Fluoroquinolones Various antibiotics belonging to this category include norfloxacin, ciprofloxacin, and temafloxacin. Occasional cases of peripheral neuropathy have been reported in association with fluoroquinolones. Two cases of painful dysesthesias associated with ciprofloxacin treatment have been reported (Zehnder et  al. 1995). Paresthesia was the most common peripheral nerve disorder associated with fluoroquinolone treatment for bacterial infection in a survey conducted in Sweden (Hedenmalm and Spigset 1996). There is a paucity of literature about peripheral neuropathy due to fluoroquinolones. Despite the relatively sparse evidence of a link between fluoroquinolones and neuropathy, in 2013, the FDA announced the requirement of all makers of oral and intravenous fluoroquinolones to add the risk of the serious side effect of peripheral neuropathy. There is a clear link to drug initiation and neuropathic symptoms that often persist; however, the true

Pathomechanisms of Drug-Induced Neuropathies

incidence and neurological impact remains to be determined (Staff NP and Dyck 2019). Predisposing factors for peripheral nerve disorders in patients on fluoroquinolone therapy are: • • • •

Impaired renal function Diabetes mellitus Lymphatic malignancy Treatment with another drug known to cause neuropathy

Isoniazid Isoniazid (INH) is one of the most effective antituberculous drugs. INH polyneuropathy occurs in approximately 2% of patients receiving conventional doses (3–5 mg/kg), and its incidence increases with higher doses. Symptoms appear in about 6 months and are characterized by paresthesias, impaired sensation in distal part of the lower extremities, and weakness. The main pathological process is axonal degeneration affecting both myelinated and unmyelinated fibers, accompanied by prominent axonal regeneration. Mild sensory neuropathy may be accompanied by retrobulbar neuritis as in a case reported by Leppert and Waespe (1988). The following factors should be taken into consideration to explain the pathomechanism of INH neuropathy: • INH interferes with the metabolism of pyridoxine which is an essential cofactor in protein, carbohydrate, and fatty acid metabolism. Pyridoxine is also involved in the synthesis of sphingomyelin. Pyridoxine deficiency interferes with vitamin B6-dependent enzymes, and vitamin B6 deficiency may be the culprit. • Neurotoxicity might be a direct effect of INH since this compound can easily penetrate a nerve as only 40% of it is protein bound. • Patients who are rapid acetylators seldom develop neuropathy whereas slow acetylators do as they maintain higher blood levels of free INH for a longer time. • Patients with low zinc level are at special risk for developing neurotoxicity from INH. • Immune mechanisms initiated by the tubercle bacillus rather than INH may be the culprit.

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After absorption, INH is acetylated in the liver by acetyl transferase (an enzyme). INH neuropathy can be prevented by use of pyridoxine (vitamin B6, 10–100  mg daily). Sensory and motor neuropathy has been reported in a patient on high-­dose isoniazid (5 mg/kg/day) without pyridoxine supplements, which partially improved after pyridoxine supplement despite isoniazid continuation (Arsalan and Sabzwari 2015).

Mefloquine This is used for chemoprophylaxis of malaria. Only one case of paresthesias and painful dysesthesias associated with mefloquine has been reported in literature (Olson et  al. 1992). The patient recovered after discontinuation of mefloquine. Nerve conduction studies were unremarkable. There are several spontaneous ­ reports of paresthesias associated with this drug in the safety database of the manufacturer (Hoffmann-La Roche, Basel), and in some of these cases, there was mixed sensory and motor peripheral neuropathy. EMG and/or nerve biopsy showed axonal degeneration in cases where the causal relation to the drug was considered possible. There was partial improvement of the symptoms in these cases after discontinuation of the drug. On this basis, mefloquine should be added to the list of drugs which can induce peripheral neuropathy. Linezolid Linezolid is a synthetic oxazolidinone antibiotic used against methicillin-resistant and vancomycin-­resistant gram-positive microorganisms and increasingly against multidrug-resistant tuberculosis. It binds to the 50S ribosomal subunit and prevents the formation of the initiation complex required to translate mRNA into protein. Linezolid was reclassified as a Group A drug in 2019 by the World Health Organization for the treatment of multidrug-resistant tuberculosis. Linezolid can cause a predominantly sensory axonal neuropathy and neuronopathy when used for months and at a high dose. Vibration and proprioception senses are severely affected. Chronic use is associated with a painful, predominantly sensory polyneuropathy, optic neuropathy, and

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deafness. The mechanism of nerve injury is unknown but may involve impairment of mitochondrial protein synthesis. Treatment consists of symptomatic measures and discontinuation of the drug or decrease of the dose. Prolonged linezolid treatment induced a mild, predominantly small sensory fiber neuropathy in mice (Bobylev et  al. 2016). Linezolid exposure caused mitochondrial dysfunction primarily in cultured sensory neurons and less prominently in Schwann cells. Sensory axonopathy could be partially prevented by co-administration of KB-R7943, a Na(+)/Ca(2+) exchanger blocker.

28  Drug-Induced Peripheral Neuropathies

effect. Renal failure is a major risk factor for the development of this toxic neuropathy, and toxic levels of nitrofurantoin have been reported in patients with renal insufficiency who develop symptoms of a sensorimotor neuropathy during the course of treatment. Nitrofurantoin can unmask peripheral neuropathy in type 2 diabetic patients. Initial symptoms are distal paresthesias and sensory loss. Weakness which invariably follows sensory loss may be pronounced and resemble that of Guillain-Barré syndrome. A slight decrease in nerve conduction velocity and electrophysiological evidence of denervation has been found in a proportion of treated subjects Metronidazole without symptoms. It is an antiprotozoal and broad-spectrum antiHistological studies show axonal degenerabacterial agent used widely for the treatment of tion with alterations in dorsal root ganglia and amebiasis, Trichomonas vaginalis, and Crohn’s chromolytic changes in anterior horn cells. The disease. A predominantly sensory type of neu- presumed pathomechanism is dose-dependent ropathy has been reported in patients treated with depletion of glutathione due to conjugation of metronidazole for several months. Electron drug metabolites with glutathione. Patients with microscopy shows axonal degeneration of both glutathione synthetase deficiency are more susthe myelinated and unmyelinated fibers. The ceptible to nitrofurantoin toxicity. Morphological symptoms usually improve 4 weeks after finish- changes, such as clustered terminal nerve swelling the medication. Most of the cases reported ings, in skin biopsy samples have supported the received more than 1.5 g/day of metronidazole diagnosis of two cases of clinical nitrofurantoin-­ for more than a month. induced neuropathy despite normal sensory and The incident of metronidazole-induced neu- motor nerve conduction studies (Tan et al. 2012). ropathy is not known, but up to 50% of the patients Prevention of nitrofurantoin-induced neuropamay have evidence of peripheral nerve dysfunc- thy is likely best accomplished by awareness of tion. A proposed mechanism of metronidazole-­ this complication and avoidance of nitrofurantoin induced peripheral neuropathy is metronidazole in patients with renal insufficiency. The drug binding to RNA in nerve cells which has been should be discontinued at the onset of symptoms documented in rats. Binding of neuronal RNA such as numbness and tingling. may inhibit neuronal protein synthesis, resulting in peripheral axonal degeneration. Metronidazole- Podophyllum Resin induced neuropathy is generally reversible, Podophyllum resins are used as topical solutions although the recovery may take up to 2 years. for the treatment of genital condyloma acumiA meta-analysis of published reports con- nata, and several derivatives are used as antineocluded that peripheral neuropathy was rare if plastic agents and carry similar risks of dose was kept below 42 g total and duration less neurotoxicity as vincristine and etoposide. than 4 weeks (Goolsby et  al. 2018). However, Neurotoxicity may occur after absorption from cases starting very soon after drug initiation are local application, and an axonal sensorimotor reported (Oaku et al. 2020). neuropathy occurs in combination with encephalopathy. Multiorgan failure may occur. The neuropathy may progress for several months after Nitrofurantoin This is a broad-spectrum antimicrobial agent used cessation of application of the drug, and improvefor urinary tract infections and has no systemic ment may take months.

Pathomechanisms of Drug-Induced Neuropathies

Prevention is by avoiding application over ulcerated or bleeding areas. Immediate treatment includes local irrigation to remove the residual drug and supportive medical treatment.

Sulfonamides The older sulfonamides were neurotoxic, but the newer compounds have a low rate of adverse reactions which seldom involve the nervous system. Occasional cases of peripheral neuropathy have been reported in association with trimethoprim-sulfamethoxazole.

Cardiovascular Drugs Antiarrhythmic drugs are particularly associated with peripheral neuropathy. In one study, electrophysiological investigations revealed polyneuropathy in 25% of the patients who had been taking antiarrhythmic agents for 6 months to 10 years (Beghi 1994). However, clinical manifestations of polyneuropathy were present in only 3% of the patients. The incidence was similar with various agents which included amiodarone, propafenone, atenolol, verapamil, mexiletine, and flecainide, singly or in combination. In comparison, only 18% of the patients with cardiovascular disorders not treated with antiarrhythmic drugs had electrophysiological polyneuropathy.

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zymes and bind irreversibly to polar lipids. There is accumulation of lipids within lysozymes in neural tissues including peripheral nerves. Storage of amiodarone in muscle cells results in a proximal myopathy, storage in Schwann cells results in a secondary neuropathy, and storage in Purkinje cells may be responsible for cerebellar gait disorders. Therefore, these authors term the clinical picture neurotoxic amiodarone syndrome rather than amiodarone neuropathy. Hydralazine  This is an antihypertensive drug which may produce sensory neuropathy in 15% of the patients. The usual manifestations are paresthesias without clinical signs. Axonal ­ degeneration has been described in some patients. Slow acetylators are more likely to develop this complication. Pathomechanism may be based on pyridoxine deficiency as hydralazine is structurally related to isoniazid. Symptoms usually improve after withdrawal of the drug or vitamin B6> replacement.

Perhexiline  This is an antianginal agent. Painful neuropathy is commonly seen in patients treated with 300–400  mg/day for 4  months to 1 year (Bousser et  al. 1976). In 15% of the patients on perhexiline, the initial complaints are painful paresthesias; muscle weakness, loss of tendon reflexes, and ataxia may develop later (Wijesekera et  al. 1980). Autonomic abnorAmiodarone  This drug is used in the treatment malities (postural hypotension) have also been of cardiac arrhythmias. Sensorimotor neuropathy described. Sensory symptoms occur in nearly all is a common finding in patients on this therapy. the cases. Most of the adverse effects are reversThis complication has been reported in approxi- ible, but the recovery may be prolonged and mately 6% of patients treated for several months incomplete. with amiodarone. There are symmetrical sensory There is marked reduction of conduction impairment, absent tendon reflexes, and sensory velocity of peripheral nerves in these patients ataxia. Muscle wasting and weakness may occur suggesting segmental demyelination. This has progressing to quadriplegia. Severe forms of this been confirmed by a clinicopathological studies. neuropathy may not improve after discontinua- Electron microscopy showed lipid inclusions in tion of the drug. many structures including Schwann cells. The explanation for this is that perhexiline, like amioThere is segmental demyelination, and sural darone, is a lipophilic drug capable of penetrating nerve biopsies show characteristic amiodarone-­ lysozymes. induced lamellated inclusion in many cell types. Perhexiline neuropathy is induced by excesPathomechanism is based on lipophilic proper- sive drug levels either due to slow metabolism or ties of this drug and its capacity to penetrate lyso- an overdose or renal or hepatic insufficiency.

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Susceptibility to the adverse effects of this drug is probably genetically determined depending on its oxidation rate. Patients who develop perhexiline neuropathy have also impaired oxidation of debrisoquine, suggesting that patients at risk of developing neuropathy can be identified by a test dose (10 mg) of debrisoquine and estimating the ratio of the drug to its metabolite in urine. Miscellaneous cardiovascular drugs  Peripheral neuropathy has been reported in patients using enalapril, captopril, and flecainide. The underlying cardiovascular disease plays some role in the development of peripheral neuropathy. Up to 25% of the cardiac patients, regardless of the antiarrhythmic used, develop peripheral neuropathies. Most of these patients are asymptomatic and are discovered to have electrophysiological abnormalities. For comparison, 18% of cardiac patients who are not on treatment with antiarrhythmic drugs also have evidence of peripheral nerve dysfunction.

Central Nervous System (CNS) Drugs Amitriptyline  This is a tricyclic antidepressant which is commonly used for the treatment of painful neuropathies. It has been associated with several cases of sensorimotor neuropathy with axonal degeneration, mainly in the elderly patients and those on high doses for long terms. Acute polyneuropathy has also been reported after amitriptyline overdose. Paresthesias were relieved by use of pyridoxine in some cases, leading to the speculation that these patients belong to a subgroup of individuals who rapidly metabolize amitriptyline to the primary amine desmethylnortriptyline, which would then bind with the aldehyde moiety pyridoxal phosphate to cause pyridoxine deficiency. Protriptyline which is similar in structure and metabolism has also been reported to be associated with a similar type of peripheral neuropathy.

Antiepileptic Drugs Phenytoin is a widely used anticonvulsant drug and can cause an asymptomatic neuropathy

28  Drug-Induced Peripheral Neuropathies

which rarely becomes symptomatic. The manifestations are distal sensory loss, lower limb areflexia, and mildly reduced conduction velocities of peripheral nerves. One mechanism of phenytoin-­ induced neurotoxicity is glutathione depletion which has been demonstrated in the rat peripheral nerve (Raya et al. 1995). Lower limb areflexia is reported after at least 5 years of phenytoin therapy rising to 50% after more than 15 years. Axonal shrinkage with secondary demyelination but without loss of nerve fibers has been reported on sural nerve biopsy of a patient with moderately severe neuropathy after 30 years of phenytoin use and high blood levels of the drug (Ramirez et  al. 1986). There was clinical improvement after discontinuation of the drug. The use of carbamazepine, primidone, and phenobarbital in epileptic patients has also been shown to be associated with sensory neuropathy. More than 50% of patients treated with one or more antiepileptic drugs show either symptoms of neuropathy or electrophysiological abnormalities. One case of a newer antiepileptic gabapentin has been reported in a patient where this drug was being used for relief of head pain (Gould 1998).

Chlorprothixene This is a neuroleptic used in psychiatry. There are several reports of polyneuropathy as an adverse reaction to high doses of this drug (500 mg/day). The initial symptoms are sensory: numbness or pain in limbs and motor weakness develops later. Symptoms clear up gradually in several months after discontinuation of the drug. Electromyographic studies are consistent with axonal neuropathy. Chlorprothixene has been shown to block axonal transport in animal studies. It inhibits the action of calmodulin, a calcium-­ binding protein, which is widely distributed in the nervous tissue. Gangliosides These substances have a role in promoting nerve repair in mammalian cells by increasing collateral sprouting. Gangliosides have been used for the treatment of peripheral neuropathies. One case of motor neuropathy with multifocal con-

Pathomechanisms of Drug-Induced Neuropathies

duction blocks has been reported following ganglioside therapy (Garcia-Monco et  al. 1992). Several cases of acute motor polyneuropathy have been reported from Spain (Figueras et  al. 1992). Other cases of demyelinating polyradiculoneuritis (Guillain-Barré syndrome) have been reported following ganglioside treatment (see Chap. 37). Antibodies against asialo-GM1 ganglioside are present in CSF, suggesting that this may be an immune-mediated neuropathy. Antibodies to GM1 ganglioside are found in some patients with the Guillain-Barré syndrome and multifocal motor neuropathy and may alter neuronal excitability.

Lithium Lithium carbonate is used for acute mania and to reduce the severity of manic-depressive episodes. CNS intoxication by lithium is well known, but peripheral neuropathy is rare. This is a sensorimotor neuropathy with predominance of motor symptoms and signs. Paresthesia but not pain is a frequent complaint. The signs and symptoms of lithium-induced neuropathy are not usually recognized until the acute CNS disorder has resolved. Recovery begins after drug withdrawal but may not be complete. Sural nerve biopsies show axonal degeneration and loss of myelinated fibers. Diminution of the caliber of axons and nerve fibers has been shown in sural nerves of rats with raised serum levels of lithium. The pathomechanism of lithium neuropathy is not known. Electromyographic abnormalities are noted in asymptomatic patients on therapeutic doses of lithium, and overdose is not the only factor for development of neuropathy. A study comparing lithium-treated with nonlithium-treated patients suggested that lithium, if used within therapeutic levels, is just one among many factors which contribute to proximal neuropathy in psychiatric patients. Lithium-induced neuropathy may be prevented by frequent monitoring of lithium levels particularly in patients with renal dysfunction or preexisting neuropathy. Hemodialysis may lower serum lithium levels in case of intoxication but does not immediately lower tissue lithium levels.

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There is no evidence that hemodialysis improves the peripheral nerve function.

Nitrous Oxide Nitrous oxide intoxication occurs in individuals either through contamination of the operating room or by recreational use of this gas. Anesthetists and dentists are at risk of exposure to this. Chronic repeated exposure produces a predominantly sensory polyneuropathy with radicular, rather than distal, distribution of numbness. This is an axonal rather than a demyelinating neuropathy. Potential of nitrous oxide to inactivate vitamin B12 and resemblance to subacute combined degeneration of the spinal cord suggests B12 deficiency as a pathogenetic factor. Phenelzine This is an antidepressant of monoamine oxidase inhibitor type. Two patients with generalized sensorimotor neuropathy and a clear relationship to phenelzine have been reported (Goodheart et al. 1991). The electrophysiological abnormalities in these cases were consistent with axonal neuropathy, and both patients recovered after discontinuation of the drug. Pyridoxine deficiency is associated with long-term phenelzine therapy. Since phenelzine, like hydralazine and isoniazid, is a hydrazine capable of reducing pyridoxine levels in the rat, it is possible that phenelzine, like hydralazine and isoniazid, may cause a pyridoxine-­responsive peripheral neuropathy in humans. Thalidomide This was introduced as a sedative-hypnotic drug in 1955, but its use ended in disastrous embropathic effect, leading to its withdrawal in 1961. Less known is the fact that this drug caused an “epidemic” of peripheral neuropathy in Europe in 1960 and 1961. This drug is presumed to have an anti-inflammatory effect and continues to be used for several inflammatory and dermatological conditions. It has been found to be useful in controlling erythema nodosum leprosum. Thalidomide neuropathy has not been reported in patients with leprosy who invariably have neuritis due to the basic disease.

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In earlier cases, the neuropathy was reported in 0.5% of the cases, and the initial symptoms were sensory with motor weakness occurring later affecting proximal more than the distal muscles (Fullerton and Kremer 1961). Follow-up of these cases for 4–6 years showed a poor recovery from sensory symptoms; 25% recovered fully, 25% partially, and 50% remained unchanged (Fullerton and O’Sullivan 1968). After reintroduction of this drug, the frequency of polyneuropathy has been found to be 25% or higher (Heney et al. 1991; Knop et al. 1983; Wulff et al. 1985). In a prospective clinical and electromyographic survey in 29 patients treated with thalidomide, neuropathy appeared in 11 patients and a decrease of 50% of the amplitude of sensory action potential seemed to be predictive (Colamarino et  al. 1992). Some of the patients who receive thalidomide for various dermatological conditions develop neuropathy and recover incompletely after thalidomide withdrawal. The mean duration of symptoms before the initial appearance of symptoms ranges from 1 to 24 months. Electrophysiological monitoring of patients on thalidomide therapy is recommended, and the drug should be stopped at an early stage of peripheral nerve involvement to offer the best chances for recovery. The pathology is axonal degeneration and degenerative changes in the posterior columns of the spinal cord. The predominant effect is on large fibers. The pathomechanism of thalidomide toxicity is not well understood. One hypothesis is that the product of thalidomide hydrolysis inhibits glutamic acid-metabolizing enzymes involved in protein synthesis in the peripheral nervous system. Serum samples of patients with thalidomide neuropathy have been shown to produce morphological changes in cultured dorsal root ganglion cells. These observed changes support the postulate that thalidomide induces primary neuronal degeneration. Prospective clinical and electrophysiological follow-up on patients under thalidomide treatment to detect the earliest possible drug-induced peripheral neuropathy has not revealed any single reliable neurophysiological parameter for detection of thalidomide-induced neuropathy.

28  Drug-Induced Peripheral Neuropathies

Pharmacogenetic classification with regard to hydroxylation and acetylation phenotypes shows a possible relationship between slow acetylators and development of thalidomide-induced neuropathy.

Miscellaneous Drugs Allopurinol  This drug is widely used for the treatment of hyperuricemia in gout. Cases of allopurinol-induced peripheral neuropathies have been reported following long-term use of the drug. The symptoms and signs regress after withdrawal of the drug. This neuropathy is usually of sensorimotor type, and sural nerve biopsy shows a demyelinating neuropathy and to a lesser extent axonal degeneration. Pathomechanism is unknown.

Almitrine  This is a peripheral chemoreceptor agonist used in the treatment of chronic obstructive pulmonary disease (COPD) to improve the arterial blood oxygenation. Painful neuropathy may appear 2 months to 2 years after the start of therapy. The onset is insidious, beginning with symmetrical glove and stocking sensory loss in legs, and loss of tendon reflexes. Patients begin to improve 3–6 months after withdrawal of the drug. Recovery is usually complete within 12 months. The precise prevalence of this adverse effect is not known, but more than 150 cases of peripheral neuropathy have been reported in association with this drug since 1985. Symptoms of peripheral neuropathy due to hypoxia are common in patients with COPD and complicate the assessment of cases treated with almitrine. A double-­blind prospective study of the effect of almitrine versus placebo was carried out on 12 patients with COPD who were free from peripheral neuropathy before the start of the study (Allen and Prowse 1989). None of the seven patients on placebo developed any signs or symptoms of peripheral neuropathy. Three of the five patients who received almitrine developed peripheral neuropathy during the 12  months of

Pathomechanisms of Drug-Induced Neuropathies

study and a fourth who continued to receive almitrine developed neuropathy at 18 months. Sural nerve biopsy specimens show that the pathology is mainly axonal degeneration affecting mostly large myelinated fibers. Regeneration is prominent during recovery. The pathomechanism is poorly understood. The drug is lipophilic, diffuses widely through the tissues, undergoes extensive hepatic metabolism, and is excreted in bile. The drug has been detected in plasma up to 20 weeks after discontinuation of therapy, indicating that the drug is slowly released from peripheral sites. It is conceivable that delayed detoxification in certain individuals can produce neurotoxicity. Oxidative phenotyping was performed in patients with almitrine neuropathy using dextromethorphan, a test compound subject to oxidative metabolism like debrisoquine (Belec et al. 1989). Results showed that susceptibility to develop almitrine neuropathy, in contrast to perhexiline neuropathy, is not related to a poor metabolizer phenotype.

Anticoagulants Femoral neuropathy due to hemorrhagic complication of anticoagulant therapy is well known, and over 50 cases have been reported in literature. These patients suffered a typical femoral neuropathy with severe pain in the hip region aggravated by extension, sensory disturbances in cutaneous innervation zone of the femoral nerve, quadriceps paresis, and loss of patellar reflex. Pathomechanism is compression-hypoxia of the femoral nerve behind the inguinal ligament by a hematoma beneath the tight non-distensible iliac fascia. This hematoma can be detected by computer tomography of the inguinal region. Recommended treatment of this complication is as follows: • Discontinue anticoagulant therapy and take measures to stop the bleeding, e.g., protamine. • Immobilize the patient for a few days with hip flexed and externally rotated to reduce nerve compression. • Surgical decompression may be considered if there is no response to conservative treatment.

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• Physical therapy should be starting after several days when the patient is ambulatory to facilitate the absorption of the hematoma and for the rehabilitation of the muscles.

Arsenic The most frequent neurological complication of inorganic arsenic poisoning is distal symmetrical polyneuropathy which may appear acutely after ingestion of a massive dose or may develop insidiously after chronic environmental or industrial exposure. Arsenic is a constituent of some unconventional drugs and history of ingestion of such drugs should be elicited during investigation of a patient with peripheral neuropathy. It is usually a chronic poisoning, but acute and subacute forms of presentation are also documented. A case of chronic arsenic intoxication associated with macrocytosis and neuropathy, without anemia, has been reported (Heaven et al. 1994). Removal of the source of exposure resulted in resolution of macrocytosis and slight improvement of neuropathy. This case emphasizes that arsenic intoxication should be considered in patients with macrocytosis with peripheral neuropathy, even in the absence of anemia. Diagnosis  Arsenic neuropathy is usually symmetrical with involvement of both sensory and motor fibers. Clinical presentation may resemble Guillain-Barré syndrome or muscular dystrophy. Electrophysiological studies show a delay in sensory conduction velocity along with reduction of the amplitude of evoked potentials. The pathology is axonal degeneration with involvement of large myelinated fibers, although segmental demyelination has also been described. There are no specific clinical features, and laboratory analysis is required for confirmation of arsenic poisoning. The human biological samples of choice are urine and hair. Various methods of arsenic analysis done in specialized laboratories are:

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• Neutron activation analysis. This is the most sensitive method but is not easily available. • Determination of total arsenic in biological matrices using atomic absorption spectrometry. • Regular flame absorption spectrophotometry is not useful as the air-acetylene flame interferes with the sensitive resonance lines for arsenic. • Analysis of arsenic metabolites. • The presence of arsenic within myelinated fibers has been documented by laser microprobe mass analysis. Treatment  Chelation therapy with dimercaprol (British anti-lewisite, BAL) in the treatment of severe arsenic neuropathy is associated with increased urinary elimination of arsenic and dramatic clinical recovery, but it is considerably toxic and increases the arsenic content of the brain, possibly by forming a lipophilic complex which readily passes the blood-brain barrier. Dimercaptosuccinic acid (DMSA) is the antidote of choice in the treatment of arsenic poisoning. Glial-cell-derived neurotrophic factor appears to be protective against arsenite-induced peripheral neuropathy in experimental studies (Chou et  al. 2008).

Botulinum Toxin Brachial plexus neuropathy has been reported following botulinum toxin injection for the treatment of cervical or upper extremity dystonia. In addition to these, several other reports are filed with the manufacturer—Allergan Pharmaceuticals Inc. Considering the extensive worldwide use of therapeutic botulinum toxin A injection, the incidence is considered to be rare. The mechanism of brachial plexopathy is not clear. An immune-mediated mechanism is suspected. The manifestation can be radiating pain or painless weakness of the upper extremity and may occur on the side of the injection or on the opposite side. Weakness and EMG abnormalities are usually confined to C5 and C6 nerve root distribution. The onset is usually within a few weeks, and recovery takes place with a few months. Readministration of botulinum toxin has not been associated with recurrence of brachial plexopathy, but unexplained pain in the shoulder

28  Drug-Induced Peripheral Neuropathies

region after an injection of botulinum toxin contraindicates a second injection. Botulinum toxin type A (BTX-A) has been reported to have analgesic effects independent of its action on muscle tone and has been used for the treatment of peripheral neuropathic pain.

Cholesterol-Lowering Agents The most used cholesterol-lowering agents act by inhibiting hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. The drugs in this category include simvastatin, lovastatin, and pravastatin. There are isolated case reports of sensory neuropathy with lovastatin. Simvastatin has also been associated with peripheral neuropathy in several cases. The electrophysiological and pathological features of the neuropathy were those of axonal degeneration. Most of these recovered after cessation of therapy, and in a few cases, there was recurrence of symptoms after re-­ exposure to the drug. Possible mechanism by which cholesterol-­ lowering agents could damage peripheral nerves is interference with cholesterol which is an essential component of human cell membranes. Inhibition of cholesterol synthesis can reduce axon transport which is an early indicator of neurite degeneration. Simvastatin not only blocks the synthesis of cholesterol but also that of dolichol and ubiquinone which is a key enzyme in the mitochondrial respiratory chain. Intracellular deficiency of ubiquinone disturbs energy utilization of the neuron. Mitochondrial abnormalities have been reported in the muscle biopsies of patients treated with simvastatin who develop myopathy (see Chap. 31) which improves following administration of ubiquinone. Peripheral neuropathy can rarely be induced and exacerbated by several commonly used HMG-CoA reductase inhibitors including lovastatin, simvastatin, pravastatin, and atorvastatin, and the vitamin niacin. Several cases of reversible peripheral neuropathy, apparently caused by statins, have been reported. The neuropathy in all cases was axonal with involvement of both thick and thin nerve fibers. The symptoms of neuropathy persisted in some cases during an observation period lasting

Pathomechanisms of Drug-Induced Neuropathies

up to a year after statin treatment had been withdrawn. There are isolated case reports of sensory neuropathy with bezafibrates which are also used for lowering cholesterol. Motor neuropathy has been reported with clofibrate, and cases of paresthesias have been reported to various health authorities around the world including the World Health Organization. The documentation of these cases is insufficient for adequate assessment. Ellis et al. (1994) reported a case of peripheral neuropathy with bezafibrate which was substantiated by nerve conduction studies suggesting a sensory neuropathy of axonal type. The symptoms resolved on discontinuation of bezafibrate.

Cimetidine Peripheral neuropathy has been reported following cimetidine—a histamine H2-receptor antagonist used for the prophylaxis and treatment of gastroduodenal ulcers. A rapidly developing pure motor neuropathy characterized by severe weakness, areflexia, and muscle atrophy has been reported within days after initiation of therapy (Walls et al. 1980). Pouget et al. (1986) reported a case of peripheral neuropathy with pain and symmetrical motor neuropathy, predominant distally and in the lower limbs, 4 days after beginning cimetidine therapy. Motor function began to recover with a week after discontinuation of the drug, and recovery was complete within 5 months. Electrophysiological studies showed an axonal neuropathy and morphometric studies revealed loss of large myelinated fibers in some fascicles while other fascicles were normal. Microvasculitis was present in the epineurium. Small-vessel immune-complex vasculitis plays a role in the pathogenesis of cimetidine-­ induced peripheral neuropathy. Neuropathy improves within several weeks after discontinuation of the drug. Colchicine Colchicine has been used for the treatment of gout for over 200 years, but neuromuscular toxicity has been recognized less than 25 years ago. The main adverse effect is a myopathy, but peripheral neuropathy is occasionally associated. This is a sensorimotor neuropathy with axonal

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degeneration, particularly of the large fibers as seen in sural nerve biopsy specimens. Colchicine toxicity occurs in patients who have elevated drug levels because of mild renal insufficiency. The pathomechanism is based on colchicine binding to tubulin in the same way as vinblastine and has been used experimentally to block axon transport.

Dichloroacetate Peripheral neuropathy is common with chronic dichloroacetate treatment, which is used experimentally to treat lactic acidemia resulting from mitochondrial diseases. Clinical and electrophysiological signs of sensorimotor neuropathy are found. The neuropathy is significant but can be reversible over months if the drug is stopped. The neurotoxic mechanism is not fully known. The heme precursor delta-aminolevulinate is implicated in neurological complications associated with porphyria and tyrosinemia type I. The compound is elevated in the urine of animals and humans on dichloroacetate and appears to damage Schwann cells in part by reducing the levels of myelin-associated lipids and proteins. It is currently unclear but suspected that patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) may be at increased risk of developing the toxic neuropathy. The drug is also under investigation in the treatment of glioblastoma. Dichloroacetate may help minimize treatment resistance mediated by changes in mitochondria that reduce cancer cell apoptosis in part by a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. However, studies in humans have been limited by dose-dependent peripheral neuropathy (Michelakis et al. 2010). Dichloroacetate has the interesting property of inhibiting its own metabolism on repeat dosing, resulting in alteration of its pharmacokinetics. This dichloroacetate effect on its own metabolism complicates the selection of an effective dose with minimal side effects (James et al. 2017). Disulfiram Disulfiram (Antabuse) has been in use for the treatment of alcoholism since 1947 and occasionally

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produces peripheral neuropathy, which should be distinguished from alcoholic neuropathy. A systematic review of adverse reactions to disulfiram in Denmark indicates that neuropathy is a frequent complication (Enghusen Poulsen et al. 1992). The incidence is dose related, and most patients receiving more than 500 mg/day develop nerve damage after 6 months. Disulfamine-induced peripheral neuropathy does not occur below a dose of 250 mg/day. The initial symptoms are sensory, but muscle weakness, more marked proximally, may occur if the drug is continued. Optic neuritis and encephalopathy are other manifestations of neurotoxicity of disulfiram but not necessarily in patients who develop neuropathy. Improvement takes place over a period of months after the drug is discontinued. However, there are instances of severe motor deficits of disulfiram neuropathy where the patients did not recover. Characteristics of disulfiram neuropathy are: • Disulfiram neuropathy is a dose-dependent phenomenon. • Recovery depends primarily on the initial degree of impairment. • Chloral hydrate as a comedication can potentiate disulfiram-induced neuropathy, and concomitant use with disulfiram should be avoided. Nerve conduction velocity may be slightly reduced suggesting primary axonal pathology. Axonal degeneration is the usual finding in sural nerve biopsies. In some cases, electron microscopy examination reveals axons distended by neurofilaments. The pathomechanism involves carbon disulfide, a neurotoxin produced during metabolism of disulfiram. Axonal swelling and accumulation of neurofilaments like that in disulfiram neuropathy has been induced in experimental animals treated with carbon disulfide. Carbon disulfide causes neuropathy by reacting with amino groups to form dithiocarbonates which also chelate with the trace metals of enzyme systems, particularly affecting glycolytic processes.

Etretinate This is a retinoid used for the treatment of psoriasis. Peripheral neuropathy has been reported after

28  Drug-Induced Peripheral Neuropathies

long-term use of the drug. This is a sensory neuropathy, and proximal axons or dorsal root ganglia are probable target sites. Reversal of ­ signs and symptoms after discontinuation of the drug favors a toxic rather than an idiopathic or disease-­related sensory neuropathy.

Gold Gold, usually in the form of sodium aurothiomalate, has been in use for the treatment of rheumatoid arthritis since 1927. There are systemic toxic effects, but peripheral neuropathy is rare—4 patients (0.5%) among 900 patients (Hartfall et al. 1937). Encephalopathy and cranial as well as peripheral neuropathies have been described. Koh and Boey (1992) reported a patient with rheumatoid arthritis who developed rapid onset of a sensorimotor neuropathy while on treatment with intramuscular gold (sodium aurothiomalate). The patient’s condition improved after cessation of gold therapy. Polyneuropathy resembling Guillain-Barré syndrome develops in some patients (see Chap. 22). Rarely, a dose-related distal sensorimotor neuropathy may develop. Sural nerve biopsies have shown a mixture of axonal degeneration and segmental demyelination in these patients. Myokymia and autonomic dysfunction may occur in these patients. Improvement generally occurs after the drug is discontinued. Drug-induced neuropathies need to be distinguished from varied manifestations of rheumatoid neuropathies. The pathomechanism of gold neuropathy is presumed to be a dose-dependent direct toxic effect as both axonal degeneration and segmental demyelination have been produced in nerves of hens with aurothiomalate. In case of Guillain-Barré syndrome, neuropathy is immune-mediated. Interferons Interferons are glycoproteins secreted in the body in response to viral infections and are presumed to confer protection on other cells against viral infection. Two types of interferons have been identified: type 1 (interferon alpha and interferon beta) and type 2 (interferon gamma). Interferon

Pathomechanisms of Drug-Induced Neuropathies

alpha has been developed mostly for applications in virology and oncology. Interferon beta-1b is approved for the treatment of multiple sclerosis. Peripheral neuropathy is a rare neurological side effect of interferon. Cases of axonal neuropathy have been reported during treatment with interferon alpha-2a in patients with chronic leukemia and chronic hepatitis C.  In a case of peripheral neuropathy which developed during treatment with interferon alpha for chronic hepatitis C, the onset was insidious, beginning symmetrically in the hands with paresthesia (Quattrini et  al. 1997). Neurophysiological investigation revealed a predominantly sensory axonal neuropathy. A sural nerve biopsy confirmed primary axonal damage. Immunofluorescence studies showed increased expression of HLA-DR molecules prevalently on Schwann cells of non-myelin-forming type. Interferon alpha-2b treatment may exacerbate a preexisting neuropathy. La Civita et al. (1996) have described a hepatitis B virus (HBV)-positive patient with mixed cryoglobulinemia with recurrent purpura, mild sensory peripheral neuropathy, and active hepatitis who was treated with interferon alpha-2b. Rapid improvement of the purpura, liver enzymes, and cryocrit and disappearance of serum HBV DNA were observed after 4 weeks of treatment. However, concomitant aggravation of the neuropathy required discontinuation of interferon therapy.

Interleukin-2 Interleukin-2 (IL-2) is an immunomodulating cytokine used in the treatment of renal cell carcinoma, melanoma, and other malignant conditions. Neurological adverse effects mainly involve the CNS and include encephalopathy and cerebral edema. Two cases of brachial plexopathy have been reported by Loh et al. (1992) which presented during treatment of cancer patients by IL-2 and where other causes such as invasion by tumor metastases were ruled out. These patients recovered completely after discontinuation of therapy. Electrophysiological examination showed active degeneration, indicating some axon loss. Rapid and complete recovery, however, suggests a demyelinating element. The

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pathomechanism is postulated to be focal immune-mediated demyelination. Carpal tunnel syndrome has also been associated with IL-2 and is considered to result from increased vascular permeability and soft tissue edema which leads to compression of the median nerve at the wrist. This usually resolves after conclusion of IL-2 treatment and resolution of limb edema.

Lidocaine Subarachnoid lidocaine has been used for anesthesia, and peripheral nerve root involvement resulting in persistent peripheral neuropathy has been linked to it. Transient peripheral nerve disturbances have been recorded following subarachnoid anesthesia with 5% lidocaine hyperbaric solution. Exposure of rat sciatic nerve to 2.5% lidocaine results in selective damage to the unmyelinated fiber Schwann cells. Neurotoxic effects of lidocaine are dose dependent and increase with duration of drug exposure. Possible pathomechanisms are altered peripheral nerve permeability, nerve fascicular edema, and increased endoneural fluid pressure. Oral Contraceptives Oral contraceptives may result in folate and vitamin B12 deficiency. The development of megaloblastic anemia is rare, and neurological complication of this is peripheral sensorimotor polyneuropathy after years of oral contraceptive use. Vitamin therapy for low levels of folate and B12 leads to recovery. Subdermal contraceptive implants (Norplant) are now used as an alternative to the pill. Seventy to 80% of women using Norplant have reported side effects, such as uterine bleeding, headache, mastalgia, and local pain at the site of insertion. Hueston et al. (1995) reported two patients who presented with peripheral neuropathy associated with the implants. One patient responded to removal of the device. The second patient, whose symptoms were thought to be related to trauma, was successfully treated with nonsteroidal anti-­ inflammatory agents. There are case reports of peripheral nerve injury during removal of implants, and a case of sensorimotor ulnar neu-

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ropathy associated with subdermal contraceptive implant has been reported (Marin and McMillian 1998).

28  Drug-Induced Peripheral Neuropathies

glia, which is due to increased neurofilament protein synthesis, and results in mechanical obstruction of axon transport. Various experimental studies suggest that high doses of pyriPyridoxine doxine produce a ganglion neuropathy. The Pyridoxine is a water-soluble vitamin that func- findings of studies on healthy human volunteers tions as a coenzyme in several essential meta- suggest that (1) pyridoxine-­induced neuropathy bolic reactions and plays an important role in is dose related; (2) quantitative sensory threshmaintaining lipid membrane integrity. Pyridoxine old abnormalities precede changes in nerve conhas been prescribed for the treatment of INH-­ duction studies; (3) symptoms continue to induced neuropathy, pyridoxine-dependent epi- progress for a few weeks despite stopping pyrilepsy, carpal tunnel syndrome, and many other doxine; and (4) a dose-dependent vulnerability disorders. The normal daily requirement of pyri- may exist among nerve fibers of different caliber doxine (vitamin B6>) is 2–4 mg/day. Megavitamin when exposed to pyridoxine. therapy with pyridoxine (2–6 g/day) has been Public and physician education is important used for the treatment of several disorders, none for prevention of pyridoxine-induced neuropathy. of which has been shown to be due to pyridoxine Megadoses as a dietary supplement without any deficiency. medical rationale should be discouraged. Schaumburg et  al. (1983) were the first to describe severe sensory neuropathy due to pyri- Penicillamine doxine megadosage, the salient features of which Penicillamine has been used successfully for the were ataxia and absence of motor weakness. On treatment of rheumatoid arthritis for several electrophysiological examination, absence of years. Immune-mediated adverse reactions such nerve action potentials and preservation of motor as thrombocytopenia, glomerulonephritis, myasconduction velocity are characteristic. Sural thenia gravis, and systemic lupus erythematosus nerve biopsies showed axonal degeneration of are known with this drug. Guillain-Barré synboth large and small diameter fibers. In a further drome has been described as a complication (see study, Parry and Bredesen (1985) reported 16 Chap. 37). A case of motor neuropathy was patients who developed sensory neuropathy with described within 2 months of the start of penicillower doses of pyridoxine, as low as 200 mg/day. lamine therapy (Pedersen and Hogenhaven The clinical patterns were like that of neuropathy 1990). The patient recovered after discontinuaresulting from higher doses. Improvement usu- tion of the drug. Polyneuropathy was reported 6 ally occurs after discontinuation of pyridoxine weeks after commencing therapy with therapy, but there are reports of cases where sen- D-penicillamine in a patient with chronic rheusory abnormalities were profound and persisted matoid arthritis (Mayr et  al. 1983). The patient at the time of follow-up a year later (Albin and developed bilateral oculomotor palsy and axonal Albers 1990). Further cases of peripheral peripheral neuropathy with high levels of antineuropathy-­associated long-term megadose pyri- nuclear antibodies and antibodies against native doxine therapy have been reported. DNA.  The appearance of polyneuropathy after The pathomechanism is based on direct neu- repeated administration of penicillamine and the rotoxicity of pyridoxine. In cell cultures of dor- regression of symptoms with rapid decrease in sal root ganglia, pyridoxine inhibits outgrowth antinuclear antibodies after discontinuation of of neurites at low concentrations and results in the drug indicate the causal relationship. cell death at higher concentrations. There is Pyridoxine deficiency has been suggested as a accumulation of neurofilaments in proximal possible pathomechanism as penicillamine is a axons and microtubule-neurofilament dissocia- pyridoxine antagonist and recovery followed use tion in the cyton and axons of dorsal root gan- of pyridoxine in one case.

Prevention of Drug-Induced Peripheral Neuropathy

Sulfasalazine This is an enteric drug used for the treatment of ulcerative colitis. It is poorly absorbed, but several systemic side effects have been reported. Peripheral neuropathy is a well-known complication. Sulfasalazine is split by colonic bacteria into 5-aminosalicylic acid and sulfapyridine moieties. The latter is absorbed and causes a reversible sensorimotor neuropathy with delayed recovery. A case of peripheral neuropathy due to mesalazine (enteric-coated 5-aminosalicylic acid) has been reported (Woodward 1989). The patient recovered after discontinuation of the drug.

463

L-tryptophan, its metabolic products, or contaminants within L-tryptophan products.

Vaccines Neurological complications of vaccination are well known. Postvaccinal leukoencephalomyelitis is described in Chap. 10. Tetanus toxoid is reported to produce brachial plexus neuropathy (Beghi et al. 1985) and relapsing demyelinating neuropathy (Pollard and Selby 1978). There is a case report of systemic vasculitis following influenza virus vaccine and manifesting as sensorimotor polyneuropathy (Gavaghan and Webber 1993). A plexus neuropathy was reported following vaccination against tick-borne encephalitis (TBE) followed by an inoculation of tetanus toxoid 6 days later (Sander et al. 1995). Decrease of T-helper cells and a significant lowered CD4/ CD8 ratio could be detected indicating a possible link between an altered immune state and postvaccinal neuropathy.

Tacrolimus FK506 is an important immunosuppressant that has shown great promise in the treatment of autoimmune diseases. Approximately 5% of patients receiving FK506 develop major central nervous system toxicity, but the peripheral nerves are usually spared. During 1990–1991, some 1000 patients received liver transplants under FK506 immunosuppression. Of these, three patients developed severe multifocal demyelinating sen- Prevention of Drug-Induced sorimotor polyneuropathy 2–10 weeks after ini- Peripheral Neuropathy tiation of FK506 therapy and improvement followed plasmapheresis or intravenous immu- The following measures are aimed at reducing noglobulin (IVIG), suggesting an immune-­ the frequency of occurrence of drug-induced mediated cause (Wilson et  al. 1994). Another neuropathies: liver transplant patient developed demyelinating sensorimotor polyneuropathy 8 weeks after the • The most important step in prevention is the start of FK506 therapy (Bronster et  al. 1995). awareness of drugs being a cause of peripheral FK506 was discontinued and therapy was neuropathy. If a patient is on a drug known to replaced by cyclosporine and azathioprine. The cause peripheral neuropathy, monitoring patient recovered and had no sequelae at followshould be instituted for any early symptoms ­up 1 year later. and signs. If there is occult neuropathy, decision regarding possible discontinuation of the drug should be made. Tryptophan Peripheral neuropathy has been associated with • Most of the drug-induced neuropathies are dose dependent. Care should be taken not to tryptophan use. These neuropathies were preuse any more than the minimum necessary dominantly motor and maximal in the lower dose of these drugs. extremities. Electrophysiological studies show marked multifocal conduction blocks indicat- • If the pathomechanism of a particular drug-­ induced neuropathy is known and if it can be ing segmental demyelination. Sural nerve biopcorrected, steps should be taken at the earliest sies showed axonal degeneration. The cause of stage to do so before considering discontinuathis neuropathy is unknown but may include tion of the drug. An example is vitamin defiimmune mechanisms, or toxicity of eosinophils,

464

ciency which should be verified by laboratory examination, and appropriate vitamin supplement should be given. • Care should be taken in administering drugs known to cause dose-dependent peripheral neuropathy to patients with known risk factors or systemic disease which slows the excretion of drugs and raises serum levels.

Neuroprotection Against Anticancer Drug-Induced Peripheral Neuropathy

28  Drug-Induced Peripheral Neuropathies

ous cases of neuropathy induced by the suspected drug.

Management of Drug-Induced Peripheral Neuropathy Measures against neuropathies caused by various drugs were already discussed in the preceding sections. Some general measures are as follows:

• Discontinue the offending drug while the improvement is still possible. Platinum-based chemotherapy-induced periph- • Promote the excretion of the drug. For exameral neuropathy is one of the most common ple, 2,3-dimercaptopropanol (BAL) can procauses of dose reduction and discontinuation of mote excretion of metals such as gold. life-saving chemotherapy in cancer treatment; • In cases with immunological etiology, plasit often causes permanent impairment of quality mapheresis and immunosuppressive treatof life in cancer patients. A study has shown that ment with corticosteroids should be that SIRT2 protected mice against cisplatin-­ considered. induced peripheral neuropathy (CIPN) as it • If vitamin deficiency is identified, appropriate accumulated in the nuclei of dorsal root ganvitamins should be given. glion sensory neurons and prevented neuronal • Autonomic dysfunction accompanying cell death following cisplatin treatment (Zhang peripheral neuropathy should be treated et  al. 2020). SIRT2, an NAD+-dependent symptomatically. deacetylase, protected neurons from cisplatin cytotoxicity by promoting transcription-couThe following measures can be considered for pled nucleotide excision repair of cisplatin- the treatment of painful peripheral neuropathy: induced DNA cross-links and warrants future investigation of SIRT2 activation-­ mediated • Peripherally acting analgesics, e.g., neuroprotection during platinum-­based cancer acetaminophen. treatment. • Centrally acting analgesics for neuropathic pain. • Transcutaneous electrical stimulation. • Physical therapy should be instituted early in Diagnosis of Drug-Induced the management of these patients. Peripheral Neuropathy An accurate history of suspected drug exposure is the most important tool in the diagnosis of drug-­ induced neuropathy. The intensity and temporal onset of symptoms reflect the level and duration of exposure to the drug. In mild cases, improvement follows discontinuation of the drug. Electrophysiological investigations are the same as other peripheral neuropathies. The pattern of clinical and electrophysiological deficit reflects that known to occur in previ-

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466 Hedenmalm K, Spigset O.  Peripheral sensory disturbances related to treatment with fluoroquinolones. J Animicrob Chemother. 1996;37:831–7. Helgren ME, Cliffer KD, Torrento K, et al. Neurotrophin-3 administration attenuates deficits of pyridoxine-­ induced large-fiber sensory neuropathy. J Neurosci. 1997;17:372–82. Heney D, Norfolk DR, Wheeldon J, et  al. Thalidomide treatment for chronic graft-versus-host disease. Br J Hematol. 1991;78:23–7. Herbst RS, Kelly K, Chansky K, et  al. Phase II selection design trial of concurrent chemotherapy and cetuximab versus chemotherapy followed by cetuximab in advanced-stage non-small-cell lung cancer: Southwest Oncology Group study S0342. J Clin Oncol. 2010;28:4747–54. Hottinger AF.  Neurologic complications of immune checkpoint inhibitors. Curr Opin Neurol. 2016;29:806–12. Hueston WJ, Locke KT, et  al. Norplant neuropathy: peripheral neurologic symptoms associated with subdermal contraceptive implants. J Fam Pract. 1995;40:184–6. Imrie KR, Couture F, Turner CC, et  al. Peripheral neuropathy following high-dose etoposide and autologous bone marrow transplantation. Bone Marrow Transplant. 1994;13:77–9. Iniguez C, Larrode P, Mayordomo JI, et  al. Reversible peripheral neuropathy induced by a single administration of high-dose paclitaxel. Neurology. 1998;51:868–70. Jain KK. Handbook of neuroprotection. 2nd ed. New York: Springer Science; 2019. James MO, Jahn SC, Zhong G, et al. Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1. Pharmacol Ther. 2017;170:166–80. Kao JC, Liao B, Markovic SN, et al. Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol. 2017;74:1216–22. Knop J, Bonsmann G, Hepple R. Thalidomide in the treatment of 60 cases of chronic discoid lupus erythematosus. Br J Dermatol. 1983;108:461–6. Koh WH, Boey ML.  Polyneuropathy following intra-­ muscular sodium aurothiomalate for rheumatoid arthritis--a case report. Ann Acad Med Singap. 1992;21:821–2. La Civita L, Zignego AL, Lombardini F, et al. Exacerbation of peripheral neuropathy during alpha-interferon therapy in a patient with mixed cryoglobulinemia and hepatitis B virus infection. J Rheumatol. 1996;23:1641–3. Larkin J, Chmielowski B, Lao CD, et al. Neurologic serious adverse events associated with nivolumab plus ipilimumab or nivolumab alone in advanced melanoma, including a case series of encephalitis. Oncologist. 2017;22:709–18. LeLacheur SF, Simon GL. Exacerbation of dideoxycytidine-induced neuropathy with Dideoxynosine. J Acquir Immune Defic Syndr. 1991;4:538–539. Leppert D, Waespe W.  Neurotoxicity of antituberculous drugs in a patient with active tuberculosis. Ital J Neurosci. 1988;9:31–4.

28  Drug-Induced Peripheral Neuropathies Loh FL, Herkovitz S, Berger AR, et al. Brachial plexopathy associated with interleukin-2 therapy. Neurology. 1992;42:462. Lu D, Gillespie WR, Girish S, et  al. Time-to-event analysis of polatuzumab vedotin-induced peripheral ­neuropathy to assist in the comparison of clinical dosing regimens. CPT Pharmacometrics Syst Pharmacol. 2017;6:401–8. Marin R, McMillian D.  Ulnar neuropathy associated with subdermal contraceptive implant. South Med J. 1998;91:875–8. Mariotto S, Ferrari S, Monaco S.  Brentuximab vedotin-­ induced peripheral neuropathy: looking at microtubules. J Neuro-Oncol. 2018;137:665–6. Mayr N, Graninger W, Wessely P. A chemically induced polyneuropathy in chronic polyarthritis treated with D-Penicillamine? Wien Klin Wochenschr. 1983;95(3):86–8. Melli G, Taiana M, Camozzi F, et  al. Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy. Exp Neurol. 2008;214:276–84. Michelakis ED, Sutendra G, Dromparis P, et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med. 2010;2:31–4. Moyle GJ, Sadler M. Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. Drug Saf. 1998;19:481–94. Muralikrishnan S, Ronan LK, Coker S, et  al. Treatment considerations for patients with unresectable metastatic melanoma who develop pembrolizumab-­ induced Guillain-Barré toxicity: a case report. Case Rep Oncol. 2020;13:43–8. New PZ, Jackson CE, Rinaldi D, et  al. Peripheral neuropathy secondary to docetaxel (Taxotere). Neurology. 1996;46:108–11. Nguyen GH, Guo EL, Norris D. A rare case of erythema elevatum diutinum presenting as diffuse neuropathy. JAAD Case Rep. 2016;3(1):1–3. Oaku T, Yamada N, Ikeda K, et  al. Early onset of metronidazole-­ induced peripheral neuropathy in a patient with amoebic colitis:a case report. Nihon Shokakibyo Gakkai Zasshi. 2020;117(1):72–7. Olson PE, Kennedy CH, Morte PD. Paresthesias and mefloquine prophylaxis. Ann Intern Med. 1992;117:1058–9. Pace A, Bove L, Nistico C, et al. Vinorelbine neurotoxicity: clinical and neurophysiological findings in 23 patients. J Neurol Neurosurg Psychiatry. 1996;61:409–411. Parry GJ, Bredesen DE.  Sensory neuropathy with low dose pyridoxine. Neurology. 1985;35:1466–8. Pastorelli F, Derenzini E, Plasmati R, et al. Severe peripheral motor neuropathy in a patient with Hodgkin lymphoma treated with brentuximab vedotin. Leuk Lymphoma. 2013;54(10):2318–21. Pedersen PB, Hogenhaven H.  Pencillamin-induced neuropathy in rheumatoid arthritis. Acta Neurol Scand. 1990;81:188–90. Pollard JD, Selby G. Relapsing neuropathy due to tetanus toxoid. J Neurol Sci. 1978;37:113–25.

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467 Sittl R, Lampert A, Huth T, et al. Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype NaV1.6-resurgent and persistent current. Proc Natl Acad Sci U S A. 2012;109:6704–9. Staff NP, Dyck PJB.  On the association between fluoroquinolones and neuropathy. JAMA Neurol. 2019;76(7):753–4. Tan IL, Polydefkis MJ, Ebenezer GJ, et  al. Peripheral nerve toxic effects of nitrofurantoin. Arch Neurol. 2012;69(2):265–8. Tanaka R, Maruyama H, Tomidokoro Y, et al. Nivolumab-­ induced chronic inflammatory demyelinating polyradiculoneuropathy mimicking rapid-onset Guillain-Barré syndrome: a case report. Jpn J Clin Oncol. 2016;46:875–8. Tilly H, Morschhauser F, Bartlett NL, et al. Polatuzumab vedotin in combination with immunochemotherapy in patients with previously untreated diffuse large B-cell lymphoma: an open-label, non-randomised, phase 1b-2 study. Lancet Oncol. 2019;20:998–1010. van Gerven JMA, Hovenstadt A, Moll JWB, et  al. The effects of an ACTH (4-9) analogue on the development of cisplatin neuropathy in testicular cancer: a randomized trial. J Neurol. 1994;241:432–5. van Kooten B, van Diemen HAM, Groenhout KM, et al. A pilot study on the influence of a corticotropin (4-9) analogue on vinca alkaloid-induced neuropathy. Arch Neurol. 1992;49:1027–31. Walls TJ, Pearce SJ, Venables GS.  Motor neuropathy associated with cimetidine. BMJ. 1980;281:974–5. Wijesekera JC, Critchley EMR, Fahim Y, et al. Peripheral neuropathy due to perhexiline maleate. J Neurol Sci. 1980;46:303–9. Wilson JR, Conwit RA, Eidelman BH, et al. Sensorimotor neuropathy resembling CIDP in patients receiving FK506. Muscle Nerve. 1994;17:528–32. Woodward DK.  Peripheral neuropathy and mesalazine. BMJ. 1989;299:1224. Wulff CH, Hoyer H, Asboe-Hansen G, et al. Development of polyneuropathy during thalidomide therapy. Br J Dermatol. 1985;112:475–80. Zehnder D, Hoigne R, Neftel KA, et al. Painful dysaesthesias with ciprofloxacin. BMJ. 1995;310:1204. Zhang M, Du W, Acklin S, et al. SIRT2 protects peripheral neurons from cisplatin-induced injury by enhancing nucleotide excision repair. J Clin Invest. 2020;130:2953–65.

Drug-Induced Disorders of the Autonomic Nervous System

Introduction The autonomic nervous system (ANS) supplies and influences virtually every organ in the body. The ANS is affected by afferent signals from different parts of the body as well as neurons in the spinal cord and in the brain, mainly in the hypothalamus and brainstem. The efferent component of the ANS has two divisions: sympathetic and parasympathetic. Disorders of the ANS are also referred to by the term “autonomic failure.” A detailed description of these is given in the book by Bannister and Mathias (2013). These disorders can be primary or secondary. Drug-induced disorders belong to the second category.

Classification of Drug-Induced Disorders of the ANS Drugs may act by stimulating or inhibiting either of the two divisions of the ANS.  This is only a partial dissociation of the effect. The agonists and antagonists are often close cousins and share each other’s properties to some extent. Drugs not normally acting on the ANS may have side effects involving the ANS.  A minor side effect may aggravate or unmask an autonomic deficiency, e.g., hypotension in Shy-Drager syndrome is enhanced by levodopa. Autonomic disorders are not always discreet. Some of them are part of

29

other neurological syndromes such as neuroleptic malignant syndrome. Some of the autonomic side effects of drugs are mentioned along with other drug-induced syndromes, but in this chapter, the emphasis will be placed on the autonomic effects. A practical classification of drug-induced autonomic disorders is shown in Table 29.1.

Anticholinergic Syndrome Anticholinergic intoxication has been described since early written history. Datura stramonium (a toxic anticholinergic plant) is described as a poison by Homer in The Odyssey. It occurs during the postoperative period in about 1% of the cases following general anesthesia and 4% following regional anesthesia. It may occur as an effect of drugs used during this period or due to insufficient release of acetylcholine.

Clinical Manifestations The anticholinergic syndrome has both physical signs and neuropsychiatric manifestations. Physical signs include tachycardia, dilated and unreactive pupils, blurred vision, flushed face, warm dry skin, dry mouth/throat, and hyperpyrexia.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_29

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29  Drug-Induced Disorders of the Autonomic Nervous System

Table 29.1  A practical classification of drug-induced autonomic disorders Decrease of sympathetic activity  Centrally acting drugs  Anesthetics  Barbiturates  Clonidine  Methyldopa  Peripherally acting drugs  Sympathetic neuron: guanethidine  Alpha-adrenoceptor blockade: phenoxybenzamine  Beta-adrenoceptor blockade: propranolol Increase of sympathetic activity: sympathomimetic syndromes Decrease of parasympathetic activity: anticholinergic syndromes Increase of parasympathetic activity: cholinergic syndromes As part of other drug-induced neurological disorders  Drug-induced transverse myelitis (see Chap. 32)  Drug-induced Guillain-Barré syndrome (see Chap. 37)  Lambert-Eaton syndrome (see Chap. 30) Autonomic neuropathy Postural hypotension (see Chap. 15) Autonomic disturbances associated with drug withdrawal Reflex sympathetic dystrophy

Neuropsychiatric Effects These include anxiety, agitation, confusion, delirium, hallucinations, delusions, fluctuating level of consciousness, impairment of memory, and seizures. Neurological manifestations of chronic low-dose anticholinergic drug use may be subtle. Anticholinergic medications predispose elderly persons to falls. A retrospective study of elderly patients with mild cognitive impairment or dementia and two or more additional chronic conditions showed that the greatest increase in risk of falls or fall-related injuries occurred when level 2 and level 3 drugs were used in combination with a score of 5 on the anticholinergic cognitive burden scale (Green et  al. 2019). Other neurological adverse effects include the following. Cognitive Impairment A retrospective cohort study conducted over a period of 2 years showed that taking two or more anticholinergic medications significantly increases the risk of hospitalization for confusion

or dementia (Kalisch Ellett et al. 2014). An association has been shown between anticholinergic drug use and cognitive decline in Parkinson disease (Ehrt et  al. 2010). Use of anticholinergic drugs by elderly persons increases the risk for cognitive decline and dementia, whereas discontinuation of these drugs decreases the risk (Carrière et  al. 2009). Use of anticholinergics increases the risk of cognitive impairment if they are carriers of the epsilon4 allele of the APOE gene (Nebes et  al. 2012). Anticholinergic drugs are a potential risk factor for psychosis in Alzheimer disease (Cancelli et  al. 2009). The dose of anticholinergic medicines in patients with Alzheimer disease should be reduced prior to start of therapy with cholinesterase inhibitors as the concomitant use of both increases anticholinergic load and can lead to aggravation of cognitive impairment (Bell et  al. 2012). A double-blind, placebo-controlled, randomized, parallel-group study has shown that the anticholinergic antidepressant amitriptyline can profoundly suppress REM sleep and can impair procedural memory consolidation in healthy subjects, whereas selective serotonin reuptake inhibitors do not show this effect (Goerke et al. 2014). A systematic review of randomized controlled trials has revealed that drugs with anticholinergic effects are associated with risks of cognitive impairment in the elderly (Ruxton et al. 2015). Particularly, olanzapine and trazodone increased the risk of falls, whereas amitriptyline, paroxetine, and risperidone did not. In a retrospective cohort study on persons 65 years or older, increasing use of strong anticholinergics calculated by total standard daily dose increased the odds of transition from normal cognition to mild cognitive impairment (Campbell et al. 2018). Results of this study suggest that interventions, which involve discontinuation of drugs, in older adults with normal cognition should test anticholinergics as potentially modifiable risk factors for cognitive impairment. In a retrospective study, one-third of elderly patients who were consulted for loss of memory were taking anticholinergic drugs, and there was a greater tendency to cognitive impairment among those exposed to ­ these drugs (López-Matons et al. 2018). A case-control study has shown that exposure to several types of strong anticholinergic drugs is

Anticholinergic Syndrome

associated with an increased risk of dementia and the attributable fraction associated with total anticholinergic drug exposure during the 1 to 11 years before diagnosis was 10.3% (Coupland et  al. 2019). Associations in this study were stronger in cases diagnosed before the age of 80  years and in those with vascular dementia rather than Alzheimer disease.

Drug-Induced Anticholinergic Syndrome Neurotoxicity of anticholinergics is termed “acute anticholinergic syndrome,” and other manifestations besides those of delirium include cognitive impairment and visual, auditory, and sensory hallucinations. Seizures, coma, and death may occur rarely. Neurological signs of anticholinergic toxicity include ataxia, pupil dilation with blurred vision, and diplopia. Effects in the central nervous system resemble those associated with delirium. Although anticholinergic drugs may contribute to delirium due to the cumulative effect of multiple medications with modest antimuscarinic activity, multivariable logistic regression analysis, after adjustment for dementia and malnutrition, fails to prove a causative role in delirium (Pasina et al. 2019). Further studies are needed to clarify this association. Two scales have been used to assess risk of adverse effects of anticholinergic drugs: (1) the Anticholinergic Drug Scale, which is based on serum anticholinergic values, and (2) the Anticholinergic Risk Scale, which is a ranked list of commonly prescribed medications with anticholinergic potential. Both anticholinergic scales can help detect an increased risk of appearance of peripheral anticholinergic signs, but not the central signs such as delirium (Gouraud-Tanguy et  al. 2012). Anticholinergic syndrome is more likely to be caused by drugs with central anticholinergic effects that cross the blood-brain barrier and block muscarinic cholinergic receptors. There are over 600 medications that have some degree of serum anticholinergic activity. Some of the drugs reported to be associated with anticholinergic syndrome are listed in Table 29.2.

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Pathomechanism of Anticholinergic Syndrome Acetylcholine has an important function in modulating the interaction between several other central neurotransmitters. The effect of most of the drugs is easy to explain because of their known effect in decreasing parasympathetic activity. Anticholinergic syndrome is more likely to be caused by drugs with central anticholinergic effects that cross the blood-brain barrier and block muscarinic cholinergic receptors. The most important of these are drugs used in anesthesia and perioperative period will be considered separately.

Differential Diagnosis Conditions from which the central anticholinergic syndrome should be differentiated are shown in Table 29.3.

Anticholinergic Syndrome in Anesthesia Many of the drugs used in anesthesia and intensive care may cause blockade of the central cholinergic transmission and produce a central cholinergic syndrome. This may also result when the central cholinergic sites are occupied by specific drugs and there is insufficient release of acetylcholine. The etiology of central anticholinergic syndrome is multifactorial, but the diagnosis should be considered in all patients who demonstrate abnormal postanesthetic awakening. Central anticholinergic syndrome may follow general anesthesia where premedication with hyoscine has been carried out. In one study, 18 of the 962 anesthetized patients developed the syndrome (Link et al. 1997). The findings of this study indicate that the diagnosis of central anticholinergic syndrome should be considered when there is delayed recovery from anesthesia and if other causes for that condition have been excluded. A nested case-control study in general practices in England evaluated whether exposure to 56 anticholinergic drugs was associated with risk of

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29  Drug-Induced Disorders of the Autonomic Nervous System

Table 29.2 Drugs that can produce anticholinergic syndrome Anesthesia, analgesia, and postoperative medications  Atropine sulfate  Benzodiazepines  Halothane  Hyoscine  Enflurane  Ketamine  Opioids  Transdermal scopolamine Antiarrhythmics: propafenone, quinidine Antiasthmatic: ipratropium bromide Antibiotics  Ampicillin  Clindamycin  Gentamicin  Piperacillin  Vancomycin Antiemetics: cyclizine and meclizine Antihistaminics with anticholinergic activity  Brompheniramine  Carbinoxamine  Chlorpheniramine  Cyclizine  Cyproheptadine  Diphenhydramine  Doxylamine  Hydroxyzine  Promethazine Anti-incontinence agents  Flavoxate  Oxybutynin  Propantheline bromide Antiparkinsonian medications  Amantadine  Benztropine  Biperiden  Ethopropazine  Procyclidine  Trihexyphenidyl Antipsychotics  Clozapine  Chlorpromazine  Chlorprothixene  Olanzapine  Quetiapine  Thioridazine Antispasmodics for the gastrointestinal tract  Dicyclomine  Hexocyclium  Hyoscyamine  Isopropamide  Oxyphenonium

Table 29.2 (continued)  Propantheline  Tridihexethyl Baclofen Ophthalmic preparations  Atropine 1% ophthalmic solution  Cyclopentolate  Eucatropine  Tropicamide Tricyclic antidepressants  Amitriptyline  Amoxapine  Clomipramine  Desipramine  Doxepin  Imipramine  Nortriptyline Drug interactions  Desipramine and venlafaxine  Venlafaxine-fluoxetine  Paroxetine and clozapine Herbal medications   Datura species (e.g., angel’s-trumpet)   Solanum erianthum (contains anticholinergic tropane alkaloids)

Table 29.3  Differential diagnosis of central anticholinergic syndrome Overdose of anesthetic drugs Altered hydration Electrolyte disturbances Hypoglycemia Hypoxia Hypercapnia, hyperthermia Endocrine disorders Neurological damage resulting from surgery

dementia in 55  years or older persons compared with controls matched by age, sex, and calendar time (Nishtala et  al. 2016). Information on prescriptions for drugs with strong anticholinergic properties was used to calculate measures of cumulative anticholinergic drug exposure. Anticholinergic burden, measured in several ways that consider number, dose, and/or degree of anticholinergic activity of medicines, was shown to be a predictor of adverse health and functional outcomes. It is suggested that anticholinergic burden on the elderly should be minimized by avoiding, reducing dose and deprescribing medicines with anticholinergic activity where clinically possible.

Cholinergic Syndrome

Treatment General Measures  The priority in the treatment of severe cholinergic syndrome is the support of vital functions. In addition to neurological manifestations, there may be respiratory or cardiac arrest. Acute anticholinergic syndrome is completely reversible and subsides once all of the toxin has been excreted. Usually no specific treatment is indicated, but in severe cases, especially those that involve severe distortions of mental state, a reversible cholinergic agent such as physostigmine may be used. A 1 mg dose of intravenous physostigmine produces a rapid return to a normal level of consciousness. Bethanechol, a parasympathomimetic agent, can counteract the adverse effects of nortriptyline. Thiamine has been shown to reduce the scopolamine-­induced cognitive deficits by its cholinomimetic action. Anticholinergic Effects of Antidepressants  The anticholinergic effects of antidepressants are most marked with some tricyclic antidepressants and can be peripheral or central. The most frequently occurring are sedation and memory impairment (central effects) as well as dry mouth and blurred vision (peripheral effects). Selective serotonin reuptake inhibitors have much less anticholinergic side effects, and selective monoamine oxidase A inhibitors such as moclobemide do not have such side effects at all. The elderly are more susceptible to the anticholinergic effects of antidepressants, and because of polypharmacy, they are more likely to have drug interactions which accentuate anticholinergic effects. Anticholinergic properties of amitriptyline may have a euphoric effect leading to abuse potential and toxicity. Important points of management of anticholinergic effects of antidepressants and their prevention are: • Use antidepressants with the least anticholinergic effects and reduce the dose. • Caffeine attenuates the anticholinergic effects. • Avoid the use of comedications which increase the anticholinergic effect.

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Anticholinergic Syndrome After Topical Applications  Systemic absorption of topical ophthalmic anticholinergic drugs may lead to systemic toxicity. Anticholinergic toxicity can be confirmed by anticholinergic radioreceptor assay after application of homatropine ophthalmic solution. Central anticholinergic syndrome may also occur after transdermal application of scopolamine patch.

Cholinergic Syndrome Drugs which produce this syndrome are: • Cholinomimetics such as carbachol • Anticholinesterases such as physostigmine and neostigmine Signs of excessive cholinergic stimulation are as follows: Muscarinic  Increased bronchial, salivary, ocular, and intestinal secretions; sweating; miosis; bronchospasm; intestinal hypermobility and bradycardia Nicotinic  Muscle twitching; weakness and paralysis

fasciculations;

CNS  Loss of consciousness; convulsions; respiratory depression

Sympathomimetic Syndromes Drugs that produce these syndromes are listed in Table 29.4. Common signs are: • • • • • •

Delusions Paranoia Hypertension Hyperreflexia Seizures Dysrhythmias

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29  Drug-Induced Disorders of the Autonomic Nervous System

Table 29.4 Drugs that produce sympathomimetic syndromes Amphetamine Beta-adrenoceptor stimulants (isoprenaline) Caffeine overdose Cocaine Ephedrine Phenylpropanolamine Theophylline

Autonomic Neuropathy Autonomic dysfunction is well recognized as a complication of peripheral neuropathy. Most of the nerve fibers in both divisions of the ANS are small myelinated (2–6 Fm) and unmyelinated fibers. Diseases such as diabetes mellitus and amyloidosis that primarily affect small nerve fibers in peripheral neuropathy, or Guillain-Barré syndrome, which causes demyelination of small myelinated fibers, are most likely to cause autonomic dysfunction. Hyperhidrosis of the extremities is common in peripheral neuropathy and is usually caused by the degeneration and impaired function of the cholinergic postganglionic sympathetic unmyelinated fibers that travel with peripheral nerves to innervate the sweat glands. Orthostatic hypotension is most likely to occur when autonomic fibers in the splanchnic bed are damaged. The term acute autonomic neuropathy was first used by Thomashefsky et  al. (1972) to describe a case with acute onset of pupillotonia, dry mouth, urinary and fecal retention, and hypohidrosis with gradual and incomplete recovery. No cause could be identified, but the features were consistent with diffuse abnormality of postganglionic cholinergic function. Categories of various causes of peripheral autonomic disorders are listed in Table 29.5.

Drug-Induced Autonomic Neuropathy Drugs which have been reported to cause autonomic neuropathy are listed in Table 29.6.

Table 29.5  Categories of causes of peripheral autonomic disorders Acute dysautonomia Antineoplastic drugs Drug-induced autonomic neuropathy Drugs and toxins Drugs which have been reported to cause autonomic neuropathy are listed in Table 29.6. Hereditary Immunologic disorders Infections Inflammatory Metabolic and nutritional disorders Paraneoplastic syndromes

Table 29.6 Drug neuropathy

reported

to

cause

autonomic

Amiodarone Antineoplastics  Ara-C  Cisplatin  Gemcitabine  Paclitaxel  Vincristine Ergot compounds Perhexiline maleate

Antineoplastic Drugs Antineoplastic drugs produce a peripheral neuropathy of the “dying back” type which affects both the large and the small fibers (see Chap. 28). Hansen (1990) observed autonomic dysfunction in 10 of the 28 patients with lasting remissions following treatment of cancer with chemotherapy and no obvious signs of peripheral neuropathy. None of the subjects had postural hypotension. The incidence of cardiovascular autonomic neuropathies is higher in cancer patients treated with vinca alkaloids as compared with control cancer patients not treated with chemotherapy. Ara-C (Cytosine Arabinoside)  Nevill et  al. (1989) described a patient with acute leukemia who developed Horner’s syndrome and a severe demyelinating peripheral neuropathy leading to death after receiving high-dose cytosine arabinoside therapy.

Autonomic Disturbances Associated with Drug Withdrawal

Cisplatin  Cisplatin causes a dose-dependent pandysautonomic neuropathy, observed in subjects receiving a cumulative dose of up to 825 mg/ m2. Other associated features include peripheral neuropathy, ototoxicity, and retrobulbar neuritis. Gemcitabine  One patient with non-small cell lung cancer was reported to develop autonomic neuropathy following treatment with gemcitabine (Dormann et al. 1998). The symptoms were acid regurgitation, difficulty in swallowing, and constipation. The patient was given parenteral nutrition and cisapride. He recovered 4  weeks after the completion of chemotherapy. Paclitaxel  It may cause autonomic neuropathy once the cumulative dose reaches 600  mg/m2 (range 50–750 mg/m2). Paclitaxel causes aggregation of microtubules, and abnormalities of cardiovagal and adrenergic function are observed. Autonomic neuropathy with severe orthostatic hypotension has been reported in following treatment with Taxol for ovarian cancer. Vincristine  Autonomic complications of treatment with vincristine manifest as constipation, abdominal pain, paralytic ileus, and urinary retention. Vincristine causes a dose-related neuropathy with a cumulative dose of up to 50 mg. Both parasympathetic and sympathetic clinical features are observed. The mechanism of action of vincristineinduced autonomic neuropathy is secondary to disruption of microtubules by vinca alkaloids, causing an increase in microfilaments and paracrystalline structures in axons, with unmyelinated fibers being more susceptible than myelinated axons.

 ther Drugs Causing Autonomic O Neuropathy Amiodarone  Amiodarone usually produces a sensorimotor neuropathy (see Chap. 28), but autonomic failure with postural hypotension has also been reported. Ergot  A case of autonomic dysesthesias due to ergot toxicity has been reported by Evans et al.

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(1980). It was determined that pain was not due to vasoconstrictor effect of ergotamine. The pain was relieved by sympathetic block. Perhexiline Maleate  This drug can cause peripheral neuropathy as well as autonomic neuropathy manifested by postural hypotension and abnormal Valsalva ratio.

 utonomic Disturbances Associated A with Drug Withdrawal Withdrawal of drugs such as alcohol, opiates, and clonidine may result in reverse sympathetic overactivity, with increased sweating, hypertension, and piloerection. A withdrawal syndrome has been reported after intrathecal administration of morphine (Tung et  al. 1980) and withdrawal of clonidine used for the treatment of hypertension (Ropiquet et al. 1984).

 eflex Sympathetic Dystrophy/ R Complex Regional Pain Syndrome Various names are given to reflex sympathetic dystrophy (RSD): Sudeck’s atrophy in German-­ speaking and algodystrophy in French-speaking countries. It is now called complex regional pain syndrome (CRPS) type I.  The pathophysiology of this disorder is not known. A related term “causalgia” is now CRPS type II.

Clinical Features Reflex sympathetic dystrophy (RSD) affects one or more extremities and is characterized by distal pain, tenderness, swelling, and vasomotor instability. Pain and sensory disturbances are the most frequent early symptoms. Tissue atrophy involving the skin, muscles, and bone (osteoporosis) develops later. Sympathetic signs such as hyperhidrosis are frequent but are not considered to be of diagnostic value. The controversial issue of the relationship of sympathetic activity to the pain

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29  Drug-Induced Disorders of the Autonomic Nervous System

was resolved by adding to the description of CRPS I that the pain might be “sympathetically maintained,” “sympathetically independent,” or a combination (Merskey 2005). “Sympathetically maintained” pain improves with sympathetic blockade; “sympathetically independent” pain does not.

Causes of RSD/CRPS I It is usually a complication observed after an injury (e.g., fracture) or an operation on a limb. Changes like RSD may appear with a myocardial infarction (shoulder-hand syndrome), after peripheral nerve injury (causalgia), after local cold injury (trench foot), revascularization of an ischemic extremity (reperfusion syndrome), or may be drug-induced. In 10–26% of cases, no precipitating factor can be found. RSD has been reported in association with the following drugs: Antitubercular Drugs  Gemperli (1969) described isoniazid-induced algodystrophy or fibrosing arthropathy which cleared up on discontinuation of the medication. Twenty-two cases due to various antitubercular drugs were reported by Deshayes et al. (1969). The most frequent form was shoulderhand syndrome. The pathomechanism is not known. Vitamin B6 deficiency and serotonin disturbances have been ruled out as causes. Antiepileptic Drugs  The symptoms of RSD in association with barbiturate therapy were first described by Beriel and Barbier (1934). Horton and Gerster (1984) reported that among 149 cases of RSD, 25 (16.8%) were treated with barbiturates at the time of onset of symptoms. In onethird of the cases, other provocating factors for RSD were absent. Joints were involved bilaterally in 76% of the cases, upper limbs in 76%, and Dupuytren’s contracture was found in 20% of the cases. Recovery was prompt after discontinuation of the medication. Recurrence of RSD occurred in six cases after rechallenge with barbiturates. Several other reports support the relation of phenobarbital to RSD (Mattson et  al. 1989).

Taylor and Posner (1989) noted shoulder-hand syndrome in 12% of patients with brain tumor treated with phenobarbital as compared with 5% in patients not so treated. Van der Korst et  al. (1966) reported that one-third of patients with shoulder-hand syndrome had been receiving phenobarbital. Sanchez-Navarro et  al. (1987) have reported a case treated with phenobarbital where the diagnosis was made by bone scintigraphy before radiological signs of osteoporosis appeared. In other cases reviewed by them, the outcome was favorable only in those where phenobarbital was discontinued. Phenobarbital is associated with other connective tissue disorders as well. The pathomechanism of RSD with phenobarbital is not known. Barbiturates produce hyperalgesia at low doses by disinhibition of lower level pain control neurons and also have an effect at the level of sympathetic ganglia. These properties may have a bearing on the pathomechanism of RSD. The association of RSD with AEDs other than phenobarbital is less well established. No definite relationship has been identified with phenytoin and carbamazepine. Falasca et  al. (1994) have reported a case in association with valproic acid. This patient recovered after discontinuation of valproic acid and treatment with prednisone despite continuation of barbiturate. There is no consensus regarding management of AED-associated RSD. Discontinuation of the medication, corticosteroids, and physical therapy are the usual treatments. If instituted early, the response may be rapid, but some cases have significant residual disability. Cyclosporine  Seven patients were reported to develop RSD in the lower extremities among 240 renal transplant patients who received cyclosporine as an immunosuppressant (Munoz-Gomez et al. 1991). The manifestations were severe pain, periarticular soft tissue swelling, and vasomotor changes in affected areas. A patchy osteoporotic pattern was seen radiographically with increase uptake of 99m technetium. The manifestations occurred at plasma cyclosporine levels of >200 ng/ml and improved when the plasma levels of cyclosporine declined to G (rs683369) and ABCB1 c.3435C>T (rs1045642), is a predictor for efficacy as well as muscle toxicity of imatinib (Galeotti et  al. 2017). The inflammatory myopathy usually resolves on discontinuation of imatinib, but persistence of muscle pain has been reported in some cases (Katagiri et al. 2016). Pathomechanism of Telbivudine-­ Induced Myopathy Telbivudine, a commonly prescribed drug for the treatment of chronic hepatitis B, causes adverse reactions ranging from creatine kinase (CK) elevation to myopathy. A study has shown that telbivudine induces a dose-dependent increase in

Prevention of Drug-Induced Myopathy

creatine kinase activity following 72 hours of treatment (Jianfei et al. 2017). In addition, telbivudine increases Ca2+ production and generation of reactive oxygen species, which are attenuated by a calcium chelator. These findings indicate that telbivudine induces creatine kinase elevation and oxidative stress associated with imbalance of intracellular Ca2+. These findings can help develop new tools for the prevention and treatment of diseases associated with drug-induced creatine kinase elevation.

Epidemiology of Drug-Induced Myopathy The incidence of various drug-induced myopathies varies according to the drug involved or type of myopathy.

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Cerivastatin was the statin implicated the most and has been removed from the market. There is an extremely low risk for myopathy and rhabdomyolysis associated with lovastatin. Mitochondrial myopathy with zidovudine  Clinical and biochemical evidence of myopathy was seen in 17% of the AIDS patients who had been receiving zidovudine for more than 260 days and in none of those on short-term therapy.

Prevention of Drug-Induced Myopathy Measures for preventing drug-induced myopathy are as follows:

• The monitoring of patients receiving drugs known to produce myopathy for early detecSteroid myopathy  As manifested by clinically tion and discontinuation of medication. detectable proximal muscle weakness, steroid • Avoidance of known risk factors such as alcomyopathy is seen in as many as 60% of patients hol consumption. receiving steroids. • Avoidance of depolarizing muscle relaxants such as suxamethonium during general anesCholesterol-lowering agents  Various studies thesia in patients susceptible to myotonia. estimate that 10–15% of statin users develop Depolarizing muscle relaxants should be substatin-related muscle side effects ranging from stituted with nondepolarizing relaxants. Some mild myalgia to more severe muscle symptoms of the nondepolarizing neuromuscular blockwith significant creatine phosphokinase elevaing agents, such as doxacurium chloride, are tions. The incidence of myopathy is approxisteroid based and can also lead to myopathy if mately similar for all lipid-lowering drugs and is combined with high-dose steroids. in the range of 0.1–0.5% with monotherapy, • Various anesthetic agents and depolarizing increasing to 0.5–2.5% with combination thermuscle relaxants are implicated in the causaapy. Fibrates are associated with a slightly tion of rhabdomyolysis. Malignant hypertherincreased risk for myopathy. Although a transient mia with rhabdomyolysis occurs in 1 out of increase in serum creatine kinase is common 20,000 anesthetized adults who are presumed after treatment with lovastatin, clinically manito have a genetic predisposition to it. fest myopathy has been reported in less than 1% Anesthetics may act as a trigger for the onset of patients on this drug. The incidence of statin-­ of rhabdomyolysis in patients with preexisting induced autoimmune myopathy is approximately occult causes. Acute rhabdomyolysis has been 2–3 per 100,000 patients treated with statins. reported after halothane. Anesthesia-induced rhabdomyolysis has been reported in infants Approximately 1 case of rhabdomyolysis is with unsuspected Duchenne dystrophy. A dysreported for every 100,000 treatment-years. Of trophin test in addition to creatine kinase 4000 patients participating in several clinical tridetermination should be considered for the als with this drug, 17 cases (0.04%) of lovastatin-­ detection of this condition in patients underassociated rhabdomyolysis were reported. going anesthesia.

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31  Drug-Induced Myopathies

• Overdosage of suspected drugs should be patient after discontinuation of the offending avoided. drug is further proof that myopathy is drug • Avoidance of a combination of the simultane- induced. Some points of importance are as ous use of two drugs known to cause myopathy. follows. Combination of colchicine with cyclosporine in renal transplant patients increases the risk of Differentiation of myopathies and neuropadevelopment of myopathy. thies  This is important because HMG-CoA • Avoidance of a combination of neuromuscular reductase inhibitors can, in addition to causing blocking agents with corticosteroids, because myopathy, also produce neuropathy. Motor and this increases the risk of myopathy. sensory nerve conduction studies and F-wave and • Identification of patients with genetic suscep- H-reflex studies may be appropriate to exclude tibility to adverse effects of certain drugs the possibility that the patient’s symptoms are might help to avoid the use of drugs that are due to a peripheral neuropathy or even to confirm prone to induce myopathy in such patients. the coexistence of a neuropathy. Chronic alcohol Further advances in pharmacogenetics should abuse is a common cause of toxic myopathy as enable this. well as peripheral neuropathy. • Statins should be avoided in patients with disorders characterized by energy deficit and Differential diagnosis of muscle pain  Muscle chloride channel malfunction. A pilot study pain can be a manifestation of some myopathies has shown that patients who experience myal- and of several other conditions. Drug-induced gia after starting statin therapy have a 40% myalgia without any muscle weakness usually reduction of ClC-1, a chloride channel pro- resolves promptly after withdrawal of the drug. tein, compared to nonmyopathic subjects not Finding of muscle weakness and elevated serum using lipid-lowering drugs (Camerino et  al. creatine kinase levels suggests a necrotizing 2017). Measurement of ClC-1 expression is a myopathy, and a muscle biopsy is required for the reliable biomarker for assessing statin-­ confirmation of diagnosis. dependent risk of myopathy. • A randomized, double-blind trial has shown that Hypokalemic myopathy  This is usually caused the incidence of myopathy is approximately 3 by diuretics. Hypokalemic myopathy differs times as high with the 80 mg dose of simvastatin from hypokalemic periodic paralysis as follows: compared to the equally effective 20 mg dose of atorvastatin (Egan and Colman 2011). • There is an underlying cause such as a drug or Therefore, it is recommended that the 80  mg disease. In hypokalemic periodic paralysis, dose of simvastatin should be restricted to only the cause of hypokalemia is unexplained. those patients who have been taking it for a long • Muscle glycogen is absent, whereas in hypotime without symptoms of myotoxicity. kalemic periodic paralysis muscle is overloaded with glycogen. • Enzymes derived from muscles are elevated and rhabdomyolysis may occur, whereas such Differential Diagnosis an event is not a presenting feature in hypokalemic periodic paralysis. Differential diagnosis of myopathy, whether due to drugs or other causes, follows the same clinical • It requires a large quantity of therapeutic potassium supplementation for an extended pattern. The attempt is not to prove the diagnosis term until recovery. of drug-induced myopathy, but to determine if a drug is responsible in a patient undergoing investigations for myopathy. The most important con- Steroid myopathy  Serum levels of creatine sideration is the history of intake of a drug kinase and other enzymes are normal in steroid reported to cause myopathy. Recovery of the myopathy. If creatine kinase is elevated, another

Differential Diagnosis

type of myopathy should be considered. EMG shows myopathic changes in proximal muscles with reduction in motor unit duration and amplitude without spontaneous muscle fiber potentials. Muscle biopsy shows a characteristic atrophy of type 2 muscle fibers. Critical illness myopathy  Differentiation between drug-induced and nondrug-induced myopathy in critically ill patients is important to avoid unnecessary investigations and unreasonably pessimistic prognosis. Electromyography is essential for the diagnosis and for planning further clinical management. Biopsy needs to be done only when necessary. Differential diagnosis of rhabdomyolysis and myoglobinuria  Various hereditary and acquired disorders may lead to episodes of severe, widespread muscle fiber destruction and myoglobinuria. Malignant hyperthermia  In patients with malignant hyperthermia, muscle rigidity, fever, and rhabdomyolysis develop during anesthesia (halothane or other inhalational agents) in susceptible patients. Laboratory findings include a rise in serum creatine kinase and myoglobinuria. Rhabdomyolysis may also occur. However, such episodes may also be triggered by stress, strenuous physical activity, or a systemic infection. Patients presenting with rhabdomyolysis for the first time should undergo a detailed clinical assessment for drug-induced, toxic, or infective causes. Muscle biopsy and appropriate biochemical investigations should be done for detecting an underlying genetic disorder such as susceptibility to malignant hyperthermia or metabolic disorder. Malignant hyperthermia myopathy should be considered in the differential diagnosis. It is usually subclinical, but some muscle wasting may occur. Serum creatine kinase may be raised but is usually normal. Structural changes in the muscle are nonspecific. Neuroleptic malignant syndrome (see Chap. 38)  This syndrome should be considered in the differential diagnosis of patients with malignant

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hyperthermia and rhabdomyolysis. Some of the symptoms of neuroleptic malignant syndrome are like those of malignant hyperthermia: fever, muscle rigidity, myoglobinuria, and a rise in creatine kinase. One important difference is that neuroleptic malignant syndrome is usually associated with neuroleptic use in psychiatric patients and requires certain criteria for diagnosis. These include disturbances of consciousness and autonomic disturbances. Differential diagnosis of inflammatory myopathies  Patients with autoimmune disease are hypersensitive to cholesterol-lowering drugs. Muscular symptoms in patient on treatment with cholesterollowering drugs may be the first manifestation of a polymyositis precipitated by this treatment and is an indication for antinuclear antibodies screening, particularly if there is proximal muscular weakness along with increased muscle enzyme levels. MHC-I antigens are expressed on the surface of intact muscle fibers in statin-associated necrotizing autoimmune myopathy and are associated with an autoantibody targeting the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in 66% of cases (Pasnoor et al. 2018). This autoantibody is a biomarker for necrotizing autoimmune myopathy, regardless of statin exposure. An international multicenter study confirmed that anti-HMGCR autoantibodies, when found in conjunction with statin use, characterize a subset of idiopathic inflammatory myopathy necrosis on muscle biopsy, and testing for anti-HMGCR antibodies is important in the differential diagnosis of drug-induced myopathies (Musset et al. 2016). Macrophagic myofasciitis is an inflammatory myopathy  Genetic predisposition probably accounts for the variability in the prevalence of macrophagic myofasciitis in different populations. Intramuscular injection of aluminum-­ containing vaccines may produce myofasciitis that is characterized by a typical muscular infiltrate of large macrophages with aluminum inclusions. Muscle biopsy is essential for confirmation of the diagnosis of inflammatory myopathy, although clinical diagnosis of muscle weakness

31  Drug-Induced Myopathies

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and characteristic skin changes is suggestive of a patient with a connective tissue disorder. Immunohistological techniques are used for studying immune complex deposition, major histocompatibility complexes, and intracellular adhesion molecule expression. Investigations are directed toward any underlying immune or infective disorder or malignancy. Diagnosis of drug-­ induced myositis is based on history of drug use and exclusion of other causes. • Acute myopathy of intensive care  This has been reported in critically ill patients treated with intravenous corticosteroids and neuromuscular junction-blocking agents in the intensive care unit. However, comatose and critically ill patients have been reported to develop muscle weakness or paralysis (quadriplegia) during sepsis and multiple organ failure where drugs such as steroids, neuromuscular blocking agents, and aminoglycosides are not responsible for paralysis, and they may become completely paralyzed because of nondrug-induced neuromuscular disorders. The diagnosis is important to avoid unnecessary investigations and unreasonably pessimistic prognosis. Electroneurography and electromyography of peripheral nerves and muscles are essential for the diagnosis and for planning further clinical management. Biopsy should be done only when necessary.

Diagnostic Workup Neurologic examination should focus on the evaluation of muscle strength, muscle atrophy, sensory examination, and tendon reflexes. Important laboratory investigations are as follows: • Serum creatine kinase. This is the most sensitive indicator of muscle damage. Elevated creatine kinase levels in serum indicate their leakage out of damaged muscles into the bloodstream. Creatine kinase levels, which are more than 10 times the upper limit of normal, indicate drug-induced myopathy. Isoenzymes of creatine kinase are used to distinguish skel-

etal muscle damage from myocardial damage or damage to brain or nerve tissue. Slight increases in serum creatine kinase (up to 3 times the normal maximum concentration) are not necessarily due to muscle disease and may occur transiently due to strenuous exercise, minor muscle trauma including intramuscular injection, insertion of EMG needle electrodes, or viral illness. In patients who develop myopathy after statin exposure, a positive test for anti-HMG-CoA reductase autoantibodies strongly supports the diagnosis of an autoimmune process. ­One-­third of the positive tests also occur in patients who have not been exposed to statins. • EMG may show evidence of muscle damage, but similar changes may be seen in conditions that impair function of the neuromuscular junction. Nerve conduction studies may be helpful in differentiating the site of lesion. • Muscle biopsy is required to provide a definitive diagnosis in the case of many muscle diseases. It is used to determine the site and extent of muscle damage and inflammatory changes, such as those that occur in myositis. Atrophy of type 2 fibers usually occurs early. Histochemical analysis of the biopsy specimen and electron microscopy enables differentiation of actin and myosin proteins of the myofilaments. The most common finding in diseased muscle is the disruption or destruction of the entire filament structure. These examinations are required for the definitive diagnosis of congenital myopathies. Diagnosis of autophagic vacuolar myopathy due to chloroquine, hydroxychloroquine, or colchicine currently requires electron microscopy that is costly and time-consuming. Immunohistochemical staining for either LC3- or p62-positive fibers, the percentage of which is significantly higher in the autophagic myopathy group compared to the normal control, improves the speed and accuracy of diagnosis (Lee et  al. 2012). Muscle cell necrosis and regeneration are the most prominent histological features in muscle biopsy specimens from patients with statin-associated autoimmune myopathy.

Management

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• Muscle imaging by CT and MRI can provide Management options for patients who do not information on the cross-sectional area of the tolerate statins include switching to low-dose, limb or axial muscles and is, therefore, useful non-daily doses of long-acting statins, such as in detecting muscle atrophy. MRI findings rosuvastatin and atorvastatin, and other non-­ may be nonspecific. Changes in muscles in statin lipid-lowering agents, such as ezetimibe autoimmune, paraneoplastic, and drug-­and colesevelam (Abd and Jacobson 2011). induced myositis tend to be symmetrical, Myopathic symptoms usually resolve after diswhereas infection, radiation-induced injury, continuing the offending statin, and the same and myonecrosis are focal asymmetric pro- statin can be restarted at a lower dosage, or cesses (Smitaman et al. 2018). patients can be switched to a different statin • Radioisotope techniques with muscle scan- (Gillett Jr and Norrell 2011). Because myotoxic ning after administration can be useful for events are more frequent at higher doses, statins detection of areas of muscles involved in that are effective at lower doses should be used. inflammatory myopathy. Supplementation with CoQ10 should be consid• Molecular diagnosis is useful for the evaluation ered based on demonstration of its decreased of a patient with muscle disease to identify the level in muscles with statin use. gene mutations causing the disease or increasA rare case of compartment syndrome due to ing susceptibility for developing drug-­induced simvastatin-induced myositis has been reported myopathy in the patient or in a family. and required 4-compartment fasciotomy (Walker et al. 2008). Controlled trials of coenzyme Q10 supplementation in statin myopathy have yielded Management contradictory results. Most patients with statin-induced myopathy The basic treatment is discontinuation of the offend- improve spontaneously after discontinuation of ing drug and symptomatic management of the com- the drug, with exception of statin-induced autoplications. The approach to management depends immune necrotizing myopathy, which is reverson the drug and the type of myopathy induced. ible with immunosuppressants if treatment is initiated early using oral prednisone or intraveMyopathy due to cholesterol-lowering nous immune globulin (Guemara et  al. 2017). agents  Diagnosis of statin myopathies should be Immune checkpoint inhibitors, emerging antibased on pathophysiologic mechanisms, pathol- cancer agents, are potential therapeutics for ogy as determined by biopsy, clearance properties statin-induced autoimmune necrotizing myopaof creatine kinase, drug challenge/dechallenge/ thy (Pasnoor et al. 2018). rechallenge, and differential diagnoses, rather than on temporal association with the drug to Corticosteroid myopathy  Corticosteroid reduce diagnostic errors and healthcare costs. myopathy is the most frequent drug-induced myopathy and is characterized by muscle weakMyopathy may be avoided by identifying ness without pain. It is usually reversible if the patients at risk of myotoxic effects such as the drug is withdrawn, if the dose is reduced, or if elderly or female patients, or those with concom- prednisone is substituted for a fluorinated glucoitant medications or impaired metabolic pro- corticoid, such as dexamethasone. Corticosteroid-­ cesses. In a case-control study including first- and induced muscle atrophy and weakness can be second-degree relatives, statin-induced muscle partially prevented or reversed by a program of toxicity was significantly associated with suscep- physical exercise. Experimental treatments tibility to malignant hyperthermia (Hedenmalm include insulin-like growth factor-I, branched-­ et al. 2015). Genetic analysis for mutations rele- chain amino acids, creatine, testosterone, nandrovant to statin myopathy may provide predisposi- lone and dehydroepiandrosterone, and glutamine tion testing for safe use of statins. (Pereira and Freire de Carvalho 2011).

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Myopathy due to neuromuscular blocking drugs  Management of these patients is mostly supportive, consisting of nutritional support, physical therapy, and gradual weaning from ventilatory support. According to published guidelines, neuromuscular blocking drugs should be used in critically ill patients only when necessary and when the depth of muscle paralysis can be monitored to avoid overdosing and accumulation of metabolites. Mitochondrial myopathy due to zidovudine  L-Carnitine used concurrently with AZT in patients with AIDS has been reported to rescue the myotubules and their mitochondria from the AZT-associated destruction and lipid storage. One possible rationale of this effect is the observation that muscle biopsy in patients with AIDS who have zidovudine-induced myopathy have a reduction in muscle carnitine levels. Management of drug-induced rhabdomyolysis  Guidelines recommended for the management of rhabdomyolysis are shown in Table 31.10. Table 31.10  Guidelines recommended for management of rhabdomyolysis Routine estimation of serum creatine kinase and urinary myoglobin Detection of localized areas of myonecrosis by CT scan Fluid replacement Bicarbonate infusion  To alkalinize urine and to prevent dissociation of myoglobin to its nephrotoxic  Metabolite ferrihemate Promotion of diuresis: mannitol  To dilute nephrotoxic substances  To flush through blocked renal tubules Treatment of complications of rhabdomyolysis  Hyperphosphatemia: oral phosphate-binding antacids  Hyperkalemia: usually corrects itself  Renal failure: dialysis  Disseminated intravascular coagulation: heparin useless  Compartment syndromes: decompressive fasciotomy  Seizures: anticonvulsants  Hyperthermia: cooling © Jain PharmaBiotech

References Abd TT, Jacobson TA. Statin-induced myopathy: a review and update. Expert Opin Drug Saf. 2011;10(3):373– 87. PMID 21342078. Adenis A, Bouché O, Bertucci F, et  al. Serum creatine kinase increase in patients treated with tyrosine kinase inhibitors for solid tumors. Med Oncol. 2012;29(4):3003–8. PMID 22447483. Bokuda K, Sugaya K, Tamura S, Miyamoto K, Matsubara S, Komori T.  Minocycline-associated rimmed vacuolar myopathy in a patient with rheumatoid arthritis. BMC Neurol. 2012;12:140. PMID 23171360. Camerino GM, Musumeci O, Conte E, et  al. Risk of myopathy in patients in therapy with statins: identification of biological markers in a pilot study. Front Pharmacol. 2017;8:500.** PMID 28798690. Chaouch N, Mejid M, Zarrouk M, et al. Isoniazid-induced myopathy. Rev Pneumol Clin. 2011;67(6):354–8. PMID 22137279. Coupal TM, Chang DR, Pennycooke K, Ouellette HA, Munk PL. Radiologic findings in gabapentin-induced myositis. J Radiol Case Rep. 2017;11(4):30–7. PMID 28567183. de Oliveira LP, Vieira CP, Da Ré Guerra F, de Almeida Mdos S, Pimentel ER.  Statins induce biochemical changes in the Achilles tendon after chronic treatment. Toxicology. 2013;311(3):162–8. PMID 23831763. Ding H, Li Z, Zhang J.  A case report of cyclosporine-­ induced myopathy with subacute muscular atrophy as initial presentation. Medicine (Baltimore). 2019;98(16):e15206. PMID 31008947. Egan A, Colman E.  Weighing the benefits of high-dose simvastatin against the risk of myopathy. N Engl J Med. 2011;365(4):285–7. PMID 21675881. Ferrera C, Vilacosta I, Vivas D, Olmos C.  Severe daptomycin-induced myopathy. Med Clin (Barc). 2012;139(3):138–9. PMID 22285497. Fleet JL, McArthur E, Patel A, Weir MA, MonteroOdasso M, Garg AX.  Risk of rhabdomyolysis with donepezil compared with rivastigmine or galantamine: a population-­ based cohort study. CMAJ. 2019;191(37):E1018–24. PMID 31527187. Galeotti L, Ceccherini F, Domingo D, et al. Association of the hOCT1/ABCB1 genotype with efficacy and tolerability of imatinib in patients affected by chronic myeloid leukemia. Cancer Chemother Pharmacol. 2017;79(4):767–73. PMID 28289867. Gillett RC Jr, Norrell A.  Considerations for safe use of statins: liver enzyme abnormalities and muscle toxicity. Am Fam Physician. 2011;83(6):711–6. PMID 21404982. Guemara R, Lazarou I, Guerne IA. Drug-induced myopathies. Rev Med Suisse. 2017;13(562):1013–7. PMID 28627846. Hazin R, Abuzetun JY, Suker M, Porter J. Rhabdomyolysis induced by simvastatin-fluconazole combination. J Natl Med Assoc. 2008;100(4):444–6. PMID 18481486.

References Hedenmalm K, Granberg AG, Dahl ML.  Statin-induced muscle toxicity and susceptibility to malignant hyperthermia and other muscle diseases: a population-­ based case-control study including 1st and 2nd degree relatives. Eur J Clin Pharmacol. 2015;71(1):117–24. PMID 25367069. Hohenegger M. Drug induced rhabdomyolysis. Curr Opin Pharmacol. 2012;12(3):335–9. PMID 22560920. Jianfei L, Min W, Chunlai M, Bicui C, Jiming Z, Bin W. The Ca2+/CaMKK2 axis mediates the telbivudine induced upregulation of creatine kinase: Implications for mechanism of antiviral nucleoside analogs’ side effect. Biochem Pharmacol. 2017;146:224–32. PMID 29038020. Jones JD, Kirsch HL, Wortmann RL, Pillinger MH. The causes of drug-induced muscle toxicity. Curr Opin Rheumatol. 2014;26(6):697–703. PMID 25191992. Katagiri S, Tauchi T, Saito Y, et al. Musculoskeletal pain after stopping tyrosine kinase inhibitor in patients with chronic myeloid leukemia: a questionnaire survey. Rinsho Ketsueki. 2016;57(7):873–6. PMID 27498732. Kolikonda MK, Cherlopalle S, Enja M, Lippmann S.  Atypical myopathy: pentazocine induced. Innov Clin Neurosci. 2015;12(3–4):24–6. PMID 26000202. Larsen S, Stride N, Hey-Mogensen M, et al. Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance. J Am Coll Cardiol. 2013;61(1):44–53. PMID 23287371. Lee HS, Daniels BH, Salas E, et  al. Clinical utility of LC3 and p62 immunohistochemistry in diagnosis of drug-induced autophagic vacuolar myopathies: a case-­ control study. PLoS One. 2012;7(4):e36221. PMID 22558391. Li D, Li A, Zhou H, et al. Uncover the underlying mechanism of drug-induced myopathy by using systems biology approaches. Int J Genomics. 2017;2017:9264034. PMID 28831389. Lo YC, Lin KP, Lin CY, et al. Fatigue as the only clinical manifestation of colchicine induced myopathy. Acta Neurol Taiwan. 2010;19(3):184–8. PMID 20824538. Luigetti M, Capone F, Monforte M, DiLazzaro V. Muscle cramps and weakness after teriparatide therapy: a new drug-induced myopathy. Muscle Nerve. 2013;47(4):615. PMID 23322619. Mammen AL.  Statin-associated autoimmune myopathy. N Engl J Med. 2016;374(7):664–9. PMID 26886523. Matas-García A, Milisenda JC, Selva-O’Callaghan A, et al. Emerging PD-1 and PD-1L inhibitors-associated myopathy with a characteristic histopathological pattern. Autoimmun Rev. 2020;19(2):102455.** PMID 31838162. Meador BM, Huey KA. Statin-associated changes in skeletal muscle function and stress response after novel or accustomed exercise. Muscle Nerve. 2011;44(6):882– 9. PMID 22102458. Musset L, Allenbach Y, Benveniste O, et al. Anti-HMGCR antibodies as a biomarker for immune-mediated necrotizing myopathies: a history of statins and experience from a large international multi-center study. Autoimmun Rev. 2016;15(10):983–93. PMID 27491568.

509 Pasnoor M, Barohn RJ, Dimachkie MM.  Toxic myopathies. Curr Opin Neurol. 2018;31(5):575–82.** PMID 30080718. Pearse R, Visagan R, Reddy K, Dev S.  Drug-induced paraspinal myositis mimicking acute bilateral sciatica. BMJ Case Rep. 2019;12(2);pii: bcr-2018-224480. PMID 30796068. Pereira RM, Freire de Carvalho J. Glucocorticoid-induced myopathy. Joint Bone Spine. 2011;78(1):41–4. PMID 20471889. Ronnqvist J, Hallberg P, Yue QY, Wadelius M.  Fusidic acid: a neglected risk factor for statin-­ associated myopathy. Clin Med Insights Cardiol. 2018;12:1179546818815162. PMID 30618488. Saraswat N, Verma R, Neema S, Kumar S.  A case of capecitabine-induced dermatomyositis. Indian J Pharmacol. 2018;50(6):350–3. PMID 30783329. SEARCH Collaborative Group. SLCO1B1 variants and statin-induced myopathy--a genomewide study. N Engl J Med. 2008;359(8):789–99. PMID 18650507. Selimoglu O, Basaran M, Ugurlucan M, Ogus T.  Rhabdomyolysis following accidental intraarterial injection of local anesthetic. Angiology. 2009;60(1):120–1. PMID 18388104. Shah R, Venkatesan P.  Drug-induced myopathy in a patient with pulmonary tuberculosis. BMJ Case Rep. 2015;2015. PMID 26177994. Sheik Ali S, Goddard AL, Luke JJ, et al. Drug-associated dermatomyositis following ipilimumab therapy: a novel immune-mediated adverse event associated with cytotoxic T-lymphocyte antigen 4 blockade. JAMA Dermatol. 2015;151(2):195–9. PMID 25321335. Simsek Ozek N, Bal IB, Sara Y, Onur R, Severcan F.  Structural and functional characterization of simvastatin-­induced myotoxicity in different skeletal muscles. Biochim Biophys Acta. 2014;1840(1):406– 15. PMID 24045089. Smitaman E, Flores DV, Mejía Gómez C, Pathria MN.  MR imaging of atraumatic muscle disorders. Radiographics. 2018;38(2):500–22. ** PMID 29451848. Soliman M, Akanbi O, Harding C, El-Helw M, Anstead M.  Voriconazole-induced myositis in a double lung transplant recipient. Cureus. 2019;11(2):e3998. PMID 30989007. Uri O, Behrbalk E.  Tissue necrosis following intramuscular administration of various drugs (Nicolau syndrome): clinical presentation, pathophysiology and treatment. Harefuah. 2009;148(3):186–8, 209. PMID 19485279. Walker JL, Smith GH, Gaston MS, Robinson CM. Spontaneous compartment syndrome in association with simvastatin-induced myositis. Emerg Med J. 2008;25(5):305–6. PMID 18434476. Wang M, Da Y, Cai H, Lu Y, Wu L, Jia J.  Telbivudine myopathy in a patient with chronic hepatitis B. Int J Clin Pharm. 2012;34(3):422–5. PMID 22527478. Yang CY, Park SA, Kim HS, Shin YI.  Polymyositis in patients taking antiviral clevudine therapy: a report of two cases. NeuroRehabilitation. 2010;26(2):159–62.

Drug-Induced Spinal Disorders

Introduction Drugs may affect the spinal column or the spinal cord. Various adverse effects will be discussed according to the classification shown in Table 32.1.

Clinical Manifestations Clinical manifestations of spinal disorders are quite variable and may be reported as adverse effects without any mention of involvement of the spine or the spinal cord. A patient may report only backache or sensory disturbances below the level of lesion in the spinal cord or only impairment of bladder function. Motor impairment may be reported as paraplegia or quadriplegia or by the term “transverse myelitis.” Very high cervical lesions may produce respiratory difficulties. Some processes such as steroid-induced epidural lipomatosis may produce the same clinical picture as an intraspinal neoplasm.

Backache Backache is a nonspecific symptom. It may be due to any drug producing generalized myositis or musculoskeletal pain. Filgrastim (recombinant

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Table 32.1  Classification of drug-induced neurological disorders of the spine and spinal cord Backache Affection of the spinal column Affections of the spinal cord  Toxicity of intrathecal agents  Drug-induced myelopathies  Anterior horn cells and nerve root lesions  Intraspinal/extradural hemorrhage Lhermitte’s sign © Jain PharmaBiotech

granulocyte colony-stimulating factor) is associated with musculoskeletal pain in 20% of the cases, and in some, the only complaint is backache. The pathomechanism is not known, but the bone pain may be associated with increased hematopoiesis induced by the drug. Backache may be the result of the degenerative process in the intervertebral disc, or it may also be a symptom of serious intraspinal events such as hematomyelia. Streptokinase infusion has been reported to produce severe low-back pain which sometimes radiates down to the lower extremities and resolves promptly on discontinuation of the drug. The pathomechanism is not known, but backache has not been reported with tissue plasminogen activator, which is used for the same indication, i.e., for dissolving the clot in coronary artery thrombosis.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_32

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Drugs Affecting the Vertebral Column Vertebral column is affected by all drugs affecting the skeletal system, and the discussion of this topic is beyond the scope of this work. Drugs producing osteoporosis can lead to fractures of the vertebrae and compression of the spinal cord. Deformities of the spinal column may be due to muscular disorders induced by drugs. A case of intractable backache secondary to vertebral compression has been reported after intravertebral alcohol injection for the treatment of vertebral hemangioma (Heiss et al. 1996). This required surgical treatment involving removal of the vertebral body and spinal fusion. Histological examination of the vertebral tissue showed focal osteonecrosis.

Toxicity of Intrathecal Agents Several drugs, when introduced into the intrathecal space either for diagnostic or therapeutic purposes, or inadvertently, may produce undesirable effects on the spinal cord or its coverings (Table 32.2).

 dverse Effects of Intrathecal Drug A Administration Adverse effects due to intrathecally administered drugs and biologicals include the following: • The most well-known adverse effect with intrathecal therapy is drug-induced aseptic or chemical meningitis due to direct irritation of the meninges by the drug. This usually resolves on discontinuation of the drug. Chemical meningitis accounts for half of the Table 32.2  Intrathecal drugs that may affect the spinal cord adversely Antineoplastic agents Baclofen Chymopapain Corticosteroids Lidocaine for spinal anesthesia Morphine Radiologic contrast materials

•

• •

•

serious complications of an intrathecal injection of methylprednisolone. Reactions to preservative solutions can produce arachnoiditis. The intrathecal administration of solutions preserved with benzyl alcohol has been shown to increase the risk of adverse neurological events. Spinal injection should not contain any preservatives (such as benzyl alcohol or polyethylene glycol). High concentrations of local anesthetics in the cerebrospinal fluid are neurotoxic. Other reported complications of intrathecal administration of drugs include transverse myelitis, cauda equina syndrome, lumbar radiculitis, and urinary retention. Some complications of intrathecal administration are due to drugs not meant to be given by this route of administration. Severe neurologicalcomplications have been reported to be associated with inadvertent administration of methadone by means of implanted intrathecal catheters to a group of patients.

I ntrathecal Antineoplastic Agents Leukoencephalopathy (see Chap. 13) and aseptic meningitis (see Chap. 11) have been reported as complications of this treatment. Two serious complications relevant to the spinal cord are ascending myelopathy and paraplegia. Over 60 such cases have been reported, some of whom recovered partially or completely, some remained permanently paraplegic, while there were deaths either due to complications associated with myeloencephalopathy or progression of malignancy. Methotrexate (MTX)  MTX is given intrathecally and usually combined with radiation therapy as prophylaxis against meningeal involvement in leukemias. Ascending myelopathy leading to quadriplegia and respiratory difficulties have been reported following intrathecal methotrexate. In one case, ascending spinal cord necrosis and polyradiculopathy following intrathecal MTX therapy led to respiratory failure and death (Bellon et al. 1995). Although there are several case reports of paraplegia following intrathecal MTX therapy, overall frequency of occurrence of paraplegia remains low.

Clinical Manifestations

In some series, no case of paraplegia was observed in patients where intrathecal methotrexate was used for the prophylaxis of meningeal leukemia or acute lymphoblastic leukemia. One case of leukoencephalopathy with predominant involvement of the cervical spinal cord was reported following intrathecal methotrexate and radiotherapy (Case Records of the Massachusetts General Hospital 1984). In this case, there was massive destruction of both the gray and the white matter of the spinal cord predominantly in the dorsal and lateral columns. Edema associated with necrosis extended down to the sacral region. Histological examination showed that the destruction involved both the myelin and the axons with formation of axon retraction balls, a finding previously reported in methotrexate leukoencephalopathy. The pathomechanism is not fully understood, but it is like that of methotrexate-induced encephalopathy (see Chap. 13). The findings cannot be explained by the effect of radiotherapy alone. In the case of a woman with breast cancer and meningeal carcinomatosis who developed severe progressive myelopathy after intrathecal MTX administration, high doses of the key metabolites of the methyl-transfer pathway (S-adenosylmethionine, folinate, cyanocobalamin, and methionine) were substituted with improvement in paraparesis as shown by MRI (Ackermann et  al. 2010). Genetic analysis in this case revealed homozygosity for the Allele of methylene tetrahydrofolate reductase, whereas other genetic variants of folate/methionine metabolism associated with MTX neurotoxicity were not present. Substitution with multiple folate metabolites may be a promising strategy for the treatment of MTX-induced neurotoxicity. Intrathecal administration of cytosine arabinoside is used to treat leptomeningeal metastases. Diagnosis and management  If the onset of paraplegia is acute after intraspinal injection, in cancer patients with thrombocytopenia, the possibility of acute subdural or extradural hemorrhage should be considered. If the onset is subacute, the differential diagnosis includes the following:

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• Infiltration of the nerve roots with tumor • Metastatic lesions of the spinal cord • Radiation myelopathy if radiotherapy has been used previously Preservative-free solutions and diluents should be used for MTX injection. Steroids have been used for the treatment, but the use of intrathecal steroids carries the risk of spinal arachnoiditis. Cytosine arabinoside (Ara-C)  Intrathecal administration of Ara-C is used to treat leptomeningeal metastases and can cause a transverse myelopathy like that seen with intrathecal methotrexate (Kwong et al. 2009). A 22-year-old male with malignant immunoblastic leukemia was reported to develop a “locked-in” syndrome within 48 hours of receiving a single 100  mg intrathecal dose of Ara-C plus intravenous Ara-C, cisplatin, and doxorubicin, and remained quadriplegic but alert until his death 3  weeks later (Kleinschmidt-DeMasters and Yeh 1992). Autopsy showed infarction of the medulla and the spinal cord. Another case of myelopathy has been reported in a patient on a combination of Ara-C and fludarabine.

Pathomechanism of Ara-C neurotoxicity  This has been reviewed in Chap. 13. Ara-C is detoxified in peripheral tissues by a ubiquitous enzyme, cytidine deaminase, but this enzyme is almost absent in the brain and the CSF. Intrathecal AraC, particularly when combined with intravenous Ara-C, can have additive toxic effects. No data is available to establish the correlation between Ara-C metabolites in CSF and neurotoxicity, and without routine monitoring of concentration of Ara-C in the CSF, it is difficult to ascertain the schedule of IT Ara-C which maximizes dose intensity and minimizes neurotoxicity. Therefore, an interval of at least 2–3  days should elapse between Ara-C treatments.

Baclofen Adverse effects of intrathecal baclofen therapy include the following:

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• Drowsiness. • Psychosis has been reported during therapy with baclofen but resolves after discontinuation of the drug. • Autonomic dysreflexia. • Drug-induced seizures. Structural brain disease seems to be a prerequisite for baclofen-­ induced seizures because they have not been reported to occur in patients receiving intrathecal baclofen for spasticity of solely spinal origin. Abrupt cessation of long-term baclofen therapy in such patients has been associated with various forms of seizure activity. Caution should be exercised with major reductions in dosage or discontinuation of baclofen therapy. Intravenous diazepam or phenobarbital or both are suggested for control of these seizures. • After prolonged use, an increase in intrathecal baclofen dose may result in paradoxical unresponsiveness to baclofen, manifesting as increased tone and functional decline, which can be improved by reduction of dose. • Severe withdrawal symptoms. These can occur if intrathecal baclofen is abruptly withdrawn due to equipment malfunctions or human error. Several cases have been reported over the preceding decade, including some deaths. Warning signs of advanced intrathecal baclofen withdrawal syndrome include autonomic dysreflexia, sepsis, malignant hyperthermia, neuroleptic malignant syndrome, or other conditions associated with hypermetabolic state or widespread rhabdomyolysis. Delirium has been associated with baclofen withdrawal and resolves completely on reinstatement of the drug. High-dose oral or enteral baclofen administration is recommended until restoration of intrathecal baclofen therapy is possible under the guidance of an experienced clinician. If this is not possible or is unlikely to be beneficial, benzodiazepines may be administered intravenously until intrathecal baclofen therapy is restored. Another strategy for prevention of baclofen withdrawal syndrome is tapering of the infusion and simultaneous substitution with progressively higher doses of oral antispasmodics (Bellinger et al. 2009). Withdrawal due to low

32  Drug-Induced Spinal Disorders

pump reservoir levels can be avoided by refilling before the lowest level at which the alarm sounds is reached or resetting the alarm at a level higher than recommended. • A case of myelopathy following intrathecal baclofen has been reported. However, baclofen in concentrations of 2000 mug/ml (higher than those used in patients) has failed to show any adverse effect on meninges, nerve roots, or the spinal cords in toxicology studies using dogs.

Chymopapain This is a proteolytic enzyme derived from the fruit Carica papaya and is used for chemonucleolysis, i.e., injection into the intervertebral disc space for the treatment of herniated lumbar disc. A case of paraplegia at the 10th thoracic level was reported, which developed 1 week after chemonucleolysis of the last three lumbar discs (Smith and Brown 1967). At surgery, hemorrhagic arachnoiditis was found and the cause was not ascertained but postulated to be related to the hemorrhage from the procedure interacting with the retained oily contrast medium used for myelography. Further cases of paraplegia were reported, but the pathomechanism was not determined. In some cases chymopapain injection was considered to cause extrusion of a degenerated lumbar disc and surgery was required to remove it. As newer and safer techniques are available for the treatment of lumbar intervertebral disc lesion, chymopapain is rarely used these days. Corticosteroids In the 1960s, intrathecal methylprednisolone was used for the treatment of arachnoiditis due to Pantopaque myelography and other causes and was claimed to be safe (Sehgal et  al. 1963). Depo-Medrol, the preparation used for this purpose, contains a carrier, polyethylene glycol, which may produce arachnoiditis and myelitis. The intrathecal use of this product is ­contraindicated. Repeated epidural injections of steroids over long periods may also induce extradural lipomatosis. Bacterial meningitis and cauda equina syndrome have been reported after epidural steroid injection. Two cases have been

Clinical Manifestations

reported of intrinsic cervical spinal cord damage which occurred when cervical epidural steroid injections were administered while the patient was under sedation (Hodges et al. 1998).

Lidocaine Intrathecal lidocaine is used for spinal anesthesia. Neurological deficits following spinal anesthesia are rare. Two cases of persistent sacral nerve root deficits were reported after continuous spinal anesthesia performed with high-dose hyperbaric lidocaine using a microcatheter (Schell et al. 1991). In the immediate postoperative period, there were lower extremity paresis, perianal anesthesia, and urinary retention. Perianal hypesthesia and difficulty with defecation persisted. Transient radicular irritation after hyperbaric lidocaine leading to backache has also been reported (Newman et al. 1997). Six cases of cauda equina syndrome were reported in association with spinal anesthesia using hyperbaric 5% lidocaine (Loo and Irestedt 1999). These effects were likely the result of direct neurotoxicity and persisted in all the six patients at follow-up 5–17 months after spinal anesthesia. The authors recommended that hyperbaric lidocaine should not be administered in concentrations greater than 2% and the total dose should not exceed 60 mg. Morphine Epidural or intrathecal infusion of morphine and bupivacaine mixtures is presently used for the treatment of refractory cancer pain. It is difficult to evaluate any involvement of the spinal cord in patients with advanced malignancy with extension to the spinal cord who have been treated with neurotoxic chemotherapy. In an autopsy study of patients who had received these treatments, several lesions of the spinal cord as well as thickening of the leptomeninges were noted (Sjöberg et  al. 1992). The role of intrathecal morphine in the pathogenesis of these lesions cannot be assessed. Patients undergoing repair of a thoracoabdominal aortic aneurysm suffer from transient spinal cord ischemia, and in one case, epidural morphine for relief of pain during this period produced paraplegia, which was reversed with naloxone (Kakinohana et al. 2003). The authors

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studied this problem further on a rat spinal ischemia model to define the effects of intrathecal morphine administered at various times after reflow on behavior and spinal histopathology. Their findings show that during the immediate reflow following a noninjurious interval of spinal ischemia, intrathecal morphine potentiates motor dysfunction. Reversal by naloxone suggests that this effect results from an opioid receptor-­ mediated potentiation of a transient block of inhibitory neurons initiated by spinal ischemia.

 adiologic Contrast Materials R The older oily contrast materials such as Pantopaque for myelography were considered to react with blood introduced into the CSF from a traumatic lumbar puncture and produce arachnoiditis. In a review of 111 cases of myelography with Pantopaque, 12.6% had pain in the sacrum and buttocks following the procedure (Keogh 1974). Newer water-soluble contrast media are safer, but rare cases of transient paraplegia have been reported following metrizamide myelography.

Drug-Induced Myelopathy The term “myelopathy” means functional disturbances of the spinal cord or nonspecific pathological processes involving the substance of the spinal cord. The term “myelitis” indicates an inflammatory process involving the spinal cord. Apart from drugs introduced intrathecally, systemically given drugs may cross the BBB and have a direct toxic effect on the spinal cord. Myelopathy may also be caused indirectly by the drugs which impair the spinal cord circulation by hypotension or by inducing vasospasm or vasculitis of the spinal arteries. Myelopathy is not always an isolated finding. It may be associated with involvement of the brain when the term “encephalomyelopathy” is used or may be accompanied by polyneuropathy when the term “myeloneuropathy” is used. Drugs associated with myelopathy are listed in Table 32.3.

516 Table 32.3 Drugs reported to be associated with myelopathy Antineoplasticsa  Cisplatin  Cladribine  Cytosine arabinoside  Docetaxel  Doxorubicin  DFMO  Fludarabine  Immune checkpoint inhibitors  Interferon alpha  Methotrexate  Mitoxantrone  Taxotere  Thiotepa  Vincristine Corticosteroidsa Cyclosporine Folic acid Germanium Heroina Muzolimine Nitrous oxide Penicillin Vaccinesa: antirabies, hepatitis B, influenza, measles/ mumps/rubella, tick-borne encephalitis Well documented. Other drugs have isolated case reports; causal relationship is not established

a

Antineoplastics Neurotoxicity of antineoplastic agents was discussed in Chap. 9. Systemic use of cytosine arabinoside, cisplatin, and methotrexate has been reported to induce myelopathy. Cytosine arabinoside (Ara-C)  Given as a lowdose intravenous infusion, Ara-C has been reported to produce myelopathy in a patient with leukemia. (Hoffman et  al. 1993). This patient developed urinary retention and decreased sensation below T7 dermatome on the 23rd day of therapy when hematological recovery had already occurred. CT scan and myelography did not show any lesion, but CSF examination showed pleocytosis and elevated protein. There was no evidence of involvement of the spinal cord by leukemia. This patient eventually developed an encephalopathy but recovered from it, but the myelopathy remained unchanged. Adverse effects of combination of intravenous Ara-C with intrathecal Ara-C have already been discussed.

32  Drug-Induced Spinal Disorders

Cisplatin  Cisplatin is associated with several other manifestations of neurotoxicity such as ototoxicity, leukoencephalopathy, seizures, and peripheral neuropathy. Lhermitte’s sign (sudden electric shock-like sensation traveling down the spine to the legs after flexion of the neck), which indicates pathology of the spinal cord such as demyelinating disease, tumor, or radiation myelopathy, has been reported after cisplatin therapy (Dewar et al. 1986; Eales et al. 1986; List and Kummet 1990; Walther et al. 1987). This myelopathy usually resolves after discontinuation of cisplatin, but sensory and motor deficits persist in some cases. Paraneoplastic myelopathy was ruled out in these cases as it usually precedes the diagnosis of cancer and improves with treatment of cancer. Direct involvement of the spinal cord with malignancy was also ruled out in these cases. Immune checkpoint inhibitors  These agents block specific immune checkpoint molecules (programmed cell death protein 1 and its ligand as well as cytotoxic T-lymphocyte-associated antigen 4) that normally downregulate the immune response. These new agents show a specific range of adverse effects induced by abnormal immunologic activation. Myelopathy has been reported among various neurological complications of immune checkpoint inhibitors (Astaras et al. 2018).

Corticosteroids Epidural lipomatosis or collection of unencapsulated fat in the extradural space can occur in Cushing’s syndrome (Nöel et al. 1992). It is a rare but well-known complication of chronic corticosteroid therapy, and over 31 cases have been reported in the literature (Bischoff 1988; Kaneda et al. 1984; Laroche et  al. 1993; Roy-Camille et  al. 1991; Taborn 1991; Zampella et al. 1987). The epidural mass can lead to compression of the spinal cord. Clinical manifestations include sensory and motor loss, weakness of the limbs, and sphincter disturbances. These may progress to inability to walk and paraplegia. Diagnosis is established by CT scan (Buthiau et  al. 1988; Jungreis and Cohen 1987) and/or myelography. First-line treatment is reduction of dose of corticosteroids. There may be some regression of the mass after discontinuation of steroids, but surgical decompression with exci-

Clinical Manifestations

sion of extradural fat mass may be necessary (Haddad et  al. 1991). Eleven of the 13 cases reviewed by Roy-Camille et al. (Roy-Camille et al. 1991) had surgical treatment with good results. Cases of distal spinal cord and conus injury with resulting paraplegia have been reported following transforaminal corticosteroid injections at lumbar levels conforming with the probability of radicular-medullary arteries forming an arteria radicularis magna at lumbar levels (Kennedy et al. 2009). In these cases, particulate formulation of corticosteroids was used, which promotes embolization in a radicular artery as the likely mechanism of injury. The risk of this complication can be reduced, and potentially eliminated, by using particulate free steroids, testing for intra-arterial injection with digital subtraction angiography, and a preliminary injection of local anesthetic.

Cyclosporine Spastic paraparesis developed in a man after he took cyclosporine following a liver transplant (Jalan et  al. 1994). The patient’s cyclosporine levels ranged between 180 and 280 nmol/L (therapeutic range 170–240). The cyclosporine dose was reduced to maintain a trough level between 70 and 100 nmol/L, and his paraparesis gradually improved. The reason for this patient’s sensitivity to cyclosporine dose at the upper limit of therapeutic range is not clear. Other cases of reversible symmetrical polyneuropathy with paraplegia have been reported following use of cyclosporine in conjunction with transplantation (Jalan et  al. 1994; Terrovitis et al. 1998). The patient recovered after tapering of the dose of cyclosporine.  iscellaneous Agents That Induce M Myelopathy Folic acid  When given to patients with vitamin B12 deficiency, folic acid can aggravate subacute combined degeneration of the spinal cord. Germanium  Kamijo et  al. (1991) reported the case of a girl who had been given preparations containing germanium compounds for 28 months and developed various symptoms of neurotoxicity. She died of renal failure, and postmortem examination showed gliosis and degeneration of the dorsal columns of the spinal cord.

517

Heroin  There are several reports of transverse myelitis as a complication of intravenous heroin abuse. There is usually swelling of the spinal cord at the site of the lesion, and in some cases, there is evidence of vasculitis as a cause of these lesions. The pathomechanism is not known, but it may be a hypersensitivity reaction to some of the diluents used in the preparation of the solution for injection. Muzolimine  Pohlman-Eden et  al. (1991) described seven patients with renal failure who developed fatal myeloencephalopathy after treatment with high doses of muzolimine, a diuretic. The most severe deficits like severe tetraspastic paresis were seen in non-dialyzed renal insufficiency patients leading to the hypothesis that a partially dialyzable toxic metabolite of muzolimine may be responsible for this complication. Nitrous oxide  Myeloneuropathy has been described as a sequel of chronic exposure to nitrous oxide for recreational purposes. No evidence of impaired neurological function was found in dentists who utilized nitrous oxide in their practices. There are several case reports of patients who developed paraplegia after nitrous oxide anesthesia. In some of these, the risk factor was vitamin B12 deficiency which was corrected after the onset of neurological deficit; one of these recovered completely (King et  al. 1995), the second improved (Rosener and Dichgans 1996), whereas the third who also had phenylketonuria did not improve (Lee et  al. 1999). Holloway and Alberico (1990) reported two patients with undiagnosed B12 deficiency who developed myelopathy after prolonged spinal surgery under nitrous oxide anesthesia. This was corrected by administration of vitamin B12, and the patients recovered. Nitrous oxide produces multifocal reversible symptoms in the nervous system like those of vitamin B12 deficiency. Neurological dysfunction is due to progressive demyelination sometimes followed by axonal loss. It is like subacute combined degeneration of the spinal cord and may be accompanied by polyneuropathy. There is a published case of a 22-year-old male with daily abuse of inhaled nitrous oxide in the

518

form of “Whip-its,” who presented with initial symptoms of presumed drug-induced psychosis and gradually developed neurological focal deficits, and findings of sensorimotor peripheral neuropathy with myelopathy of the cervical spine and vitamin B12 deficiency (Al-Sadawi et al. 2018). Pathomechanism The mechanism responsible for neurotoxicity of and myelotoxicity of nitrous oxide involves the inhibition of methionine synthase (MetSyn) and resulting reduction in S-adenosylmethionine (SAM) and tetrahydrofolate (THF). Nitrous oxide inactivates vitamin B12 and prevents its utilization, whereas in subacute combined degeneration of pernicious anemia, there is problem with the absorption of B12. Management  The following methods have been used: Discontinuation of nitrous oxide and treatment with vitamin B12. Partial to complete recovery followed in most of the cases reported. Folinic acid and methionine have been shown to protect against megaloblastosis and neurotoxicity occurring following nitrous oxide administration. Methionine is converted to SAM and elevates the SAM/SAH methylation ratio, thereby enhancing methylation of myelin. Penicillin  Tesio et al. (1992) reviewed six cases from literature and presented two further cases of paraplegia following intramuscular injection of penicillin in the gluteal region. Another case was reported by Runge and Röder (1989). The hypothesized pathomechanism is inadvertent injection of penicillin into the superior gluteal artery with retrograde propulsion of the drug into the aorta and entry into the anterior spinal artery which may be obstructed or undergo spasm. The resulting paraplegia is usually irreversible, and in one case of Tesio et al. (1992), MRI some years later showed spinal cord atrophy which could be the sequel of spinal cord infarction. Vaccines  In rare cases, vaccines may be associated with autoimmune phenomena such as trans-

32  Drug-Induced Spinal Disorders

verse myelitis. The associations of different vaccines with a single autoimmune phenomenon suggest that a common denominator of these vaccines, such as an adjuvant, might trigger this syndrome (Agmon-Levin et al. 2009). Semple antirabies vaccine  This is a suspension of phenol-inactivated rabies virus in the brains of sheep and is used in many developing countries. Neuroparalytic complications occur in about 1:2200 cases. Guillain-Barré syndrome has been reported in association with this virus (see Chap. 37). Swamy et  al. (1992) reported a case of Brown-Sequard syndrome due to Semple antirabies vaccine who recovered completely with immunosuppressive therapy. Bahri et  al. (1996) who also reported a case of myelitis are of the opinion that Semple-type adult animal nerve tissue vaccine produces an unacceptable rate of severe postvaccinal neurological complications in adults and that human diploid cell rabies vaccine should be used for postexposure rabies vaccination. Hepatitis B vaccine  This has been reported to be associated with myelitis in three case reports (Shaw et al. 1988; Travisani et al. 1993; Mahassin et  al. 1993). The causal link in these cases was based on the temporal relationship and exclusion of other causes of myelitis. The pathomechanism is not known but may be like that of vaccine-­ associated encephalomyelitis (see Chap. 13). Vaccine against tick-borne encephalitis (TBE)  This has been reported to be associated with various neurological complications including a case of subacute myeloradiculopathy which recovered (Goerre et al. 1993). Measles, mumps, and rubella vaccine  A case of transverse myelitis with flaccid paraplegia and a sensory level at T1 level is reported in a 20-year-­ old man following vaccination (Joyce and Rees 1995). The patient was treated with intravenous steroids with slight improvement, but paralysis persisted below T6 level. There are three other cases of transverse myelitis associated with rubella vaccine.

Clinical Manifestations

Influenza vaccine  One case of Brown-Sequard syndrome occurred in a patient following the administration of trivalent influenza vaccine (Antony et al. 1995). The patient responded well to intravenous steroids and physical therapy. Another reversible paralytic syndrome was reported following influenza virus vaccination (Aggarwal et al. 1995). It was possibly a postviral or postvaccinial autoimmune illness that was triggered by influenza vaccine.

 esions of the Anterior Horn Cells L and Anterior Nerve Roots Anterior horn cells are usually resistant to neurotoxic effects of pharmaceutical agents. Leys and Petit (1990) reported a case with lesions of the anterior horn cells as shown on EMG developing after polyradiculopathy following amitriptyline therapy. Poliomyelitis resulting from vaccine to prevent it is an example of adverse reaction involving anterior horn cells. Mermel et  al. (1993) reported a case of vaccine-associated poliomyelitis in an immunocompetent man who had received a threedose primary series of oral polio vaccine as a child. MRI showed high signal abnormalities in the anterior horn cells. The overall risk of paralytic poliomyelitis associated with oral polio vaccine in the United States is one case per 2.5 million doses (Prevots et al. 1994). In Latin America, the overall risk of vaccine-­associated paralytic poliomyelitis is one case per 1.5–2.2 million doses of oral poliovirus vaccine administered. Since polio is eradicated and there are no vaccination programs, adverse effect reports are lacking.

Drug-Induced Lhermitte’s Sign This sign is elicited by flexion of the neck leading to sudden electric sensation traveling down the spine to the arms and legs. Neck flexion leads to the stimulation of abnormally excited demyelinated nerve fibers and leads to the generation of ectopic sensory discharges in nerves. It was first reported as a symptom of multiple sclerosis (Lhermitte 1920). It is associated with a few other conditions which include the following:

519

• Cervical spondylosis • Cervical spinal cord tumor • Subacute combined degeneration of the spinal cord • Radiation myelopathy • Bone marrow transplantation • Drugs: chemotherapy, nitrous oxide, withdrawal from selective serotonin reuptake inhibitors Bone marrow transplantation (BMT)  Wen et  al. (1992) reported four patients who developed Lhermitte’s sign after BMT.  The cause is not clear, but multiple factors are involved in such patients which include the use of immunosuppressants such as cyclosporine and antineoplastic agents with potential for myelotoxicity. Drugs  Lhermitte’s sign has been reported in patients with myelopathy resulting from nitrous oxide abuse (Vishnubhakat and Beresford 1991). It is seen in cisplatin chemotherapy (Martinez Lopez et al. 1995). Van den Bent (1998) observed a transient Lhermitte’s sign in 5 of 87 patients treated with more than two cycles of docetaxel which developed either concurrently or after the onset of docetaxel-induced sensory neuropathy and disappeared after the discontinuation or dose reduction of chemotherapy. Withdrawal from selective serotonin reuptake inhibitors (SSRIs)  Brief electric shocks throughout the body, which last 1 or 2 seconds, have been reported during withdrawal from SSRIs (Bryois et  al. 1998). One patient with Lhermitte’s sign was reported after withdrawal from paroxetine therapy (Reeves and Pinkofsky 1996).

Drug-Induced Spinal Hemorrhage Spinal cord hemorrhages are rare conditions that can be classified based on the primary location of bleeding as intramedullary (hematomyelia), subarachnoid hemorrhage, subdural hemorrhage, and epidural hemorrhage. Hemorrhage is usually due to anticoagulants, but thrombolytic therapy and aspirin may also cause it.

32  Drug-Induced Spinal Disorders

520

Anticoagulants  Intracranial hemorrhage as a complication of anticoagulant therapy has been discussed in Chap. 23. Unlike intracranial hemorrhage, which is mostly subdural or intracerebral, intraspinal hemorrhage due to anticoagulants is mostly extradural and in the thoracic region. The spinal extradural space is large and has profuse venous plexuses. Rupture of one of the delicate veins is followed by considerable bleeding in the extradural space. Trauma or lumbar puncture performed inadvertently in a patient on anticoagulants may start such a bleeding. The patient may become paraplegic in a short time. The diagnosis can be confirmed by CT scan or MRI. Prompt surgical evacuation of the hematoma, which is usually located posteriorly, leads to recovery of function of the spinal cord. Less frequent anteriorly located hematomas may be more difficult to evacuate and require an anterior surgical approach to the spine. Paraplegia was reported to be caused by spontaneous epidural hemorrhage in a patient undergoing rivaroxaban therapy for atrial fibrillation (Feret et  al. 2020). Although rivaroxaban, a new oral anticoagulant, has been shown to be more effective than warfarin in stroke prevention in patients with atrial fibrillation, physicians must remember that its use also carries the risk of major bleeding. Subarachnoid as well as subdural hemorrhage was found on surgery in a patient on anticoagulant therapy who experienced sudden excruciating back pain and became paraplegic (Bernsen and Hoogenraad 1992). Brown-Sequard syndrome (lesion of one-half of the spinal cord leading to ipsilateral paralysis and loss of position sense with contralateral loss of pain and temperature sense) has been reported in a patient with subarachnoid hemorrhage due to anticoagulants (Koehler and Kuiters 1986). After substitution of coagulation factors, subdural hematoma can be managed by irrigation and suction drainage through a catheter placed in the subarachnoid space via lumbar puncture. Intramedullary hemorrhage due to anticoagulation is rare. The outlook for recovery from paraplegia is poor after evacuation of the intramedullary hematoma.

Low molecular weight heparin (enoxaparin)  From 1993 to 1998, the FDA received reports of 43 patients in the United States who had spinal or epidural bleeding after receiving enoxaparin mostly for prophylaxis of deep vein thrombosis associated with surgery (Wysowski et al. 1998). Emergency laminectomy to evacuate the hematoma was performed in 28 of these patients, and permanent paraplegia often due to delay in diagnosis occurred in 16 patients. The following risk factors were identified in these patients: • Use of higher than recommended doses • Administration to patients before establishing hemostasis in surgery • Use of epidural catheters and spinal puncture • Concomitant administrations of medications known to increase bleeding • Vertebral column abnormalities • Old age The incidence of spinal hemorrhage is low considering that 33 million doses of enoxaparin were dispensed during 1993–1998 (Chaikin et al. 1998). Currently, enoxaparin product labeling includes a warning about this potential complication. Thrombolytic therapy  A case of intramedullary spinal cord hemorrhage has also been reported after streptokinase treatment for myocardial infarction (Cruickshank et al. 1992). Aspirin  Several cases of spinal extradural hematoma have been reported in patients on use of aspirin as a low-dose prophylaxis or excessive intake. Because aspirin is widely used, its role in causing spinal epidural hematoma remains conjectural. However, coagulation abnormalities and improvement after discontinuation of aspirin point to a causal link.

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522 Komp DM, Fernandez CH, Falletta JM, et al. CNS prophylaxis in acute lymphoblastic leukemia. Comparison of two methods. A Southwest Oncology Group Study. Cancer. 1982;50:1031–6. Kwong YL, Yeung DY, Chan JC. Intrathecal chemotherapy for hematologic malignancies: drugs and toxicities. Ann Hematol. 2009;88:193–201. Laroche F, Chemouilli P, Carlier R, et  al. Efficacy of conservative treatment in a patient with spinal cord compression due to corticosteroid-induced epidural lipomatosis. Rev Rhumatisme. 1993;60:729–31. Lear J, Rajapakse R, Pohl J.  Low back pain associated with streptokinase. Lancet. 1992;340:851. Lee P, Smith I, Piesowicz A, et  al. Spastic paraparesis after anaesthesia. Lancet. 1999;353(9152):554. Leys D, Petit H. Clinical signs of amyotrophic lateral sclerosis developing after polyradiculoneuropathy associated with amitriptyline. BMJ. 1990;300:614. Lhermitte J. Les formes doloureuses de la commotion de la moelle epiniere. Rev Neurol. 1920;36:257–62. List AF, Kummet TD. Spinal cord toxicity complicating treatment with cisplatin and etoposide. Am J Clin Oncol. 1990;13:256–8. Loo CC, Irestedt L. Cauda equina syndrome after spinal anaesthesia with hyperbaric 5% lignocaine: a review of six cases of cauda equina syndrome reported to the Swedish Pharmaceutical Insurance 1993–1997. Acta Anaesthesiol Scand. 1999;43(4):371–9. Mahassin F, Algayres JP, Valmary J, et  al. Acute myelitis following hepatitis B vaccination. Presse Med. 1993;22:1997–8. Martinez Lopez E, Gallego Cullere J, Illarramendi Manas JJ, et al. Lhermitte's sign as a complication of cisplatin treatment. Med Clin (Barc). 1995;104(8):317–8. Mermel L, de Mora DS, Sutter RW.  Vaccine-associated paralytic poliomyelitis. NEJM. 1993;329:810–1. Newman LM, Iyeer NR, Truman KJ. Transient radicular irritation after hyperbaric lidocaine spinal anesthesia in parturients. Int J Obstet Anesth. 1997;6:132–4. Nöel P, Pepersack T, Vanbinst A, et  al. Spinal epidural lipomatosis in Cushing’s syndrome secondary to an adrenal tumor. Neurology. 1992;42:1250–1. Pohlman-Eden B, Berli P, Maibach EA.  Muzolimine-­ induced severe neuromyeloencephalopathy: report of seven cases. Act Neurol Scand. 1991;83:41–4. Prevots DR, et  al. Completeness of reporting for paralytic poliomyelitis, United States, 1980 through 1991: implications for estimating the risk of vaccine-­ associated disease. Arch Pediatr Adolescent Med. 1994;148:479–85. Reeves RR, Pinkofsky HB.  Lhermitte's sign in paroxetine withdrawal. J Clin Psychopharmacol. 1996;16(5):411–2. Rosener M, Dichgans J.  Severe combined degeneration of the spinal cord after nitrous oxide anaesthesia in a vegetarian. J Neurol Neurosurg Psychiatry. 1996;60(3):354. Roy-Camille R, Mazel C, Husson JL, et al. Symptomatic spinal epidural lipomatosis induced by long-term steroid treatment. Spine. 1991;16:1365–71.

32  Drug-Induced Spinal Disorders Runge U, Röder H.  Querschnittsyndrom nach intramuskulärer Penicillininjektion. Z Ärztl Fortbild. 1989;83:537–8. Schell RM, Brauer FS, Cole DJ, et  al. Persistent sacral nerve root deficits after continuous spinal anesthesia. Can J Anesth. 1991;38:908–11. Sehgal AD, Tweed DC, Gardner WJ, et  al. Laboratory studies after intrathecal corticosteroids. Arch Neurol. 1963;9:74–8. Shaw FE, Graham DJ, Guess HA, et  al. Post-marketing surveillance for neurological adverse events reported after hepatitis B vaccination. Am J Epidemiol. 1988;127:337–52. Sjöberg M, Karlsson PA, Nordborg C, et  al. Neuropathologic findings after a long-term intrathecal infusion of morphine and bupivacaine for pain treatment in cancer patients. Anesthesiology. 1992;76:173–86. Smith L, Brown JE.  Treatment of lumbar intervertebral disc lesions by direct injection of chymopapain. J Bone Joint Surg. 1967;49-B:502–17. Swamy HS, Vasanth A. Sasikumar: Brown-Sequard syndrome due to Semple antirabies vaccine: case report. Paraplegia. 1992;30:181–3. Taborn J. Epidural lipomatosis as a cause of spinal cord compression in polymyalgia rheumatica. J Rheumatol. 1991;18:286–8. Terrovitis IV, Nanas SN, Rombos AK, et  al. Reversible symmetric polyneuropathy with paraplegia after heart transplantation. Transplantation. 1998;65(10):1394–5. Tesio L, Bassi L, Strada L. Spinal cord lesion after penicillin gluteal injection. Paraplegia. 1992;30:442–4. Travisani F, Gattinara GC, Caraceni P, et  al. Transverse myelitis following hepatitis B vaccination. J Hepatol. 1993;19:317–8. van den Bent MJ, Hilkens PH, Sillevis Smitt PA, et  al. Lhermitte's sign following chemotherapy with docetaxel. Neurology. 1998;50(2):563–4. Vishnubhakat SM, Beresford HR. Reversible myeloneuropathy of nitrous oxide abuse: serial electrophysiological studies. Muscle Nerve. 1991;14(1):22–6. Walther PJ, Rossitch E, Bullard DE.  The development of Lhermitte's sign during cisplatin chemotherapy. Cancer. 1987;60:2170–2. Wen PY, Blanchard KL, Block CC, et  al. Development of Lhermitte's sign after bone marrow transplantation. Cancer. 1992;69:2262–6. Wysowski DK, Talarico L, Bacsanyi J, et al. Spinal and epidural hematoma and low molecular weight heparin. NEJM. 1998;338:1774–5. (letter). Yapa RS.  Folic acid therapy dangers. Practitioner. 1988;232:987. Zampella JK, Duvall ER, Sekar BC, et al. Symptomatic spinal epidural lipomatosis as complication of steroid immunosuppression in cardiac transplant patients. Report of two cases. J Neurosurg. 1987;67:760–4.

Drug-Induced Cerebellar Disorders

Introduction Several drugs produce cerebellar dysfunction as a part of encephalopathy (see Chap. 13). Cerebellar hemorrhage may occur following use of anticoagulants or thrombolytics (see Chap. 23). This chapter includes discussion of drug-induced adverse effects where cerebellar disorder either is mentioned specifically or is a prominent feature.

33

Table 33.1  Causes of cerebellar symptoms Initial manifestations of multisystem atrophies such as olivopontocerebellar atrophy Idiopathic late-onset cerebellar ataxia Tumors: these lesions have a space-occupying effect leading to rise of intracranial pressure Infections: cerebellar abscess Vascular lesions of the cerebellum involving the neighboring structures such as the brain stem Metabolic disorders Adverse effect of drugs and toxins

Clinical Manifestations of Cerebellar Disorders

presenting with cerebellar symptoms may have any of the several causes shown in Table 33.1.

The main clinical manifestations of cerebellar disorders with anatomical correlations are as follows:

 linical Features of Drug-Induced C Cerebellar Disorders

• Dyssynergia, dysmetria, and dysarthria are usually due to lesions of the lateral parts of posterior cerebellar hemispheres. • Ataxia of stance and gait is usually due to damage to the cerebellar vermis and anterior lobe. The present understanding of the physiologic mechanism of cerebellar dysfunction is based mostly on animal experiments. Precise clinicopathological correlations in humans are limited because cerebellar atrophies result in diffuse loss of Purkinje cells and deterioration of both afferent and efferent cerebellar pathways. Patients

Drug-induced disorders of the cerebellum can be distinguished from the naturally occurring diseases of the cerebellum and are characterized by the following three features: 1. They are not progressive. 2. They are not usually associated with rise of intracranial pressure. 3. They may regress after discontinuation of the offending drug. It is well known that the cerebellum is particularly sensitive to a variety of metabolic insults such as hypoxia, hypoglycemia, heavy metals

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_33

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33  Drug-Induced Cerebellar Disorders

524

and other intoxications, nutritional deficiencies, and metabolic disorders. The reason for this selective cerebellar vulnerability has not been fully understood. In the thiamin deficiency-­ induced model of cerebellar ataxia, there is a selective involvement of 5-HT fibers. Drug-­ induced ataxia and dysarthria, symptoms of cerebellar dysfunction, were described in Chap. 2.

Table 33.2  Drugs associated with cerebellar disorders Alcohola Antibiotics  Cephalosporins  Metronidazole  Penicillins  Trimethoprim-sulfamethoxazole Antidepressants Antiepileptic drugs  Carbamazepine  Phenytoina  Valproic acid Antineoplastic drugs  5-Fluorouracil  Cytosine arabinosidea  Dabis maleate  Docetaxel  Doxyfluridine  Hexamethylmelamine  Ifosfamide  Interleukin-2  Procarbazine  Tamoxifen  Thalidomide  Vincristine  Zarnestra Cimetidine Cyclosporinea Drug interactions  Amiodarone and phenytoin  Carbamazepine and clarithromycin  Carbamazepine and lithium Histamine H2 receptor antagonists Isoniazid Lithiuma Metronidazolea Nefazodone Omeprazole Procainamide Vaccines

 rugs Associated with Cerebellar D Disorders Drugs associated with cerebellar disorders are listed in Table 33.2.

Alcohol Alcoholic cerebellar degeneration is well recognized. Long-standing alcoholics may develop ataxia due to degeneration of the Purkinje cells of the cerebellar cortex. This cell loss is particularly severe in those who have Wernicke-Korsakoff syndrome. This indicates that cerebellar degeneration does not result only from the direct toxic effect of alcohol but other factors such as thiamine deficiency also play a part. Abstinence from alcohol and thiamine replacement may lead to some improvement in these cases. History of alcoholism should be obtained in all patients presenting with cerebellar degeneration, particularly those where a drug-induced cause is suspected.

Antibiotics Seizures, encephalopathy (see Chap. 13), optic neuropathy, peripheral neuropathy, and exacerbation of myasthenia gravis are important examples of neurotoxic adverse events associated with the use of antibiotics. Some antibiotics have a specific association with cerebellar toxicity.

Isoniazid A case of cerebellar syndrome has been reported following isoniazid treatment of a patient with tuberculosis on hemodialysis (Blumberg and Gil 1990). MRI showed cerebellar atrophy, but the

Causal relationship is well established, and these are described in more detail in the text. For the others there are isolated case reports, but causal relationship is not established

a

patient improved following discontinuation of isoniazid. Pathomechanism is considered to involve pyridoxine deficiency. A case has been reported of cerebellar ataxia in a 10-year-old child on isoniazid therapy who recovered following discontinuation of the drug and treatment with pyridoxine (Lewin and McGreal 1993). Toxicology studies have shown that the rat cerebellum is prone to develop vacuolation with age,

Clinical Features of Drug-Induced Cerebellar Disorders

but isoniazid may accelerate or enhance this tendency in young rats (Wells and Krinke 2008).

Metronidazole Metronidazole, a 5-nitroimidazole, is widely used for the treatment of trichomoniasis, giardiasis, amebiasis, and anaerobic infections. It produces several neurological adverse effects including peripheral neuropathy, encephalopathy, cerebellar dysfunction, and seizures. Cerebellar toxicity, manifesting by ataxia and dysarthria, has been reported with high doses of metronidazole therapy for amebiasis. Ahmed et al. (1995) have reported a case with metronidazole toxicity who presented with ataxia, dizziness, confusion, and vertigo. MRI showed abnormal increased signal within the cerebellum as well as supratentorial white matter. The patient improved after withdrawal of the drug and MRI lesions resolved. Metronidazole has been used to reduce bacterial production of ammonia and other bacteria-derived toxins through suppression of intestinal flora in patients with hepatic encephalopathy. Long-term use of metronidazole has been associated with neurotoxicity in patients with cirrhosis (Phongsamran et al. 2010). These adverse effects usually develop with the long-­ term use of the medication and resolve after its discontinuation. The underlying mechanism is unknown, but axonal swelling secondary to metronidazole-­ induced vasogenic edema has been proposed as an explanation. A 34-year-old man, who was on metronidazole therapy for 3 months, presented with garbled speech (dysarthria) and word finding difficulty, and MRI of the brain showed abnormal signal intensities in the splenium of the corpus callosum and dentate nuclei of the cerebellum (Cheema et al. 2019). Diagnosis of metronidazole-induced neurotoxicity was made based on MRI findings. The antibiotic was stopped leading to resolution of abnormal MRI findings.

Antidepressants Cerebellar disorders including dysmetria, ataxia, and intention tremor have been reported during treatment with antidepressants. Pathomechanism

525

is explained by the effect of neurotransmitter alterations on the noradrenergic afferents of the cerebellar cortex. Ataxia resulting from high-­ dose antidepressant therapy is also considered to be due to reversible intoxication of the cerebellar structures. Dosage reduction is usually enough to reverse the symptoms of cerebellar toxicity, and there are no permanent sequelae.

Antiepileptic Drugs Some of the several antiepileptic drugs are associated with encephalopathy and cerebellar toxicity, which was first described as due to phenytoin.

Phenytoin Phenytoin is used for partial and generalized seizures. The most characteristic feature of phenytoin neurotoxicity is cerebellar dysfunction: nystagmus, tremor, and ataxia. There is some controversy regarding the role of phenytoin in producing cerebellar disorders. In the past cerebellar degeneration has been attributed mostly to hypoxia caused by seizures. Spielmeyer (Spielmeyer 1930) observed degeneration of Purkinje cells in the brains of epileptic patients long before phenytoin was introduced as an anticonvulsant in 1930. This finding as well as cerebellar atrophy found in epileptic patients due to perinatal anoxic-ischemic damage can be differentiated from phenytoin-induced cerebellar disease. Cerebellar degeneration has been reported in a patient with tubercular meningitis who received phenytoin as prophylactic therapy but never had a seizure (Rapport and Shaw 1977). Subacute phenytoin neurotoxicity has also been reported in non-epileptic patients where the indication for use is cardiac arrhythmia. Neurotoxicity (including cerebellar signs) has been reported in five patients abusing cocaine adulterated with phenytoin (Katz et al. 1993; Koppel et al. 1995). Most of the cerebellar disorders following phenytoin therapy are transient, but persistent cerebellar deficits have also been described. Progressive irreversible ataxia has been documented in patients on long-term phenytoin treatment with levels not generally considered excessive. Unlike that found in acute toxicity, this type of ataxia is permanent

526

(Benabou et  al. 1995). Cerebellar degeneration following long-term therapy with phenytoin has been documented by several authors (Ghatak et al. 1976; Koller et  al. 1980; McLain et  al. 1980; Rosich 1980). Cases of cerebellar atrophy with persisting neurological deficits provide evidence for the chronic irreversible damage with phenytoin (Pulliainen et al. 1998; Pumar et al. 1995). Pathology  In the pre-CT era, pneumoencephalography in cases of phenytoin-induced cerebellar toxicity showed enlargement of fourth ventricle, enlarged cerebellopontine angle cistern, and widened interfolial sulci indicating cerebellar atrophy. Cerebellar atrophy as demonstrated by MRI has been reported following acute intoxication with phenytoin (Masur et al. 1989). This case was followed up for more than 4 years, and no change was seen in cerebellar atrophy, thus ruling out cerebellar degenerative disorders (Masur et  al. 1990). Cerebellar atrophy documented by CT scan has also been reported in irreversible cases of cerebellar ataxia following overdose of phenytoin (Imamura et al. 1992; Kim et al. 1991; Lindwall and Nilsson 1984; Baier et  al. 1984; McCrea et  al. 1980). Atrophy has also been demonstrated by MRI scan (Luef et al. 1993) and at autopsy (Abe and Yagishita 1991) in cases of chronic phenytoin toxicity. In a case control study, cerebellar atrophy was seen in patients with epilepsy exposed to phenytoin in the absence of seizures and preexisting cerebellar damage (Ney et al. 1994). Neuropathological examination in phenytoin-­induced cerebellar atrophy shows loss of Purkinje cells with multilamellar structures within the degenerating Purkinje cells (BreidenArends and Gullota 1981). Similar loss of Purkinje cells was observed in biopsies in patients with epilepsy on phenytoin therapy (Salcman et al. 1978). Pathomechanism  This is not well understood but the following explanations have been considered: • Folic acid deficiency associated with use of phenytoin has been suggested as an explanation of cerebellar atrophy. • Experimental studies on mature mice have demonstrated degeneration of granular cell layer of the cerebellum caused by phenytoin (Volk et al. 1986). The terminal stage is char-

33  Drug-Induced Cerebellar Disorders

acterized by three axonal events as seen on electron microscopy: rarefaction, coagulation necrosis, and phagocytosis of spheroidal cells by glial elements (Takeichi 1983). • Administration of phenytoin to newborn mice has been shown to induce damage to the developing cerebellum (Ohmori et  al. 1992). One experimental study failed to show any changes in the cerebellar cortex after phenytoin intoxication (Garcia et al. 1984). • Focal seizures in humans mediate cell injury in the cerebellum by inducing concomitant aberrant discharges with resulting neuroexcitatory-­ mediated damage. A specific site for binding phenytoin has been identified in the vicinity of Purkinje cells (Hammond and Wilder 1983), and phenytoin has been shown to induce increased firing rates in cerebellar neurons (Julien and Halpern 1972). Seizure-induced neuronal excitability and phenytoin-induced neuronal excitability may act in combination to cause cerebellar atrophy (Ney et al. 1994). The question whether phenytoin seizures play a part in the pathogenesis of cerebellar atrophy remains unanswered. Large prospective studies are required to settle this issue. Management  The following are important considerations in management: • Early detection of cerebellar disturbances in patients on phenytoin therapy is important because the manifestations such as ataxia reverse when the drug is stopped, whereas in chronic toxicity, cerebellar ataxia is usually considered irreversible (Botez et  al. 1985). SPECT scan has been shown to detect early abnormalities of regional cerebral blood flow (rCBF) in the cerebellum in epileptic patients on long-term phenytoin therapy, and this abnormality is reversed by reduction of dose or discontinuation of the drug (Jibiki et al. 1993). • Periodic monitoring of phenytoin serum levels is important as a guide to prevent neurotoxicity due to high concentrations of the drug. • Phenytoin should be used with caution in epileptic patients who have evidence of cerebellar atrophy even though they have no clinical manifestations of cerebellar dysfunction.

Clinical Features of Drug-Induced Cerebellar Disorders

527

• Carbamazepine can be considered as an alternative medication in these cases because it has been shown that cerebellar atrophy does not increase susceptibility to carbamazepine neurotoxicity (Specht et al. 1994). Although therapeutic blood levels of carbamazepine are not associated with cerebellar toxicity, cerebellar dysfunction has been reported with toxic levels of carbamazepine (Haefeli et al. 1994) and as a drug interaction with dextropropoxyphene (Allen 1994).

the various drugs reported, only cytosine arabinoside is well documented.

Antineoplastic Drugs Cerebellar dysfunction is common among cancer patients, and various causes include those shown in Table 33.3. Evaluation of a cancer patient with cerebellar signs is not always easy because of the multiplicity of factors involved. These patients usually have metabolic and nutritional deficiencies, and patients with severe cancer cachexia may develop Wernicke’s encephalopathy with resulting loss of Purkinje’s cells in the cerebellum and difficulty with gait. Rapid correction of hyponatremia is well known to cause the syndrome of central pontine myelinolysis and degenerative lesions of the superior vermis of the cerebellum in experimental animals. Paraneoplastic syndromes often involve the cerebellum. Peripheral neuropathies associated with cancer and/or antineoplastic therapy may produce gait disturbances that may resemble cerebellar ataxia. Neuroimaging techniques such as CT scan and MRI help to identify metastatic lesions and cerebellar atrophy. Among Table 33.3  Some causes of cerebellar disorders in cancer patients Paraneoplastic syndromes: remote effects of cancer Cancer metastases Metabolic disorders in cancer patients  Hypoxia-ischemia  Hypoglycemia  Electrolyte disturbances  Rapid correction of hyponatremia  Hyperthermia Neurotoxicity of antineoplastic drugs

Cytosine Arabinoside Cytosine arabinoside (ARA-C) has been used widely in the treatment of acute non-lymphatic leukemia (ANLL) for years without any report of significant neurotoxicity. Since 1979, high doses of ARA-C (up to 30 times the usual dose) have been shown to induce remissions in patients with ANNL refractory to conventional treatment. Reports of neurotoxicity with this regimen have included aseptic meningitis, myelopathy, and encephalopathy with prominent cerebellar dysfunction. Risk factors for the development of neurotoxicity are age (over 50 years) and renal dysfunction. Symptoms are usually reversible, but persistent cerebellar dysfunction has been reported and attributed to cumulative effect of the drug rather than high plasma levels of the drug. Such cumulative effects may occur even with low dose ARA-C. Clinicopathological Features  Cerebellar neurotoxicity due to ARA-C is manifested by ataxia of gait, limb movements, dysarthria, and nystagmus. Pathological examination shows loss of Purkinje cells in cerebellar hemispheres. Cerebellar atrophy has been demonstrated by CT and MRI.

Pathomechanism  ARA-C neurotoxicity is mediated primarily through inhibition of DNA synthesis; accordingly, cytotoxicity to tumor cells is restricted to cells in S-phase. Experimental studies in mice have shown that neonatal administration of ARA-C causes necrosis of proliferating cells in the external granular layer of the mouse cerebellum and the mice thus treated develop severe cerebellar abnormalities. Although it has been shown that ARA-C is preferentially toxic to cerebellar Purkinje cells and cerebellar granule neurons, later studies suggest that ARA-C targets both lineage-committed progenitor cell populations and nondividing oligodendrocytes, which are the myelin-forming cells in the CNS. Thus, some of the neurotoxic adverse reactions and symptoms seen in patients may be

528

33  Drug-Induced Cerebellar Disorders

a direct consequence of both oligodendrocyte Doxyfluridine  This is an antineoplastic agent of toxicity and impairment of progenitor self-­ fluoropyrimidine group related to 5-FU.  One renewal in the germinal zones of the CNS. patient with acute reversible cerebellar syndrome has been reported after second course of therapy Prevention  Avoidance of high doses of the drug, with doxyfluridine and developed encephalopaespecially in patients with renal impairment, has thy after the next two cycles (Heier and Fossa led to a decline in the incidence of this syndrome 1985). (Lindner et al. 2008).

5-Fluorouracil High doses of 5-fluorouracil (5-FU) have been associated with cerebellar syndromes and occur in approximately 5% of patients. This usually begins weeks or months after treatment and is characterized by the acute onset of ataxia, dysmetria, dysarthria, and nystagmus. The drug should be discontinued in any patient who develops a cerebellar syndrome. With time, these symptoms usually resolve completely. The development of a cerebellar syndrome may be explained partly by the fact that 5-FU readily crosses the blood-brain barrier. Highest concentrations are found in the cerebellum. This syndrome is rarely seen with the doses used these days. Acute cerebellar syndrome was also reported with flucytosine, the active metabolite of which is 5-FU (Cubo Delgado et al. 1997). This subsided after replacement of flucytosine by fluconazole. Methotrexate Cases of irreversible cerebellar atrophy following intrathecal methotrexate have been described (Masterson et  al. 2008). Neurotoxicity characterized by dysarthria, gait dysfunction, dysmetria, and weakness has also been described after low-­dose subcutaneous methotrexate injection for rheumatoid arthritis. Symptoms were reversible, however, and resolved after discontinuation of treatment.  iscellaneous Antineoplastic Drugs M Dabis Maleate  This is an alkylating quaternary nitrogen compound used as an antineoplastic agent. Cerebellar ataxia has been reported as a complication of its use (van der Burg et al 1991). Docetaxel  One case of ataxia has been reported following docetaxel therapy, and it resolved after discontinuation of therapy (Hofstra et al. 1997).

Cyclosporine Cyclosporine is an immunosuppressant used primarily in conjunction with organ transplant. Leucoencephalopathy related to this drug is described in Chap. 3. Some of the neurological complications associated with the use of this drug are attributed to liver disease and liver transplantation. Poor liver function before transplantation may damage the blood-brain barrier and facilitate cyclosporine neurotoxicity. Cerebellar ataxia and tremor have been reported in patients treated with cyclosporine after bone marrow transplantation. A case of cyclosporine-­ associated leukoencephalopathy presenting with cerebellar ataxia and dysarthria was reported (Belli et  al. 1993). This complication presented 6 months after liver transplantation and 3 months after steroid withdrawal, whereas the neurological complications are usually seen within the first month after transplantation. Hyperintensities of the white matter in the cerebellum were shown on MRI, and these resolved on withdrawal of c­ yclosporine. Resumption of cyclosporine at a low dose was associated with a rapid, recurrent neurotoxicity. This patient did not suffer from hypertension, and cyclosporine levels were always found to be within normal limits. The late occurrence as well as association with acute hepatitis suggests the possibility of graft dysfunction as a contributing factor. One patient developed cerebellar edema with brain stem compression following use of cyclosporine as an immunosuppressant for lung transplant (Nussbaum et  al. 1995). Replacement of cyclosporine by FK506 was accompanied by a rapid recovery. Cyclosporine precipitated cerebellar syndrome and psychiatric symptoms in another patient with rejection of renal allograft

Clinical Features of Drug-Induced Cerebellar Disorders

(Sharma et al. 1995). The symptoms resolved 8 hours after discontinuation of cyclosporine but recurred when cyclosporine was resumed. After the final withdrawal of cyclosporine, the patient recovered completely from neurotoxic effects.

Cimetidine This is a histamine H2-receptor antagonist used for gastritis. One case of cerebellar ataxia has been reported following use of this medication at therapeutic doses for 4 days (Hamano et al. 1998). Drugs of this category pass through the bloodbrain barrier and possibly block the H2 receptors in the brain producing CNS adverse effects.

Lithium Lithium has been used widely for the treatment of manic depressive illness over the past two decades. Neurological sequelae of acute lithium intoxication, including cerebellar disorders, are common and well known. Chronic sequelae are less common and less known. In a report of 23 cases and review of 100 cases from literature, 10% of the patients were found to have permanent neurological sequelae and 14% died (Hansen and Amdisen 1978). Cerebellar ataxia and scanning speech are usual manifestations. Although there are multiple lesions in the brain, the major involvement is of the cerebellum. A review identified 90 cases of SILENT (syndrome of irreversible lithium-effectuated neurotoxicity) in peer-reviewed publications, and persistent cerebellar dysfunction was the most reported manifestation (Adityanjee and Thampy 2005). Cerebellar atrophy has been demonstrated by CT scan, and cerebellar degeneration with vacuolization and loss of Purkinje cells has been demonstrated on autopsy. Pathomechanism of lithium neurotoxicity is not known but the risk factors are shown in Table 33.4. Management  There is no specific antidote for lithium toxicity. Initial management is the same as for any overdose. Recovery usually occurs if lithium neurotoxicity is detected early and lith-

529 Table 33.4  Risk factors for lithium neurotoxicity Somatic illnesses with fever, e.g., Q fever Concomitant treatment with other antipsychotic drugs such as haloperidol Concomitant treatment with diuretics Renal insufficiency High serum levels of lithium Individual susceptibility in the absence of the above risk factors

ium is discontinued. Techniques aimed at lowering high serum levels result in brisk recovery from acute toxic effects but do not prevent long-­ term neurotoxicity. In serious cases with plasma lithium levels above 3.5 mmol/L, dialysis is required to enhance elimination. Except the use of lithium for suicide, acute as well as chronic toxicity can be prevented in most cases by careful use of lithium and recognition that this drug has a narrow therapeutic window.

Vaccines Neurotoxicity of vaccines is discussed in Chap. 10. This section will focus on toxicity involving the cerebellum. A 5-year-old child has been reported to develop an acute cerebellar syndrome 8 days after receiving influenza vaccine (Saito and Yanagisawa 1989). CT scan was normal and CSF examination showed moderate pleocytosis. Symptoms disappeared after 4 months but recurred 33 months later without any obvious precipitating factor and persisted. Cerebellar atrophy was documented by CT and MRI. The incidence of gait disturbances after measles, mumps, and rubella virus vaccine in Denmark since 1987 has been estimated to be 6 per 100,000. There were 24 such cases reported by physicians of which a cerebellar disorder was diagnosed in 3 (Plesner 1995).

References Abe H, Yagishita S.  Chronic phenytoin intoxication occurred below the toxic concentration in serum and its pathological findings. No To Shinkei. 1991;43:89–94.

530 Adityanjee MKR, Thampy A.  The syndrome of irreversible lithium-effectuated neurotoxicity. Clin Neuropharmacol. 2005;28:38–49. Ahnad S.  Amiodarone and phenytoin interaction. J Am Geriatr Soc. 1995;43:1449–50. Allen S.  Cerebellar dysfunction following dextropropoxyphene-­induced carbamazepine toxicity. Postgrad Med J. 1994;70:764. Baier WK, Beck U, Doose H. Cerebellar atrophy following diphenylhydantoin intoxication. Neuropediatrics. 1984;15:76–81. Belli LS, De Carlis L, Romani F, et  al. Dysarthria and cerebellar ataxia: late occurrence of severe neurotoxicity in a liver transplant recipient. Transpl Int. 1993;6:176–8. Benabou R, Carpenter S, Andermann F.  Progressive irreversible ataxia after long-term phenytoin therapy (abstract). Neurology. 1995;45(suppl 4):A368. Blumberg EA, Gil RA.  Cerebellar syndrome caused by isoniazid. DICP Ann Pharmacother. 1990;24:829–31. Botez MI, Gravel J, Attig E, et al. Reversible chronic cerebellar ataxia after phenytoin intoxication. Neurology. 1985;35:1152–7. Breiden-Arends C, Gullota F.  Diphenylhydantoin, epilepsy, cerebellar atrophy: histological and electron microscopical examinations (German). Fortschr Neurol Psychiatr. 1981;49:406–14. Cheema MA, Salman F, Ullah W, Zain MA.  Garbled speech: a rare presentation of metronidazole-induced neurotoxicity. BMJ Case Rep. 2019;12:e227804. Cubo Delgado E, Sanz Boza R, Garcia Urra D, et  al. Acute cerebellopathy as a probable toxic effect of flucytosine. Eur J Clin Pharmacol. 1997;51:505–6. Garcia HF, Crespo JV, Otero SO, et  al. Experimental study of the cerebellar cortex about diphenylhydantoin administration. Arch Neurobiol. 1984;6:353–62. Ghatak NR, Santoso RA, McKinney WM.  Cerebellar degeneration following long-term phenytoin therapy. Neurology. 1976;26:818–20. Haefeli WE, Meyer PG, Lüscher TF.  Circadian carbamazepine toxicity. Epilepsia. 1994;35:400–2. Hamano T, Takano A, Miyao S. Reversible adverse effects on the CNS induced by histamine H2 receptor antagonists. Eur Neurol. 1998;39:242. Hammond EJ, Wilder BJ.  Immunofluorescent evidence for the specific binding site for phenytoin in the cerebellum. Epilepsia. 1983;24:269–74. Hansen HE, Amdisen A. Lithium intoxication. (Report of 23 cases and review of 100 cases from the literature). Q J Med. 1978;47:123–44. Heier M, Fossa SD.  Neurological manifestations in a phase 2 study of 13 patients treated with doxyfluridine. Acta Neurol Scand. 1985;72:171–5. Hofstra LS, van der Graaf WT, de Vries EG, et  al. Ataxia following docetaxel infusion. Ann Oncol. 1997;8(8):812–3. Imamura T, Ejima A, Sahara M, et al. Cerebellar atrophy and persistent cerebellar ataxia after acute intoxication with phenytoin. No To Shinkei. 1992;44(2):149–53.

33  Drug-Induced Cerebellar Disorders Jibiki I, Kido H, Yamaguchi N, et  al. Probable cerebellar abnormality on N-isopropyl-(iodine-123)p-­ iodoamphetamine single photon emission computed tomography scans in an epileptic patient receiving long-term high-dose phenytoin therapy. Neuropsychobiology. 1993;27:204–9. Julien RM, Halpern LM.  Effects of diphenylhydantoin and other antiepileptic drugs on epileptiform activity and Purkinje cell discharge rates. Epilepsia. 1972;13:387–400. Katz AA, Hoffman RS, Silverman RA, et  al. Phenytoin toxicity from smoking crack cocaine adulterated with phenytoin. Ann Emerg Med. 1993;22:1485–7. Kim JH, Kwon SH, Lee MS, et al. Cerebellar atrophy following long-term anticonvulsant therapy–three cases. J Korean Med Assoc. 1991;34:1251–6. Koller WC, Glatt SL, Fox JH. Phenytoin-induced cerebellar degeneration. Ann Neurol. 1980;8:203–4. Koppel BS, Daras M, Samkoff L. Phenytoin toxicity from illicit use (letter). Neurology. 1995;45:198. Lewin PK, McGreal D. Isoniazid toxicity with cerebellar ataxia in a child. Can Med Assoc J. 1993;148:49–50. Lindner LH, Ostermann H, Hiddemann W, et  al. AraU accumulation in patients with renal insufficiency as a potential mechanism for cytarabine neurotoxicity. Int J Hematol. 2008;88:381–6. Lindwall O, Nilsson B. Cerebellar atrophy following phenytoin intoxication. Ann Neurol. 1984;16:258–60. Luef G, Marosi M, Felber S, et al. Kleinhirnatrophie und Phenytoinintoxikation. Nervenarzt. 1993;64:548–51. Masterson K, Merlini L, Lovblad KO.  Coexistence of reversible cerebral neurotoxicity and irreversible cerebellar atrophy following an intrathecal methotrexate chemotherapy: two case reports. J Neuroradiol. 2008;36:112–4. Masur H, Ludolph AC, Galanski M.  Cerebellar atrophy following acute intoxication with phenytoin. Neurology. 1989;39:432–3. Masur H, Fahrendorf G, Oberwittler C, et al. Cerebellar atrophy following acute intoxication with phenytoin. Neurology. 1990;40:1800. McCrea ES, Rao CV, Diaconis JN.  Roentgenographic changes during long-term diphenylhydantoin therapy. South Med J. 1980;73:312–7. McLain LW, Martin JT, Allen JH.  Cerebellar degeneration due to chronic phenytoin therapy. Ann Neurol. 1980;7:18–23. Ney GC, Lantos G, Barr WB, et al. Cerebellar atrophy in patients with long-term phenytoin exposure and epilepsy. Arch Neurol. 1994;51:767–71. Nussbaum ES, Maxwell RE, Bitterman PB, et  al. Cyclosporine A toxicity presenting with acute cerebellar edema and brainstem compression. J Neurosurg. 1995;82:1068–70. Ohmori H, Kobahashi T, Yasuda M. Neurotoxicity of phenytoin administered to newborn mice on developing cerebellum. Neurotoxicol Teratol. 1992;14:159–65. Phongsamran PV, Kim JW, Cupo Abbott J, Rosenblatt A.  Pharmacotherapy for hepatic encephalopathy. Drugs. 2010;70:1131–48.

References Plesner A.  Gait disturbances after measles, mumps and rubella vaccine. Lancet. 1995;345:316. Pulliainen V, Jokelainen M, Hedman C, et  al. A case of cerebellar atrophy after phenytoin intoxication: neurologic, neuroradiologic and neuropsychological findings. J Epilepsy. 1998;11:241–7. Pumar JM, Villalun J, Martinez de Alegria A, et  al. Cerebellar atrophy after protracted phenytoin treatment. Revista Espanola de Neurologia. 1995;10:201–2. Rapport RL, Shaw CM.  Phenytoin-related cerebellar degeneration without seizures. Ann Neurol. 1977;2(5):437–9. Rosich A.  Degeneration cerebelosa permanente secundaria a la difenil hidantoina. Med Clin (Barcelona). 1980;75:387–90. Saito H, Yanagisawa T. Acute cerebellar ataxia after influenza vaccination with recurrence and marked cerebellar atrophy. Tohoku J Exp Med. 1989;158:95–103. Salcman M, Defendi R, Correll J, et al. Neuropathological changes in cerebellar biopsies of epileptic patients. Ann Neurol. 1978;3:10–9. Sharma RK, Kumar P, Rai P, et  al. Cyclosporin neurotoxicity in a renal transplant recipient. Nephron. 1995;70:269.

531 Specht U, Rohde M, Schmidt T, et al. Cerebellar atrophy does not increase susceptibility to carbamazepine toxicity. Acta Neurol Scand. 1994;89:1–4. Spielmeyer W. The anatomical substrate of the convulsive state. Arch Neurol Psychiatr. 1930;23:869–75. Takeichi M.  Neurobiological studies of experimental diphenylhydantoin intoxication–III.  Electron microscopic studies on development and disintegration mechanism of altered axon terminals and synaptic endings in rat cerebellum with chronic diphenylhydantoin intoxication. Folia Psychiatr Neurol Jpn. 1983;37:455–64. van der Burg MEL, Planting AST, Stoter G, et al. Phase I study of DABIS maleate given once every 3 weeks. Eur J Cancer. 1991;27:1635–7. Volk B, Kirchgässer N, Detmar N. Degeneration of granule cells following chronic phenytoin administration: an electron microscopic investigation of the mouse cerebellum. Exp Neurol. 1986;91:60–70. Wells MY, Krinke GJ.  Cerebral vacuolation induced in rats by the administration of LUP-3FDC, an anti-­ tuberculosis cocktail. Exp Toxicol Pathol. 2008;59:365–72.

Eosinophilia-Myalgia Syndrome

Introduction Eosinophilia-myalgia syndrome (EMS) was first recognized in 1989 by physicians in New Mexico in patients who had consumed tryptophan prior to the onset of illness (Center for Disease Control 1989; Eidson et al. 1990; Hertzman et al. 1990). Tryptophan, the agent involved, is an essential amino acid. Based on reports in the literature during the past 20 years, tryptophan has been recommended for treatment of depression, insomnia, schizophrenia, and behavioral disorders assuming that serotonin content of the brain could be altered by exogenously administered tryptophan. A warning was issued by the FDA in 1989 advising consumers to discontinue the use of tryptophan as a food supplement and self-­ medication. Several other cases were uncovered later, and over 1,000 cases had been reported to the CDC (Centers for Disease Control and Prevention, Atlanta, Georgia) by mid-1990. Following the general discontinuation of tryptophan use, the number of new cases dropped remarkably. The case definition developed by the CDC on review of initial cases included the following criteria: • Eosinophil count greater than 1000/mm3 • Incapacitating myalgia • No evidence of infection or neoplasm that could explain the findings

34

Investigations on this topic continued for some years and a considerable amount of literature accumulated on this topic including excellent reviews (Belongia et al. 1992; Harati 1994; Kaufman and Philen 1993). Cases have been reported from outside the United States including two in Belgium (Van Garsse and Boeykens 1990), five in Scotland (Douglas et al. 1990), and five in Japan (Tsutsui et al. 1996). Tryptophan was also withdrawn from the market in the United Kingdom in 1989. A 20-year follow-up of EMS was published in Japan (Maitani and Saitoh 2009).

Epidemiology of EMS There were 1531 cases of EMS reported to CDC by mid-1992, including 36 deaths. There are estimated to be twice as many cases which did not meet the criteria of CDC.  The prevalence was higher in the Western states possibly because of the higher rate of consumption of tryptophan in those states. High prevalence was also reported in South Carolina, New Mexico, Minnesota, and Oregon because of active surveillance in these states. Reviews of epidemiological studies demonstrated that EMS was not triggered by tryptophan per se but rather by exposure to a contaminant in tryptophan manufactured by one company (Showa Denko, K.K., Tokyo, Japan), which used

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_34

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a fermentation process to synthesize tryptophan from its precursor using Bacillus ­amyloliquefaciens (Belongia et al. 1990; Belongia et  al. 1992; Slutsker et  al. 1990). In 1988, this company introduced a new strain (strain V) of this bacillus, which had been genetically modified to increase the synthesis of intermediates in tryptophan biosynthetic pathway and thus increase the yield of tryptophan. Chromatographic analysis of tryptophan manufactures this way showed the presence of peak E, the chemical structure of which was subsequently determined to be 1,1-ethylidenebis-­tryptophan (EBT). This chemical is later hydrolyzed under acidic conditions, and preliminary studies suggested that it may cause abnormalities of the fascia and microvasculature (Love et  al. 1991). Tryptophan consumed by EMS patients was traced back to Showa Denko, and chromatographic analysis of tryptophan from rest of the cases showed no convincing evidence that it was manufactured by companies other than Showa Denko. The pooled attack rate among persons exposed to contaminated tryptophan may have been as high as 52%. Further investigations have raised the possibility that other chemical contaminants in tryptophan may modify the effect of EBT or that the cause may be an entirely different compound (Philen et al. 1993). One of these compounds is 3-(phenylamino)-alanine which is quite like the contaminant that caused the onset of EMS-like toxic oil syndrome in Spain in 1981. An epidemiologic study in Germany supported the role of a contaminant in L-tryptophan (LT) in the occurrence of EMS (Carr et al. 1994). Evidence from an array of scientific studies strongly supports the conclusion that ingestion of products containing LT produced by Showa Denko K.K. caused the 1989 epidemic of eosinophilia-­ myalgia syndrome (EMS) in the United States (Kilbourne et  al. 1996). In case control studies of EMS, LT exposure was essentially universal among cases but rare among controls. Of six manufacturers of LT, only LT manufactured by Showa Denko K.K. was clearly associated with illness. The data meet other Hill criteria for inferring a causal relationship. Consistent findings were found in multiple inde-

34  Eosinophilia-Myalgia Syndrome

pendently conducted studies. There was a dose-­ response effect, with risk of illness increasing as a function of the amount of tryptophan consumed. The extremely small p values observed in the multiple independently conducted studies effectively rule out the possibility that the tryptophan-­ EMS association was the result of chance. Moreover, no potential confounding factor or bias explains the association. The incidence of EMS in the United States diminished abruptly once LT-containing products were recalled.

Risk Factors for EMS Few risk factors for EMS have been identified other than the consumption of contaminated tryptophan. There is a dose-response relationship between the amount of contaminated tryptophan consumed and the risk of EMS. Other risk factors are: • Old age. The risk of EMS may be increased in older patients independent of dose. Physiologic changes in hepatic and renal functions with aging may delay the clearance of the toxic substance. • Female sex. This is a possible risk factor. Another explanation is the greater use of tryptophan by females. • Asthma. Underlying asthma has been noted in 25% of patients who are also females (Henning et  al. 1993). There are increased levels of eosinophils and eosinophil-derived toxins, markers of eosinophil activation, in the sera of these patients. This suggests that eosinophil activation prior to exposure to contaminated tryptophan may potentiate the pathogenic effect of such a contaminant. • Psychotropic drugs. Concomitant use of psychotropic drugs such as antidepressants is suspected to be a risk factor.

Clinical and Pathological Features Major manifestations of EMS are shown in Table 34.1.

Differential Diagnosis Table 34.2  Conditions to be considered in the differential diagnosis of EMS Idiopathic eosinophilic fasciitis Idiopathic eosinophilic myositis Paraneoplastic myositis Parasitic infections such as trichinosis Polymyositis Sarcoidosis Toxic oil syndrome Vasculitic conditions such as Churg-Strauss syndrome Table 34.1  Distribution of major manifestations of EMS among the first 1000 cases Manifestation Myalgia Arthralgia Rash Peripheral edema Cough or dyspnea Fever Scleroderma Periorbital edema Alopecia Neuropathy

Percentage of affected patient population (%) 100 73 60 59 59 36 32 28 28 27

Late symptoms and signs differ from the initial presentation, and the proportion of various manifestations in later studies differs. This broad range of clinical signs and symptoms reported in patients with EMS indicates that a strict case definition may identify only about half the cases (Kamb et al. 1992).

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Polymyositis Polymyositis is best defined as an inflammatory myopathy of subacute onset (weeks to months) and steady progression occurring in adults not presenting the following symptoms: (1) rash, (2) involvement of eye and facial muscles, (3) family history of a neuromuscular disease, (4) endocrinopathy, (5) history of exposure to myotoxic drugs or toxins, and (6) neurogenic or dystrophic disorder, metabolic myopathy, or inclusion body myositis or necrotizing autoimmune myositis, as determined by muscle enzyme histochemistry and biochemistry. Polymyositis has no unique clinical features, and its diagnosis is one of exclusion (Dalakas and Karpati 2010).

Toxic Oil Syndrome This multisystem disease appeared as an epidemic in Spain in 1981 in relation to the intake of rapeseed cooking oil. Eosinophilia, myalgia, and rash are the presenting features in the first 4 months. The pathology of this syndrome is marked by chronic interstitial infiltrates, non-­ necrotizing angitis, endothelial proliferation, and fibrotic changes (Alonso-Ruiz et al. 1993).

Peripheral Neuropathy and EMS

Idiopathic Eosinophilic Myositis

A diffuse sensory or sensorimotor neuropathy, identified by clinical examination or EMG, has been reported in one- to two-third of patients seen in various clinical centers (Thacker 1991; Varga et al 1993). These may be the initial presentation of the disease and may be accompanied by Guillain-Barré-like ascending paralysis (Heiman-Patterson et al. 1990). Smith and Dyck (1990) described ten patients with EMS who presented with one of the following three patterns:

This is a rare form of polymyositis characterized by eosinophilia in the peripheral blood and eosinophilic infiltrations in the endomysial tissue, where no cause is identified.

1. Myopathy and neuropathy with connective tissue involvement 2. Painful predominantly sensory neuropathy 3. Sensorimotor neuropathy

Differential Diagnosis EMS should be differentiated from conditions with eosinophilia and inflammatory muscular and fascial diseases shown in Table 34.2.

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EMG examination showed that sensory fibers were involved more than the motor ones, and sural nerve biopsy findings were: • Axonal degeneration of various degrees • Epineural and perivascular inflammation with mononuclear or eosinophil cells • Inflammatory vasculopathy The term neuromyopathy is used for the lymphocytic perineuritis and neuritis along with EMS (Turi et al. 1990).

Natural History of EMS There is a median latency period of 127 days from exposure to tryptophan and manifestations of EMS. EMS is a long-term illness characterized by improvement during the first 25 weeks followed by a protracted period of symptom resolution (Culpepper et al. 1991). Most of the patients in population-based cohort were still symptomatic 1 year after the onset of illness (Hedberg et al. 1992). No method of treatment has been shown to reduce the long-term sequelae or the duration of the disease.

Pathomechanism Although the bulk of the available evidence links contamination of tryptophan to EMS, pathogenesis of EMS may be related to abnormalities of tryptophan metabolism.

34  Eosinophilia-Myalgia Syndrome

TRYPTOPHAN tryptophan hydroxilase

5 - Hydroxytryptophan decarboxylase

tryptophan dioxygenase

Formylkynurenine formamamidase

5 – Hydroxytryptamine (serotonin) Kynurenine monoamineoxidase

5 - Hydroxyindolaetic acid

Quinolinic acid

Fig. 34.1  Major metabolic pathways of tryptophan

5-HTP plays a major role both in neurologic and metabolic diseases, and its synthesis from tryptophan represents the limiting step in serotonin and melatonin biosynthesis. 5-HTP has natural sources, but molecular engineering is used for biosynthesis and microbial production (Maffei 2020). These methods are based on biochemical reactions (such as TPH catalysis) and the use of alternative cofactors to improve the biosynthetic ability of bacterial and fungal cells to produce 5-HTP at industrial levels. The reasons given in support of EMS being an adverse reaction to tryptophan itself, rather than to a contaminant, are as follows:

• Clinical similarity of EMS to eosinophilic fasciitis which may have mononuclear cells as predominant cellular infiltrate rather than eosinophils. • Hypereosinophilic rash and pulmonary disRole of Tryptophan ease seen in patients with EMS suggest that a hypersensitivity reaction may be responsible L-5-hydroxytryptophan (5-HTP) is both a drug for some features of the syndrome. and a natural component of some dietary supple- • Patients who develop toxic reaction to tryptoments. 5-HTP is produced from tryptophan by phan may have errors in tryptophan metabotryptophan hydroxylase (TPH), which is present lism with abnormal enzyme activity that in two isoforms (TPH1 and TPH2). functions adequately with normal daily intake Decarboxylation of 5-HTP yields serotonin of tryptophan but shunt metabolites to kyn(5-hydroxytryptamine, 5-HT) that is further urenine pathway in the presence of large transformed to melatonin (N-acetyl-5-­ amounts of the substance. An abnormal accumethoxytryptamine). Normal metabolic pathmulation of metabolites of tryptophan may ways of tryptophan are shown in Figure 34.1. lead to EMS.  Abnormal serotonin (5-HT)

Natural History of EMS

metabolism has been implicated in the ­pathogenesis of scleroderma (Stachow et  al. 1977). Scleroderma-like changes and myositis occur in carcinoid syndrome characterized by excessive production of serotonin and its metabolites. • Concomitant use of antidepressants which inhibit uptake of serotonin may result in accumulation of metabolites of tryptophan. • Pyridoxine deficiency has been reported in some patients with EMS and may lead to abnormal metabolism of tryptophan because 5-HT decarboxylase is quite sensitive to deficiency of this cofactor.

Role of Tryptophan Contamination The etiological agent, e.g., contaminant, may trigger the onset of immunologically mediated inflammatory response. Autoantibodies to nuclear lamin C have been demonstrated in the serum of patients with EMS. The antibody titer declines dramatically after discontinuation of tryptophan and treatment with prednisone. This is evidence for autoimmune response in EMS.  Cellular and humoral immunological abnormalities in EMS are shown in Table 34.3. Polymorphisms in immune response genes may underlie the development of certain xenobiotic-­induced immune-mediated disorders. Genotyping in EMS spectrum disorder has shown DRB1*04 as a risk factor and DRB1*07 as well as DQA1*0201 being protective (Okada et  al. 2009). These findings may have implications for similar epidemics in the future.

Role of Eosinophils These play a role in the pathogenesis of EMS as effector cells. The growth and maturation of eosinophils, their migration to the site of action, and their viability and function are regulated by three cytokines: GM-CSF, IL-3, and IL-5 which are produced by activated T lymphocytes, mast cells, neutrophils, and eosinophils themselves. Cytokine-induced stimulation of eosinophils is

537 Table 34.3  Cellular and humoral immunological abnormalities in EMS Cellular Inflammatory cell infiltration in fascia and muscles: monocytes, macrophages, lymphocytes Activated monocellular cells: in tissues and in blood Preponderance of CD8 and T cells in affected tissues Humoral Circulating immune complex Antinuclear antibodies

an important feature of EMS. Patients with EMS have increased levels of IL-5. An EMS-like syndrome has been described in a patient without tryptophan use and increased level of serum GM-CSF (Bochner et al. 1991). Activated eosinophils release toxic granules which appear to be an important feature of EMS. An eosinophil-derived neurotoxin is postulated to be responsible for producing neuropathy in EMS.  Eosinophil-derived granular proteins induce secretion of platelet α-granule component of fibrogenic cytokines including TGF-alpha. Fibrosis of connective tissue is a consistent finding late in the course of EMS. EMS fibroblasts in situ display elevated expression of transforming growth factors (TGF)-alpha1 which plays a crucial role in the physiologic regulation of connective tissue metabolism and appears to participate in the pathogenesis of several experimentally induced and spontaneously occurring fibrotic conditions.

CNS Involvement in EMS Clinical Features In initial studies, symptoms such as loss of memory and difficulty in concentration were reported in 15% of patients with EMS (Culpepper et al. 1991). Other studies of CNS-EMS have shown that amnesia occurs in 88%, intermittent confusion in 38%, motor disorders in 31%, recurrent headache in 19%, and dementia in 6% (Armstrong et al 1997). Clinicopathological Correlations Adair et al. (1992) reported a case of acute leukoencephalopathy and seizures associated with axonal polyneuropathy 4 months after the onset of EMS. A lesion of the hemispheric white m ­ atter

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with signal characteristics suggestive of demyelination was detected on MRI in this case. Another patient with EMS was reported to develop progressive CNS involvement that did not improve despite discontinuation of tryptophan (Lynn et al. 1992). Initially there was spastic monoparesis and ataxia, but cognitive deficits suggestive of subcortical dementia developed later. MRI showed multiple white matter lesions in the cerebral hemispheres. Krupp et al. (1992) carried out a small survey for the detection of cognitive deficits in EMS patients by questionnaires and neuropsychological testing and found that cognitive abnormalities suggestive of CNS involvement were frequent among EMS patients. Comprehensive neuropsychological testing revealed neurocognitive impairment in a series of patients, and these were correlated with changes in white matter shown on MRI scans of these patients. In patients with EMS and CNS abnormalities, proton MR spectroscopy and MRI show subcortical focal lesions, focal lesions in deep white matter, cortical atrophy, ventricular dilatation, and diffuse and periventricular white matter abnormalities. MR spectroscopic findings have two distinct spectral patterns: 1. Increased choline-containing compounds, decreased N-acetylaspartate, and increased lipid macromolecules, consistent with inflammatory cerebrovascular disease 2. Increased glutamine, decreased myo-inositol, and decreased choline, consistent with acute CNS injury or metabolic encephalopathy The pattern of cerebral lesions and neurometabolites is consistent with widespread inflammatory cerebrovascular disease. However, a subgroup of patients with CNS-EMS has neurometabolic changes consistent with a metabolic encephalopathy identical or like hepatic encephalopathy.

 ognitive Deficits Due to Quinolinic C Acid Overproduction Since L-tryptophan and metabolites are well known as aryl hydrocarbon receptor (AHR)

34  Eosinophilia-Myalgia Syndrome

ligands, their interaction with AHR may induce Th17 cell differentiation and autoinflammation in these disorders (Rieber and Belohradsky 2010). Cognitive deficits may be related to excessive production of quinolinic acid, a known neurotoxin, in patients with EMS.  This seems to be mediated by interferon-gamma. Quinolinic acid binds to NMDA receptors on brain cell surfaces. NMDA receptors in the basal ganglia, hippocampus, and cerebral cortex mediate cognitive functions such as memory and learning as well as synaptic plasticity. Levels of quinolinic acid rise 1000-fold in patients with AIDS-dementia complex.

 nimal Models of EMS A Lewis rat has been proposed as an animal model of EMS (Crofford et al. 1990). Although the animals do not develop eosinophilia, the animals treated with contaminated tryptophan developed significant fascial thickening as compared to rats that received pure tryptophan.

Treatment of EMS There is no generally accepted effective treatment for EMS.  Corticosteroids may provide symptomatic relief of myalgia, but they do not prevent the development of neuromuscular disease. The use of immunosuppressive therapy and plasmapheresis has been disappointing, but methotrexate has been reported to be helpful (Martinez-Osuna et  al. 1991). Reduced severity of EMS has been reported to be associated with consumption of vitamin supplements including ascorbic acid before the onset of illness (Hatch and Goldman 1993).

Concluding Remarks EMS is a striking example of how a presumably harmless food supplement and over-the-counter self-medication can produce a serious illness. Finding the etiologic factor is medical detective work. More research is needed to determine how the etiological agent is synthesized during the

References

manufacturing process. Monitoring procedures are required to ensure that similar contamination does not occur in other biotechnology products. Investigation of pathomechanism of EMS will increase our understanding of eosinophilic and immunologic disorders and help in devising new therapies for these. Two lessons have been learned from this tragedy. The first is the dubious advisability of allowing tryptophan to be sold without a physician’s prescription. The second lesson is that the FDA, without power to approve alterations of manufacturing process of a substance, cannot protect the consumers from such episodes. Mayeno and Gleich (1994) have pointed out that we had two epidemics related to food contamination (EMS and TOS) during the past decade. Neither the mechanism nor the specific contaminant has been demonstrated unequivocally. They are concerned that unless such agents are identified and proper preventive measures are taken, another food-related epidemic like TOS and EMS can still occur.

References Adair JC, Rose JW, Digre KB.  Acute encephalopathy associated with the eosinophilia-myalgia syndrome. Neurology. 1992;42:461–2. Alonso-Ruiz A, Calabozo M, Perez-Ruiz F, et al. Toxic oil syndrome. Medicine. 1993;72:285–95. Armstrong C, Lewis T, D’Esposito M, et al. Eosinophiliamyalgia syndrome: selective cognitive impairment, longitudinal effects, and neuroimaging findings. J Neurol Neurosurg Psychiatry. 1997;63:633–41. Belongia EA, Hedberg CW, Gleich GJ, et  al. An investigation of the cause of eosinophilia-myalgia syndrome associated with tryptophane use. NEJM. 1990;323:357–65. Belongia EA, Mayeno AN, Osterholm MLT.  The eosinophilia-­myalgia syndrome and tryptophan. Ann Rev Nutr. 1992;12:235–56. Bochner BS, Friedman B, Krosjnaswamy B, et  al. Episodic eosinophilia-myalgia-like syndrome in a patient without L-tryptophan use: association with eosinophil activation and increased serum levels of granulocyte-macrophage colony-stimulating factor. J Allergy Clin Immunol. 1991;88:629–36. Carr L, Rüther E, Berg PA, et  al. Eosinophilia myalgia syndrome in Germany: an epidemiologic review. Mayo Clin Proc. 1994;69:620–5.

539 Center for Disease Control. Eosinophilia myalgia syndrome – New Mexico. MMWR. 1989;38:765–7. Crofford LJ, Rader JI, Dalakas MC, et  al. L-tryptophan implicated in human eosinophilia-myalgia syndrome causes fasciitis and perimyositis in the Lewis rat. J Clin Investig. 1990;86:1757–63. Culpepper RC, Williams RG, Mease PJ, et al. Natural history of eosinophilia-myalgia syndrome. Ann Int Med. 1991;115:437–42. Dalakas MC, Karpati G.  Inflammatory myopathies. In: Karpati G, Hilton-Jones, Bushby K, Griggs RC, editors. Disorders of voluntary muscle. 8th ed. Cambridge, UK: Cambridge University Press; 2010. p. 427–52. Douglas AS, Eaglesd JM, Mowat NAG.  Eosinophilia-­ myalgia syndrome associated with tryptophan. BMJ. 1990;301:387. Eidson M, Philen RM, Sewell CM, et  al. L-tryptophan and eosinophilia myalgia syndrome in New Mexico. Lancet. 1990;335:645–8. Harati Y.  Eosinophilia-myalgia syndrome and its relation to toxic oil syndrome. In: de Wolff FA, editor. Handbook of clinical neurology, vol. 20. Amsterdam: Elsevier; 1994. p. 249–71. Hatch DL, Goldman LR. Reduced severity of eosinophilia-­ myalgia syndrome associated with the consumption of vitamin-containing supplements before illness. Arch Int Med. 1993;153:2368–73. Hedberg K, Urbach D, Slutsker L, et  al. Eosinophilia-­ myalgia syndrome: natural history in a population-­ based cohort. Arch Int Med. 1992;152:1889–92. Heiman-Patterson TD, Bird SJ, Parry GJ, et al. Peripheral neuropathy associated with eosinophilia myalgia syndrome. Ann Neurol. 1990;28:522–8. Henning KJ, Jean-Baptiste E, Singh T, et al. Eosinophilia-­ myalgia syndrome in patients ingesting a single source of L-tryptophan. J Rheumatol. 1993;20:273–8. Hertzman PA, Blevilns LWWL, Mayer J, et al. Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. NEJM. 1990;322:869–73. Kamb ML, Murphy JL, Jones JL, et  al. Eosinophilia-­ myalgia syndrome in L-tryptophan exposed patients. JAMA. 1992;267:77–82. Kaufman LD, Philen RM.  Tryptophan: current status and future trends for oral application. Drug Saf. 1993;8:89–98. Kilbourne EM, Philen RM, Kamb ML, Falk H. Tryptophan produced by Showa Denko and epidemic eosinophilia-­ myalgia syndrome. J Rheumatol Suppl. 1996;46:81– 8; discussion 89–91. Krupp LB, Pepper C, Jandorf L, et  al. Central nervous system involvement in eosinophilia-myalgia syndrome. Neurology. 1992;42(suppl 3):294. Love LA, Rader JI, Crofford L, et  al. L-tryptophan (L-TRP) and 1,1′-ethylidenebis-tryptophan (EBT), a contaminant in eosinophilia myalgia syndrome (EMS) case-associated L-TRP, causes myofascial thickening and pancreatic fibrosis. Arthr Rheum. 1991;34(suppl):S131.

540 Lynn J, Rammohan KW, Bornstein RA, et al. Central nervous system involvement in the eosinophilia-myalgia syndrome. Arch Neurol. 1992;49:1082–5. Maffei ME. 5-hydroxytryptophan (5-HTP): natural occurrence, analysis, biosynthesis, biotechnology, physiology and toxicology. Int J Mol Sci. 2020;22:181. Maitani T, Saitoh H.  Eosinophilia myalgia syndrome (EMS) caused by L-tryptophan product and toxic oil syndrome (TOS) caused by denatured rape-seed oil. Shokuhin Eiseigaku Zasshi. 2009;50:279–91. Martinez-Osuna P, Wallach PM, Seleznick MJ, et  al. Treatment of eosinophilia myalgia syndrome. Sem Arthr Rheum. 1991;21:110–21. Mayeno AN, Gleich GJ.  The eosinophilia-Myalgia syndrome: lessons from Germany. Mayo Clin Proc. 1994;69:702–4. Okada S, Kamb ML, Pandey JP, et  al. Immunogenetic risk and protective factors for the development of L-tryptophan-associated eosinophilia-myalgia syndrome and associated symptoms. Arthritis Rheum. 2009;61:1305–11. Philen RM, Hill RH, Flanders WD, et al. Tryptophan contaminant associated with eosinophilia-myalgia syndrome. Am J Epidemiol. 1993;138:154–9. Rieber N, Belohradsky BH.  AHR activation by tryptophan--pathogenic hallmark of Th17-mediated inflammation in eosinophilic fasciitis, eosinophilia-­

34  Eosinophilia-Myalgia Syndrome myalgia-­syndrome and toxic oil syndrome? Immunol Lett. 2010;128:154–5. Slutsker L, Hoesley FC, Miller L, et al. Eosinophilia-­myalgia syndrome associated with exposure to tryptophan from a single manufacturer. JAMA. 1990;264:213–7. Smith BE, Dyck PJ.  Peripheral neuropathy in the eosinophilia-­ myalgia syndrome associated with L-tryptophan ingestion. Neurology. 1990;40:1035–40. Stachow A, Jablonska S, Skiendzielewska A. 5-­ hydroxytryptamine and tryptamine pathway in scleroderma. Br J Dermatol. 1977;97:147–54. Thacker HL.  Eosinophilia-myalgia syndrome: the Cleveland Clinic experience. Cleve Clin J Med. 1991;58:400–8. Tsutsui K, Taniuchi K, Mori T, et  al. Eosinophilia-­ myalgia syndrome: a report of two cases in Japan. Eur J Dermatol. 1996;6:113–5. Turi GK, Solitare GB, James N, et  al. Eosinophilia-­ myalgia syndrome associated with neuromyopathy. Neurology. 1990;40:1793–6. Van Garsse LGMM, Boeykens PPH.  Two patients with eosinophilia-myalgia associated with tryptophan. BMJ. 1990;301:21. Varga J, Jimenez SA, Uitto J. L-tryptophan and the eosinophilia-myalgia syndrome: current understanding of the etiology and pathogenesis. J Invest Dermatol. 1993;97S–105S.

Drug-Induced Pituitary Disorders

Introduction The pituitary is the master gland that conducts the endocrine orchestra of the human body. Several drugs affect the pituitary gland, but there is a paucity of studies on this organ of the effect of xenobiotics (pharmacologically, endocrinologically, and toxicologically active substances which are not produced endogenously). Reasons for the relative shortage of studies of the toxic effects of xenobiotics on the pituitary are as follows: • Relatively low exposure of the pituitary cells to xenobiotics as the vascular supply and concentrating ability of the gland are less than the major organs of excretion and metabolism such as the liver and the kidneys. • Low frequency of published reports describing histopathologic lesions in the pituitary as compared with other endocrine glands. • Manifestations of pituitary toxicity are usually expressed as functional and structural changes in target endocrine glands under its control, thus shifting attention away from it. Toxic substances affect the pituitary gland function or structure in the following ways: • Disturbance of pituitary function by direct effect on cells within the gland

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• Producing complications in preexisting lesions within the pituitary gland such as tumors • Vascular disturbances in the pituitary gland • Disruption of the hypothalamo-pituitary-­ adrenal axis with disturbances of other endocrines and peripheral hormones which disturb the pituitary function • Alteration of neurogenic signals (neuropeptides/neurotransmitters) that regulate the activity of the adenohypophyseal cells • A combination of more than one of the above

 irect Effects of Drugs D on the Pituitary This has been studied mostly in animal toxicology studies. An unidentified “novel anticancer drug” produced vacuolation and apoptosis in monkey anterior pituitary cells without predilection for any specific cell type (Gopinath et  al. 1987). Hypertrophy and hyperplasia of lactotrophs have been observed in experimental animals administered with natural or synthetic estrogens. This is like the pituitary enlargement that occurs during pregnancy when endogenous estrogens are produced in large quantities, and the effect is directly on estrogen receptors in the pituitary. In animals, hypertrophy may proceed to neoplasm formation, but estrogen treatment does not induce tumor formation de novo in humans.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_35

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 odification of Drug Effect by M Preexisting Lesions in the Pituitary This is a significant factor because of the following reasons: • Some drugs are used to treat pituitary tumors. • Silent pituitary tumors discovered at autopsy are present in as high as 20% of the general population. Various lesions that have been encountered are: • Pituitary apoplexy (infarction or hemorrhage) • Enlargement of a pituitary tumor • Cerebrospinal fluid leakage due to shrinking of the pituitary tumor

Pituitary Apoplexy Various causes of pituitary apoplexy are shown in Table 35.1. Postpartum ischemic necrosis of the anterior pituitary was described as occurring due to spasm of the infundibular arteries (Sheehan Table 35.1  Causes of pituitary apoplexy Postpartum pituitary necrosis (Sheehan’s syndrome) Spontaneous hemorrhages in adenomas Idiopathic pituitary hemorrhages Iatrogenic pituitary infarction due to surgery in sellar or parasellar region Drugs  Anesthesia  Anticoagulants  Bromocriptine  Cabergoline for treatment of cystic macroprolactinoma (Balarini Lima et al. 2008)  Chemotherapy for acute myeloid leukemia (Silberstein et al. 2008)  Chlorpromazine  Clomiphene  Cocaine consumption  Estrogens  Hormones for testing pituitary function: insulin  Hormones for diagnosis of pituitary adenomas: TRH and GnRH  Luteinizing hormone-releasing hormone (LHRH) used therapeutically: leuprorelin  Gonadotropin-releasing hormone agonists: goserelin

35  Drug-Induced Pituitary Disorders

1937). However, since the original description of Sheehan’s syndrome, the disorder is seen most frequently from severe hemorrhage of the capillary network during parturition but may also result from anesthesia or poisoning.

 recipitating Factors for Pituitary P Apoplexy The presence of pituitary tumors predisposes to pituitary apoplexy which occurs frequently in glands in which adenomas are and is seen more commonly with somatotroph, lactotroph, or corticotroph adenomas. Softening or degenerative changes within the adenoma may predispose to hemorrhage. Pituitary apoplexy may be precipitated by the administration of estrogens or anticoagulants. Heparin therapy for myocardial infarction triggered pituitary apoplexy in one case (Oo et al. 1997).  ituitary Apoplexy After Pituitary P Function Tests Apoplexy may occur in a pituitary with little or no evidence of previous disease. Pituitary apoplexy can follow pituitary stimulation tests. A case has been reported in which pituitary infarction was precipitated by hypoglycemia induced by insulin stress testing for suspected hypothyroidism (Harvey et al. 1989). Preoperative assessment of pituitary adenomas includes a combined testing of growth hormone (GH) and ACTH release stimulated by hypoglycemia, thyroid-­ stimulating hormone (TSH) release by thyroid-­ releasing hormone (TRH), and gonadotropin release by gonadotropin-releasing hormone (GnRH). Complications with these tests are rare, but several cases have been reported of pituitary apoplexy with combined dynamic testing of pituitary hormones. A single intravenous administration of GnRH led to infarction of the pituitary in a patient with prolactinoma (Arafah et al. 1989). Repeat injection after removal of the hemorrhage and adenoma did not produce any adverse effects. Pituitary apoplexy has also occurred in a patient with glycoprotein secreting adenoma after GnRH administration (Masson et al. 1993). Pituitary infarction occurred in another case of follicle-stimulating hormone (FSH) secreting

Direct Effects of Drugs on the Pituitary

pituitary adenoma 2 hours after therapeutic injection of luteinizing hormone-releasing hormone (LHRH) which normalized FSH level (Korsic et al. 1984). Pituitary apoplexy has been reported after injection of goserelin (LHRH analog) in a patient with advanced prostatic carcinoma (Ando et al. 1995). Pituitary apoplexy was reported after an intravenous injection of TRH (200 g) as a stimulation test, which was missed by brain imaging but found at surgery (Wang et al. 2007). Two cases of pituitary apoplexy were reported following a dynamic combined test of pituitary function involving intravenous injection of TRH, GnRH, and regular insulin (Masago et al. 1995). These authors also reviewed the literature on this topic and found 22 cases that had precipitation of pituitary apoplexy following pituitary function tests. Pituitary apoplexy can also occur with dynamic endocrine tests such as the dexamethasone suppression test (Kuzu et al. 2018).

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Bromocriptine  Bromocriptine which is used for treatment of prolactinomas has been found to be associated with intratumoral hemorrhage (Onesti et  al. 1990; Endoh et  al. 1994; Lazaro et  al. 1994). Bromocriptine produces rapid shrinkage of the prolactin-secreting tumor cells, and this may lead to disruption of the tissue texture and hemorrhage. Chlorpromazine  One case of pituitary apoplexy in a prolactinoma was reported following chlorpromazine injection (Silverman et al. 1978). Postural hypotension induced by chlorpromazine was the precipitating factor. Clomiphene  This is used for the treatment of infertility. One case of clomiphene-induced pituitary apoplexy occurred in a young women with acromegaly (Walker et al. 1996). This was treated surgically.

Leuprorelin  This is used for the treatment of prostate cancer based on the inhibition of pituitary gonadal function and suppression of gonadal steroid hormone. The aim of therapy is inhibition of sex hormone-dependent tumors. One patient • TRH has vasoactive properties and also ele- developed pituitary apoplexy after the first injecvates serum levels of norepinephrine. TRH-­ tion of leuprorelin depot (Reznik et  al. 1997). induced vasospasm or pressor effect may MRI scan showed hemorrhage in a previously precipitate pituitary infarction. TRH also undiagnosed pituitary adenoma which was directly activates tumor cells. The subsequent removed surgically. increase in blood flow, blood volume, and tumor size may lead to stretch and occlusion Goserelin  Gonadotropin-releasing hormone agonists (GnRHAs) are used in many clinical condiof many vessels resulting in their rupture. • GnRH may increase the cell metabolism tions, particularly prostate cancer. There have been underlying the excessive gonadotropin pro- a few case reports of apoplexy from a previously duction to such an extent that a vascular acci- undiagnosed pituitary tumor, occurring within hours to days of initiation of GnRHA therapy. A dent can occur. • Insulin induces hypoglycemia which reduces case of delayed onset pituitary apoplexy has been CBF.  Catecholamine release in response to reported following subcutaneous GnRHA (goserehypoglycemia may affect the cerebrovascular lin) implant for treatment of locally advanced prostate cancer (Sinnadurai et  al. 2010). The circulation. patient presented headache and vision loss. MRI scan revealed a large sellar/suprasellar mass. His Pituitary Apoplexy as an Adverse Effect follicle-stimulating hormone (FSH) and luteinizof Drugs There are only a few drugs involved and a limited ing hormone (LH) levels were grossly elevated. A number of case reports in the literature. Some of transsphenoidal endoscopic decompression of the pituitary tumor was performed. His vision these are as follows.

Pathomechanism of Apoplexy The pathomechanism of apoplexy is not understood but mechanisms related to functional tests are:

544

improved postoperatively, and his FSH, LH, testosterone, prostate specific antigen levels returned to normal levels. Histopathologic studies revealed a pituitary adenoma, which stained positive for FSH and LH.  The prostate cancer management was changed to an anti-androgen agent and a GnRH antagonist. This case demonstrates that pituitary apoplexy can develop up to 8 weeks after the initiation of treatment for prostate cancer with GnRHAs.

 linical Aspects of Pituitary Apoplexy, C Diagnosis, and Treatment These include deterioration of vision, ophthalmoplegia, and headache. Hemiparesis and coma may occur in severe cases. Diagnosis is established by CT scan and MRI. Treatment of pituitary apoplexy is surgical, i.e., transsphenoidal removal of the necrotic mass. The results of surgery are generally good with recovery of vision, but in some cases, the visual deficits do not recover. Some cases have been managed conservatively and followed up by MRI examinations.

 erebrospinal Fluid Rhinorrhea (CSF) C Due to Shrinking of Prolactinoma CSF rhinorrhea has been reported in ten cases as a sequel of shrinking of macroprolactinomas as an effect of bromocriptine therapy (Barlas et al. 1994; Bronstein et al. 1989; Clayton et al. 1985; Coculescu and Finer 1994; Eljamel et  al. 1992; Pascal-Vigneron et  al. 1994). Some of these tumors invade the sella floor and plug it. Shrinking of the tumor mass unplugs this leading to CSF leakage. In some cases, discontinuation of bromocriptine led to cessation of CSF leak. The risk of meningitis requires closure of the CSF fistula. The treatment is surgical repair of the CSF leak, or as an alternative, a CSF shunting procedure is done to promote healing of the CSF fistula.

35  Drug-Induced Pituitary Disorders

pituitary hormone secretion and results from pituitary or hypothalamic disease. The manifestations may be due to deficiency of corticotrophin, gonadotropins, androgen, or growth hormone. Drugs may induce hypopituitarism and some examples are. • Antineoplastic drugs • Interferon • Corticosteroids

Drug-Induced Disorders of the Pituitary Due to Disturbances of Other Endocrines Pituitary is the master gland of the endocrine orchestra and is affected by the brain as well as feedback influences from the target glands and their effects on the peripheral tissues. The relationships of the pituitary are shown schematically in Fig. 35.1. Several drugs have a secondary effect on the pituitary via induction of changes in the other endocrine function. The scope of this work does not allow any

CENTRAL NERVOUS SYSTEM

stimuli HYPOTHALAMUS releasing factors

PITUITARY trophic hormones

TARGET GLANDS

hormones

Pituitary Insufficiency

PHYSIOLOGICAL ACTION ON TISSUES

Hypopituitarism is the partial or complete insufficiency (panhypopituitarism) of anterior-­Fig. 35.1  Relationships of the pituitary

Direct Effects of Drugs on the Pituitary

discussion of the complex endocrine interrelationships and adverse effects of drugs on other endocrines. Drug may also influence the pituitary via their effects on the central nervous systems and neurotransmitter changes. Some adverse reactions involving various hypothalamo-­ pituitary-target endocrine axes will be mentioned briefly. Many of the drugs administered routinely in the intensive care unit significantly impact the neuroendocrine system and can disrupt the hypothalamo-pituitary-adrenal axis and hypothalamo-pituitary-thyroid axis (Thomas et al. 2010). Few studies have systematically addressed drug-induced endocrine disorders in the critically ill. Timely identification and appropriate management of drug-induced endocrine adverse events may potentially improve outcomes in the critically ill.

Hypothalamo-Pituitary-Thyroid Axis Therapeutic doses of thyroid hormone can suppress TSH secretion. In addition to this, several glucocorticoids and dopaminergic drugs can inhibit thyroid-stimulating hormone (TSH) secretion and reduce the TSH response to thyroid-­ releasing hormone (TRH). Neuroleptics such as chlorpromazine and haloperidol can raise basal TSH levels and enhance the TSH response to goitrogenic medications that produce hypothyroidism. This leads to a compensatory increase in TSH levels. Drugs which alter thyrotropin secretion are listed in Table 35.2. Hypothalamo-Pituitary-Adrenal Axis (HPA) Arginine vasopressin is the most important of various hormones that influence adrenocorticotrophin Table 35.2  Drugs that alter thyrotropin secretion Increase Amiodarone Domperidone Estrogens Glucocorticoids Heparins Lithium Metoclopramide Sulpiride

Decrease Androgens Antiepileptics: carbamazepine, phenytoin Atypical antipsychotics Corticosteroids Dopamine agonists: bromocriptine, levodopa Lithium Octreotide Verapamil

545

(ACTH) secretion by the pituitary. ACTH secretion is impaired by the feedback effect on the hypothalamus and the pituitary of prolonged highdose glucocorticosteroid therapy. Drugs which alter ACTH secretion are shown in Table 35.3. Iatrogenic Cushing’s syndrome can occur with pharmacological doses of glucocorticoids or ACTH.  Cytokines activate the HPA axis and cause release of ACTH and glucocorticoids. Interleukin (IL)-1 is one of the most potent activators of HPA axis, but other cytokines such as IL-2, IL-6, and tumor necrosis factor (TNF)-alpha can act synergistically with it. Peripheral or central administration of IL-1 or IL-6 causes release of corticotrophin-releasing hormone (CRH), which subsequently stimulates the release of ACTH and glucocorticoids, although cytokines can act directly at the level of the pituitary.

Hypothalamo-Gonadal Axis The secretion of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) are under the negative feedback control of testosterone and estradiol. Drugs that alter gonadotropin secretion are listed in Table 35.4. Table 35.3  Drugs that alter ACTH secretion Increase Alcohol CNS stimulants: amphetamine, methylphenidate Cytokines: IL-2, IL-6, TNF-α Nicotine Opiate antagonists Physostigmine Tricyclic antidepressants: imipramine, desipramine

Decrease Benzodiazepines Etomidate Glucocorticoids Opiates Phenobarbital Phenytoin Statins

Table 35.4  Drugs that alter gonadotropin secretion Increase Alcohol Antineoplastic agents Ketoconazole Opiate antagonists

Decrease Androgen Cytokines: Interleukin-1 Digitoxin Dopamine agonists: bromocriptine Estrogens Glucocorticoids Opiates Verapamil

546

Glucocorticoid excess can inhibit pituitary gonadotropin secretion. Chronic administration of IL-1beta into the CNS disrupts the estrous cycle by inhibiting the synthesis and release of luteinizing hormone-releasing hormone (LHRH) and inhibits luteolysis via increased production of prolactin.

Hypothalamo-Pituitary-Prolactin Secretion Prolactin is a polypeptide trophic hormone secreted by the anterior pituitary. Its secretion is primarily under the inhibitory control of hypothalamic dopamine and stimulatory influence of serotonergic system. TRH is also a stimulant of prolactin. Hyperprolactinemia  Various physiological stimuli such as sleep, stress, exercise, sexual intercourse, menstrual cycle, and pregnancy also stimulate prolactin secretion. Hyperprolactinemia frequently produces galactorrhea. Occasionally galactorrhea can occur without hyperprolactinemia. About 20% of the women with galactorrhea have prolactinomas of the pituitary demonstrated radiologically. This frequency Table 35.5  Causes of hyperprolactinemia Hypothalamic lesions  Infiltrative diseases: sarcoidosis  Ischemia  Neuraxis radiation  Trauma  Tumors Pituitary lesions  Acromegaly  Cushing’s disease  Empty sella syndrome  Pituitary stalk section  Prolactinomas Neurogenic  Breast stimulation  Chest wall lesions  Spinal cord lesions Other conditions  Chronic renal failure  Cirrhosis of liver  Hypothyroidism Drugs (see Table 35.3) Idiopathic

35  Drug-Induced Pituitary Disorders

increases to 34% in women with galactorrhea and amenorrhea. Causes of hyperprolactinemia are shown in Table 35.5, and drugs which can induce hyperprolactinemia are shown in Table 35.6. Pathomechanism  Many of these drugs act on the hypothalamus via neurotransmitter systems and some of the examples are as follows. Depletion of Catecholamine Stores  Reserpine and methyldopa are examples. Table 35.6  Drugs that cause hyperprolactinemia Alcohol Anesthetics Antidepressants  Tricyclic  Amitriptyline  Clomipramine  Imipramine  Monoamine oxidase inhibitors Antiemetics  Metoclopramide  Sulpiride Antihypertensives  Methyldopa  Reserpine Antipsychotics  Phenothiazines  Chlorpromazine  Fluphenazine  Perphenazine  Prochlorperazine  Promazine  Thioridazine  Trifluoperazine  Haloperidol Benzodiazepines: chlordiazepoxide Cocaine Dexamphetamine and fenfluramine Histamine H2-receptor blockers>  Cimetidine  Ranitidine Hormones  Estrogens  Oral contraceptives  Thyrotropin-releasing hormone Nicotine Opioids Physostigmine Serotonin precursors: tryptophan Verapamil

Direct Effects of Drugs on the Pituitary

547

Blockage of Dopamine Receptors  Antipsychotic (neuroleptic) phenothiazines and butyrophenones block dopamine receptors.

Table 35.2. If no cause can be demonstrated, it is labeled as idiopathic hypoprolactinemia and is treated with drugs. Prolactinomas can be treated with drugs, surgery, or radiation therapy. Bromocriptine has been the standard therapy Clozapine is an antipsychotic agent that displays atypical pharmacological and clinical prop- for hyperprolactinemia for the over 30 years. It is erties as compared to classic antipsychotics. It a dopamine agonist that not only inhibits the synhas a relatively weak central dopaminergic activ- thesis and secretion of prolactin but also reduces ity and affects serum prolactin levels in a manner cellular DNA synthesis and tumor growth. different from other antipsychotics. In rats, clo- Approximately 80% of the patients with prolactizapine produces rapid elevations in serum prolac- nomas respond to bromocriptine with shrinkage tin levels similar in magnitude to those produced of the tumor and substantial reduction of the by haloperidol, but they are of much shorter dura- serum prolactin levels. A randomized, placebo-­ tion than those elicited by haloperidol. In humans controlled study has shown that administration of treated with clozapine under a single-dose sched- bromocriptine is a safe method for treating ule, prolactin levels are normal most of the time. antipsychotic-­drug-induced hyperprolactinemia Clozapine’s weak D2-receptor blocking effects, without exacerbating either psychotic symptoms combined with increased activity of tuberoinfun- or extrapyramidal symptoms (Lee et  al. 2010). dibular neurons, may explain its weak effect on New dopamine agonists drugs including quinaprolactin secretion. Secondary effects of hyperp- golide, pergolide, and cabergoline have been rolactinemia such as amenorrhea, galactorrhea, developed as alternatives for patients who do not and gynecomastia are seldom seen in patients on tolerate bromocriptine. In drug-induced hyperprolactinemia, considclozapine therapy. eration is given to the withdrawal of the offendDisturbances of Serotonin  Antidepressants ing drug if possible. Treatment cannot be always probably stimulate prolactin release by blocking discontinued in psychiatric patients with the reuptake of serotonin or enhancing the sensi- neuroleptic-­induced hyperprolactinemia. A study tivity of postsynaptic serotonin receptors. used concomitant bromocriptine with neurolepMonoamine oxidase inhibitors may shift the bal- tics in six psychiatric outpatients suffering from ance between dopaminergic inhibition and sero- neuroleptic-induced hyperprolactinemia with tonergic stimulation of prolactin release. amenorrhea/oligomenorrhea (Smith 1992). Three of the patients had the menstrual irregularity corIncreased Responsiveness to Prolactin-­rected successfully with bromocriptine. Releasing Stimuli  Estrogens may increase mean Controlled clinical studies are required to evaluserum prolactin levels by this mechanism. ate this combination. As an alternative, bromocriptine can be switched over to clozapine, an Histamine  Brain histamine may play a role in atypical neuroleptic, which is unlikely to induce prolactin release. Antihistaminic cimetidine may hyperprolactinemia. rarely increase prolactin secretion and produce galactorrhea. Hypothalamo-Pituitary-Growth

Management of Hyperprolactinemia Hyperprolactinemia is a frequent cause of amenorrhea, infertility, and galactorrhea in women and decreased libido and impotence in men. Investigations of patients with raised serum prolactin levels includes search for pituitary prolactinomas, drugs, and other causes listed in

Hormone Axis Various organs and hormones involved in this axis are as follows.

Hypothalamus  Growth hormone-releasing hormone stimulates growth hormone (GH) gene transcription and GH secretion, whereas somatostatin inhibits GH secretion.

548

Pituitary  GH stimulates insulin-like growth factor (IGF)-1 production and antagonizes insulin action. Drugs may affect growth through their effect on GH secretion at hypothalamic or pituitary level through effect on IGF-1 which can be produced in the liver and extrahepatic tissues and stimulates bone growth and cell replication. Prolonged use of steroids in children may affect growth, but it is not certain if the effect is due to alteration of growth hormone secretion or direct effect on the target tissues. Drugs which affect growth hormone secretion are shown in Table 35.7.

Posterior Pituitary This will be considered because of its connection with the syndrome of inappropriate antidiuretic hormone secretion which has been described as Table 35.7  Drugs that influence growth hormone (GH) secretion Increase of GH secretion Alpha-agonists: clonidine, apomorphine Amino acids Androgens: testosterone Beta-blockers: propranolol CNS stimulants: amphetamine, methylphenidate, nicotine Dopamine agonists: levodopa, bromocriptine Estrogens Fentanyl GABAergic drugs: baclofen, diazepam Opioids: methadone, nalorphine Physostigmine Pyridostigmine Serotonin precursors: tryptophan Tricyclic antidepressants: imipramine, desipramine Decrease of GH secretion Alpha-blockers: phentolamine, phenoxybenzamine Atropine Cimetidine Dopamine receptor blockers: chlorpromazine Haloperidol Glucocorticoids Insulin-like growth factor-1 Serotonin receptor blockers: cyproheptadine Somatostatin

35  Drug-Induced Pituitary Disorders

an adverse reaction to several drugs. The antidiuretic hormone (ADH) is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and transported down to axon terminals in the posterior pituitary where it is stored until release into peripheral circulation. A large number of stimuli such as vomiting and hypoglycemia can cause release of ADH. Under normal condition, the major regular of water homeostasis is plasma osmotic pressure which exerts its influence through specific osmoreceptor neurons located in the anterior hypothalamus. In the kidneys, the antidiuretic effect of ADH is mediated mainly by vasopressin-2 receptors located on the cells of the collecting ducts. These cells are relatively impermeable to water in the absence of ADH, and the receptors initiate the series of steps that increase the permeability of the cells lining the lumen of collecting ducts so that reabsorption of water is facilitated along a concentration gradient.

 yndrome of Inappropriate Secretion S of Antidiuretic Hormone (SIADH) This syndrome was first described by Bartter and Schwartz (1967). It is characterized by sustained release of ADH in the absence of either osmotic or non-osmotic stimuli or by an enhanced renal action of ADH. The patients are unable to excrete diluted urine, and ingested water is retained leading to hyponatremia. Symptoms of hyponatremia usually do not appear until serum sodium level falls below 130 mmol/L.  Common early symptoms are weakness, confusion, lethargy, headache, and weight gain. Persistent severe hyponatremia may lead to convulsions and coma.

Causes of SIADH Various causes of SIADH are shown in Table 35.8. Investigations of SIADH The investigation of a patient with SIADH includes a careful history taking with the various causes in mind and a list of medications that the patient may be taking. In addition to the basic

Posterior Pituitary

laboratory investigations, the following special tests should be done: • Serum electrolytes and osmolality • Urine electrolytes and osmolality, specific gravity • Endocrine function screening tests • EEG in patients with hyponatremic encephalopathy • Diagnostic tests according to the cause suspected

549

mia, and seizures are well-recognized complications of treatment with vasopressin and its analogues, particularly by the use of intranasal Table 35.9  Drugs reported to induce SIADH Angiotensin-converting enzyme (ACE) inhibitors Amiloride Anesthesia Antiepileptic drugs  Carbamazepinea  Oxcarbazepinea Antineoplastics  Cyclophosphamide  Etoposide  Vinca alkaloids Antipsychoticsa  Clozapine  Chlorpromazine  Fluphenazine  Flupenthixol  Haloperidol  Trifluoperazine  Thioridazine  Thiothixene Antidepressants  Tricyclic antidepressantsa    Amoxapine   Clomipramine   Desipramine   Dothiepin   Doxepin   Imipramine  Selective serotonin reuptake inhibitors   Citalopram   Fluoxetine   Fluvoxamine   Paroxetine   Sertraline    Venlafaxine  Trazodone  MAO inhibitors: tranylcypromine Benzodiazepines Bromocriptine Clofibrate Chlorpropamidea Nonsteroidal anti-inflammatory drugs Omeprazole Posterior pituitary hormonesa  Vasopressin  Desmopressin  Oxytocin Thiazide diureticsa

Drug-Induced SIADH Various drugs which have been reported to cause SIADH are listed in Table 35.9. While many drugs have been sporadically associated with SIADH, several medication classes are more often implicated, including antidepressants, antipsychotic agents, anticonvulsants, analgesics, and cytotoxic agents (Shepshelovich et al. 2017). Vasopressin  This drug as well as its analogues is used in the treatment of cranial diabetes insipidus. Desmopressin has a longer duration of action than vasopressin. Water intoxication, hyponatreTable 35.8  Causes of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Malignant tumors producing ADH  Small cell lung carcinoma, cancer of the pancreas  Prostate and duodenum  Carcinomas of the reticuloendothelial system  Malignant thymomas Pulmonary diseases  Acute respiratory failure  Chronic obstructive pulmonary disease  Empyema  Pneumonia  Tuberculosis Disorders of the central nervous system  Cerebrovascular accidents; subarachnoid hemorrhage  Cerebral atrophy  Encephalitis  Head injuries: skull fracture, subdural hematoma  Hydrocephalus  Infections: meningitis, brain abscess  Postoperative: neurosurgical procedures in the  Pituitary area Drugs (see Table 35.6)

Well documented. Other drugs are linked with SIADH in isolated case reports

a

550

desmopressin for nocturnal enuresis in children (Kallio et al. 1993). Thiazide Diuretics  These often cause a syndrome resembling SIADH except that the hyponatremia is accompanied by hypokalemia and alkalosis. Strictly speaking, it cannot be called SIADH because ADH secretion is physiologically appropriate in this case. Carbamazepine  Hyponatremia is a well-known adverse effect of carbamazepine in patients with epilepsy and trigeminal neuralgia with an incidence as high as 22% (Lahr 1985). Including psychiatric disorders as indications for treatment, CBZ-induced hyponatremia has been reported to range from 4.8 to 40% (Van Amelsvoort et  al. 1994) and 33 to 50% (Gandelman 1994). It is postulated to be due to antidiuretic effect by stimulation of ADH release as a result of altered sensitivity of hypothalamic osmoreceptors to ­ serum osmolality. Carbamazepine, in doses of 600–2000 mg per day, produces statistically significant hyponatremia in patients with affective disorders, but clinical manifestations are rare (Joffe et  al. 1986). Oxcarbazepine, which is structurally like carbamazepine, has similar effect in producing hyponatremia and has been reported in a 25% of epileptic patients treated with this medication. Antidepressants and Antipsychotics  Hyponatremia is associated with administration of antipsychotics and antidepressants. The incidence of hyponatremia induced by antipsychotics may be much higher than is currently thought as both the newer atypical antipsychotics and the older drugs have been associated with the development of hyponatremia (Meulendijks et  al. 2010). In evaluating the development of hyponatremia in psychiatric patients, the following factors should be taken into consideration: • An important risk factor for the development of SIADH is psychiatric disorders with polydipsia. • There is a transient increase in the release of ADH during exacerbation of psychosis.

35  Drug-Induced Pituitary Disorders

• Anticholinergic effects of tricyclic antidepressants may lead to dry mouth and increased thirst. • Drug interactions.

Pathomechanism of SIADH Some of the basic mechanisms of ADH increase are not well understood, but some of the mechanisms which are applicable to drug-induced SIADH are as follows. Increased ADH Production  Noradrenaline induces release of ADH via alpha1-adrenergic receptors. Stimulation of serotonergic systems also increases ADH.  Antidepressants, antipsychotics, and dopaminergic drugs may induce SIADH by these mechanisms. Increased Responsiveness of Distal Renal Tubules to ADH  Carbamazepine is an example. Role of Dopamine  This has both a stimulatory and an inhibitory effect on ADH release. Under certain circumstances such as schizophrenic patients with low plasma osmolality, dopamine-­ antagonist neuroleptics may have an increase in ADH secretion. Dopamine agonists such as bromocriptine are known to stimulate both central and peripheral dopaminergic receptors predominantly in the kidney. They can modify diuresis and sodium excretion. A patient with Parkinson’s disease can develop hyponatremia following treatment with bromocriptine. Hypotension  Drug-induced hypotension may cause SIADH.

Management of SIADH SIADH may be treated with urea, diuretics, lithium, demeclocycline, and/or fluid restriction based on expert recommendations as there is paucity of class I evidence from literature on hyponatremia (Rahman and Friedman 2009). Patients with serum sodium values around 125 mmol/L and no clinical manifestations can be managed conservatively by water restriction and change of therapy. The dose of the suspected drug may be reduced or switched over to a drug

References

not associated with this adverse reaction. Patients with serum sodium values below 125 mmol/L and clinical manifestations, who do not respond to withdrawal of the offending drug and water restriction, should receive infusion of hypertonic sodium chloride. Rapid sodium correction should be avoided because of danger of central pontine myelinolysis. In patients with chronic SIADH, an infusion of 0.9% saline has been recommended. Furosemide, which enhances the excretion of hypotonic urine, may be used as an adjunct. After the initial hyponatremia has improved, rechallenge with the suspected drug may be considered for determination of the causal role. If the use of the drug inducing hyponatremia is essential for the patient, water restriction and sodium supplementation may be tried. Demeclocycline (a tetracycline derivative) inhibits the renal effects of ADH and has been used successfully in patients who do not respond to water restriction. Demeclocycline has been shown to prevent hyponatremia in psychiatric patients on carbamazepine therapy. Lithium also inhibits the renal action of ADH and has been used with some success in the management of chronic SIADH.

Diabetes Insipidus This is a condition that is characterized by excretion of large amounts of dilute urine. Thirst and polydipsia are prominent features. There are relatively few physical signs. Routine laboratory rests are usually normal. Plasma osmolality and sodium concentration are not significantly elevated. Any abnormalities seen are usually due to underlying disease. There are two main types of diabetes insipidus which should be differentiated from primary polydipsia (excessive water intake) which may be psychogenic or due to medical disorders. Neurogenic or central diabetes insipidus is due to vasopressin deficiency which may result from increased metabolism such as in pregnancy or decreased secretion which may occur in the following conditions:

551 Table 35.10  Drugs that have been reported to induce nephrogenic diabetes insipidus Demeclocycline Ifosfamide Lithium toxicity (long-term administration) Methicillin Methoxyflurane

• • • • • •

Trauma: accidental or surgery Malignant tumors in the sellar region Infections Vascular lesions: aneurysm, ischemia Anorexia nervosa Exposure to environmental toxins: carbon monoxide • Congenital malformations • Adverse effects of drugs Vasopressin-Resistant or Nephrogenic Diabetes Insipidus  This may be due to several underlying diseases or drugs. Drugs leading to nephrogenic diabetes insipidus are shown in Table 35.10. Of these, lithium is the most commonly involved.

References Ando S, Hoshino T, Mihara S.  Pituitary apoplexy after goserelin (letter). Lancet. 1995;345:458. Arafah BM, Taylor HC, Salazar R, et  al. Apoplexy of a pituitary adenoma after dynamic testing with Gonadotropin-releasing hormone. Am J Med. 1989;87:103–5. Balarini Lima GA, Machado Ede O, Dos Santos Silva CM, et al. Pituitary apoplexy during treatment of cystic macroprolactinomas with cabergoline. Pituitary. 2008;11:287–92. Barlas O, Bayindir C, Hepgul K, et  al. Bromocriptine-­ induced cerebrospinal fistula in patients with macroprolactinomas: report of three cases and a review of the literature. Surg Neurol. 1994;41:486–9. Bartter FC, Schwartz WB.  The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med. 1967;42:790–806. Bronstein MD, Musolino NR, Benabou S, et  al. Cerebrospinal fluid rhinorrhea occurring in long-term bromocriptine treatment for macroprolactinomas. Surg Neurol. 1989;32:346–9. Clayton RN, Webb J, Heath DA, et  al. Dramatic and rapid shrinkage of a massive invasive prolactinoma

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with bromocriptine, a case report. Clin Endocrinol. Onesti ST, Wisniewski T, Post KD.  Clinical versus subclinical pituitary apoplexy: presentation, surgical man1985;22:573–81. agement, and outcome in surgical management, and Coculescu R, Finer N.  Cerebrospinal fluid rhinoroutcome in 21 patients. Neurosurgery. 1990;26:980–6. rhea and meningitis after bromocriptine therapy for an invasive macroprolactinoma. J Endocrinol. Oo MM, Krishna AY, Bonavita GJ, et al. Heparin therapy for myocardial infarction: an unusual trigger for pitu1994;140(suppl):57. itary apoplexy. Am J Med Sci. 1997;314:351–3. Eljamel MS, Foy PM, Swift AC, et al. Cerebrospinal fluid rhinorrhea occurring in long-term bromocriptine treat- Pascal-Vigneron V, Werya G, Braun M, et al. La rhinorrhee et l'otorrhea: des complication rares du traitment ment for macroprolactinomas (letter). Surg Neurol. medical des prolactinomes invasifs. Ann Endocrinol 1992;38:321. (Paris). 1994;54:347–51. Endoh M, Wakai S, Iouh S, et  al. Massive intraventricular hemorrhage from prolactinoma during bro- Rahman M, Friedman WA.  Hyponatremia in neurosurgical patients: clinical guidelines development. mocriptine therapy: case report. No Shinkei Geka. Neurosurgery. 2009;65:925–35. 1994;22(7):661–4. Gandelman MS.  Review of carbamazepine-induced Reznik Y, Chapon F, Lahlou N, et al. Pituitary apoplexy of a gonadotroph adenoma following Gonadotropin hyponatremia. Prog Neuro-Psychopharmacol Biol releasing hormone agonist therapy for prostatic canPsychiatry. 1994;18:211–33. cer. J Endocrinol Investig. 1997;20(9):566–8. Gopinath C, Prentice DE, Lewis DJ. Atlas of experimental toxicological pathology, vol. 13. Boston: MTP Sheehan HL.  Post-partum necrosis of the anterior pituitary. J Pathol Bacteriol. 1937;45:189–214. Press; 1987. p. 104–21. Harvey R, Michelagnoli M, McHenry P, et  al. Pituitary Shepshelovich D, Schechter A, Calvarysky B, et  al. Medication-induced SIADH: distribution and apoplexy (letter). BMJ. 1989;298:258. ­characterization according to medication class. Br J Joffe RT, Post RM, Uhde TW.  Effects of carbamazeClin Pharmacol. 2017;83(8):1801–7. pine on serum electrolytes in affectively ill patients. Silberstein L, Johnston C, Bhagat A, Tibi L, Harrison Psychol Med. 1986;16:331–5. J.  Pituitary apoplexy during induction chemotherKallio J, Rautava P, Huupponen R, et al. Severe hyponaapy for acute myeloid leukaemia. Br J Haematol. tremia caused by intranasal desmopressin for noctur2008;143:151. nal enuresis. Acta Paediatr. 1993;82:881–2. Korsic M, Lelas-Bahun N, Surdonja P, et al. Infarction of Silverman VE, Boyd AE, McCrary JA, et al. Pituitary apoplexy following chlorpromazine stimulation. Arch Int FSH-secreting pituitary adenoma. Acta Endocrinol. Med. 1978;138:1738–9. 1984;107:149–54. Kuzu F, Unal M, Gul S, Bayraktaroglu T. Pituitary apo- Sinnadurai M, Cherukuri RK, Moses RG, Nasser E.  Delayed pituitary apoplexy in patient with plexy due to the diagnostic test in a Cushing’s disease advanced prostate cancer treated with gonadotrophin-­ patient. Turk Neurosurg. 2018;28:323–5. releasing hormone agonists. J Clin Neurosci. Lahr MB.  Hyponatremia during carbamazepine therapy. 2010;17(9):1201–3. Clin Pharmacol Ther. 1985;37:693–6. Lazaro CM, Guo WY, Sami M, et al. Hemorrhagic pitu- Smith S.  Neuroleptic associated hyperprolactinemia. Can it be treated with bromocriptine? J Reprod Med. itary tumors. Neuroradiology. 1994;36:111–4. 1992;37:737–40. Lee MS, Song HC, An H, et al. Effect of bromocriptine on antipsychotic drug-induced hyperprolactinemia: Thomas Z, Bandali F, McCowen K, Malhotra A.  Drug-­ induced endocrine disorders in the intensive care unit. eight-week randomized, single-blind, placebo-­ Crit Care Med. 2010;38(6 Suppl):S219–30. controlled, multicenter study. Psychiatry Clin Van Amelsvoort T, Bakshi R, Devaux CB, et  al. Neurosci. 2010;64:19–27. Hyponatremia associated with carbamazepine Masago A, Ueda Y, Kanai H, et al. Pituitary apoplexy after and oxcarbazepine therapy: a review. Epilepsia. pituitary function test: a report of two cases and review 1994;35:181–8. of the literature. Surg Neurol. 1995;43:158–65. Masson EA, Atkin SL, Diver M, et al. Pituitary apoplexy Walker AB, Eldridge PR, MacFarlane IA.  Clomiphene-­ induced pituitary apoplexy in a patient with acromegand sudden blindness following the administration of aly. Postgrad Med J. 1996;72:172–3. Gonadotropin releasing hormone. Clin Endocrinol. Wang HF, Huang CC, Chen YF, et al. Pituitary apoplexy 1993;38:109–10. after thyrotropin-releasing hormone stimulation test in Meulendijks D, Mannesse CK, Jansen PA, et  al. a patient with pituitary macroadenoma. J Chin Med Antipsychotic-induced hyponatraemia: a systemAssoc. 2007;70:392–5. atic review of the published evidence. Drug Saf. 2010;33:101–14.

Serotonin Syndrome

36

Introduction

Clinical Manifestations

Serotonin (5-hydroxytryptamine) was discovered in 1948 (Rapport et al. 1948) and has been shown to have a major role in several psychiatric as well as nonpsychiatric disorders (anxiety, depression, migraine, etc.). Coadministration of L-tryptophan (a precursor of serotonin) with MAO inhibitors was reported to induce delirium in a patient, and the clinical picture resembled that of what is today described as serotonin syndrome (Oates and Sjoerdsma 1960). Excess of serotonin activity may lead to serotonin syndrome. Initially, the serotonin syndrome was described in animals, and the characteristic features were tremor, rigidity, hypertonicity, hind limb abduction, Straub tail, lateral head shaking, hyperactivity to auditory stimuli, myoclonus, general seizures, and various autonomic responses such as salivation, penile erection, and ejaculation (Gerson and Baldessarini 1980). Subsequently, this syndrome was defined in humans in 1982 (Insel et  al. 1982) and was followed with the publication of several case reports and reviews (Bodner et al. 1995; Sporer 1996). Due to consumption of grains contaminated with ergot, epidemics of “convulsive ergotism” were widespread east of the Rhine River in Europe from 1085 to 1927 (Eadie 2003). Ergot alkaloids are now known to induce serotonin syndrome. Thus, serotonin syndrome might have been a public health problem long before it was recognized as a complication of modern psychopharmacology (Eadie 2003).

Clinical manifestations of the syndrome are as follows: • • • • • • • • • •

Mental status change (confusion, hypomania) Agitation Myoclonus Hyperreflexia Diaphoresis Shivering Tremor Diarrhea Incoordination Fever

The onset of serotonin syndrome ranges from minutes after receiving the second drug to weeks after a stable dosage. Most of the patients present with symptoms of serotonin syndrome within 24  hours of medication initiation, overdose, or change in dosage. Most cases involve only minor symptoms that resolve over 12–24  hours; other cases may proceed on to more serious sequelae. Severity of overall clinical presentation varies from mild state of serotonin-related symptoms to fullblown serotonin syndrome. A severe case of serotonin syndrome due to overdose of venlafaxine presented with ocular flutter in addition to agitation, myoclonus, fever, and tachycardia (Sim and Sun 2016). Myoclonus and autonomic hyperactivity abated after injection of midazolam, but ocular flutter persisted, and the patient died a few days later.

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There are some difficulties with the clinical diagnosis of serotonin toxicity, particularly using Sternbach’s criteria (Sternbach 1991). Retrospective analysis of prospectively collected data show that, of numerous clinical features associated with serotonin toxicity, only clonus (inducible, spontaneous, or ocular), agitation, diaphoresis, tremor, and hyperreflexia are needed for accurate prediction of serotonin toxicity as diagnosed by a clinical toxicologist. The Hunter Serotonin Toxicity Criteria were developed using these seven clinical features and were found to be simpler, more sensitive, and more specific than Sternbach’s criteria (Dunkley et al. 2003).

Prognosis and Complications Most patients recover from serotonin syndrome following drug withdrawal and minor supporting therapy, as this is a self-limiting condition. There are, however, reports of severe complications such as seizures, disseminated intravascular coagulation, respiratory failure, and severe hypothermia, with deaths in a few cases. A young man, following MDMA 3, 4-methylenedioxymethamphetamine (ecstasy) ingestion, presented with severe rhabdomyolysis, multiple organ failure, and severe serotonin syndrome with temperature 108.9  °F (42.7  °C), but he made a full recovery within 3  weeks following aggressive supportive care including ventilatory support (Davies et al. 2014). A female patient with a preliminary diagnosis of serotonin syndrome, as she was on several SSRIs including venlafaxine, presented with altered level of consciousness, headaches, seizure, and visual changes, and her imaging findings were consistent with posterior reversible encephalopathy syndrome (Malik et  al. 2020). She recovered following discontinuation of medications.

Pathomechanism Serotonin syndrome may result from overdose of serotonergic drugs as well as some drugs of abuse with serotonergic effect. However, the most com-

36  Serotonin Syndrome

mon cause is the interaction between serotonergic agents and MAO inhibitors. It may also result as an adverse effect of serotomimetic drugs. A study has devised a serotonergic expanded bioactivity matrix by using a molecular bioinformatics, polypharmacologic approach for assessment of the participation of individual 5-HT drugs in serotonin syndrome reports (Culbertson et  al. 2018). The results of this study suggest a possible polypharmacologic role in serotonin syndrome, and off-target receptor activity may help explain differences in severity of toxicity as well as clinical presentation. High doses of stimulants such as methamphetamine and cocaine with ecstasy increase the risk of serotonin syndrome (Silins et  al. 2007). Serotonin precursors also influence the course of serotonin syndrome when used with ecstasy. Monoamine oxidase inhibitors are most likely to lead to serious increases in serotonin when used with ecstasy. Serotonin syndrome has been reported in patients treated with tricyclic antidepressants, such as clomipramine and moclobemide, which are known to increase synaptic serotonin level and serotonergic activity in the brain. Serotonin syndrome due to monotherapy with reversible MAO inhibitors is extremely rare. Serotonin syndrome has been described as an adverse effect of rasagiline, an irreversible MAO-B inhibitor (Fernandes et al. 2011). Serotonin syndrome may result from serotonin reuptake inhibitor monotherapy but is not common because of the wide therapeutic window of these drugs. Rapid titration of fluoxetine has been reported to contribute to serotonin syndrome under the stress of deployment (Lawyer et al. 2010). Mirtazapine monotherapy has been reported to induce serotonin syndrome. A possible mechanism is overstimulation of serotonin type 1A receptors in the brain stem and spinal cord in an individual with risk factors for hyperserotoninemia due to reduced acquired ­endogenous serotonin metabolism. Diagnosis of serotonin syndrome induced by mirtazapine and venlafaxine was confirmed in a patient by positive challenge, de-challenge, and rechallenge, with final resolution of symptoms 48 hours after

Pathomechanism

discontinuation of both drugs (Decoutere et al. 2012). Escitalopram, the newest selective serotonin reuptake inhibitor, has also been associated with serotonin syndrome. Overdose of vilazodone, a SSRI with partial 5-HT1A agonism, is associated with serotonin syndrome (Heise et al. 2017). Serotonin syndrome has been reported with use of milnacipran, an antidepressant that inhibits the reuptake of serotonin and norepinephrine and is also used for the treatment of fibromyalgia (Yacoub et al. 2010). HIV-positive patients receiving antiretroviral and antidepressant therapies may develop serotonin syndrome. In these cases, serum antidepressant levels rise due to inhibition of P450 enzymes by antiretroviral drugs such as protease inhibitors and nonnucleoside reverse transcriptase inhibitors; relief of symptoms occurs by reduction of antidepressant dosage. Serotonin syndrome has been reported as a rare adverse effect of ziprasidone monotherapy (Lin et  al. 2010). It is an agonist of 5-HT1A receptor and potent antagonist of 5-HT1D, 5-HT2A, and 5-HT2C receptors as well as moderate inhibitor of serotonin reuptake. Antimigraine Drugs  Patients with migraine are reported to have developed symptoms suggestive of serotonin syndrome. Several drugs were used in these cases. Dihydroergotamine, an ergot derivative, is associated with serotonin syndrome. In each instance, the symptoms were transient, and there was full recovery. Sumatriptan has agonist action on the presynaptic and postsynaptic 5-HTID receptor, but none of the controlled studies of it reported serotonin syndrome. There are, however, case reports of serotonin syndrome associated with triptan monotherapy (Soldin et al. 2008). In 2006, the FDA issued an alert that risk of serotonin syndrome increases due to interaction of triptans with other serotonergic drugs. A 14-year study that used electronic health record data from the Partners Research Data Registry concluded that the risk of serotonin syndrome associated with concomitant use of triptans and SSRIs or SNRIs was low, although coprescription of these drugs is common and did not

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decrease after the 2006 FDA advisory (Orlova et al. 2018). These results question the validity of the FDA warning and suggest that it should be reconsidered. Overdose  The following antidepressants have been reported to be associated with serotonin syndrome: • Fluvoxamine, a 5-hydroxytryptamine uptake inhibitor • Sertraline • Tranylcypromine Combined overdose of MAO inhibitors and serotonergic drugs can result in serotonin syndrome with a fatal outcome. Symptoms and signs of the syndrome may not develop until 6–12 hours after the overdose. Miscellaneous Drugs  Serotonin syndrome has been reported to be induced by dextromethorphan administrated as an antitussive at the conventional dose (Kinoshita et al. 2011). Serotonin syndrome has been reported following overdose of a centrally acting muscle relaxant, metaxalone, in patients on SSRI therapy (Martini et al. 2015). The mechanism of action of metaxalone is not known but is assumed to have serotonergic effects. Serotonin syndrome was reported in a young female following treatment with the atypical antipsychotic paliperidone for new-onset psychosis when the dose was increased to 12  mg per day (Yang et  al. 2016). Paliperidone (9-hydroxyrisperidone), a dopamine antagonist and 5-HT2A antagonist, is the primary active metabolite of risperidone and is assumed to act via similar pathways. A patient with bipolar disorder II who was well controlled with lithium and quetiapine therapy developed serotonin syndrome on treatment with tramadol for fibromyalgic pain, but symptoms resolved after discontinuation of tramadol (Sharma 2016). Tramadol, a synthetic opioid that binds to μ-opioid receptors, is also a weak inhibitor of reuptake of norepinephrine and serotonin.

36  Serotonin Syndrome

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Poisoning  Serotonin syndrome is rarely reported with herbal medicines. It may occur in some cases of poisoning with plants. Serotonin syndrome has been reported in three cases of psilocybin mushroom poisoning (Suzuki 2016).

Drug Interactions Drug interactions are the most important and most frequent causes of serotonin syndrome. A classification of these interactions according to drug category is shown in Table 36.1.

I nteractions Involving Serotonin Reuptake Inhibitors Interaction of Two Serotonin Reuptake Inhibitors  Serotonin syndrome can be induced by the synergistic effect of two drugs from this category, such as venlafaxine and fluoxetine or fluvoxamine and mirtazapine. Serotonin Reuptake Inhibitors and MAO Inhibitors  The use of fluoxetine and MAO inhibitors, either together or in close succession, has been reported to be accompanied by serotonin syndrome in several cases. Serotonin syndrome has also been reported to be induced by the interaction of moclobemide with the serotonin reuptake inhibitor, imipramine. Serotonin syndrome due to the interaction of fluoxetine with selegiline has been described. Serotonin syndrome has been described as an interaction of citalopram with the antibiotic linezolid, which is a weak monoamine oxidase inhibitor (McClean et al. 2011). An integrated approach suggests that linezolid is more likely to cause serotonin syndrome when coadministered with serotonergic agents such as citalopram as inferred from their pharmacological properties (Gatti et  al. 2020). Another case of serotonin syndrome was described as drug interaction when linezolid was added to a drug regimen of lithium, venlafaxine, and imipramine (Miller and Lovell 2011). Cases of serotonin syndrome have been described as an interaction between sertraline selective serotonin reuptake inhibitor and MAO

Table 36.1  Drug interactions associated with serotonin syndrome Serotonin reuptake inhibitors combined with the following: (1) MAO inhibitors: isocarboxazid, phenelzine, selegiline, tranylcypromine, nortriptyline, amitriptyline, moclobemide (2) Dopaminergic agents (serotomimetic effect) (3) Tryptophan (4) Dexfenfluramine (5) Carbamazepine (6) Lithium (7) Pentazocine (8) Cold remedy containing ephedrine and dextromethorphan (9) Nefazodone (10) Anesthetics (11) Clonazepam (12) Serotonergic opioids: tramadol, oxycodone, fentanyl, methadone, meperidine (Rastogi et al. 2011; Nelson and Philbrick 2012) (13) Risperidone (14) Proserotoninergic drugs: cyclobenzaprine, phenelzine, duloxetine (Hadikusumo and Ng 2009) (15) Linezolid (16) Methylene blue Tricyclic antidepressant (clomipramine) combined with the following: (1) MAO inhibitors (2) Atypical antipsychotics (3) S-adenosylmethionine (4) Lithium MAO inhibitors combined with the following: (1) Venlafaxine (2) Tryptophan (3) Lithium (4) Cold remedy containing dextromethorphan (5) Opioids: meperidine (6) Ecstasy Miscellaneous interactions: (1) Levodopa and bromocriptine (2) Clozapine and lithium (3) Trazodone with buspirone (5) Trazodone with isocarboxazid and methylphenidate (6) Antidepressants (paroxetine and venlafaxine) with St. John’s Wort (Izzo et al. 2016) (7) 5-Hydroxytryptamine 3 antagonist therapy for control of nausea associated with chemotherapy when combined with mirtazapine use (8) Olanzapine added to a regimen of lithium and citalopram (9) Tranylcypromine (an MAO inhibitor) and ziprasidone (10) Oxycodone and pregabalin to control postoperative pain (Song 2013) © Jain PharmaBiotech

Pathomechanism

inhibitors: isocarboxazid, phenelzine, and tranylcypromine. This syndrome can also occur if fluoxetine is started within 2 weeks after discontinuation of tranylcypromine, a MAO inhibitor. Serotonin Reuptake Inhibitors and Tryptophan  Fluoxetine, a specific inhibitor of serotonin reuptake into neurons, has been found to be effective in the treatment of obsessive-­ compulsive disorders. Fluoxetine, when combined with L-tryptophan, can lead to the development of a toxic reaction resembling serotonin syndrome. Such reactions have occurred in patients who had no adverse effects while on treatment previously with fluoxetine alone. A possible mechanism of this adverse reaction is that tryptophan increases the central nervous system levels of serotonin. Serotonin Reuptake Inhibitors and Dexfenfluramine  Concern has been expressed that a combination of these two medications could produce serotonin syndrome. However, no such cases have been reported yet. Selective Serotonin Reuptake Inhibitor and Carbamazepine  Serotonin syndrome has been reported with combination of carbamazepine and fluoxetine therapy for affective disorders, but the symptoms usually resolve after discontinuation of fluoxetine. The pathomechanism of serotonin syndrome in such cases is not clear. A fatal case of serotonin syndrome has been reported with concomitant use of paroxetine and carbamazepine. Serotonin Reuptake Inhibitors and Lithium  Serotonin syndrome has been reported when fluvoxamine is added to long-standing lithium therapy. Recovery usually occurs after discontinuation of fluvoxamine and replacement by an antidepressant that is not a serotonin reuptake inhibitor. Serotonin Reuptake Inhibitors and Opioids  Serotonin syndrome has been reported as an interaction among fentanyl, an opioid, and citalopram. However, there is a case report of a

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child who developed serotonin syndrome from the use of fentanyl alone, without concomitant medications known to cause serotonin syndrome (Robles 2015). Discontinuation of fentanyl in this case led to complete recovery. Serotonin Reuptake Inhibitors and Linezolid or Methylene Blue  Serotonin reuptake inhibitors and linezolid (an antibiotic) or methylene blue (a drug used to treat methemoglobinemia) can interact to trigger serotonin syndrome according to a warning issued by the FDA in 2011. Concomitant use of linezolid, an antibiotic, with methadone (a serotonin reuptake inhibitor) has been reported to be involved in serotonin syndrome (Mastroianni and Ravaglia 2017). Serotonin Reuptake Inhibitor (Paroxetine) and Cold Remedy  Serotonin syndrome has been described as an interaction between paroxetine and an over-the-counter cold remedy containing ephedrine and dextromethorphan. Serotonin syndrome has also been reported as an interaction of SSRI escitalopram with dextromethorphan (Dy et al. 2017). Serotonin Reuptake Inhibitor (Sertraline) and Anesthetics  Serotonin syndrome has been described after local anesthetic blocks on a patient who was on sertraline therapy. The likely explanation is that that the medications used for anesthesia (lidocaine, midazolam, and fentanyl) bind to plasma proteins and cause an increased free fraction of sertraline owing to displacement from plasma proteins. Serotonin Reuptake Inhibitors and Methylene Blue  Methylene blue (a MAO inhibitor) is used for the treatment of ifosfamide-induced encephalopathy, and serotonin syndrome has been reported by their concomitant use (McDonnell et al. 2012). Serotonin Reuptake Inhibitor (Paroxetine) and Clonazepam  There is a case report of serotonin syndrome following use of clonazepam in a patient who was on paroxetine therapy for anxiety. Her symptoms resolved after treatment with

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36  Serotonin Syndrome

intravenous lorazepam. This interaction is of clinical importance because patients with anxiety disorders may take these two medications together and may develop serotonin syndrome.

lithium to clomipramine therapy. Treatment with lithium alone, after discontinuation of clomipramine, does not lead to a recurrence of serotonin syndrome.

Interactions Involving Tricyclic Antidepressants Tricyclic Antidepressants and MAO Inhibitors  This combination is generally considered to be without risk of an interaction. However, serious side effects, including fatalities, can occur with the combination of imipramine, a tricyclic antidepressant, and MAO inhibitors. Clomipramine, a tricyclic antidepressant, is involved in several interactions with MAO inhibitors.

I nteractions Involving MAO Inhibitors MAO Inhibitor and Tricyclic Antidepressants  Selegiline, a selective MAO inhibitor, is used in the treatment of Parkinson disease. Selegiline’s package insert was revised to reflect the potential risk of adverse effects when it is used in combination with selective serotonin reuptake inhibitors and tricyclic antidepressants.

Clomipramine, a tricyclic antidepressant, given together with moclobemide, a selective MAO inhibitor, has been reported to produce serotonin syndrome fulfilling the criteria of Sternbach. Fatal cases of serotonin syndrome due to simultaneous ingestion of an overdose of moclobemide and clomipramine have been reported. Serotonin syndrome has also been reported as the result of an interaction between clomipramine and phenelzine, an MAO inhibitor.

MAO Inhibitors and Serotonin Reuptake Inhibitors  MAO inhibitors are known to cause serotonin toxicity when administered with selective serotonin reuptake inhibitors. Intravenous methylene blue, used for identification of parathyroid gland during surgery, is a MAO inhibitor and has been reported to precipitate serotonin syndrome in patients using selective serotonin reuptake inhibitors. Venlafaxine, a selective serotonin reuptake inhibitor, has been reported to interact with MAO inhibitors to produce serotonin syndrome.

Tricyclic Antidepressants and Antipsychotics  Serotonin syndrome occurred with simultaneous use of the olanzapine (an atypical antipsychotic) and a clomipramine tricyclic antidepressant but resolved after discontinuation of antidepressants and administration of biperiden and cyproheptadine.

MAO Inhibitors and Tryptophan  The combination of MAO inhibitors and tryptophan can produce serotonin syndrome.

Clomipramine and Lithium  Serotonin syndrome has been reported after the addition of

MAO Inhibitors and Meperidine  Meperidine (pethidine) blocks the neuronal uptake of

MAO Inhibitors and Lithium  Serotonin syndrome has been reported following treatment with this combination. It is possible that lithium may intensify the effect of serotonin, although it Clomipramine and S-Adenosylmethionine  S-­ is not involved in the metabolism of serotonin. adenosylmethionine stimulates serotonin and norepinephrine metabolism in the brain and is MAO Inhibitors and used in the treatment of depression. Serotonin Dextromethorphan  Serotonin syndrome can syndrome has been reported in patients with develop after taking an over-the-counter cold combined clomipramine and remedy containing dextromethorphan, which can S-adenosylmethionine therapy and is attributed block the neural uptake of serotonin. to the synergic action of these two drugs.

Pathomechanism

5-hydroxytryptamine, and its interaction with MAO inhibitors can lead to serotonin syndrome. The MAO inhibitor and meperidine interaction has two distinct forms: an excitatory and a depressive form. Meperidine should not be used in the presence of MAO inhibitors because of the risk of fatal excitatory interaction (serotonin syndrome). Cases have been reported of meperidine-­ induced serotonin syndrome. Morphine does not cause this excitatory reaction and is the drug of choice under these circumstances. MAO Inhibitors and Ecstasy  Marked hypertension, diaphoresis, hypertonicity, and altered mental status can develop after ingesting ecstasy and phenelzine. Sympathomimetic-MAO inhibitor interaction can cause excessive release of endogenous bioactive amines leading to a reaction that resembles serotonin syndrome but does not fulfill the diagnostic criteria.

Miscellaneous Interactions L-Dopa and Bromocriptine  L-dopa-induced serotonin syndrome can follow the use of bromocriptine therapy in Parkinson disease. Acute administration of levodopa-carbidopa could have produced a sudden displacement of endogenous serotonin into the synaptic cleft and on to serotonin receptor sites, thus increasing the availability of serotonin in the synapse. Because bromocriptine also enhances serotonin metabolism in the CNS, serotonin syndrome could have resulted from a synergistic effect of the two drugs. An atypical case of serotonin syndrome related to levodopa use in a patient with probable Lewy body dementia and an absence of history of a known serotonergic drug has been reported, indicating that levodopa can contribute to its occurrence (Kushwaha et al. 2014). Lithium and Clozapine  Patients treated with a combination of lithium and clozapine can develop reversible neurologic symptoms such as myoclonus and agitation. Some of these neurologic symptoms appear to be early manifestations of serotonin syndrome, and the pathomechanism of these symptoms may be the interaction of the serotonergic effects of clozapine and lithium. Lithium has

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also been shown to facilitate the onset of serotonin syndrome with L-tryptophan and MAO inhibitor combination without rise of its serum levels. Mirtazapine and metoclopramide. Mirtazapine, an antidepressant, acts as an antagonist of certain adrenergic and serotonin receptors. Metoclopramide, used for the treatment of gastroesophageal reflux disorder, interacts with receptors for acetylcholine and dopamine. A patient with bipolar disorder who was taking mirtazapine presented developed serotonin syndrome after taking metoclopramide, but the symptoms subsided after reduction of dose of mirtazapine and treatment with lorazepam (Harada et al. 2017). Ritonavir and SSRIs. Ritonavir is used in combination with therapy for COVID-19 and can trigger serotonin syndrome in patients with ­concomitant treatment with SSRIs and SNRIs, mainly due to diminished elimination. In the first two reported cases, the respective administration of lopinavir/ritonavir with an SNRI (duloxetine) and lithium, and lopinavir/ritonavir with risperidone (a second generation antipsychotic) and morphine, resulted in a combination that triggered typical serotonin syndrome with rapid improvement of the symptoms after their withdrawal (Mas Serrano et al. 2020). As risperidone is a CYP2D6 and CYP3A4 substrate, both of which are inhibited by ritonavir, an increase in its serum concentrations likely occurred. Trazodone and Buspirone  Buspirone, a partial 5-hydroxytryptamine 1 agonist, can contribute to the development of serotonin syndrome in patients who have been on trazodone therapy previously. Trazodone with Isocarboxazid and Methylphenidate  Serotonin syndrome has been reported with simultaneous use of trazodone (a nontricyclic, nontetracyclic antidepressant) and methylphenidate. Trazodone has a weak 5-hydroxytryptamine reuptake inhibiting action and a metabolite, m-chlorophenylpiperazine, which has partial agonist activity at many 5-hydroxytryptamine subtypes.

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St. John’s Wort Combined with Antidepressants  Hypericin, the major active ingredient of St. John’s Wort, has many psychoactive properties and is used as a nonprescription herbal medicine for the treatment of several conditions, including depression, anxiety, insomnia, and inflammation. Several cases of serotonergic syndrome have been reported in patients who have combined prescription antidepressants with St. John’s Wort. L-Tryptophan  This is a precursor of 5-­ hydroxytryptamine. Ingestion of excessive amounts of pure L-tryptophan by normal subjects can produce significant CNS signs and symptoms. The synthesis of serotonin begins when ingested tryptophan crosses the blood-brain barrier via a nonspecific amino acid transporter and enters neurons to be hydrolyzed, resulting in placement into storage vesicles ready for release into the synaptic cleft with depolarization of presynaptic neurons. The following manifestations have been recorded in well-designed experiments in human volunteers: • Euphoria • Headache and dizziness • Hyperreflexia These effects were due to raised levels of 5-hydroxytryptamine induced by L-tryptophan ingestion. These symptoms may be present in serotonin syndrome, but pure L-tryptophan has not been shown to induce the full-blown serotonin syndrome. The enzyme MAO (MAO inhibitor) is involved in the degradation of 5-hydroxytryptamine, and concomitant use of MAO inhibitors may lead to accumulation of 5-hydroxytryptamine and its neurologic effects. The syndrome can be blocked by using various 5-hydroxytryptamine precursors in combination with medications that increase their bioavailability. According to 5-hydroxytryptaminergic hypothesis of obsessive-compulsive disorders, there is hypersensitivity of 5-hydroxytryptamine receptors. This lends support to the use of 5-hydroxytryptamine uptake inhibitors in obsessive-­compulsive disorders. Serotonin syn-

36  Serotonin Syndrome

drome may be due to drug effects causing enhanced transmission at the 5-­hydroxytryptamine 1A level or at the postsynaptic level.

 athomechanism of Drug Interactions P in Causing Serotonin Syndrome The reports of serotonin syndrome due to drug interaction are mostly anecdotal, but the evidence that symptoms are due to 5-hydroxytryptamine is basedonanimal experiments.5-Hydroxytryptamine 1A activation of serotonin receptors in the brain stem and spinal cord with overall enhancement of neurotransmission is a possible mechanism. The mechanism underlying serotonin syndrome following interaction between a MAO inhibitor and a serotonin reuptake inhibitor is that MAO can no longer perform its function of degrading serotonin. Restoration of enzymes that perform the degradation takes about 2  weeks following cessation of therapy, and serotonin syndrome can develop if a MAO inhibitor is switched over to a serotonin reuptake inhibitor within less than 2 weeks after discontinuation of the MAO inhibitor. The recreational drug ecstasy stimulates the release and inhibits the reuptake of serotonin. Ecstasy can produce mild versions of the serotonin syndrome and can aggravate the symptoms by interacting with MAO inhibitors. Serotonin syndrome bears a striking clinical resemblance to high-pressure neurologic syndrome, which is a sequela of deep diving and is an additional support for the serotonin theory of high-pressure neurologic syndrome. Central 5-hydroxytryptamine 1A receptor is not the only receptor subtype that is involved in the etiology of serotonin syndrome. Other factors that may contribute are the endogenous as well as iatrogenic deficits in the peripheral 5-­ hydroxytryptamine metabolism, the activation of several 5-hydroxytryptamine subtypes, and a stimulus for the release of 5-hydroxytryptamine.  redisposing Factors for Serotonin P Syndrome Predisposing factors for the development of serotonin syndrome are shown in Table 36.2.

Epidemiology Table 36.2  Predisposing factors for the development of serotonin syndrome Inherited disorders  Low endogenous MAO inhibitor activity  Decreased metabolism of serotonergic drugs  Cardiovascular diseases: hypertension and hyperlipidemia Acquired diseases  Liver diseases: hepatitis  Pulmonary disease  Cardiovascular disease

Epidemiology The incidence of serotonin syndrome in humans is difficult to determine as there are no universally accepted criteria for its diagnosis. The syndrome may be underreported due to the lack of awareness of this syndrome among medical professionals. The prevalence of this syndrome appears to be increasing, and the two likely explanations are increase in the use of drugs and combinations that lead to it as well as increasing recognition of this syndrome. More than 150 cases have been reported in the literature so far. Considering the millions of patients who are exposed to a combination of drugs that can produce serotonin syndrome, the frequency of occurrence is rare. There has never been a population-based prospective study on serotonin syndrome, but other studies give some insight into the relative incidence of this disease. Some studies have used a combination of MAO inhibitors and tryptophan in a prospective manner to measure clinical efficiency and adverse effects. The patients who showed improvement frequently experienced adverse symptoms such as the feeling of intoxication, ataxia, and drowsiness, which were not seen in the control group receiving MAO inhibitor and placebo. These symptoms did not completely fulfill the criteria of serotonin syndrome and were seldom the cause for withdrawal of therapy. In a large pharmacovigilance database in France, 125 cases (84%) were associated with a serotonergic drug, of which SSRIs were the most frequent (42%) and serotonin-noradrenalin reuptake inhibitors were involved to a lesser extent (Abadie et  al. 2015). Most of the cases (59%) resulted from pharmacodynamic drug-drug inter-

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actions, most often involving serotonin reuptake inhibitors and opioids, but also occurred with a single serotonergic drug in 40% of cases. Finally, a major pharmacokinetic drug-drug interaction may have played a role in 20 of cases.

Prevention Substances that deplete 5-hydroxytryptamine or block 5-hydroxytryptamine receptors have been shown to prevent serotonin syndrome in experimental ­ animals. Blockade of 5-­hydroxytryptamine 1 receptors rather than of 5-hydroxytryptamine 2 receptors is required. Cyproheptadine, a nonspecific 5-hydroxytryptamine receptor antagonist, can block serotonin syndrome in animal models. A patient on multiple serotonergic agents who was at high risk for development of serotonin syndrome received prophylactic treatment with cyproheptadine, which was effective and well tolerated (Deardorff et al. 2016). Beta-blockers have been reported to block 5-­hydroxytryptamine receptors and prevent serotonin syndrome. The combination of drugs known to produce serotonin syndrome should be avoided as a preventive measure. Caution should be exercised in prescribing serotomimetic agents after the discontinuation of an MAO inhibitor or when commencing an MAO inhibitor after discontinuation of a serotomimetic agent. Most of the MAO inhibitors are irreversible enzyme inhibitors, and following their cessation, enzyme replacement may take a few weeks. Serotonin syndrome has been reported in patients prescribed with clomipramine up to 4  weeks after terminating clorgyline. Therefore, 4–6 weeks should elapse between the switch over of these two classes of medications. Long-term administration of high-dose fluoxetine may require a 3-month washout period.

Diagnosis of Serotonin Syndrome Differential Diagnosis In the older literature on adverse effects of antidepressants and their interactions with other drugs,

36  Serotonin Syndrome

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serotonin syndrome was not recognized. Conditions to be considered in differential diagnosis of serotonin syndrome include the following: • Carcinoid syndrome • Neuroleptic malignant syndrome • Tyramine “cheese reaction”

Carcinoid Syndrome This is due to tumors of enterochromaffin cells that originate mainly in the gastrointestinal tract and secrete a variety of hormones. Serotonin is the most common secretory product of carcinoid tumors and is synthesized by enzymatic modification of circulating tryptophan. Manifestations include the classic triad of flushing, diarrhea, and valvular heart disease. This occurs in 5% of all patients with carcinoid tumors. The diagnosis of this syndrome is established by the presence of a carcinoid tumor, and it is differentiated from serotonin syndrome by absence of relationship to medications known to produce the serotonin syndrome. Carcinoid syndrome can be controlled with somatostatin analogues, and surgery is the mainstay of treatment.  euroleptic Malignant Syndrome N Some of the cases of serotonin syndrome are difficult to differentiate from neuroleptic malignant syndrome (see Chap. 38). A comparison of the clinical features of neuroleptic malignant syndrome and serotonin syndrome is shown in Table 36.3. Table 36.3  Comparison of the clinical features of neuroleptic malignant syndrome and serotonin syndrome

Clinical features Myoclonus Muscular rigidity Hyperreflexia Hyperthermia Autonomic dysfunction Agitation Diaphoresis Incoordination Altered consciousness

Neuroleptic malignant syndrome

Serotonin syndrome X

X X X

X X

© Jain PharmaBiotech

X X

X X X

Adverse drug reactions related to neuroleptics and serotonergic agents could produce symptoms compatible with both conditions. A feature common to both syndromes is hyperthermia. Serotonin and dopamine are both important neurotransmitters in temperature regulation, and it is likely that hyperthermic reactions result from drug-induced changes in the levels of these neurotransmitters. Toxic reactions to the designer drug ecstasy resemble both serotonin syndrome and neuroleptic malignant syndrome because it affects both serotonin- and dopamine-­ containing neurons. The predominant manifestations, however, are those of serotonin syndrome. The two syndromes can overlap as shown by the case of a child who presented with fever, hypertonia, tremors, and clonus 1 day after starting metoclopramide; the clinical course was suggestive of neuroleptic malignant syndrome (as well as serotonin syndrome, which can both be triggered by metoclopramide) (Aussedat et al. 2020).

Tyramine “Cheese Reaction” and Overdose of MAO Inhibitors This is well known following ingestion of cheese by patients on MAO inhibitor. The distinguishing feature of this is hypertension, which is not a characteristic of serotonin syndrome. Patients with an overdose of MAO inhibitors may show symptoms like those of serotonin syndrome. In severe cases death may result from hyperthermia, cardiopulmonary arrest, or disseminated intravascular coagulation with renal failure. The diagnosis of serotonin syndrome may be overlooked in patients with Parkinson disease who are on serotonin reuptake inhibitors because of depression.

Diagnostic Workup Most commonly used diagnostic criteria of serotonin syndrome are those suggested by Sternbach (1991): • Coincident with addition of or increase in a known serotonergic agent to an established medication regimen and at least three of the

Management

clinical features (listed in the section on clinical features) are present. • Other causes (e.g., infections, metabolic, substance abuse, or withdrawal) have been ruled out. • A neuroleptic had not been started or increased in dosage prior to the onset of signs and symptoms.

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• Cyproheptadine, a nonspecific 5-hydroxytryp­ tamine 1 and 5-­hydroxytryptamine 2 receptor antagonist that blunts the clinical manifestations of serotonin syndrome The following drugs have been used for alleviating rigidity and tremor, but no clear cut benefit on serotonin syndrome has been established:

The diagnosis is based on history and clinical features. Various EEG abnormalities that are noted in cases of serotonin syndrome are delta range activity, slow waves, spikes and waves, and triphasic waves. This may be an important test in the setting of concomitant neurologic disorders.

• Clonazepam • Benztropine • Diphenhydramine

Management

1. Lorazepam 1–2  mg by slow IV push until excessive sedation develops. 2. If there is no improvement with lorazepam, use propranolol 1–3 mg every 5 minutes up to 0.1 mg/kg. 3. Cyproheptadine, a serotonin antagonist, 4 mg orally every 4 hours up to 20 mg per 24 hours. If no response, try other experimental approaches, e.g., nitroglycerine. An 11-year retrospective review of cyproheptadine use in serotonin syndrome reported to the California Poison Control System concluded that the benefits of and indications for cyproheptadine are uncertain and questionable for the management of a serotonin syndrome (Nguyen et al. 2019). The use of cyproheptadine should be based on diagnostic criteria, severity of symptoms, and management in conjunction with other supportive measures. 4. Chlorpromazine. An analysis of reported cases of serotonin syndrome treated with chlorpromazine showed that this drug was effective. 5. Memantine prevents the development of hyperthermia and the increase in the noradrenaline levels in animal models of serotonin syndrome. Because memantine is already approved for Alzheimer disease and is clinically well tolerated, it is a particularly promising therapy for serotonin syndrome.

In clinical practice, serotonin syndrome is often transient and does not require discontinuation of the offending medication or any special treatment. If the clinical features are a cause for concern, the offending medication should be discontinued, and supportive measures should be used. There are no prospective studies of the evaluation of treatment of serotonin syndrome in man. Management strategies are based on studies in animal models and case reports on human patients. In most of the reported cases, symptoms resolved after discontinuation of the offending medications. After discontinuation of the contributing agents, milder cases can be sent home and followed up. Management of moderate to severe cases involves hospitalization with close monitoring and appropriate supporting measures. Apnea and coma may occur in serotonin syndrome and require intensive care. The following medications have been investigated for counteracting the serotonin syndrome: • Lorazepam • Methysergide, a nonspecific 5-­ hydroxytryptamine antagonist for movement disorders • Propranolol, which has a specific affinity for 5-hydroxytryptamine 1A receptor and suppresses the serotonin syndrome effectively

For practical management of the patient, the following medications may be tried in the order listed.

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6. Cerebral vasoconstriction syndrome in the setting of serotonin syndrome is characterized by acute onset of severe headaches, with or without neurologic deficit. In two patients with this syndrome, intra-arterial nicardipine infusion improved angiographic appearance of stenosis (John et al. 2013). 7. Dexmedetomidine, an alpha-2 receptor agonist, may be considered as adjunctive therapy for patients with severe serotonin syndrome who are refractory to standard treatment (Rushton and Charlton 2014). Dexmedetomidine stabilizes the autonomic nervous system, improves agitation, and allows successful extubation. Serotonin syndrome can be treated successfully with sedative propofol and muscle relaxant rocuronium followed by intubation, artificial respiration, and cooling with a hypothermia blanket. Electroconvulsive therapy was used effectively for the treatment of severe serotonin syndrome in two patients (Okamoto et al. 2010). Aripiprazole, a drug with high affinity to 5-HT1A as well as 5-HT2A receptors, was reported to prevent severe symptoms of serotonin syndrome despite high serotonin levels as it protects both postsynaptic receptors from a surplus of serotonin (Rittmannsberger and Werl 2012).

 anagement of Serotonin Syndrome M During Pregnancy The low reported incidence of serotonin syndrome during pregnancy is mostly due to underrecognition, as the syndrome can mimic other more common obstetric diagnoses such as preeclampsia. A case of a pregnant patient with schizophrenia was admitted to an intensive care unit where she was managed conservatively by discontinuation of the offending drug, intravenous fluids, supplemental oxygen, telemetry, hourly neurologic assessments, and monitoring of fetal status (Asusta et al. 2019). After ­stabilization, the patient was transferred to daily inpatient psychiatry for continued care.

Infants exposed to selective serotonin reuptake inhibitors during late pregnancy are at increased risk for serotonergic central nervous system adverse effects. There is a case report of an infant with suspected serotonin toxicity following in utero exposure to 20 mg escitalopram throughout pregnancy (Degiacomo and Luedtke 2016). Close monitoring for symptoms of serotonin toxicity and prolongation of QTc on electrocardiograph of infants exposed to escitalopram during pregnancy is recommended. The severity of these symptoms is significantly related to cord blood 5-hydroxyindoleacetic acid levels.

Anesthesia and Serotonin Syndrome Serotonin syndrome may complicate the administration of drugs frequently used in anesthetic practice, including pethidine and tramadol. Although most cases improve with symptomatic and supportive care, severe cases need intensive care and frequently require mechanical ventilation (Jones and Story 2005). A patient was being treated with fluoxetine (a selective serotonin reuptake inhibitor), developed serotonin syndrome during intravenous anesthesia with remifentanil (an opioid) and propofol, but recovered following discontinuation of remifentanil (Davis et  al. 2013). Serotonin syndrome has been reported due to an interaction between selective serotonin reuptake inhibitors and fentanyl, a commonly used opioid in anesthesia practice (Greenier et al. 2014).

References Abadie D, Rousseau V, Logerot S, Cottin J, Montastruc JL, Montastruc F.  Serotonin syndrome: analysis of cases registered in the French Pharmacovigilance Database. J Clin Psychopharmacol. 2015;35(4):382– 8. PMID 26082973. Asusta HB, Keyser E, Dominguez P, Miller M, Odedokun T.  Serotonin syndrome in obstetrics: a case report and review of management. Mil Med. 2019;184(1– 2):e284–6. PMID 29901770. Aussedat M, Lavoie A, Bussières JF, Kleiber N. Suspected overlap between serotonin syndrome and neuroleptic malignant syndrome in a child treated with metoclo-

References pramide? J Pediatr Pharmacol Ther. 2020;25(6):552– 8. PMID 32839660. Bodner RA, Lynch T, Lewis L, et al. Serotonin syndrome. Neurology. 1995;45:219–23. Culbertson VL, Rahman SE, Bosen GC, Caylor ML, Echevarria MM, Xu D.  Implications of off-target serotoninergic drug activity: an analysis of serotonin syndrome reports using a systematic bioinformatics approach. Pharmacotherapy. 2018;38(9):888–98. PMID 29972695. Davies O, Batajoo-Shrestha B, Sosa-Popoteur J, Olibrice M. Full recovery after severe serotonin syndrome, severe rhabdomyolysis, multi-organ failure and disseminated intravascular coagulopathy from MDMA.  Heart Lung. 2014;43(2):117–9. PMID 24373952. Davis JJ, Buck NS, Swenson JD, Johnson KB, Greis PE. Serotonin syndrome manifesting as patient movement during total intravenous anesthesia with propofol and remifentanil. J Clin Anesth. 2013;25(1):52–4. PMID 23391344. Deardorff OG, Khan T, Kulkarni G, Doisy R, Loehr C.  Serotonin syndrome: prophylactic treatment with cyproheptadine. Prim Care Companion CNS Disord. 2016;18(4). PMID 27828700. Decoutere L, De Winter S, Vander Weyden L, et al. A venlafaxine and mirtazapine-induced serotonin syndrome confirmed by de- and re-challenge. Int J Clin Pharm. 2012;34(5):686–8. PMID 22752315. Degiacomo J, Luedtke S. Neonatal toxicity from escitalopram use in utero: a case report. J Pediatr Pharmacol Ther. 2016;21(6):522–6. PMID 28018155. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96(9):635–42. PMID 12925718. Dy P, Arcega V, Ghali W, Wolfe W. Serotonin syndrome caused by drug to drug interaction between escitalopram and dextromethorphan. BMJ Case Rep. 2017;2017. PMID 28784915. Eadie MJ.  Convulsive ergotism: epidemics of the serotonin syndrome. Lancet Neurol. 2003;2:429–34. PMID 12849122. Fernandes C, Reddy P, Kessel B.  Rasagiline-induced serotonin syndrome. Mov Disord. 2011;26(4):766–7. PMID 21370275. Gatti M, Raschi E, De Ponti F.  Serotonin syndrome by drug interactions with linezolid: clues from pharmacovigilance-­p harmacokinetic/pharmacodynamic analysis. Eur J Clin Pharmacol. 2020. [Epub ahead of print] PMID 32901348. Gerson SC, Baldessarini RJ. Motor effects of serotonin in the central nervous system. Life Sci. 1980;27:1435– 51. PMID 6160367. Greenier E, Lukyanova V, Reede L. Serotonin syndrome: fentanyl and selective serotonin reuptake inhibitor interactions. AANA J. 2014;82(5):340–5. PMID 25842648.

565 Hadikusumo B, Ng B.  Serotonin syndrome induced by duloxetine. Aust N Z J Psychiatry. 2009;43(6):581–2. PMID 19452666. Harada T, Hirosawa T, Morinaga K, Shimizu T.  Metoclopramide-induced serotonin syndrome. Intern Med. 2017;56(6):737–9. PMID 28321081. Heise CW, Malashock H, Brooks DE. A review of vilazodone exposures with focus on serotonin syndrome effects. Clin Toxicol (Phila). 2017;55(9):1004–7. PMID 28594246. Insel TR, Roy BF, Cohen RM, Murphy DL.  Possible development of serotonin syndrome in man. Am J Psychiatry. 1982;139:954–5. PMID 7091416. Izzo AA, Hoon-Kim S, Radhakrishnan R, Williamson EM.  A critical approach to evaluating clinical efficacy, adverse events and drug interactions of herbal remedies. Phytother Res. 2016;30(5):691–700. PMID 26887532. John S, Donnelly M, Uchino K.  Catastrophic reversible cerebral vasoconstriction syndrome associated with serotonin syndrome. Headache. 2013;53(9):1482–7. PMID 24001215. Jones D, Story DA.  Serotonin syndrome and the anaesthetist. Anaesth Intensive Care. 2005;33:181–7. PMID 15960399. Kinoshita H, Ohkubo T, Yasuda M, Yakushiji F. Serotonin syndrome induced by dextromethorphan (Medicon) administrated at the conventional dose. Geriatr Gerontol Int. 2011;11(1):121–2. PMID 21166968. Kushwaha S, Panda AK, Malhotra HS, Kaur M. Serotonin syndrome following levodopa treatment in diffuse Lewy body disease. BMJ Case Rep. 2014;2014. PMID 25246451. Lawyer TI, Jensen J, Welton RS. Serotonin syndrome in the deployed setting. Mil Med. 2010;175(12):950–2. PMID 21265300. Lin PY, Hong CJ, Tsai SJ.  Serotonin syndrome caused by ziprasidone alone. Psychiatry Clin Neurosci. 2010;64(3):338–9. PMID 20602736. Malik MT, Majeed MF, Zand R.  Serotonin syndrome presenting as a posterior reversible encephalopathy syndrome. Case Rep Neurol. 2020;12(1):63–8. PMID 32231545. Martini DI, Nacca N, Haswell D, Cobb T, Hodgman M.  Serotonin syndrome following metaxalone overdose and therapeutic use of a selective serotonin reuptake inhibitor. Clin Toxicol (Phila). 2015;53(3):185–7. PMID 25671244. Mas Serrano M, Pérez-Sánchez JR, Portela Sánchez S, et  al. Serotonin syndrome in two COVID-19 patients treated with lopinavir/ritonavir. J Neurol Sci. 2020;415:116944. PMID 32531579. Mastroianni A, Ravaglia G.  Serotonin syndrome due to co-administration of linezolid and methadone. Infez Med. 2017;25(3):263–6. PMID 28956544. McClean M, Walsh JC, Condon F. Serotonin syndrome in an orthopaedic patient secondary to linezolid therapy for MRSA infection. Ir J Med Sci. 2011;180(1):285–6. PMID 20886306.

566 McDonnell AM, Rybak I, Wadleigh M, Fisher DC. Suspected serotonin syndrome in a patient being treated with methylene blue for ifosfamide encephalopathy. J Oncol Pharm Pract. 2012;18(4):436–9. PMID 22235061. Miller DG, Lovell EO.  Antibiotic-induced serotonin syndrome. J Emerg Med. 2011;40(1):25–7. PMID 18455905. Nelson EM, Philbrick AM.  Avoiding serotonin syndrome: the nature of the interaction between tramadol and selective serotonin reuptake inhibitors. Ann Pharmacother. 2012;46(12):1712–6. PMID 23212934. Nguyen H, Pan A, Smollin C, Cantrell LF, Kearney T.  An 11-year retrospective review of cyproheptadine use in serotonin syndrome cases reported to the California Poison Control System. J Clin Pharm Ther. 2019;44(2):327–34. PMID 30650197. Oates JA, Sjoerdsma A. Neurologic effects of tryptophan in patients receiving a MAO inhibitor. Neurology. 1960;10:1076–8. PMID 13730138. Okamoto N, Sakamoto K, Nagafusa Y, Ichikawa M, Nakai T, Higuchi T.  Electroconvulsive therapy as a potentially effective treatment for severe serotonin syndrome: two case reports. J Clin Psychopharmacol. 2010;30(3):350–2. PMID 20473084. Orlova Y, Rizzoli P, Loder E. Association of coprescription of triptan antimigraine drugs and selective serotonin reuptake inhibitor or selective norepinephrine reuptake inhibitor antidepressants with serotonin syndrome. JAMA Neurol. 2018;75(5):566–72. PMID 29482205. Rapport MM, Green AA, Page IH. Serum vasoconstrictor (serotonin) IV: isolation and characterization. J Biol Chem. 1948;176:1243–51. PMID 18100415. Rastogi R, Swarm RA, Patel TA.  Case scenario: opioid association with serotonin syndrome: implications to the practitioners. Anesthesiology. 2011;115(6):1291– 8. PMID 22037635. Rittmannsberger H, Werl R.  Does aripiprazole protect from serotonin syndrome. Psychiatr Danub. 2012;24(1):100–1. PMID 22447095.

36  Serotonin Syndrome Robles LA.  Serotonin syndrome induced by fentanyl in a child: case report. Clin Neuropharmacol. 2015;38(5):206–8. PMID 26366964. Rushton WF, Charlton NP.  Dexmedetomidine in the treatment of serotonin syndrome. Ann Pharmacother. 2014;48(12):1651–4. PMID 25169248. Sharma V.  Tramadol-induced hypomania and serotonin syndrome. Prim Care Companion CNS Disord. 2016;18(6). PMID 28002658. Silins E, Copeland J, Dillon P. Qualitative review of serotonin syndrome, ecstasy (MDMA) and the use of other serotonergic substances: hierarchy of risk. Aust N Z J Psychiatry. 2007;41(8):649–55. PMID 17620161. Sim SS, Sun JT. Ocular flutter in the serotonin syndrome. N Engl J Med. 2016;375(18):e38. PMID 27806222. Soldin OP, Tonning JM, Obstetric-Fetal Pharmacology Research Unit Network. Serotonin syndrome associated with triptan monotherapy. N Engl J Med. 2008;358(20):2185–6. PMID 18480219. Song HK.  Serotonin syndrome with perioperative oxycodone and pregabalin. Pain Physician. 2013;16(5):E632–3. PMID 24077214. Sporer KA.  The serotonin syndrome. Drug Saf. 1996;13:94–104. Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991;148:705–13. PMID 2035713. Suzuki K. Three cases of acute serotonin syndrome due to psilocybin mushroom poisoning. [Article in Japanese] Chudoku Kenkyu. 2016;29(1):33–5. Japanese. PMID 27255023. Yacoub HA, Johnson WG, Souayah N.  Serotonin syndrome after administration of milnacipran for fibromyalgia. Neurology. 2010;74(8):699–700. PMID 20177126. Yang CH, Juang KD, Chou PH, Chan CH.  A case report of probable paliperidone ER-induced serotonin syndrome in a 17-year-old Taiwanese female with new onset psychosis. Medicine (Baltimore). 2016;95(9):e2930. PMID 26945397.

Drug-Induced Guillain-Barré Syndrome

37

Introduction

normal cell count (albuminocytologic dissociation). Electrophysiological studies show slowing Guillain-Barré syndrome (GBS) is an eponym of nerve conduction suggesting demyelination. that is also designated as the Landry-Guillain-­ GBS is a significant cause of acute generalized Barré-Strohl syndrome in recognition of the paralysis with an annual incidence of 1–2 descriptions provided by these authors. An cases/100,000 population. acute, ascending, predominantly motor paralyThe most recognizable variant of GBS is sis with respiratory failure and death was first Miller Fisher syndrome, which presented with a reported by Landry (1859). In 1916, G Guillain triad of total external ophthalmoplegia, ataxia, and JA Barré, then French army neurologists, and areflexia following upper respiratory tract along with A Strohl, who conducted electro- infection (Fisher 1956). The presence of CSF physiological studies, reported two patients albuminocytologic dissociation and antecedent with acute polyradiculoneuritis and introduced infection likened Miller Fisher syndrome to the concept of “albuminocytologic dissociation” GBS. Another syndrome where the cause is like in the cerebrospinal fluid as a laboratory bio- that of GBS is where a patient presents with marker to distinguish this disorder from other prominent drowsiness followed by brain stem neuropathies and from poliomyelitis (Guillain signs causing ophthalmoplegia, facial palsy, bulet al. 1916). bar palsy, ataxia, areflexia and CSF albuminocytologic dissociation following a prodrome of infective illness, and subsequent recovery of neuVariants and Clinical Aspects of GBS rologic symptoms (Bickerstaff and Cloake 1951). One variant of GBS, acute motor axonal neuThe most frequent variant of GBS is an acute ropathy, also called “Chinese paralytic syninflammatory demyelinating polyradiculopathy drome,” is characterized by acute weakness or (AIDP) causing progressive weakness of the paralysis without sensory loss and is closely assolimbs (Landry’s ascending paralysis) and loss of ciated with antecedent C. jejuni infection. Other tendon reflexes. The supporting clinical criteria variants of GBS include pharyngeal-­ cervical-­ are relatively symmetrical weakness, mild sen- brachial variant, acute pandysautonomia, and sensory signs, cranial nerve involvement (particu- sory GBS.  The pharyngeal-cervical-brachial larly facial), autonomic dysfunction, and absence variant manifests as dysphagia and neck and of fever. The main supporting laboratory criterion shoulder muscle weakness and may be associated is increase of protein concentration in CSF with with IgG anti-GT1a antibody. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 K. K. Jain, Drug-induced Neurological Disorders, https://doi.org/10.1007/978-3-030-73503-6_37

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One of the important criteria for GBS is that the paralysis should not progress for longer than 4 weeks. If it does persist, the question rises whether the patient may be developing chronic polyradiculopathy, also referred to as chronic relapsing GBS.  There is still controversy about the nomenclature and diagnostic criteria of GBS or AIDP, and it should be considered as a family of closely related disorders that might be divided by the following criteria: • Class of axon involved: motor, sensory, autonomic, or mixtures • Pathologic process: inflammatory, demyelinating, direct antibody attack, or others • Preceding infection • Associated antibody • Underlying disease mechanisms • Response to treatment

by the location of the specific epitopes under attack in the peripheral nervous system  – the myelin, the axolemma, or both (Griffin and Ho 1993). Recent observations suggest that GBS may have more than one pathomechanism depending on the variant.

Drugs and Other Therapies Associated with Guillain-Barré Syndrome Various pharmaceutical preparations which have been reported to be associated with onset of GBS or Guillain-Barré-like syndromes are listed in Table 37.1.

Table 37.1  Drugs and other therapies associated with onset of Guillain-Barré syndrome Drugs Aripiprazole Arsenicals (organic) Cantharidin Captopril Corticosteroids Fansidar Gangliosidesa Gold salts Immune checkpoint inhibitors for cancer therapy Ofloxacin Oxytocin Monoclonal antibodies Penicillamine Streptokinasea Thrombolytic agents Zimelidine (withdrawn from the market in 1983) Drug abuse: heroin Vaccines Hepatitis B vaccine Influenza vaccinesa Measles mumps and rubella vaccine Oral poliomyelitis vaccine Rabies vaccinea Tetanus toxoid Typhoid vaccine Therapeutic procedures Bone marrow stem cell transplantation Surgery with postoperative epidural morphine analgesia

Pathophysiology Approximately two-thirds of patients with GBS have presented after infections with organisms such as HIV, cytomegalovirus, Epstein-Barr virus, and Campylobacter jejuni. Infections have been suggested as possible triggers of GBS, and it is mediated, at least partially, by autoimmune mechanisms. The pathological concept of this syndrome as an inflammatory disorder is based on the classical studies showing lymphocytes and macrophages surrounding endoneurial vessels and causing adjacent demyelination (Asbury et  al. 1969). Demyelination may be produced mainly by the T-lymphocytes in some cases, whereas in others macrophages may be involved and the process may be antibody-mediated. Antibodies against gangliosides GM-1 and P-2, cerebroside, and peripheral myelin glycolipids, which are all components of myelin, have been identified in patients with GBS. These antibodies attack the myelin and remove it from intact axons. Cytotoxins of C. jejuni are poorly understood, and an immune mechanism remains the most likely explanation. The specific disease manifestations of post-C. jejuni GBS may be determined

Well documented © Jain PharmaBiotech

a

Drugs and Other Therapies Associated with Guillain-Barré Syndrome

Drugs Aripiprazole  Cranial polyneuropathy, a variant of GBS, has been reported in a 12-year-old boy on aripiprazole therapy for attention-deficit hyperactivity disorder (Han et  al. 2017). The patient was admitted with dysarthria, tongue discomfort, and tinnitus. On examination, he showed curtaining of the pharyngeal wall, tongue fasciculation and deviation, and a weak gag reflex. Cranial MRI suggested lower cranial nerve involvement. Serum anti-GM1 IgG and anti-­ GD1b IgG antibodies were positive. After stopping aripiprazole, his bulbar symptoms improved. However, on readministration of aripiprazole 7 weeks later, dysarthria recurred and again resolved after stopping the drug. Arsenicals (Organic)  These compounds are used for the treatment of human trypanosomiasis. Neurotoxicity of these compounds is known to manifest as encephalopathy (see Chap. 13). Guillain-Barré-like syndrome was reported in a patient treated with melarsoprol (Gherardi et al. 1990). Electrophysiological data in this case were misleading for GBS.  Neuropathological findings included massive distal Wallerian degeneration in peripheral nerves and abnormalities in the dorsal ganglia and spinal cord with vacuolation of anterior horn cells. Cantharidin  Cantharides are herbal agents used as abortifacients and aphrodisiacs. Two cases of cantharidin toxicity with symptoms resembling GBS have been reported in South Africa (Harrisberg et  al. 1984). Cantharidin poisoning has not been reported in the United States where only the topical cantharides are available for application on benign epithelial lesions. Captopril  This is an ACE inhibitor used for the treatment of hypertension. Peripheral neuropathy as an adverse reaction to the drug is described in Chap. 11. There are case reports of GBS as well during treatment with captopril (Atkinson et  al. 1980a, b; Chakraborty and Ruddell 1987). Captopril is chemically similar to D-penicillamine (both have sulfhydryl groups) and causes similar

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side effects which appear to be due to an autoimmune reaction which may precipitate GBS. Corticosteroids  Steiner et  al. (1986) reported three patients who developed GBS while on corticosteroid treatment. In each case the syndrome appeared while the dose of steroids was being tapered. The pathomechanism of GBS in these cases was postulated to be a selective effect of low-dose steroids on a specific, perhaps suppressive lymphocytic subpopulation. One of the patients had a history of multiple sclerosis. A case of GBS has been reported following danazol and corticosteroid therapy for hereditary angioedema (Hory et  al. 1985). Danazol is an androgenic anabolic agent and has been reported to exacerbate SLE. In this case either danazol or steroids or combination of both may have precipitated GBS. Fansidar  This is an antimalarial drug, and one case of GBS has been reported following its use as a prophylactic, and it was considered to have been possibly precipitated by the drug (Lorentzon 1984). Gangliosides  These have a role in promoting nerve repair by increasing collateral sprouting. They have not been proven to be effective as an adjuvant treatment for various neuropathies. The use of a parenteral bovine ganglioside (Cronassial) was suspended in Germany in 1989 because of the suspicion of their possible association with GBS. At least 20 of the approximately 14,000 patients treated with gangliosides are known to have suffered from neurological sequelae with characteristics of either amyotrophic lateral sclerosis or GBS. However, health authorities in Italy continued their surveillance on gangliosides, restricting its use to treatment of diabetic neuropathies and truncular lesions, while banning its use in all autoimmune disorders (Raschetti et  al. 1992). Landi et  al. (1993) described 244 further cases of GBS after ­ganglioside treatment. The number exceeds the estimated number expected in the unexposed population and places the increased risk of GBS

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with ganglioside close to 200-fold. The Spanish national drug surveillance system has received 17 reports of acute motor polyneuropathies associated with the use of bovine glycosides of which ten were diagnosed as GBS (Figueras et al. 1992). Antinuclear antibodies have been detected in sera of patients who developed GBS or motor neuron-like disorders following treatment with parenteral gangliosides (Latov et  al. 1991; Yuki et  al. 1991). Knorr-Held et al. (1986) reported a patient with multiple sclerosis who developed acute polyradiculoneuritis 11 days after implantation of swine brain ganglioside. Sensitization against brain nucleotides could be demonstrated by lymphocyte transformation test. Schwerer et al. (1994) reported the case of a 39-year-old woman who developed progressive motor polyneuropathy following the use of IM gangliosides and recovered after discontinuation of the therapy and plasma exchanges. She had relapses and was found to have a high level of antiganglioside GM1. Gold Salts  Patients with rheumatoid arthritis treated with gold salts have been reported to develop GBS (Dick and Raman 1982; Schlumpf et al. 1983). Miller Fisher syndrome, a variant of GBS, has been reported to develop in patients with rheumatoid arthritis during treatment with gold salts (Rocquer et al. 1985). Immune Checkpoint Inhibitors  GBS is increasingly reported in cancer patients treated with immune checkpoint inhibitors and represents the second most common immune checkpoint inhibitor-related neuromuscular complication, occurring in about 0.1% of patients (Kolb et al. 2018). The clinical and EMG features are similar to those of nonimmune checkpoint inhibitor-associated GBS, although the clinical description of these patients is frequently incomplete to confirm if the neuropathy fulfills the criteria for GBS (Johansen et  al. 2019). CSF pleocytosis is observed in 56% of patients with GBS associated with immune checkpoint inhibitors, a figure slightly higher than in idiopathic cases.

37  Drug-Induced Guillain-Barré Syndrome

Monoclonal Antibodies (MAbs)  Several case reports suggest that Miller Fisher syndrome may develop associated with immunotherapy or cancer therapy, including ipilimumab and nivolumab (Baird-Gunning et al. 2018; McNeill et al. 2019), cemiplimab (Ghosh et  al. 2020), or infliximab (Yu and Geraldi-Samara 2020); however, no anti-­ GQ1b antibodies were detected in these cases. A case of Bickerstaff brain stem encephalitis that developed after autologous stem cell transplant has also been reported (Malhotra and Latov 2020). Ofloxacin  This is one of the quinolone antibiotics which have been associated with adverse effects on the central as well as peripheral nervous systems. Schmidt et  al. (1993) reported GBS in a patient with urinary infection treated with ofloxacin with recovery after discontinuation and recurrence after resumption of therapy. They mentioned ten similar cases which have been reported to the manufacturer and in whom GBS coincided with ofloxacin treatment. Oxytocin  One case of GBS is reported in a postpartum patient who used oxytocin spray to continue lactation during a period of separation from her infant, and this followed the development of a syndrome of inappropriate secretion of antidiuretic hormone (SIADH) which led to hyponatremic encephalopathy (Seifer et  al. 1985). The patient did not have the characteristic EMG changes of GBS but gradually improved. Several other cases of GBS-like syndrome have been reported in association with SIADH. The causal relationship of oxytocin to GBS remains questionable. Penicillamine  Two cases of GBS have been reported following use of D-penicillamine therapy, but no satisfactory explanation was provided (Knezevic et al. 1984; Pool et al. 1981). Stem Cell Transplantation  A case of Bickerstaff brain stem encephalitis that developed after autologous stem cell transplant has also been reported (Malhotra and Latov 2020).

Drugs and Other Therapies Associated with Guillain-Barré Syndrome

Streptokinase  Nine published case reports have implicated that streptokinase can precipitate GBS (Ancillo et  al. 1994; Arrowsmith et  al. 1985; Barnes and Hughes 1992; Cicale 1987; Eden 1983; Leaf et  al. 1984; Rocquer et  al. 1990; Taylor et  al. 1995). The pathomechanism is unclear but streptokinase is a foreign protein and may induce the immunological reaction that is presumed to be necessary for the development of GBS.  GBS has also been reported to occur in 0.75–2/100,000 patients with myocardial infarction without treatment with streptokinase (McDonagh and Dawson 1987). Zimelidine  This serotonin reuptake inhibitor antidepressant was reported to be associated with peripheral neuropathy (see Chap. 11). Fagius et al. (1985) reviewed 13 cases of GBS in Sweden in association with introduction of zimelidine and found that risk of developing GBS was increased 25-fold in patients receiving zimelidine. An analysis of 9 of these cases by microcomputer-­ assisted Bayesian differential diagnosis revealed that these were probably causally related to zimelidine (Naranjo and Lanctot 1991). This drug was withdrawn from the market in 1983 because of its association with GBS as 10 cases in 200,000 prescriptions indicated that the population exposed to it was 25 times more liable to develop GBS than the unexposed population.

Vaccines Evidence from published literature shows that GBS follows immunization in only a small percentage of cases. The following vaccines have been implicated. Hepatitis B Vaccination  In post-marketing surveillance, GBS has been reported following hepatitis B vaccination, but this risk is unlikely to outweigh the prophylactic benefit of this vaccine (Shaw et al. 1988; Tuohy 1989). Influenza Vaccines  In 1976, there was a massive campaign in the United States for vaccination against an epidemic of influenza expected to affect

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the nation. The campaign was halted after 45 million immunizations with swine flu vaccine had been done and 1300 alleged cases of GBS had been reported to the Center for Disease Control. There was much confusion and controversy about the issue whether the cases fulfilled the criteria for the diagnosis of GBS (Kurland et al. 1985). The explanation of the apparent epidemic of GBS following swine flu vaccine remains uncertain. A reassessment of this situation by Safranek et  al. (1991), using modified criteria for assessment of cases (Asbury et  al 1978), showed that there was an increased risk of developing GBS only during the first 6 weeks following vaccination in the adults. Hemophilus influenzae type B conjugate vaccine has also been associated with GBS (D'Cruz OF et  al. 1989). This vaccine contains the H. influenzae antigen and diphtheria toxoid. The syndrome resolved in all the patients. Recent surveillance study revealed that the 2009 H1N1 vaccine safety profile is similar to that for current seasonal influenza vaccine with an excess risk of 0.8 cases per million vaccinations (Centers for Disease Control and Prevention 2009) Measles, Mumps, and Rubella Vaccine (MMR)  Morris and Rylance (1994) published the case of a child who developed GBS after MMR vaccine. The authors mentioned that two similar cases had been reported to the Medicines Control Agency in the United Kingdom and a larger number (less than 20) were reported to the manufacturer. In view of the widespread use of this vaccine, this association is extremely rare. Oral Poliomyelitis Vaccine (OPV)  Increased incidence of GBS following oral poliomyelitis vaccination has been reported from Finland (Kinnunen et  al. 1989; Uhari et  al. 1989). However, there was no increase of such an incidence in the United States. One explanation of this is that immunization in the United States is exclusively with OPV, whereas in Finland the routine immunization was with inactivated polio virus and OPV was given to individuals who may not have the same intestinal immunity as children given OPV (Salisbury 1998).

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Rabies Vaccine  The neuroparalytic illness following rabies vaccination frequently resembles GBS (Griffin 1988). The incidence of neuroparalytic complications following the use of Semple vaccine in Thailand was in the order of 1:1000 to 1:4000 (Hemachuda et  al. 1987). Cases of GBS were also reported to follow an improved variety, the suckling mouse brain vaccine, which was used in Peru (Cabrera et al. 1987). There is no theoretical reason why the human diploid cell culturederived rabies vaccine should produce GBS although two cases have been reported following this vaccine (Boe and Nyland 1980; Knittel et al. 1989). The pathomechanism of rabies vaccineinduced GBS is not clear. It may be similar to experimental allergic neuritis but the identity of the antigen is not known. Sera of the patients with vaccine-induced GBS contain autoantibodies to myelin basic protein (MBP), but the distribution of MBP in the nervous system makes it an unlikely target for pathogenetically important autoimmune reactions in GBS (Hughes 1990). Tetanus toxoid  It may precipitate GBS when given alone (Newton and Janati 1987; Pollard and Selby 1978)) or in combination with diphtheria toxoid. The evidence is not strong enough to forego tetanus toxoid in cases of potentially contaminated wounds, but its use should be avoided in patients with a past history of GBS. A background rate of 0.3 cases of Guillain-Barré syndrome per million person-weeks has been estimated (Tuttle et al. 1997). By chance, 2.2 persons with the syndrome would have received tetanus-­toxoid-containing vaccine within the 6 weeks before onset, yet only 1 person had done so. If an association exists between tetanus toxoid and GBS, it must be extremely rare and not of public health significance. Typhoid Vaccination  Cases of GBS following typhoid vaccination have been reported by Miller and Stanton (1954). It would be considered a rare occurrence. A committee of the US National Academy of Science’s Institute of Medicine has reviewed the evidence on this topic and accepted the causal

37  Drug-Induced Guillain-Barré Syndrome

relationship only of diphtheria and tetanus toxoids and oral polio vaccine to GBS (Stratton et al. 1994).

Management of Guillain-Barré Syndrome The prognosis of GBS is generally good with 80% of the patients making a good recovery. In case of suspected drug-induced GBS, the drug in question should be discontinued. The management is the same as GBS due to other nondrug-­ related causes. Supportive treatment includes respiratory intensive care management and monitoring of cardiorespiratory function. Complications associated with immobility should be prevented, particularly pneumonia and thromboembolism. Specific treatment includes plasma exchange (plasmapheresis) and intravenous immune globulins. In a randomized trial, both of these therapies were found to be equally effective (Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group 1997). In GBS due to immune checkpoint inhibitors (ICIs), the recommended treatment, besides discontinuation of ICIs, is to add prednisone to the standard treatment of intravenous immunoglobulin.

References Ancillo P, Duarte J, Cortina JJ. Guillain-Barré syndrome after acute myocardial infarction treated with anistreplase. Chest. 1994;105:1301–2. Arrowsmith JB, Milstein JB, Kuritsky JB, et  al. Streptokinase and Guillain-Barré syndrome. Ann Int Med. 1985;103:302. Asbury AK, Arnason BG, Adams RD. The inflammatory lesion in idiopathic polyneuritis: its role in pathogenesis. Medicine (Baltimore). 1969;48:173–215. Asbury AK, Arnason BG, Karp HR, et al. Criteria for diagnosis of Guillain-Barre´ syndrome. Ann Neurol. 1978;3:565–566. Atkinson AB, Brown JJ, Lever AF, et  al. Neurological dysfunction in two patients receiving captopril and cimetidine. Lancet. 1980a;2:36–7. Atkinson AB, Brown JJ, Lever AF, et al. Combined treatment of severe intractable hypertension with captopril and diuretic. Lancet. 1980b;2:105–7. Baird-Gunning JJD, Weerasinghe D, Silsby M, et  al. Miller Fisher syndrome associated with immuno-

References therapy for metastatic melanoma. Neurohospitalist. 2018;8(4):191–3. Barnes D, Hughes RAC.  Guillain-Barré syndrome after treatment with streptokinase. BMJ. 1992;304:1225. Bickerstaff ER, Cloake PC. Mesencephalitis and rhombencephalitis. Br Med J. 1951;2:77–81. Boe E, Nyland H. Guillain-Barré syndrome after vaccination with human diploid cell rabies vaccine. Scand J Infect Dis. 1980;12:231–2. Cabrera J, Griffin DE, Johnson RT.  Unusual features of GBS after rabies vaccine prepared in sucking mouse brain. J Neurol Sci. 1987;81:239–46. Centers for Disease Control and Prevention. Preliminary results: surveillance for Guillain-Barré syndrome after receipt of influenza A (H1N1) 2009 monovalent vaccine- United States, 2009–2010. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/ mm59e0602a1.htm. Chakraborty TK, Ruddell WSJ.  Guillain-Barré neuropathy during treatment with captopril. Postgraduate Med J. 1987;63:221–2. Cicale MJ.  Guillain-Barré syndrome after streptokinase therapy. South Med J. 1987;80:1068. D'Cruz OF, Shapiro ED, Spiegelman KN, et  al. Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré syndrome) after immunization with Haemophilus influenzae type b conjugate vaccine. J Pediatr. 1989;115(5 Pt 1):743–6. Dick DJ, Raman D. The Guillain-Barré syndrome following gold therapy. Scand J Rheumatol. 1982;11:119–20. Eden KV. Possible association of Guillain-Barré syndrome with thrombolytic therapy. JAMA. 1983;249:2020–1. Fagius J, Osterman PO, Siden A, et  al. Guillain-Barré syndrome following zimelidine treatment. JNNP. 1985;48:65–9. Figueras A, Morales-Olivas FJ, Capella D, et al. Bovine glycosides and acute motor polyneuropathy. BMJ. 1992;305:1330–1. Fisher M. An unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia and areflexia). N Engl J Med. 1956;255(2):57–65. Gherardi RK, Chariot P, Vanderstigel M, et  al. Organic arsenic-induced Guillain-Barré-like syndrome due to melarsoprol: a clinical, electrophysiological, and pathological study. Muscle Nerve. 1990;13:637–45. Ghosh A, Harish Bindiganavile S, Bhat N, Lee AG. A case of Miller Fisher syndrome due to the use of cemiplimab. J Neuroophthalmol. 2020; Epub ahead of print. Griffin DE. Post-infectious and post-vaccinal disorders of the central nervous system. Immunol Allergy Clin N Am. 1988;8:239–42. Griffin JW, Ho TW.  The Guillain-Barré syndrome at 75: The Campylobacter connection (editorial). Ann Neurol. 1993;34:125–7. Guillain G, Barré JA, Strohl A. Sur un syndrome de radiculonévrite avec hyperalbuminose du liquide céphalo-­ rachidien sans réaction cellulaire. Remarques sur les caractéres cliniques et graphiques des réflexes tendineux. Bull Mem Soc Med Hop Paris. 1916;40:1462–70.

573 Han TH, Kim DY, Park DW, Moon JH. Transient isolated lower bulbar palsy with elevated serum anti-GM1 and anti-GD1b antibodies during aripiprazole treatment. Pediatr Neurol. 2017;66:96–9. Harrisberg J, Deseta J, Cohen L, et al. Cantharidine poisoning with neurological complications. S Afr Med J. 1984;65:66–7. Hemachuda T, Phanuphak P, Johnson RT, et  al. Neurologic complications of Semple type rabies vaccine. Neurology. 1987;37:550–7. Hory B, Blanc D, Boillot A, et  al. Guillain-Barré syndrome following danazol and corticosteroid therapy for hereditary angioedema. Am J Med. 1985;79:111–4. Hughes RAC.  Guillain-Barré syndrome. London: Springer-Verlag; 1990. Johansen A, Christensen SJ, Scheie D, et  al. Neuromuscular adverse events associated with anti-­ PD-­ 1 monoclonal antibodies: systematic review. Neurology. 2019;92:663–74. Kinnunen E, Farkkila M, Hovi T, et  al. Incidence of Guillain-Barré syndrome during a nationwide oral poliomyelitis vaccine campaign. Neurology. 1989;39:1034–6. Knezevic W, Quinter J, Mastaglia FL, et  al. Guillain-­ Barré syndrome and pemphigus foliaceus associated with D-penicillamine therapy. Aus NZ J Med. 1984;14:50–2. Knittel T, Ramadori G, Meyer WJ, et  al. Guillain-Barré syndrome and human diploid cell rabies vaccine. Lancet. 1989;1:1334–5. Knorr-Held S, Brendel W, Kiefer H, et  al. Sensitization against brain gangliosides after therapeutic swine brain implantation in a multiple sclerosis patient. J Neurol. 1986;233:54–6. Kolb NA, Trevino CR, Waheed W, et al. Neuromuscular complications of immune checkpoint inhibitor therapy. Muscle Nerve. 2018;58:10–22. Kurland LT, Wiederholt WC, Kirkpatrick JW, et al. Swine influenza vaccine and Guillain-Barré syndrome. Arch Neurol. 1985;42:1089–90. Landi G, D'Alessandro R, Dossi BC, et al. Guillain-Barré syndrome after exogenous gangliosides in Italy. BMJ. 1993;307:1463–4. Landry O.  Note sur la paralysie ascendante aiguë. Gaz Hebd Med Paris. 1859;6:472–4. Latov N, Koski CL, Walicke P. Guillain-Barré syndrome and parenteral gangliosides. Lancet. 1991;338:757. Leaf DA, McDonald I, Kliks B, et  al. Streptokinase and Guillain-Barré syndrome. Ann Int Med. 1984;100:617. Lorentzon B.  Guillain-Barré syndrome associated with fansidar intake. Lakartidningen. 1984;81:2919. Malhotra A, Latov N.  Relapsing Bickerstaff brainstem encephalitis after autologous stem cell transplant. J Clin Neuromuscul Dis. 2020;21:225–9. McDonagh AJG, Dawson J.  Guillain-Barré syndrome after myocardial infarction. BMJ. 1987;294:213–4. McNeill CJ, Fehmi J, Gladwin J, Price C.  A rare case of Miller Fisher variant of Guillain-Barré Syndrome

574 (GBS) induced by a checkpoint inhibitor. BMJ Case Rep. 2019;12(8):e229443. Miller HG, Stanton JB.  Neurologic sequelae of prophylactic inoculation. Q J Med. 1954;23:1–27. Morris K, Rylance G.  Guillain-Barré syndrome after measles, mumps, and rubella vaccine (letter). Lancet. 1994;343:60. Naranjo C, Lanctot KL.  Microcomputer-assisted Bayesian differential diagnosis of severe adverse reactions to new drugs: a 4-year experience. Drug Inf J. 1991;25:243–50. Newton LN, Janati A. Guillain-Barré syndrome after vaccination with purified tetanus toxoid. South Med J. 1987;80:1053–4. Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group. Randomized trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Lancet. 1997;349:225–30. Pollard JD, Selby G. Relapsing neuropathy due to tetanus toxoid. J Neurol Sci. 1978;37:113–25. Pool KD, Feit H, Kirkpatrick J.  Penicillamine-induced neuropathy in rheumatoid arthritis. Ann Int Med. 1981;95:457–8. Raschetti R, Maggini M, Popoli P.  Guillain-Barré syndrome and ganglioside therapy in Italy. Lancet. 1992;340:60. Rocquer J, Herraiz J, Maymo J, et al. Miller-Fisher syndrome (Guillain-Barré syndrome with ophthalmoplegia) during treatment with gold salts in a patient with rheumatoid arthritis. Arthritis Rheum. 1985;28:838–9. Rocquer J, Herraiz J, Arnau D, et al. Guillain-Barré syndrome after treatment with streptokinase therapy. Acta Neurol Scand. 1990;82:153. Safranek TJ, Lawrence DN, Kurland LT, et  al. Reassessment of the association between Guillain-­ Barré syndrome and receipt of swine influenza vaccine in 1976–1977: results of two state study. Am J Epidemiol. 1991;133:940–51. Salisbury DM. Association between oral polio vaccine and Guillain-Barré syndrome. Lancet. 1998;351:79–80. Schlumpf U, Meyer M, Ulrich J, et al. Neurologic complications induced by gold treatment. Arthritis Rheum. 1983;26:825–31.

37  Drug-Induced Guillain-Barré Syndrome Schmidt A, Cordt-Schlegel A, Heitman R. Guillain-Barré syndrome during treatment with oflaxacin. J Neurol. 1993;240:506–7. Schwerer B, Pichler S, Bernheimer H, et al. Chronic progressive motor polyneuropathy after ganglioside treatment. JNNP. 1994;57:238. Seifer DB, Sandberg EC, Ueland K.  Water intoxication and hyponatremic encephalopathy from the use of an oxytocin nasal spray. A case report. J Reprod Med. 1985;30(3):225–8. Shaw FE, Graham DJ, Guess HA, et  al. Postmarketing surveillance for neurologic adverse events reported after hepatitis B vaccination. Am J Epidemiol. 1988;127:337–52. Steiner I, Wirguin I, Abramsky O. Appearance of Guillain-­ Barré syndrome in patients during corticosteroid treatment. J Neurol. 1986;233:221–3. Stratton KR, Howe KJ, Johnston RB.  Adverse events associated with childhood vaccines other than pertussis and rubella. JAMA. 1994;271:1602–5. Taylor BV, Mastaglia FL, Stell R.  Guillain-Barré syndrome complicating treatment with streptokinase. Med J Aust. 1995;162(4):214–5. Tuohy PG.  Guillain-Barré syndrome following immunization with synthetic hepatitis B vaccine. N Z Med J. 1989;102(863):114–5. Tuttle J, Chen RT, Rantala H, et al. The risk of Guillain-­ Barré syndrome after tetanus-toxoid-containing vaccines in adults and children in the United States. Am J Public Health. 1997;87(12):2045–8. Uhari M, Rantala H, Niemela M.  Cluster of childhood Guillain-Barré cases after oral poliovaccine campaign. Lancet. 1989;ii:440–1. Vernay D, Dubost JJ, Thevenet JP, et  al. “Choree fibrillaire de Morvan” followed by Guillain-Barré syndrome in a patient receiving gold therapy. Arthritis Rheum. 1986;29(11):1413–4. Yu EH, Geraldi-Samara D.  Pharyngeal-cervico-brachial/ Miller Fisher overlap syndrome with infliximab exposure. J Clin Neuromuscul Dis. 2020;21(3):157–8. Yuki N, Sato S, Miyatake T, et al. Motor neuron disease-­ like disorder after ganglioside therapy. Lancet. 1991;337:1109–10.

Neuroleptic Malignant Syndrome

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Introduction

Pathomechanism

Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal idiosyncratic reaction to neuroleptic medications characterized by muscular rigidity, fever, autonomic dysfunction, and altered consciousness. It was first noted during clinical trials of haloperidol and described in French literature as “syndrome malin” (Delay et al. 1960). The first description in English was in the Handbook of Clinical Neurology (Delay and Deniker 1968). The first detailed review of the clinical characteristics and differential diagnosis of NMS based on review of cases in the English literature was published in 1980 (Caroff 1980).

Pathomechanism of NMS is not completely understood. It is generally agreed that alterations in dopaminergic transmission in the CNS associated with drug therapy are the most important factor in its etiology. This is caused either by treatment with dopamine receptor antagonists or by withdrawing dopamine receptor agonists. Acute dopamine transmission block in basal ganglia and the hypothalamus is the pathophysiological mechanism of NMS (Weller and Kornhuber 1992a; Weller and Kornhuber 1992b). In this respect NMS, “the malignant dopamine depletion syndrome,” may be identical with akinetic parkinsonian crisis. Additionally, an alteration of dopaminergic-serotonergic transmission in the body, an enhanced synthesis and action of prostaglandins E1 and E2, and a modification of calcium-­mediated signal transduction in the body have been suggested (Ebadi et  al. 1990). Malfunction of the central N-methyl-D-aspartateglutamate receptors has also been postulated as pathomechanism and forms the basis of recommendation of NMDA receptor antagonists as treatment for NMS. Based on the clinical effectiveness of benzodiazepines in reversing NMS, it has been suggested that GABA plays a role in the development of NMS.  Many of the features of NMS suggest that sympathetic nervous system hyperactivity is involved in the pathophysiology of this disorder. Elevated urinary catecholamines

Epidemiology The prevalence of NMS among admissions to acute psychiatric wards has been estimated to vary from 0.2% to 2% (Keck et  al. 1991). In a prospective study of 679 hospitalized patients, NMS was diagnosed in six (0.9%) of cases (Keck et al. 1987). In a study in China, 12 (0.012%) of 9792 inpatients exposed to neuroleptics developed NMS (Deng et al. 1990). In a study in Japan, NMS occurred in 1.8% of patients who received antipsychotic therapy (Naganuma and Fujii 1994). The lack of consensus on diagnostic criteria of NMS makes comparison of incidence from various studies difficult.

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and metabolites are a frequent but inconstant feature of NMS (Gurrera and Romero 1992). Another hypothesis is that NMS is caused by a central imbalance between norepinephrine and dopamine and not by dopamine depletion (Schibuk and Schachter 1986). This view is supported by a case of NMS due to desipramine, a tricyclic antidepressant (Baca and Martinelli 1990). Desipramine inhibits the reuptake of norepinephrine with subsequent enhancement of central noradrenergic effects but does not significantly alter central dopaminergic levels. Positron emission tomography studies using C15O2 and 15O2 techniques show that cerebral oxygen metabolism and CBF are disturbed during NMS, indicating that not only dopaminergic but also the other neurotransmitter systems are involved (De Reuck et al. 1991). There is debate whether NMS is due to central or peripheral action of haloperidol. A patient with complete cervical cord transection who suffered a fatal hyperthermic episode after haloperidol administration implies that NMS in this case was a peripheral effect of haloperidol (Downey et al. 1992). No definite pathological lesions have been identified in NMS. Necrosis in the anterior and lateral nuclei of hypothalamus, the regions concerned with temperature regulation, has been described in a case of NMS (Horn et al. 1988). In other cases there are no abnormal findings in Parkinson’s disease patients who suffer NMS; the brain pathology does not differ from that of Parkinson’s disease patients without NMS.

Risk Factors for NMS

38  Neuroleptic Malignant Syndrome

• Patients on neuroleptic therapy with concomitant use of lithium and antidepressants are at risk for developing NMS.

 isk Factors Related to the Patient R • Young male patients are more likely to suffer. Mean age of NMS patients has been estimated to be 40  years. The reasons for this are not clear. Perhaps younger patients receive higher doses of neuroleptics for longer periods than the elderly patients. • Genetic factors may predispose to NMS as suggested by two case reports (Tu 1997). • About 40% of patients who develop NMS have an affective disorder (Pearlman 1986). These patients are more likely to develop NMS than those with schizophrenia. • Patients with fluid and electrolyte disturbances such as dehydration, hyponatremia, and hypernatremia, which are common in psychiatric patients, are at risk for development of NMS. • Hypothyroidism. • Patients with existing brain damage may have marginal stores of dopamine in the hypothalamus and basal ganglia and are susceptible to dopamine blocking activity of even low doses of neuroleptics (Lazarus 1992). NMS has been reported in a patient with Alzheimer’s disease after haloperidol administration (Serby 1986). Patients with Huntington’s disease and alcohol-related organic brain disease are more susceptible to NMS. Patients with mental retardation, who often receive neuroleptics, are at risk for the development of NMS.  Other risk factors are:

• Levodopa withdrawal in patients with Parkinson’s disease. • Patients with malignant disease. • Patients with medical disorders, and drug-­ related adverse effects which compromise Risk Factors Related to the Drugs thermoregulation, may be at risk for NMS. • Patients on rapidly escalating doses of high-­ potency neuroleptics given by intramuscular • Stress and physical exhaustion predispose to onset of NMS. injections for long periods are more likely to • Premenstrual period. develop NMS. The following risk factors have been identified for NMS, and these can be divided into risk factors involving the drugs and the patient risk factors.

Clinical Features and Diagnosis of NMS

 linical Features and Diagnosis C of NMS Although the classic features of NMS are well recognized, there is considerable controversy regarding the classification and diagnostic criteria of NMS. Various concepts are as follows. The Nihilistic View  There are those who do not believe that NMS is a valid entity. Alternative term is “neuroleptic-induced extrapyramidal side effects with fever.” The Traditional View  NMS has four features which must be present for diagnosis: 1. Muscular rigidity 2. Hyperthermia (