Fundamentals of Pediatric Neuro-Ophthalmology: A Practical, Case-Based Approach to Diagnosis and Management 3031161467, 9783031161469

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Gena Heidary Paul H. Phillips

Fundamentals of Pediatric NeuroOphthalmology A Practical, Case-Based Approach to Diagnosis and Management

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Fundamentals of Pediatric Neuro-Ophthalmology

Gena Heidary  •  Paul H. Phillips Editors

Fundamentals of Pediatric Neuro-Ophthalmology A Practical, Case-Based Approach to Diagnosis and Management

Editors Gena Heidary Department of Ophthalmology Boston Children’s Hospital Harvard Medical School Boston, MA, USA

Paul H. Phillips Department of Ophthalmology Arkansas Children’s Hospital University of Arkansas for Medical Sciences Little Rock, AR, USA

ISBN 978-3-031-16146-9    ISBN 978-3-031-16147-6 (eBook) https://doi.org/10.1007/978-3-031-16147-6 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 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

As one of the founders and the first Director of the Consortium of Pediatric Neuro-­ ophthalmologists (CPNO), it was with great pleasure and pride that I accepted Gena Heidary’s and Paul Phillips’ invitation to write the foreword to this book, Fundamentals of Pediatric Neuro-Ophthalmology. These two editors are prominent pediatric neuro-ophthalmologists and have had recent leadership positions in the CPNO: Dr. Phillips served as Director in 2019– 2020 and Dr. Heidary in 2020–2022. They asked numerous CPNO members, both national and international, to share their knowledge and expertise for chapters of this book, and all authors were eager to participate. Dr. Heidary and Dr. Phillips asked me to provide some introductory comments on the CPNO, and I thought I would start by describing the early years of the organization since I had a front seat during its development. In 2013, Dr. Stacy Pineles and I discussed starting a nationwide pediatric optic neuritis registry among pediatric neuro-ophthalmologists with the hope of obtaining preliminary data for a randomized treatment study proposal. During this process it became evident that this would be a great opportunity to organize pediatric neuro-­ ophthalmologists for this and other future projects by forming a Pediatric Neuro-ophthalmology Consortium. The goal was to organize pediatric neuro-ophthalmologists into a group that used standardized data collection to generate preliminary data for multicenter treatment studies for the various uncommon diseases that we manage. We thought we would start with a simple pediatric optic neuritis registry, but if we were able to be organized and productive, then our plan was to add new diseases in the future with different principal investigators. At the time I contacted about a dozen and a half pediatric neuro-ophthalmologists from throughout the world, and all were interested in participating. At the North American Neuro-Ophthalmology Society (NANOS) meeting in 2014 in Puerto Rico, the CPNO had its first formal meeting. Twenty people attended. We discussed that anyone could attend our meetings, but that membership would require being a member in either NANOS or the American Association of Pediatric Ophthalmology and Strabismus (AAPOS), and the individual had to include pediatric neuro-ophthalmology as a substantial portion of his or her clinical practice. We also composed a mission statement: to promote and advance pediatric neuro-ophthalmology by (1) enhancing the ability of pediatric neuro-ophthalmologists to perform multicenter studies, (2) providing a forum for discussing research and clinical topics, and (3) creating a sense of community to those specializing in pediatric neuro-ophthalmology. Shortly after the inaugural meeting, the members elected me to be the first Director of the CPNO, Dr. Mark Borchert the Co-Director (and the Director-Elect), and Dr. Stacy Pineles the Secretary. The acronym CPNO was chosen over PNOC because the latter was already used by a pediatric neuro-oncology organization. Since then, as we had hoped, numerous multicenter pediatric neuro-ophthalmic studies have resulted from the CPNO members’ collaboration. Instead of a registry, Dr. Pineles proposed a Pediatric Optic Neuritis Prospective Outcomes Study to the Pediatric Eye Disease Investigator Group (PEDIG), which approved and sponsored the project [1]. This longitudinal data collection study was the first large multicenter one on this topic and has produced valuable information regarding visual outcomes and distribution of pediatric optic neuritis subtypes [2–4]. Dr. Claire Sheldon coordinated a multicenter study of anthropometrics in children with v

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pediatric idiopathic intracranial hypertension (IIH). Her group found that there are three subgroups of pediatric IIH, compared with age and gender norms: (1) a population (28 cm H20) with normal constituents [1]

Clinical Discussion Treatment and Prognosis In general patients with IIH with no or mild vision loss who are overweight or obese do extremely well with weight loss (5–10%) and oral acetazolamide (15–20 mg/kg/day). When present, headaches and sixth nerve palsies tend to resolve over a few weeks, while papilledema and visual field loss usually improve over months. Once the papilledema resolves, the acetazolamide can be tapered over a month, and patients are asked to maintain a healthy weight to prevent recurrence. Uncommonly, patients with severe vision loss or vision loss despite maximal medical treatment require optic nerve sheath fenestration, a CSF shunting procedure, or venous sinus stenting. Our patient was treated with oral acetazolamide 500 mg twice per day and advised to reduce her weight with diet and exercise. Her headache and double vision resolved after three weeks, and her optic disc appearance and visual field normalized after 4.5 months. Her acetazolamide was tapered. She lost a total of 10 kg over 6 months, and since then, she has done well with no recurrence of symptoms or papilledema.

G. T. Liu

Novel Insights Pseudotumor cerebri syndrome (PTCS) is the umbrella term for the symptom complex of papilledema, normal brain parenchyma, and elevated CSF opening pressure with normal constituents [1]. IIH, or primary PTCS, should be contrasted from secondary PTCS due to identified medical conditions or medications. The mechanism of PTCS in adults and children is unclear. Indeed, pediatric PTCS can be related to a variety of chronic medical conditions including renal, Addison, and Cushing disease, in addition to medications such as tetracyclines, recombinant growth hormone, and thyroid supplementation. Together, these appear to lack a unifying pathophysiologic mechanism; however, a detailed understanding of the clinical and laboratory features of PTCS may provide insights into its pathophysiology. Currently, a prospective multicenter pediatric PTCS study is being organized to (a) better characterize the (i) anthropometrics, (ii) clinical characteristics and outcomes, and (iii) laboratory and imaging features of pediatric PTCS, and (b) elucidate the mechanism of pediatric PTCS.

Clinical Pearls

• Idiopathic intracranial hypertension (IIH) is a common condition characterized by papilledema, normal brain parenchyma on neuroimaging, and elevated intracranial pressure. • Neuroimaging in patients with IIH may demonstrate an empty sella turcica, flattening of the posterior aspect of the globe, distention of the perioptic subarachnoid space with or without tortuous optic nerves, and transverse venous sinus stenosis [1]. • In patients with IIH who are overweight or obese, weight loss is the most important treatment.

References Important Aspects of the Diagnosis Presenting signs and symptoms in IIH commonly include headache, visual disturbances (i.e., vision loss or double vision), and papilledema (optic disc swelling due to elevated intracranial pressure) [2]. IIH can occur in all ages in children, but there are three major groups. Most children as in this case who have IIH are postpubertal obese females [3]. Younger children with IIH have equal gender distribution and are often thin. There is a middle group of IIH patients with regard to age and development that are tall and overweight [4].

1. Friedman DI, Liu GT, Digre KB. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2013;81:1159–65. 2. Phillips PH, Sheldon CA. Pediatric pseudotumor cerebri syndrome. J Neuroophthalmol. 2017;37(Suppl 1):S33–40. 3. Balcer LJ, Liu GT, Forman S, et al. Pediatric pseudotumor cerebri: relationship of age and obesity. Neurology. 1999;52:870–2. 4. Sheldon CA, Paley GL, Xiao R, et  al. Pediatric idiopathic intracranial hypertension: age, gender, and anthropometric features at diagnosis in a large, retrospective, multisite cohort. Ophthalmology. 2016;123:2424–31.

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Papilledema from Secondary Pseudotumor Cerebri: A Teenager with Blurred Vision and Diplopia Ellen B. Mitchell and Ricardo Couso

Case Presentation A 17-year-old woman presented with 3 days of binocular, horizontal diplopia, and blurred vision. The diplopia was constant and worse at distance. She also noticed blurring in the temporal visual field of her left eye. In addition, she had new headaches over the past 3 weeks. Her headaches were in the bilateral frontotemporal region, present upon awakening, and exacerbated by lying supine. Ibuprofen, aspirin, acetaminophen, and caffeine did not relieve the headaches. She had no history of eye disease. She had a medical history notable for menorrhagia managed with levonorgestrel/ethinyl estradiol, and acne managed with oral minocycline and topical tretinoin. On examination, her visual acuity was 20/20 without correction at near in both eyes. Pupils were 5 mm in the dark, 3 mm in the light, briskly reactive to light, and without a relative afferent pupillary defect. Ocular motility examination showed a –0.5 limitation in abduction of both eyes. Visual fields were full to confrontation, but Humphrey automated perimetry 30-2 showed generalized depression in both eyes and an enlarged blind spot in her left eye. She correctly identified 12/12 Ishihara color plates in both eyes. Slit-lamp examination of the anterior segment was unremarkable, and intraocular pressure was 11 mmHg right eye and 16 mmHg left eye by rebound tonometry. On the dilated fundus examination, she had 360-degree blurring of disc margins both eyes without hemorrhages, exudates, or cotton wool spots. The macula, vessels, and periphery were unremarkable.

Differential Diagnosis

• Pseudotumor cerebri (idiopathic intracranial hypertension, IIH) • Pseudotumor cerebri syndrome (secondary pseudotumor cerebri/IIH) • Meningitis • Intracranial mass • Hydrocephalus • Dural venous sinus thrombosis

Diagnostic Workup In the setting of bilateral disc edema and headaches, neuroimaging was pursued. Magnetic resonance imaging (MRI) of the brain with contrast showed a partially empty sella turcica, patent dural venous sinuses, and no other acute intracranial process. The MRI ruled out a mass, hydrocephalus, and sinus thrombosis. A lumbar puncture (LP) revealed an elevated opening pressure of 50.5 cm of H20. Cerebrospinal serology and cultures were normal. Given the antecedent history of minocycline use, the findings were interpreted to be consistent with Pseudotumor cerebri syndrome secondary to drug exposure to minocycline.

Final Diagnosis Pseudotumor cerebri secondary to minocycline

Clinical Discussion Important Aspects of the Diagnosis E. B. Mitchell (*) · R. Couso Department of Ophthalmology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA e-mail: [email protected]

This patient exhibited many of the cardinal features of elevated intracranial pressure (ICP) including bilateral optic

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_8

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disc edema, headache with a positional component, visual disturbance (usually a visual field defect such as an enlarged blindspot, peripheral visual field loss, or both), and horizontal diplopia due to bilateral cranial nerve VI palsies [1, 2]. Elevated ICP was confirmed with LP that showed an opening CSF pressure of 50.5  cm H2O (>25  cm H2O in adults and >28 cm H2O in children) [3, 4]. Examination may also show retinal venous tortuosity and disc edema associated with hemorrhage, cotton wool spots, and retinal exudate. Patients may also report pulsatile tinnitus, and in severe cases may present with other signs of an optic neuropathy (including an afferent pupillary defect, dyschromatopsia, or severe vision loss). The criteria for the diagnosis of pseudotumor cerebri in adults and children have been revised [4]. Pseudotumor cerebri/IIH is a diagnosis of exclusion, and other more insidious etiologies must be ruled out before proceeding with management [2, 4]. Initial workup should include MRI brain with contrast and magnetic resonance venography (MRV) head to detect acute intracranial pathology such as an abscess or tumor that may predispose a patient towards herniation, or other emergent conditions such as cerebral venous sinus thrombosis, or hydrocephalus. Neuroimaging is also helpful in identifying signs of elevated ICP, including flattening of the posterior aspect of the globes, increased perioptic subarachnoid space, an empty or partially empty sella turcica, and stenosis of the transverse venous sinuses. Once intracranial pathology has been ruled out with neuroimaging, lumbar puncture should be obtained to evaluate the components of the CSF as well as the opening pressure. It is essential to assess the patient for associated conditions and medications that may cause pseudotumor cerebri, so-called secondary pseudotumor cerebri. Our patient had acne treated with minocycline and tretinoin which are medications that are associated with pseudotumor cerebri. Other conditions and medications associated with pseudotumor cerebri include renal disease, Addison disease, Cushing disease, growth hormone, and vitamin A. Risk factors for secondary pseudotumor cerebri are similar to idiopathic cases and include female gender and obesity [5]. If CSF studies and opening pressure are normal, and neuroimaging is unremarkable, one must consider other diagnoses that would cause disc edema that are not associated with elevated ICP. This can be divided into a few broad categories, including pseudopapilledema (e.g., optic nerve head drusen), infectious (e.g., toxoplasma, Lyme, bartonella, tuberculosis, syphilis, and herpes viruses), inflammatory (e.g., optic neuritis/multiple sclerosis), autoimmune (e.g., Lupus or Sjogren’s), infiltrative (e.g., sarcoidosis), neoplastic (e.g., leukemia or lymphoma), ischemic (e.g., AION and NAION, hypertensive optic neuropathy, or vein

E. B. Mitchell and R. Couso

occlusion), and metabolic (e.g., compression from thyroid eye disease, papillitis due to diabetes, or Leber hereditary optic neuropathy). Workup for one or more of these conditions may be indicated depending on the presentation of the patient.

Treatment and Prognosis Treatment of IIH depends on the etiology, as well as the severity of the disease. It is important to identify and address any secondary factors that may be contributing to elevated intracranial pressure, such as obesity, medications (such as tetracyclines, vitamin A, oral contraceptives, and others), and other systemic disorders (such as lupus, Behcet’s, hypothyroidism, obstructive sleep apnea, and others). Weight loss, cessation of offending medications, or treatment of the causative illness is imperative in controlling ICP in someone with elevated ICP. Treatment is often medical and is aimed at alleviating the headache, preserving vision, and preventing loss of optic nerve fibers, although surgical intervention may be warranted in severe or refractory cases. Oral acetazolamide is generally the first-line treatment for patients with IIH. Eventually, once symptoms are controlled and vision is stable, patients may be slowly tapered off medical treatment under close observation of their neuro-ophthalmologist. In this patient, she was taking multiple medications placing her at risk for IIH. At diagnosis, minocycline was discontinued, and she was started on oral acetazolamide with neuro-ophthalmologic follow-up.

Novel Insights Results from the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) have demonstrated that oral acetazolamide is safe and effective in doses up to 4 g/day in adults [6]. The dosage in children is 15–20 mg/kg/day in two to three divided doses. Initial dose depends on the severity of the optic neuropathy and magnitude of the elevation in ICP. Other medications, such as topiramate, may be used in patients who cannot tolerate acetazolamide due to side effects or other systemic conditions. In patients with severe optic neuropathy, worsening or refractory CSF pressure elevation, intractable headaches, or who do not respond to or tolerate medical treatment, surgical intervention with CSF shunting and/or optic nerve sheath fenestration may be indicated. Although many studies exclude patients with secondary causes of IIH, the prognosis for patients with IIH who are adherent to treatment is generally favorable. The IIHTT excluded patients with exposure to tetracycline or vitamin A but did include certain secondary causes such as obstructive

8  Papilledema from Secondary Pseudotumor Cerebri: A Teenager with Blurred Vision and Diplopia

sleep apnea. Acetazolamide treatment was associated with improvement in papilledema, CSF opening pressure, and OCT findings, as well as improvement in visual field and even quality of life in patients with mild visual field loss [6]. Clinical Pearls

• Pseudotumor cerebri is a diagnosis of exclusion, and secondary causes of elevated ICP must be assessed. • Risk factors for secondary pseudotumor cerebri/IIH are similar to idiopathic cases and include female gender and obesity. • The mainstay of treatment for secondary pseudotumor cerebri/IIH is addressing the underlying cause, and then medical or surgical treatment.

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References 1. Wall M, Kupersmith MJ, Kieburtz KD, et al. The idiopathic intracranial hypertension treatment trial: clinical profile at baseline. JAMA Neurol. 2014;71:693–701. 2. Phillips PH, Sheldon CA. Pediatric pseudotumor cerebri syndrome. J Neuroophthalmol. 2017;37(Suppl 1):S33–40. 3. Gaier ED, Heidary G. Pediatric idiopathic intracranial hypertension. Semin Neurol. 2019;39:704–10. 4. Friedman DI, Liu GT, Digre KB. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2013;81:1159–65. 5. Paley GL, Sheldon CA, Burrows EK, et  al. Overweight and obesity in pediatric secondary pseudotumor cerebri syndrome. Am J Ophthalmol. 2015;159:344–52. 6. Smith SV, Friedman DI.  The idiopathic intracranial hypertension treatment trial: a review of the outcomes. Headache. 2017;57:1303–10.

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Papilledema from Dural Sinus Thrombosis: A Teenager with Headaches and Diplopia Lauren C. Ditta and Jane C. Edmond

Case Presentation A 15-year-old boy was referred by his pediatrician for evaluation of new, acute onset, inward turning of the left eye and symptomatic diplopia. The patient also complained of a 3-week history of nonfocal headache, which was worse in the middle of the night and on awakening. The patient admitted to occasional nausea and vomiting, hearing “whooshing” noises episodically, and transient vision “black-outs” when getting out of bed. His past medical history was significant for a viral gastroenteritis approximately 4 weeks prior, with severe nausea, vomiting, and poor oral intake for 3 days duration. Otherwise, the past medical history was nonrevealing. Ophthalmologic examination revealed a visual acuity of 20/25  in each eye, with equal, sluggishly reactive pupils, without an afferent pupillary defect. External examination, slit-lamp examination, and intraocular pressures were normal. Color vision was slightly decreased bilaterally by Ishihara color plate testing. The motility examination revealed an esotropia of 25Δ, increasing in left gaze with moderate left lateral rectus underaction. On confrontation visual field testing, there was constriction of the field inferiorly in each eye. Humphrey visual field 24-2 testing revealed enlarged blind spots with bilateral depression of the inferior

L. C. Ditta Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA Le Bonheur Neuroscience Institute, Le Bonheur Children’s Hospital, Memphis, TN, USA

PATTERN DEVIATION

PATTERN DEVIATION

OS

OD

Fig. 9.1  Humphrey automated perimetry 24-2 demonstrating bilateral enlarged blind spots with areas of inferior visual field depression. OD: right eye; OS: left eye.

visual field (Fig.  9.1). The dilated fundus examination revealed high-grade optic disc edema bilaterally (Fig. 9.2).

Differential Diagnosis

• Papilledema due to brain tumor/intracranial mass • Papilledema due to obstruction of cerebrospinal fluid (CSF) circulation such as hydrocephalus or dural venous sinus thrombosis • Papilledema due to intracranial hemorrhage, infectious meningitis, or aseptic meningitis • Pseudotumor cerebri (idiopathic intracranial hypertension) • Optic disc edema due to inflammatory or infectious optic neuritis, infiltration (leukemia), or compressive optic neuropathy

St. Jude Children’s Research Hospital, Memphis, TN, USA J. C. Edmond (*) Department of Ophthalmology, Mitchel and Shannon Wong Eye Institute, Dell Medical School, University of Texas at Austin, Austin, TX, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_9

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L. C. Ditta and J. C. Edmond

Fig. 9.2  Bilateral high-grade optic nerve edema with peripapillary retinal hemorrhages.

Diagnostic Workup Inflammatory or infectious optic neuritis, infiltration (leukemia), and compressive optic neuropathy are less likely etiologic possibilities because these conditions, in the acute phase, typically lead to decreased visual acuity and mild optic disc edema. The diagnosis of presumptive papilledema (disc edema from elevated intracranial pressure) should be based on the following symptoms and signs: history of headache, pulsatile tinnitus, transient visual obscurations, normal visual acuity, mild dyschromatopsia, constricted confrontation visual fields, and bilateral, severe optic nerve swelling. Acute onset esotropia secondary to unilateral or bilateral abducens palsy also supports papilledema as the cause of bilateral optic nerve swelling. Urgent neuroimaging was performed, including magnetic resonance imaging (MRI) of the brain, with and without contrast, with magnetic resonance venography (MRV) of the head. MRI demonstrated normal brain parenchyma, a partially empty sella, and a dilated perioptic nerve sheaths with prominent CSF (Figs. 9.3 and 9.4). MRI and MRV confirmed thrombosis of the left sigmoid sinus (Fig.  9.5). A lumbar puncture was obtained; the opening pressure was over 50 cm H2O. CSF glucose, protein, cell count with differential, and culture were normal.

Fig. 9.3  MRI axial T2-weighted of the right orbit shows CSF distention of the right optic nerve sheath (red arrowheads), and demonstrates CSF in the sella turcica consistent with partial-empty sella (red arrow).

9  Papilledema from Dural Sinus Thrombosis: A Teenager with Headaches and Diplopia

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Final Diagnosis Severe papilledema secondary to cerebral sinovenous thrombosis (CSVT)

Clinical Discussion Treatment and Prognosis

Fig. 9.4  MRI sagittal T1-weighted image of the brain shows the pituitary parenchyma along the floor of the sella turcica demonstrating a diminutive craniocaudal dimension (red arrowhead), and the sella turcica is otherwise predominantly filled with cerebrospinal fluid (CSF) (red arrow).

Fig. 9.5  MRI axial T2-weighted image of the brain shows a heterogeneous but predominantly hyperintense appearance of the left sigmoid sinus (red arrow), as compared to the normal flow void of the patent right sigmoid sinus (short red arrow). The T2 hyperintense signal in the setting of the T1 hyperintense signal is characteristic of the predominating component of the clot as extracellular methemoglobin.

Papilledema is often a consequence of venous hypertension from CSVT, and early detection and treatment is critical in preventing vision loss. Medical management, often with carbonic anhydrase inhibitors and anticoagulation, is the first-­ line therapy to treat papilledema from CSVT, particularly in mild cases. However, papilledema secondary to elevated ICP from CSVT is often severe on presentation, with suboptimal rapid response to high-dose oral acetazolamide. Surgical interventions such as serial lumbar punctures (LP), optic nerve sheath fenestration (ONSF), or CSF diversion are often needed when papilledema is severe, intracranial pressure is very high, and vision loss is severe, progressive, or permanent (e.g., optic atrophy). The most pressing condition in our patient was management of the severe, potentially sight-threatening papilledema. Urgent reduction of intracranial pressure (ICP) was indicated, and the patient was placed on acetazolamide, extendedrelease capsule, 500 mg twice a day. The Hematology service was consulted to manage anticoagulation therapy and investigate for thrombophilic disorders. The patient was found to have Protein S Deficiency, which was also identified in the father. It was likely that the patient’s CSVT, secondary elevated intracranial pressure, and subsequent papilledema, were due to a combination of events—a heritable hypercoagulable disorder and dehydration induced by the preceding viral gastroenteritis. Low-­ molecular-­ weight heparin (LMWH) was initiated in the hospital and then transitioned to enoxaparin subcutaneously twice daily, to prevent further thrombus propagation. Thrombolysis therapy was not initiated as it places the patient at risk for cerebral hemorrhage. The patient was followed closely over the next 2 weeks. Headache symptoms improved; however, vision declined to 20/40 both eyes with worsening dyschromatopsia, persistent visual field defects, and only mildly improved papilledema. These examination findings, especially the decreasing visual acuity and progressive dyschromatopsia, strongly suggested that the optic nerves were at significant risk for secondary optic atrophy that would cause permanent vision loss. Sequential optic nerve sheath fenestrations were

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performed, first on the left, and then on the right eye, to preserve vision. Postoperatively, the patient’s papilledema improved. The patient was maintained on acetazolamide and enoxaparin. Follow-up neuroimaging two months later revealed unresolved CSVT with an interval decrease in clot burden. Three months after presentation, the patient’s esotropia and motility deficit resolved. One year later, the final examination revealed normal visual acuity, color vision, and pupillary reactivity to light. Visual field defects improved but did not completely resolve. Moderate bilateral optic atrophy was noted in addition to nerve fiber layer thinning on optical coherence tomography (OCT), due to the severity of the previous papilledema, suboptimal improvement of the papilledema after acetazolamide initiation, and prolonged presence of venous sinus clot and chronically elevated ICP.  Neuroimaging revealed residual, but, again, improved nonocclusive thrombosis.

Important Aspects of the Diagnosis CSVT is a rare diagnosis in children [1–4]. Pathophysiology of the thrombosis is explained by Virchow’s triad: hypercoagulability, venous stasis, and endovascular injury. Risk factors include infections, such as otitis media, mastoiditis, sinusitis, and sepsis; hypercoagulable states such as oral contraceptive/intrauterine device use, deficiency or dysfunction in factor V Leiden, factor II, proteins C and S, and antithrombin, elevated levels of homocysteine and factor VIII, antiphospholipid syndrome, and significant dehydration alone or in combination with other risk factors. Pediatric patients may be particularly susceptible to CSVT, often occurring in a variety of clinical settings and often due to more than one risk factor. CSVT causes decreased CSF outflow through the arachnoid granulations, which results in elevated ICP. Additionally, smaller cerebral vein and venule thrombosis can lead to elevated cerebral venous hypertension, which also leads to elevated ICP.

Novel Insights There is emerging evidence of COVID-19-associated coagulopathy with CSVT as a neuro-ophthalmologic complication [5]. Although the pathophysiology remains unknown, there is a growing consensus that viral infections may result in profound dysregulation between inherent procoagulant and

L. C. Ditta and J. C. Edmond

anticoagulant mechanisms, endothelial dysfunction, inhibition of fibrinolysis, increased blood viscosity, and septic-­ associated coagulopathy. Patients with COVID-19 have been found to have anticoagulant dysregulation resulting in elevated D-dimer levels and fibrinogen. Given that symptoms such as headache may be insidious and nonspecific, particularly in the pediatric population, it is imperative to consider CSVT in patients with COVID-19 infection who present with visual or neurologic complaints.

Clinical Pearls

• Papilledema secondary to elevated ICP from CSVT is often severe on presentation, with suboptimal rapid response to high-dose oral acetazolamide. • ONSF should be strongly considered in cases of severe papilledema, which fail to improve in a timely manner to oral acetazolamide, or at the first signs of optic nerve compromise such as declining vision (excluding macular edema), dyschromatopsia, constricted automated or confrontational visual fields, sluggish pupil reactivity to light, or an afferent pupillary defect. • Pediatric patients most at risk for permanent vision loss are those who present late in their disease process or who are at risk for long-term hypercoagulable events.

References 1. Liu KC, Bhatti MT, Chen JJ, Fairbanks AM, Foroozan R, McClelland CM, Lee MS, Satija CE, Francis CE, Wildes MT, Subramanian PS, Williams ZR, El-Dairi MA.  Presentation and progression of papilledema in cerebral venous sinus thrombosis. Am J Ophthalmol. 2020;213:1–8. 2. Costa JV, João M, Guimarães S.  Bilateral papilledema and abducens nerve palsy following cerebral venous sinus thrombosis due to Gradenigo’s syndrome in a pediatric patient. Am J Ophthalmol Case Rep. 2020;19:100824. 3. Eliseeva N, Serova N, Yakovlev S, Mikeladze K, Arkhangelskaya Y, Gasparyan S. Neuro-ophthalmological features of cerebral venous sinus thrombosis. Neuroophthalmology. 2014;39:69–76. 4. Jackson BF, Porcher FK, Zapton DT, Losek JD.  Cerebral sinovenous thrombosis in children: diagnosis and treatment. Pediatr Emerg Care. 2011;27:874–80; quiz 881-3. 5. Dakay K, Cooper J, Bloomfield J, Overby P, Mayer SA, Nuoman R, Sahni R, Gulko E, Kaur G, Santarelli J, Gandhi CD, Al-Mufti F.  Cerebral venous sinus thrombosis in COVID-19 infection: a case series and review of the literature. J Stroke Cerebrovasc Dis. 2021;30:105434.

Optic Neuritis Associated with Multiple Sclerosis: A Teenager with Painful Vision Loss

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Jennifer H. Yang and Jennifer S. Graves

Case Presentation

ment was orthophoric in all directions of gaze. She had normal smooth pursuit and saccadic eye movements. The A 16-year-old previously healthy girl presented with a one-­ remainder of her neurological exam was normal. Formal month history of progressive blurry vision in the left eye. She static perimetry (Humphrey 24-2) demonstrated a  grossly reported that her symptoms first started with dull left eye normal visual field in the right eye, and dense central loss, pain worse with eye movement that lasted 3–4 days followed more predominant in the nasal visual field  in the left eye by blurry vision and difficulty seeing colors in the left eye. (Fig. 10.1a). Optical coherence tomography (OCT) showed Otherwise, she denied any recent illness, headaches, focal normal mean global retinal nerve fiber layer  thickness weakness, numbness, gait disturbance, or bowel/bladder (RNFL, 100 μm) in the right eye and significant retinal nerve incontinence. She had three dogs at home without other ani- fiber layer thinning (RNFL, 68 um) in the left eye most premal exposure or travel exposure. She did not take any medi- dominantly in the temporal quadrant (Fig. 10.1b). Her precations and denied illicit substance use or sexual activity. sentation was consistent with clinical unilateral optic neuritis There was no contributory family history of known neuro- (ON) left eye and further workup was recommended. logical diseases. The neuro-ophthalmologic examination one month after symptom onset showed a near visual acuity J1+ right eye and Differential Diagnosis J16 left eye, 10/10 Ishihara color plates identified in the right • Multiple sclerosis (MS) eye, and 0/10 Ishihara color plates identified in the left eye, • Neuromyelitis optica spectrum disease (NMOSD) and a 2+ relative afferent pupillary defect in the left eye. • MOG-IgG+-associated disease (MOGAD) Visual fields to confrontation were full in the right eye and a • Idiopathic optic neuritis central scotoma and nasal defect in the left eye. The dilated • Systemic autoimmune disease (systemic lupus eryfundus exam demonstrated a normal optic disc in the right thematosus, sarcoidosis) eye, and disc pallor with gliotic changes but no disc edema in • Infectious (Lyme disease, ocular bartonellosis) the left eye. Her ductions were full in both eyes, and align-

J. H. Yang · J. S. Graves (*) Department of Neurosciences, University of California San Diego, San Diego, CA, USA Rady Children’s Hospital San Diego, San Diego, CA, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_10

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J. H. Yang and J. S. Graves

a

b

OD

OS

c

Fig. 10.1  (a) Formal static central 24-2 perimetry showing a central/ paracentral scotoma with more nasal depression in the left eye and grossly normal visual field in the right eye. (b) Optical coherence tomography demonstrating temporal thinning and optic atrophy left eye

and normal RNFL right eye. (c) Magnetic resonance imaging with T2 hyperintense intra-orbital segment of the left optic nerve (red arrow) with enhancement (yellow arrow). OD: right eye; OS: left eye.

Diagnostic Workup

glucose of 73 mg/dL, protein of 16 mg/dL, abnormal oligoclonal bands (OCBs) with >5 unique gamma restriction bands that were not present in the corresponding serum sample, and elevated IgG index 0.74 (ref 3 segments) transverse myelitis (LETM) lesion on MRI is suggestive of MS. 6. MS-typical imaging features on T2-weighted MRI sequences. a. Brain Lesions with orientation perpendicular to a lateral ventricular surface (Dawson fingers) b. Brain lesions adjacent to lateral ventricle in the inferior temporal lobe c. Juxtacortical lesions involving subcortical U-fibers d. Cortical lesions e. Spinal cord lesions 70%) in the peripheral cord on axial sequences g. Diffuse, indistinct signal change in the cord, suggestive of long-standing or progressive MS 7. Other non-MS non-NMOSD imaging features. Lesions with persistent (>3 months) gadolinium enhancement.

Box 12.2 The Six Clinical Characteristics of NMOSD. (Adapted from Wingerchuk et al. [1])

1. Optic neuritis 2. Acute myelitis 3. Area postrema syndrome, defined as an episode of otherwise unexplained hiccups or nausea and vomiting 4. Acute brainstem syndrome 5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions 6. Symptomatic cerebral syndrome with NMOSD-­ typical brain lesions

Box 12.3 Additional MRI Requirements for NMOSD Without AQP4-IgG or with Unknown AQP4-IgG Status. (Adapted from Wingerchuk et al. [1])

1. Acute optic neuritis requires a. normal findings on MRI brain, or b. only nonspecific white matter lesions, or c. T2-hyperintense lesion or T1-weighted Gd-­ enhancing lesion of the optic nerve extending over >½ optic nerve length, or involving optic chiasm. 2. Acute myelitis requires a. associated intramedullary MRI lesion extending over >= 3 contiguous segments (LETM), or b. ≥3 contiguous segments of focal spinal cord atrophy with history compatible with acute myelitis. 3. Area postrema syndrome requires associated dorsal medulla/area postrema lesions. 4. Acute brainstem syndrome requires associated periependymal brainstem lesion.

Treatment and Prognosis To date, there have been no large prospective clinical trials for NMOSD in the pediatric population. The pediatric optic neuritis prospective natural history study only had three participants with positive AQP4-IgG antibodies [2]. The current practice for pediatric NMOSD is based on adult data and one large retrospective multinational trial that included 53 subjects [3]. In order to reduce long-term visual impairment, it is imperative to treat the acute flares of optic neuritis in NMO spectrum disorder (NMOSD). Early treatment of NMOSD optic neuritis has been correlated with preservation of the peripapillary RNFL [4]. The mainstay of therapy is intrave-

12  Optic Neuritis Associated with Neuromyelitis Optica: A Teenager with Painful Blurred Vision

nous methylprednisolone (IVMP), which typically consists of 1 g/day for 3–5 days, with or without oral prednisone taper. Although in typical optic neuritis (idiopathic or multiple sclerosis), oral prednisone bioequivalent (1250 mg/day) was suggested to be noninferior to IVMP in accelerating visual recovery [5], prednisone has not been evaluated in NMOSD optic neuritis. Therapies that are complementary to IVMP in the acute treatment of NMOSD (and NMOSD optic neuritis) include plasma exchange (PLEX) or immunoadsorption apheresis [6]. PLEX, which is administered for 48 h for 5–7 cycles, is often initiated in IVMP-refractory NMOSD. However, there is evidence of short- and long-term benefits of PLEX as a first-line therapy in combination with IVMP [6]. The neurological dysfunction of NMOSD, including visual loss, typically relapses and progresses in a stepwise fashion. Untreated NMO in children can result in severe disability within a few years [3, 7]. Maintenance therapy is mandatory and should be chronic, and sometimes indefinite, using traditional immunosuppressive therapy. Immunomodulatory therapies such as those developed for MS (e.g., interferon-β, fingolimod, or natalizumab) could make NMOSD worse and therefore should be avoided in NMO [8]. Following an NMOSD exacerbation, oral corticosteroids are utilized to bridge to a maintenance long-term therapy that is steroid-sparing. Azathioprine and mycophenolate, which are typically used off-label with some concomitant use of oral corticosteroid, are supported mostly by retrospective studies and shown to reduce the annualized relapse rate

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(ARR). Rituximab, based on retrospective and prospective studies, significantly reduces ARR in NMOSD. In our case, the patient received 3 days of intravenous methylprednisolone (IVMP) with no improvement in vision. Long-term immunosuppression was recommended. However, the family disagreed with the diagnosis of NMOSD as the patient did not meet the Wingerchuk criteria, since the optic neuritis was never observed at the active stage. The patient declined treatment at this time. Two years later, the patient presented with bilateral decreased vision. Examination showed a visual acuity of 5/200 E right eye and Hand Motion left eye. She could not see the Ishihara control plates out of either eye. She could not count fingers on visual field testing of either eye. Pupils were bilaterally sluggish, and there was no relative afferent pupillary defect. The dilated funduscopic examination showed bilateral optic nerve head pallor: diffuse on the right and temporal on the left. There were no exudates or peripapillary hemorrhages (Fig.  12.5). OCT showed a stable RNFL on the right with slight interval increase on the left (Fig. 12.6a) and interval thinning of the GCL bilaterally (Fig.  12.6b). Orbital MRI showed enhancement of the optic chiasm (right>left, Fig. 12.7). Spine MRI was normal. Given the diagnosis of seropositive NMO with recurrent optic neuritis, she received 5 days of IVMP followed by Intravenous Immunoglobulin (IVIg) therapy. She was then placed on Mycophenolate acetate (CellceptⓇ) and monthly IVIg, which was tapered down and discontinued within 6 months. For her final outcome, visual acuity was 20/50 right eye and 20/800 left eye with bilateral central scotomas.

Fig. 12.5  Optic nerve head photographs on follow-up showing diffuse pallor on the right (shown on the left) and temporal pallor on the left (shown on the right).

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M. A. El-Dairi and K. Sleiman

a

b

Fig. 12.6  OCT at the time of recurrence. (a) Stable RNFL on the right eye (shown on the left) with slight interval increase of the RNFL on the left eye (shown on the right). (b) There has been interval thinning of the GCL in both eyes. OD: right eye; OS: left eye.

Structurally, there was bilateral advanced optic nerve head pallor and severe thinning of the RNFL and GCL.  She remains recurrence-free 7 years out with stable visual function and structure with good compliance with immunosuppression and follow-up.

Novel Insights The first FDA-approved targeted medication for AQP4-IgG seropositive NMOSD was eculizumab in 2019, which binds and activates complement component 5 (C5 protein), and

has shown promising results in a Phase 3 trial. Inebilizumab, an anti-CD19 antibody, was approved by FDA (06/2020) for NMOSD after having been tested in a phase 2/3 trial that was halted early due to conclusive demonstration of efficacy. Satralizumab, an anti-IL-6 antibody, was approved by FDA (08/2020) after having shown a clear reduction in ARR for NMOSD patients, and a more pronounced effect for AQP4-­IgG seropositive patients, in two phase 3 trials. An older IL-6 receptor antibody, tocilizumab, showed promising results in reducing the ARR in a phase 2 trial [9]. However, despite the fact that many of these medications have yet been compared to traditional immunosuppression

12  Optic Neuritis Associated with Neuromyelitis Optica: A Teenager with Painful Blurred Vision

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Fig. 12.7  Orbital MRI (axial and coronal cuts through the chiasm) showing enhancement of the proximal right optic nerve and optic chiasm (right>left).

in head-to-head comparison studies, their mechanism of action and preliminary data are promising to be effective with less side effects.

Clinical Pearls

• NMOSD can be a devastating disease that is important to recognize and treat early to prevent significant visual and systemic disabilities. Serology carries a high diagnostic accuracy. • Current treatment recommendations are with intravenous methylprednisolone, and/or immunoglobulins or plasmapheresis in the acute phase. The current recommended long-term treatment is with long-term immunosuppression to prevent relapses and further disability. • Misdiagnosis of NMOSD or mistreatment with immune modulators commonly used in multiple sclerosis can result in increased relapses and should be avoided.

References 1. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85:177–89.

2. Pineles SL, Repka MX, Writing Committee for the Pediatric Eye Disease Investigator G.  Assessment of pediatric optic neuritis visual acuity outcomes at 6 months. JAMA Ophthalmol. 2020;138:1253–61. 3. Paolilo RB, Hacohen Y, Yazbeck E, et al. Treatment and outcome of aquaporin-4 antibody-positive NMOSD: a multinational pediatric study. Neurol Neuroimmunol Neuroinflamm. 2020;7:e837. 4. Nakamura M, Nakazawa T, Doi H, et al. Early high-dose intravenous methylprednisolone is effective in preserving retinal nerve fiber layer thickness in patients with neuromyelitis optica. Graefes Arch Clin Exp Ophthalmol. 2010;248:1777–85. 5. Morrow SA, Fraser JA, Day C, et al. Effect of treating acute optic neuritis with bioequivalent oral vs intravenous corticosteroids: a randomized clinical trial. JAMA Neurol. 2018;75:690–6. 6. Gospe SM 3rd, Chen JJ, Bhatti MT.  Neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein associated disorder-­optic neuritis: a comprehensive review of diagnosis and treatment. Eye. 2021;35:753–68. 7. Collongues N, Marignier R, Zephir H, et  al. Long-term followup of neuromyelitis optica with a pediatric onset. Neurology. ­ 2010;75:1084–8. 8. Traub J, Hausser-Kinzel S, Weber MS. Differential effects of MS therapeutics on B cells-implications for their use and failure in AQP4-positive NMOSD patients. Int J Mol Sci. 2020;21:5021. 9. Zhang C, Zhang M, Qiu W, et al. Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial. Lancet Neurol. 2020;19:391–401.

Neuroretinitis: A Teenager with Painless Vision Loss

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Nina Boal and Crandall E. Peeler

Case Presentation A 15-year-old boy with a past medical history of asthma presented with 3 days of painless vision loss in his left eye. He reported a mild headache for the past week. He denied any preceding ocular injury, illness, infectious exposure, or recent travel. He was born in El Salvador and moved to the United States at the age of 10. He lived at home with his parents and several cats. On examination, the visual acuity was 20/15 right eye and 20/80 left eye. His pupils were equal, round, and reactive with a left relative afferent pupillary defect. Intraocular pres-

sures were normal. Extraocular movements were full. Color perception by Ishihara color plates was full in the right eye, and impaired in the left eye as he could only identify 4 of 11 plates. The anterior segment examination was normal in both eyes. The funduscopic examination was normal right eye but revealed significant optic disc swelling with exudates, chorioretinal folds, and macular striae left eye (Fig.  13.1). Humphrey visual field testing was full right eye and demonstrated cecocentral and inferior defects left eye (Fig. 13.2). The exam was consistent with a subacute, unilateral optic neuropathy with optic disc swelling in the left eye and further workup was pursued.

Fig. 13.1  Fundus photos at presentation. In the right eye (shown on the left), the optic nerve is normal. In the left eye (shown on the right), the optic nerve is swollen with exudates, chorioretinal folds, and macular striae.

N. Boal · C. E. Peeler (*) Department of Ophthalmology, Boston Medical Center, Boston, MA, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_13

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Fig. 13.2 Humphrey automated perimetry. The visual field is normal in the right eye and there are ceco central and inferior defects in the left eye. OD: right eye; OS: left eye.

MD: -11.76

MD: -2.48

OS

OD

Differential Diagnosis

• Infectious or inflammatory optic neuropathies (e.g., Bartonella, Lyme, syphilis, tuberculosis, toxoplasmosis, sarcoidosis) • A demyelinating process (e.g., typical optic neuritis, neuromyelitis optica, myelin oligodendrocyte glycoprotein-associated optic neuritis) • A compressive or infiltrative optic neuropathy (e.g., optic nerve glioma, lymphoma, leukemia)

Diagnostic Workup The diagnostic workup included magnetic resonance imaging (MRI) of the brain and orbits with contrast that demonstrated focal enhancement at the left optic nerve head but was otherwise normal (Fig. 13.3). A chest X-ray was normal. Bloodwork demonstrated a positive Bartonella henselae IgG titer (1:512), but a negative IgM titer.  A complete blood count and angiotensin-converting enzyme level were both normal and syphilis, Lyme, toxoplasma, and quantiferon gold testing were all negative. At a follow-up visit four days later, visual acuity in the left eye had declined to finger counting at 2 feet. A repeat dilated fundus examination revealed a new macular star left eye (Fig. 13.4). Optical coherence tomography (OCT) of the left macula demonstrated vitritis, subretinal fluid, and numerous hyperreflective exudates in the outer plexiform layer (Fig. 13.5).

Fig. 13.3 Axial, T1-weighted postcontrast MRI showing focal enhancement of the optic nerve head on the left (red circle).

The diagnostic bloodwork and appearance of a macular star established a final diagnosis of Bartonella-associated neuroretinitis. In consultation with the pediatric infectious disease service, the patient was started on doxycycline 100 mg PO BID and rifampin 300 mg PO BID.

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Final Diagnosis Neuroretinitis from Bartonella henselae

Clinical Discussion Important Aspects of the Diagnosis

Fig. 13.4  Left eye fundus appearance 4 days after initial presentation, showing interval development of a macular star.

Neuroretinitis is defined by inflammatory optic disc swelling and exudation that tracks into the macula and often forms a star-shaped pattern of hard exudate around the fovea 1–2 weeks after symptom onset. At presentation, many patients have disc edema with clear subretinal fluid prior to the formation of a macular star that occurs days to weeks later. The etiology may be infectious or idiopathic. Typical infectious etiologies include Bartonella henselae, syphilis, Lyme, or toxoplasmosis, and, if these entities are identified on laboratory testing, treatment may be directed at these

Fig. 13.5  Macular optical coherence tomography of the left eye showing vitritis, subretinal fluid, and hyperreflective exudates in the outer plexiform layer.

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Fig. 13.6  Macular optical coherence tomography of the left eye at final follow-up examination, showing resolution of vitritis, subretinal fluid, and resolution of hyperreflective exudates in the outer plexiform layer.

underlying causes [1]. Patients with neuroretinitis are not at risk for multiple sclerosis. In patients with multiple sclerosis, the autoimmune attack against myelin located behind the globe does not result in enough extracellular leakage to generate a macular star. It is essential to rule out noninflammatory causes of optic disc edema and a macular star exudate such as malignant hypertension, severe papilledema, and rarely anterior ischemic optic neuropathy. Although these entities can appear similar to neuroretinitis on clinical examination, they will not occur with systemic or ocular signs of inflammation such as fever or vitreous cells. As these entities are noninflammatory, they are not classified as neuroretinitis.

Treatment and Prognosis The natural history of Bartonella neuroretinitis is not well defined in the literature and is based on several case series with relatively few subjects, typically combining data for patients who received antibiotic treatment with those who were observed [2]. The largest series of patients (62 eyes from 53 patients) reported excellent visual outcomes at final follow-up, with 68% of patients achieving vision of 20/40 or better. In this retrospective study, there was no association between visual outcome and treatment with systemic antibiotics or steroids [3]. In our case, the positive Bartonella titer and fundus appearance, despite the initial absence of a macular star, were consistent with infectious neuroretinitis. We initially opted to observe the patient without treatment, but when he returned with profound vision loss four days later, we decided to treat with systemic doxycycline and rifampin for

a 5-week course. Nine months after his initial presentation, visual acuity in his left eye returned to 20/20 with full color perception. Dilated funduscopic exam at the final follow-up visit demonstrated subtle pallor of the left optic disc with resolution of the macular star and some mild, residual pigment mottling of the macula. OCT of the left eye showed resolution of the vitritis, subretinal fluid, and exudates (Fig. 13.6). Despite a lack of evidence that treatment with systemic antibiotics improves visual outcomes, some authors suggest that antibiotics may shorten the disease course and should be considered in patients with profound vision loss, those with prominent systemic symptoms, and in immunocompromised individuals [4]. Given the limited data available, physicians must balance the potential benefits of treating against the risk of adverse side effects. Future, prospective studies could more carefully compare visual outcomes in patients treated with antibiotics versus observation and could also explore the role of systemic corticosteroids in hastening visual recovery.

Novel Insights Whether or not the affected cat should be treated with antibiotics is rarely discussed and is controversial [5, 6]. A significant number of cats harbor this infection asymptomatically and the pet owner may be scratched attempting to treat the cat. Recurrent episodes of Bartonella neuroretinitis in the affected patient and consecutive involvement of multiple family members is rare. However, some veterinarians recommend treating the cat with antibiotics. Ticks may be a vector of transmission, and it is reasonable to have the cat evaluated for the detection and treatment of ticks.

13  Neuroretinitis: A Teenager with Painless Vision Loss

Clinical Pearls

• Neuroretinitis is characterized by painless loss of vision, optic disc swelling, and delayed appearance of macular exudates in a star-like pattern around the fovea. • Neuroretinitis may be caused by a wide variety of inflammatory processes that may be idiopathic, or infectious, with Bartonella henselae being the most common. However, patients with neuroretinitis are not at risk for multiple sclerosis. • Treatment of Bartonella-associated neuroretinitis is controversial as it is unknown if the ultimate visual outcome depends on antibiotics or corticosteroid therapy or if treatment hastens recovery. Treatment of an affected cat with antibiotics remains controversial although it is reasonable to have the cat evaluated for the detection and treatment of ticks.

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References 1. Guauri RR, Lee AG, Purvin V. Optic disk edema with a macular star. Surv Ophthalmol. 1998;43:270–4. 2. Bhatti MT, Lee MS. Should patients with bartonella neuroretinitis receive treatment? J Neuroophthalmol. 2014;34:412–6. 3. Chi SL, Stinnet S, Eggenberger E, Foroozan R, Golnik K, Lee MS, Bhatti MT.  Clinical characteristics in 53 patients with cat scratch optic neuropathy. Ophthalmology. 2012;119:183–7. 4. Reed JB, Scales DK, Wong MT, Latuada CP, Dolan MJ, Schwab IR.  Bartonella henselae neuroretinitis in cat scratch disease. Diagnosis, management, and sequelae. Ophthalmology. 2000;107:871–6. 5. Fraser CL, Sanchez S, Newman NJ, et  al. Cat scratch disease. Ophthalmology. 2012;119:1502–3. 6. Smolar ALO, Breitschwerdt EB, Phillips PH, Newman NJ, Biousse V. Cat scratch disease; What to do with the cat? Am J Ophthalmol Case Rep. 2022;28:101702.

Part III Tumors Involving the Optic Nerve

Optic Nerve Glioma in Neurofibromatosis Type I: A Girl with an Enlarging Optic Nerve

14

Robert A. Avery

Case Presentation A 3-year-old girl with neurofibromatosis type 1 (NF1) had accelerated growth concerning for precocious puberty. Therefore, magnetic resonance imaging (MRI) of the brain

was obtained and showed enlargement and contrast enhancement of her right optic nerve (Fig. 14.1). The left optic nerve, optic chiasm, and optic tracts were normal in size without enhancement. She offered no visual or systemic complaints. Her parents did not have visual concerns and denied witness-

Fig. 14.1  T1-weighted axial MRI of the brain and orbits with gadolinium shows enlargement and enhancement of the right optic nerve (solid arrow) and a normal chiasm (dashed arrow).

R. A. Avery (*) Division of Ophthalmology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA Departments of Ophthalmology and Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_14

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ing strabismus or nystagmus. She was referred for neuro-­ ophthalmologic evaluation. Her ophthalmologic examination was notable for a visual acuity of 20/40  in each eye using LEA figures. She was unable to cooperate with color vision testing. Her visual fields to confrontation were full. She could not cooperate with formal perimetry. Pupil examination showed brisk reaction to light without a relative afferent pupillary. Ocular motility was full and alignment was orthophoric. A dilated fundus examination demonstrated healthy appearing optic nerves. Cycloplegic refraction was +0.25 diopters in each eye.

Differential Diagnosis

• • • •

Infiltrative optic neuropathy Optic nerve glioma Optic neuritis Optic nerve sheath meningioma

Diagnostic Workup In children with NF1, enlargement of any of the structures comprising the anterior visual pathway (i.e., optic nerve, chiasm, or tract) with or without contrast enhancement is consistent with an optic pathway glioma (OPG). Although optic nerve sheath meningiomas can occur in tumor predisposition syndromes, enlargement of the optic nerve itself without any other surrounding enhancement of the optic nerve sheath makes this unlikely. While NF1 confirms a higher risk for

myelodysplastic cancers, infiltration usually occurs throughout the orbit and is visualized on MRI.  Our patient’s MRI shows no enhancement of the optic nerve sheath or orbital infiltration. Her normal visual acuity for age and absence of a relative afferent pupillary defect is not consistent with a diagnosis of optic neuritis. After the initial examination and MRI, no further diagnostic testing is warranted given the pathognomonic appearance of an OPG on MRI.  Standard of care would require close observation with repeated comprehensive ophthalmologic examinations and MRI. However, in this patient’s case, she left the country and returned 2 years later. Now as a 5 years old, she was having headaches, so her pediatrician ordered a repeat brain MRI that demonstrated further enlargement and contrast enhancement of her right optic nerve OPG that has now extended into her optic chiasm (Fig. 14.2). She continued to offer no visual or systemic complaints. Her parents did not have visual concerns and denied witnessing strabismus or nystagmus. Her ophthalmologic examination was notable for a visual acuity of 20/25 in each eye tested with HOTV optotypes. She identified 8/8 color plates testing each eye. Her visual fields to confrontation and kinetic perimetry were full. Pupil ­examination showed brisk reaction to light without a relative afferent pupillary defect. Ocular motility was full, and alignment was orthophoric. Dilated fundus examination demonstrated healthy appearing optic nerves. Cycloplegic refraction was +0.25 diopters in each eye. She underwent optical coherence tomography, which confirmed a normal circumpapillary retinal nerve fiber thickness in each eye.

Fig. 14.2  Axial MRI of the brain and orbits with gadolinium shows further enlargement (dashed arrow) and contrast enhancement of her right optic nerve that has now extended into her optic chiasm (solid arrow).

14  Optic Nerve Glioma in Neurofibromatosis Type I: A Girl with an Enlarging Optic Nerve

Final Diagnosis Progressive optic pathway glioma in the setting of NF1

Clinical Discussion Treatment and Prognosis OPGs occur in approximately 15–20% of all children with NF1. Treatment is considered for children that have a decline in visual function. Fortunately, less than 50% of children with NF1-OPGs will experience vision loss and require treatment [1]. Most children require treatment for their OPG when they are younger than 3 years old, although a second peak for initial therapy occurs around 5–6 years of age [2]. It is uncommon for children to require treatment for the first time after age 8 years, but this has been reported in some teenagers. Visual outcomes for those initiating treatment for the first time can vary, since most studies are retrospective and infrequently used standardized visual outcome measures. In general, treatment stabilizes or improves visual acuity in roughly two-thirds of these children, while the other one-third experience continued visual decline [2]. OPGs occurring purely in the optic nerve, or optic nerve and chiasm, tend to have more favorable visual outcomes after treatment compared to OPGs that involve the optic tract. Despite the progression of our patient’s optic nerve tumor into her optic chiasm, her normal visual acuity, visual field, and absence of optic atrophy were reassuring and thus, she did not undergo treatment for her progressive OPG. She continues to be monitored with serial eye examinations to assess visual function.

Important Aspects of the Diagnosis When an OPG is discovered, children should undergo comprehensive ophthalmologic examinations every 3 months for the first year [3]. If the examination does not suggest progressive visual acuity or visual field loss and the MRI features are stable, the frequency of examinations can then decrease to every 6 months. The frequency of MRI surveillance mirrors that of the ophthalmologic exams. However, if the 3- and 6-month ophthalmologic examination and MRI after diagnosis are stable, some centers will decrease the frequency to every 6 months thereafter. Screening MRI for OPGs is not recommended in children with NF-1 and a normal comprehensive ophthalmologic examination that includes quantitative visual acuity testing and ageappropriate assessment of visual fields. In preverbal children, this mandates obtaining Teller visual acuity or some other quantitative method to measure visual acuity such as visual evoked potentials (VEP). Failure to obtain normal visual acuity

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(whether it is actually decreased or due to poor cooperation), abnormal ocular motility, a relative afferent pupillary defect, or an abnormal optic nerve appearance are indications for magnetic resonance imaging of the brain and orbits.

Novel Insights The decision to initiate treatment should always be made in collaboration with a neuro-oncologist experienced in caring for children with NF1-OPG. A decline in the best corrected visual acuity in one eye by 0.2 logMAR or more is considered significant enough to warrant chemotherapy in treatment naïve children. In children that have previously undergone treatment for their OPG and have existing vision loss or monocular status, the threshold for treatment may change and is nuanced. The review by de Blank et al. provides a comprehensive description for these complicated cases [4]. A decline in visual field function, preferably using quantitative methods, is another indication to treat [5]. No standards for what magnitude of visual field decline warrants treatment have been established, but are actively being studied. Indications for treatment that address the presence of a relative afferent pupillary defect, color vision loss, and optic disc pallor in addition to other afferent findings is beyond the scope of this case and is addressed in the review by de Blank [4].

Clinical Pearls

• Quantitative visual acuity testing and quantitative perimetry are helpful in monitoring stability or progression of NF1-OPGs. • Not all NF1 OPGs that demonstrate growth on MRI require treatment. • Formal perimetry can successfully be performed in young children.

References 1. Avery RA, Fisher MJ, Liu GT.  Optic pathway gliomas. J Neuroophthalmol. 2011;31:269–78. 2. Fisher MJ, Loguidice M, Gutmann DH, et al. Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis. Neuro-Oncology. 2012;14:790–7. 3. Listernick R, Ferner RE, Liu GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol. 2007;61:189–98. 4. de Blank PMK, Fisher MJ, Liu GT, et al. Optic pathway gliomas in neurofibromatosis type 1: an update: surveillance, treatment indications, and biomarkers of vision. J Neuroophthalmol. 2017;37(Suppl 1):S23–32. 5. Heidary G, Fisher MJ, Liu GT, et al. Visual field outcomes in children treated for neurofibromatosis type 1-associated optic pathway gliomas: a multicenter retrospective study. J AAPOS. 2020;24(6):349.

Optic Nerve Glioma (Sporadic): A Baby with Monocular Nystagmus

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Michael X. Repka

Case Presentation The parents of a 17-month-old girl reported that their daughter had developed shimmering horizontal movements of the left eye at about 9 months of age. Emergency pediatric evaluation suggested possible spasmus nutans. A head tilt developed one month later at 10 months of age. There was no head nodding. An ophthalmologic examination was requested. A neuro-ophthalmologic evaluation at 17 months of age showed a normal qualitative vision assessment in each eye with normal versions and no strabismus. She had periodic random appearing shimmering movements of the left eye. The pupils were equal, reactive, with no relative afferent pupillary defect. Visual fields were grossly full to toy movement. Moderate bilateral disc pallor was evident with direct ophthalmoscopy. Magnetic resonance imaging (MRI) of the brain demonstrated a chiasmal region solid mass (Fig. 15.1). There were no stigmata of neurofibromatosis type 1 (NF-1). Genetic testing revealed no mutations associated with NF-1. Three-month follow-up MRI and ophthalmologic examinations were scheduled. After 3 months, there was increased size of the mass on MRI with no change in qualitative visual acuity. A biopsy was performed that confirmed the diagnosis of a pilocytic astrocytoma, WHO grade I. A 15-month course of carboplatin with vincristine was initiated and completed. At 3 years of age, she had a visual acuity of 20/300 right eye and 20/250 left eye with bilateral optic disc pallor. MRI showed further increased size of the chiasmal lesion (Fig.  15.2). Optical coherence tomography (OCT) showed

Fig. 15.1  Coronal MRI of the brain at diagnosis at 17 months of age demonstrating a solid and cystic pilocytic astrocytoma centered in the chiasm.

M. X. Repka (*) Department of Ophthalmology, Johns Hopkins University School of Medicine, Wilmer Eye Institute, Baltimore, MD, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_15

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Differential Diagnosis

• Chiasmatic/hypothalamic low-grade glioma • Other suprasellar tumor (e.g., craniopharyngioma, germinoma, high-grade glioma, meningioma) • Inflammatory mass • Rathke’s cleft cyst • Suprasellar arachnoid cyst

Diagnostic Workup

Fig. 15.2  Coronal MRI of the brain at 3 years of age demonstrating solid and cystic pilocytic astrocytoma centered in the chiasm with increased size and enhancement.

In the setting of monocular nystagmus coupled with pallor of the optic nerves, a tumor of the anterior visual pathway was suspected. MRI of the brain was pursued to evaluate the visual pathways, which revealed the mass, and further evaluation was done to characterize the tumor. The biopsy was performed for tumor classification. An understanding of tumor biology informs prognosis and treatment options in the setting of tumor mutation directed therapy. Due to the association of low-grade glioma with NF-1, genetic evaluation was conducted. Given the proximity of the tumor to the pituitary and hypothalamus, endocrinology was pursued to treat any associated dysfunction.

Final Diagnosis Sporadic Pilocytic astrocytoma, WHO grade I

Clinical Discussion Important Aspects of the Diagnosis

Fig. 15.3  Coronal MRI of the brain at 8.5 years of age demonstrating that the tumor was stable with less enhancement over time.

mean retinal nerve fiber layer (RNFL) thicknesses of 72 μm right eye and 68 μm left eye. She was enrolled in a trial of dabrafenib (BRAF kinase inhibitor). After 20 weeks of treatment, the tumor decreased in size. One year of treatment was completed without adverse events. She was followed with stable examinations and stable appearance on MRI (Fig. 15.3).

At initial diagnosis, there was qualitative evidence of impaired vision based on the presence of abnormal eye movements. The most important question at that time was whether this mass was growing and thus causing additional vision loss. While tumor growth and vision loss may occur together, it is more common that tumor growth and change in enhancement are not associated with progressive vision loss. If the optic pathway tumor is stable in size, no treatment may be indicated. If there is evidence of increasing size on serial MRIs, the question is whether surgery should be performed for biopsy, genetic analysis, and debulking. For chiasmatic hypothalamic tumors with progressive enlargement, a biopsy is often obtained as well as debulking of the tumor to remove any extrinsic pressure on the remaining retinal ganglion axons. Complete resection of an optic pathway tumor is impossible without substantial damage to visual and hypothalamic functions. When there

15  Optic Nerve Glioma (Sporadic): A Baby with Monocular Nystagmus

is enlargement of the optic nerves and chiasm, or enhancement of the optic tracts, biopsy is considered only when there is severe vision loss.

Treatment and Prognosis Following initial diagnosis, biopsy, or resection, the patient is followed for evidence of further tumor progression with neuroimaging and visual function assessment every three months. While many optic pathway gliomas will be stable, a proportion of children will have evidence of growth as in this case. Of note, some of these tumors have regressed without treatment [1]. If there is progression on imaging supported by a decline in visual function, chemotherapy is recommended as first-line therapy to delay or prevent the use of radiotherapy, which had often been prescribed in the past. The most commonly used first-line chemotherapy is a 15-month course of intravenous carboplatin with vincristine [2]. A 5-year event-free survival of 39% has been shown, worse with younger age and larger tumors [3]. More recently, a combination of thioguanine, procarbazine, CCNU, and vincristine has been used with a 5-year event-free survival of 52%, but remains less popular due to the associated risks of second malignancy and infertility. At age 8.5 years, this child had a visual acuity of 20/250 right eye and 20/300 left eye. OCT showed a mean RNFL thickness of 60 microns right eye and 54 microns left eye. Precocious puberty developed. Functional vision persisted, but the child received vision support services in school.

Novel Insights An understanding of tumor genetics has impacted treatment options for optic pathway gliomas not associated with NF-1. While vincristine/carboplatin has been the mainstay of treatment, interest in targeted therapy of low-grade optic pathway gliomas is growing. Many low-grade gliomas not associated with NF-1 have been found to have activation of the mitogen-­

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activated protein kinase (MAPK) pathways due to either fusion in BRAF or mutation in the BRAFV600E gene. MAPK activation may also occur without a BRAF alteration. BRAF fusion abnormalities are found in the majority of pilocytic astrocytomas [4]. Dabrafenib and selumetinib are oral drugs designed to inhibit the MAPK pathway, thus slowing or halting tumor growth. These agents reduce the size of low-grade gliomas with BRAF alterations [5]. Selumetinib is being compared with carboplatin/vincristine for children without BRAFV600E mutation in an ongoing clinical trial as first-line therapy.

Clinical Pearls

• Frequent serial vision examinations with quantitative optotype visual acuity testing when possible are needed. • Not all of these tumors progress, a few even regress, although predictive factors are not yet established. • Visual acuity changes do not always correlate with growth or change in enhancement on neuroimaging.

References 1. Parsa CF, Hoyt CS, Lesser RL, et  al. Spontaneous regression of optic gliomas: thirteen cases documented by serial neuroimaging. Arch Ophthalmol. 2001;119:516–29. 2. Packer RJ, Ater J, Allen J, et al. Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg. 1997;86:747–54. 3. Ater JL, Zhou T, Holmes E, et al. Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30:2641–7. 4. Bornhorst M, Frappaz D, Packer RJ. Pilocytic astrocytomas. Handb Clin Neurol. 2016;134:329–44. 5. Fangusaro JR, Onar-Thomas A, Young-Poussaint T, et al. A phase II prospective study of selumetinib in children with recurrent or refractory low-grade glioma (LGG): a pediatric brain tumor consortium (PBTC) study. J Clin Oncol. 2017;35:10504.

Optic Nerve Sheath Meningioma in the Setting of Neurofibromatosis Type II: A Boy with Painless Proptosis

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Michael D. Richards

Case Presentation A 13-year-old boy of Afghani descent presented to his primary care physician with a 1-year history of painless proptosis of the left eye (Fig. 16.1). He was visually asymptomatic and otherwise healthy. His parents were consanguineous, and the family history was negative for any childhood or ophthalmologic diseases. Initial investigations, including thyroid function tests and an ultrasound of the neck, were normal. Subsequent magnetic resonance imaging (MRI) of the brain and orbits with contrast demonstrated a large (30  mm  ×  19  mm) enhancing mass encasing the left optic nerve without intracranial extension (Fig. 16.2), and normal intracranial contents. The patient was referred urgently to the pediatric ophthalmology clinic for further evaluation of the orbital mass. On examination, the visual acuity was 20/30 in each eye. The pupils were equal and reactive to light, and there was no relative afferent pupillary defect. Color vision was normal. There was 8  mm of relative proptosis of the left eye. The ocular motility examination showed full ductions of the right eye and mildly limited adduction, abduction, and supraduction of the left eye. The anterior segment examination was normal. Dilated examination revealed an ill-defined, translucent retinal lesion nasal to the right optic disc, and a prominent epiretinal membrane (ERM) in the left macula (Fig. 16.3a, b). There were no breaks in the retinal periphery. The optic discs appeared healthy. Findings from a full neurological examination were unremarkable. Visual fields by Goldmann kinetic perimetry were full. Optical coherence tomography (OCT) of the right fundus demonstrated the intraretinal nature of the ill-defined lesion nasal to the disc, and revealed a similar second lesion in the macula that was not seen on initial exam; these findings were M. D. Richards (*) Department of Ophthalmology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada e-mail: [email protected]

Fig. 16.1  Proptosis of the left eye.

Fig. 16.2  Axial T1-weighted MRI brain and orbits with contrast showing an enhancing, intraconal lesion surrounding the left optic nerve, consistent with an optic nerve sheath meningioma.

consistent with an astrocytic hamartoma (Fig.  16.4). OCT imaging of the left ERM showed peculiar undulations and disorganization of the lamellar architecture, and a tuft extending into the vitreous (Fig. 16.5).

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_16

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Fig. 16.3  Fundus photographs of each eye. (a) The right fundus shows an ill-defined translucent retinal lesion nasal to the optic disc, indicated by a white arrow. (b) The left fundus shows a prominent epiretinal membrane, indicated by a white arrow.

Fig. 16.4  OCT imaging from the right fundus showing solid intraretinal mass lesions consistent with retinal astrocytic hamartomas. The blue line on the left-hand fundus image shows the location of the OCT scan shown to the right.

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Fig. 16.5  OCT imaging from the left macula showing the epiretinal membrane with a flame-shaped extension into the vitreous and disorganization of the retinal lamellae. The blue line on the left-hand fundus image shows the location of the OCT scan shown to the right.

Differential Diagnosis

• Optic nerve sheath meningioma (+/−  neurofibromatosis type 2, NF-2) • Optic pathway glioma • Rhabdomyosarcoma • Metastatic tumor

Diagnostic Workup In the context of the above findings, a request was made for the original MRI to be re-evaluated by a neuroradiologist. Bilateral vestibular and trigeminal schwannomas were iden-

tified. A clinical diagnosis for neurofibromatosis type 2 (NF2) was made by the Manchester criteria [1]. Subsequent investigations included an audiogram, an MRI of the spine, and genetic testing. The audiogram was normal. The MRI spine revealed a large paraspinal mass (70 × 65 × 87 mm) with intradural extension into the spinal canal (Fig. 16.6). Biopsy of the paraspinal lesion confirmed a WHO grade I schwannoma. Genetic testing identified a truncating mutation in exon 1 of the NF2 gene.

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Fig. 16.6  MRI imaging of the spine showing a large mass within the left pleural cavity with intradural extension into the spinal canal.

Final Diagnosis Optic nerve sheath meningioma associated with neurofibromatosis type 2

Clinical Discussion Treatment and Prognosis The natural history of NF2 involves tumor-related progression of sensorineural hearing loss, vestibular dysfunction, compressive spinal symptoms, cranial neuropathies, and visual loss from tumor-related optic atrophy, cataract, or retinal hamartomas. In addition to this progressive morbidity, NF2 is associated with early mortality. Symptoms typically begin in the late second to third decade, but onset varies widely from early childhood to mid-adulthood, and diagnosis is usually delayed by several years [1]. Early age of symptom onset, and to a lesser extent intracranial meningiomas, is associated with greater NF2 disease severity and increased risk of disability and early mortality. NF2 is a multiple neoplasia disorder caused by a mutation in the NF2 gene on chromosome 22. This gene encodes a tumor suppressor protein known as merlin or schwannomin. Its inheritance is autosomal dominant, but about 50% of patients are sporadically affected, meaning that half do not have a positive family history of NF2 [2]. Study of genotype-­ phenotype correlations has shown that the type of mutation has a significant bearing on the age of symptom onset and severity of disease. Patients with truncating mutations that shorten the protein product are significantly more likely to have symptom onset before the age of 20  years, and to develop at least two symptomatic CNS tumors before the age of 30 years [2].

In this case, the patient was shown to have a truncating mutation in exon 1 of the NF2 gene, helping to explain his early age of symptom onset, and prognosticating a more severe clinical course. A follow-up MRI of the brain and orbits showed no change in the tumors identified on the initial MRI. Since this patient was visually and neurologically asymptomatic, no active treatment was immediately undertaken. He was enrolled in a multidisciplinary disease surveillance program with a specialized neuro-oncology service.

Important Aspects of the Diagnosis In this case, the original MRI report was misleading as it identified only the optic nerve sheath meningioma and missed multiple intracranial tumors pathognomonic for NF2. Aspects that further obscured the correct diagnosis were that this child lacked the most common ophthalmologic association of NF2 (presenile posterior subcapsular cataract), exhibited findings that were either nonspecific (epiretinal membrane) or very subtle (retinal astrocytic hamartomas), and that he was otherwise neurologically intact despite having a large paraspinal tumor and bilateral vestibular and trigeminal schwannomas. While optic nerve glioma, rhabdomyosarcoma, and metastasis must be considered in the differential diagnosis for a childhood orbital tumor, the MRI findings of a homogeneously enhancing intraconal lesion surrounding the optic nerve and the history of slow growth suggested optic nerve sheath meningioma in this case. The main differential was therefore between an optic nerve sheath meningioma as an isolated occurrence, or as part of a multiple neoplasia syndrome. Indeed, among children diagnosed with primary optic nerve sheath meningioma, approximately one-third are eventually found to have NF2 [3, 4]. This pivotal observa-

16  Optic Nerve Sheath Meningioma in the Setting of Neurofibromatosis Type II: A Boy with Painless Proptosis

tion, first noted by Canadian-born neuro-ophthalmologist Frank B.  Walsh, necessitates a high index of suspicion for NF2  in children with optic nerve sheath meningioma. Therefore, careful evaluation for associated findings of NF2 including cranial nerve schwannomas, spinal tumors, cataracts, epiretinal membranes, retinal hamartomas, and cutaneous lesions is required.

Novel Insights Advances in OCT imaging provide new possibilities for the early detection and characterization of retinal associations of NF2 in suspected cases. As demonstrated in this case, subclinical retinal astrocytic hamartomas that may evade detection on fundoscopy can be easily identified by OCT.  This imaging modality is perhaps even more useful in differentiating idiopathic or isolated epiretinal membranes from those characteristic of NF2. Idiopathic epiretinal membranes ­typically appear as a thin hyperreflective layer at the level of the internal limiting membrane with distortion of the retinal contour but with preservation of normal retinal lamination, whereas NF2-associated epiretinal membranes commonly have a flame-shaped extension into the vitreous with underlying retinal undulation and disorganization of the retinal lamellae [5]. The OCT images obtained in this case demonstrated an epiretinal membrane with these peculiar features typical of NF2. Although retinal hamartomas and atypical epiretinal membranes are not included in the classic diagnostic criteria for NF2, their early detection by OCT imaging may help to minimize the delay to diagnosis.

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Clinical Pearls

• Young patients diagnosed with primary optic nerve sheath meningioma have a high likelihood of comorbid NF2; knowledge of this association may minimize time to diagnosis. • Optical coherence tomography is a useful tool to detect subclinical retinal hamartomas and to characterize epiretinal membranes in children with suspected NF2. • Early age of symptom onset and truncating mutations in the NF2 gene prognosticate more severe disease.

References 1. Evans DG, Baser ME, O’Reilly B, Rowe J, Gleeson M, Saeed S, et al. Management of the patient and family with neurofibromatosis 2: a consensus conference statement. Br J Neurosurg. 2005;19:5–12. 2. Evans DG, Trueman L, Wallace A, Collins S, Strachan T. Genotype/ phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations. J Med Genet. 1998;35:450–5. 3. Lee HBH, Garrity JA, Cameron JD, Strianese D, Bonavolontà G, Patrinely JR. Primary optic nerve sheath meningioma in children. Surv Ophthalmol. 2008;53:543–58. 4. Walsh FB, Glaser JS, Smith JL.  Meningiomas, primary within the orbit and optic canal. Neuro ophthalmology symposium of the University of Miami and the Bascom Palmer Eye Institute. St. Louis; 1970. 5. Waisberg V, Rodrigues LOC, Nehemy MB, Frasson M, de Miranda DM. Spectral-domain optical coherence tomography findings in neurofibromatosis type 2. Invest Ophthalmol Vis Sci. 2016;57:262–7.

Optic Nerve Infiltration in the Setting of a Brain Tumor: A Teenager with a Brain Tumor and Newly Decreased Vision

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Alon Zahavi, Helen Toledano, and Nitza Goldenberg-Cohen

Case Presentation

with a right relative afferent pupillary defect. Humphrey visual field testing continued to show a nasal step left eye A 14.5-year-old boy presented with poor vision in the right and visual field constriction right eye, and the visual field eye. His past medical history was notable for a temporo-­ findings were interpreted to be stable (Fig.  17.1c, d). The occipital primitive neuroectodermal tumor (PNET) with spi- funduscopic examination showed a pale optic disc right eye nal metastases that had been diagnosed 2 years previously. and a pink, flat optic disc left eye (Fig.  17.2a, b). Optical The tumor was treated with surgical resection, chemother- coherence tomography (OCT) showed marked thinning of apy, craniospinal irradiation, and autologous bone marrow the retinal nerve fiber layer in the right eye (Fig. 17.3a). The transplantation. Neuroimaging showed evidence of complete vision continued to deteriorate over the next 3 months with a remission. The patient received maintenance therapy with visual acuity of 1/18 right eye and a visual acuity of 20/30 retinoic acid on an experimental protocol following high-­ left eye. An active, progressive optic neuropathy in the right dose chemotherapy. One year prior to the current presenta- eye was suspected, and further workup was recommended. tion, his visual examination showed visual acuity of 20/30 right eye and 20/20 left eye with evidence of right optic neuropathy on visual field examination. At that time, Humphrey Differential Diagnosis visual field testing showed a nasal step in the left eye and • Metastatic tumor with infiltration of the optic nerve constriction of the visual field in the right eye (Fig. 17.1a, b). • Optic neuritis This optic neuropathy was interpreted to be secondary to • Neuromyelitis optica spectrum disorder (NMOSD) prior optic nerve edema secondary to tumor associated • Infection (including herpetic, HIV, and Toxoplashydrocephalus. mosis) At presentation, the ophthalmologic examination revealed • Autoimmune response a visual acuity of 20/250 right eye and 20/20 left eye. On • Radiation retinopathy Ishihara color vision testing, he identified 5/10 color plates right eye and 10/10 left eye. Pupils were equal and reactive

A. Zahavi Ophthalmology Department and Laboratory of Eye Research Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva, Israel

N. Goldenberg-Cohen (*) Department of Ophthalmology, Bnai Zion Medical Center, The Krieger Eye Research Laboratory, Faculty of Medicine, Technion, Haifa, Israel

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel H. Toledano Department of Pediatric Oncology, Schneider Children’s Medical Center of Israel, Petah Tiqwa, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_17

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Fig. 17.1  Humphrey Automated Perimetry. Baseline visual fields, which showed a nasal step left eye (a) and constricted visual field right eye (b). At presentation, the visual field in the left eye (c) and right eye (d) was interpreted as being unchanged from previous.

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Fig. 17.2  Color fundus photographs. At presentation, the right optic nerve appeared pale (a) and the left optic nerve appeared normal (b). On follow-up, the right optic nerve showed pallor (c) and optic nerve edema was noted of the left optic nerve (d).

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Fig. 17.3  Optical coherence tomography retinal nerve fiber layer thickness measurements. (a) At presentation, there was peripapillary RNFL thinning in the right eye, and a normal thickness on the left eye, averaging 49.65 μm and 66.18 μm, respectively. (b) A follow-up scan almost a year later shows a stable, thin peripapillary RNFL in the right

eye and thickening of the RNFL on the left eye, averaging 55.78 μm and 176.99  μm, respectively, compatible with optic nerve infiltration as detected on MRI and clinical optic disc edema left eye. OD: right eye; OS: left eye.

Diagnostic Workup

the brain with contrast showed thinning of the right optic nerve and thickening of the left optic nerve (Fig. 17.4a, b). Fluorescein angiography showed leakage of the left optic disc (Fig.  17.5a–f). Repeat lumbar puncture with CSF ­analysis was unremarkable (no cells, normal glucose and protein, no malignant cells on cytology). One month later, the patient complained of complete visual loss in the left eye. Fundus examination of the left eye showed a severe swollen optic disc and a central retinal artery occlusion (CRAO). The optic neuropathy in the right eye remained stable. MRI at this time showed an enhancing lesion in the left optic nerve. A biopsy was performed of the left optic nerve, which revealed a diagnosis of PNET infiltration of the optic nerve.

Magnetic resonance imaging (MRI) of the brain and orbits with contrast showed no sign of tumor recurrence. Electroretinography (ERG) of each eye was within normal limits. Lumbar puncture with cerebrospinal fluid (CSF) analysis showed normal serology with no malignancy on cytologic evaluation. Repeat evaluation 6 months after the initial presentation revealed an acute, severe, progressive decrease in vision in the left eye. The visual acuity was now 1/18 in each eye. The right optic disc showed diffuse atrophy, and the left optic disc was swollen (Fig. 17.2c, d). OCT showed a stable thin retinal nerve fiber layer right eye, and new thickening of the retinal nerve fiber layer left eye (Fig. 17.3b). Repeat MRI of

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Fig. 17.4  Magnetic resonance imaging. (a) Coronal and (b) axial images showing thinning of the para chiasmatic right optic nerve and thickening of the left optic nerve.

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Fig. 17.5  Fluorescein angiography. (a) Optic disc edema left eye and leakage of the optic disc left eye (b–f) on fluorescein angiography were demonstrated, a month prior to the left central retinal artery occlusion.

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Final Diagnosis PNET metastasis to the optic nerves with progressive optic neuropathy

Clinical Discussion Treatment and Prognosis Unfortunately, relapse of metastatic PNET is not uncommon, especially in patients who have metastasis at presentation, despite full craniospinal irradiation and chemotherapy including high-dose chemotherapy [1]. However, this case is unique in that the relapse presented clinically before it was detectable radiographically. Also, the fact that the recurrence was localized in the optic nerve has only been described twice in the literature on primitive neuroectodermal tumors/medulloblastoma [2]. Relapse in the visual tract was confirmed 8 months after initial presentation with visual deterioration, and over 3 years from the initial diagnosis. He was treated with stereotactic radiation therapy to the optic tract and chiasm combined with chemotherapy, but died 1 year later. The chances of survival after relapse when initial treatment included full-dose craniospinal irradiation are anecdotal [3].

Important Aspects of the Diagnosis Diagnosing malignant infiltration of the optic nerve poses a clinical challenge as malignancy to the optic tract may present with nonspecific symptoms of gradual vision loss. This is particularly true in cases where the patient has progressive visual loss, no additional systemic signs, and lacks findings on repeated MRI.  In these cases, other diagnoses such as optic neuritis or radiation optic neuropathy are suspected. Even though uncommon, malignancy should be considered in the differential diagnosis in patients that present with gradual visual loss. Diffusion-weighted MRI based on the value of the apparent diffusion coefficient might be useful in these cases. MRI is considered the gold standard for optic tract visualization. On MRI, the findings of malignant infiltration of the optic nerve are often nonspecific including contrast enhancement of the optic nerve on T1-weighted imaging or enlargement of the optic canal. It should be noted that enhancement or enlargement of the optic nerve and tract is also present in patients with optic neuritis, lymphoma, and leukemia [4]. Clinicians are reluctant to biopsy the optic nerve when visual recovery is still a viable option. However, since malig-

A. Zahavi et al.

nancy can be life threatening, a biopsy of infiltrated optic nerve may be necessary for accurate diagnosis and establishing a treatment protocol, particularly in patients that have severe or complete visual loss. Even after accurate diagnosis, these patients have a poor prognosis. Optic nerve metastasis is extremely uncommon, particularly in children. Therefore, in the presented case, the pediatric oncologists were hesitant in considering the diagnosis and agreeing to biopsy the optic nerve without definitive radiographic evidence of relapse. This case highlights the possibility that disease recurrence may directly infiltrate the optic nerve and reduce vision even before other signs of relapse become evident on physical examination. We recommend that when patients present with gradual vision loss, repeated imaging should be performed to enable early detection and treatment of the underlying cause. If there are minor nonspecific findings such as enlargement or enhancement of the optic nerve, then further diagnostic studies should be undertaken to rule out an inflammatory process before proceeding to an open biopsy of the lesion. If diagnosis remains unknown, optic nerve biopsy should be considered if there is severe visual loss or no light perception vision.

Novel Insights Of note, 6  years after this patient’s death, the diagnostic WHO classification of “PNET” was changed. The ­embryonal tumors other than medulloblastoma have undergone substantial changes in their classification, with removal of the term primitive neuroectodermal tumor or PNET.  Much of the reclassification was initiated by the recognition that many of these rare tumors display amplification of the C19MC region on chromosome 19 (19q13.42) [5]. No data are available for this amplification in this child.

Clinical Pearls

• Malignant primitive embryonal tumors of childhood may infiltrate the optic nerves at relapse. • Optic nerve biopsy should be considered if visual loss is severe to accurately diagnose malignant infiltration if no other etiology accounts for the visual loss. • Infiltration to the optic pathway is rare, and differential diagnosis includes primary or secondary tumors as well as inflammatory or infectious etiologies.

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References 1. Pérez-Martínez A, et al. High-dose chemotherapy with autologous stem cell rescue for children with high risk and recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors. J Neuro-Oncol. 2005;71:33–8. 2. Garrity JA, Herman DC, Dinapoli RP, Waller RR, Campbell RJ.  Isolated metastasis to optic nerve from medulloblastoma. Ophthalmology. 1989;96:207–10.

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3. Pizer BL, et  al. Analysis of patients with supratentorial primitive neuro-ectodermal tumours entered into the SIOP/UKCCSG PNET 3 study. Eur J Cancer. 2006;42:1120–8. 4. Tumialán LM, et al. Optic nerve glioma and optic neuritis mimicking one another: case report. Neurosurgery. 2005;57:190. 5. Li M, et  al. Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors. Cancer Cell. 2009;16:533–46.

Part IV Optic Atrophy

Dominant Optic Atrophy: A Teenager with Progressive Painless Vision Loss

18

Eric D. Gaier

Case Presentation A 15-year-old Puerto Rican girl presented with a history of poor vision that could not be corrected with glasses. She was first evaluated by an eye doctor in Puerto Rico at the age of 7 who prescribed glasses with regular follow-up. Approximately 2 years prior to her presentation, the patient noticed a decline in vision in both eyes that has gradually worsened. She was evaluated by a comprehensive ophthalmologist, who was unable to correct her visual acuity with a manifest refraction and noted optic disc pallor on examination. She was otherwise healthy and a high school freshman. She did not smoke, drink alcohol, or use drugs. Her family history was remarkable for a maternal grandmother with a history of diabetes mellitus with retinopathy, but upon further questioning, there was some suspicion that the grandmother’s visual loss may have begun in early adulthood prior to the onset of diabetes. Her complete review of systems was negative, including hearing loss, pain/headache, galactorrhea, dysmenorrhea, gastrointestinal dysregulation, dietary restrictions, or toxic exposures. On examination, best-corrected visual acuities were 16/100 in each eye. Manifest refraction was −3.25 +1.25 ×180 each eye. Ishihara color plate testing revealed identification of 6/8 plates right eye and 6.5/8 plates left eye. Pupils were equal and showed symmetric responses to light with no relative afferent pupillary defect. External examination revealed no ptosis or proptosis. Ocular motility was full, and align-

ment was orthotropic. There was no nystagmus. Slit-lamp examination revealed normal anterior segments bilaterally, and intraocular pressures were 18  mmHg right eye and 19  mmHg left eye by Goldmann applanation. Automated (Humphrey) perimetry showed excessive fixation losses in each eye, diffuse loss of sensitivity, and dense cecocentral scotomas versus bitemporal superior quadrantinopias (Fig.  18.1). Dilated funduscopy revealed temporal excavation and pallor of the optic discs bilaterally (Fig. 18.2) with corresponding thinning of the retinal nerve fiber layer (Fig. 18.2a, c; yellow arrows). The maculae and peripheral retina were otherwise normal. The patient presented with chronic, bilateral, and painless optic atrophy of unclear onset and further workup was pursued.

Differential Diagnosis

• Inherited optic neuropathy –– Dominant optic atrophy –– Leber hereditary optic neuropathy –– Wolfram syndrome –– Other genetic syndromes • Compressive optic neuropathy • Toxic/nutritional optic neuropathy • Glaucoma (normal/low tension) • Retinal dystrophy

E. D. Gaier (*) Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_18

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Fig. 18.1  Automated (Humphrey, SITA-fast, 24-2) perimetric performance with excessive fixation losses left eye (a) and right eye (b). There is diffuse loss of sensitivity and dense cecocentral scotomas bilaterally versus bitemporal superior quadrantinopias.

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Fig. 18.2  Dilated fundus photographs (Topcon) of the right (a, c) and left (b, d) eyes depict bilateral temporal pallor and temporal sectoral thinning of the retinal nerve fiber layer (margins of the affected areas are demarcated by yellow arrows).

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Fig. 18.2 (continued)

Diagnostic Workup The patient presented with chronic, bilateral, and painless optic atrophy of unclear onset. The optic atrophy can be characterized as primary (lacking any evidence of overlying gliosis that may signify prior edema) and symmetric. Temporal pallor and excavation were prominent features of the optic disc appearance. Corresponding retinal nerve fiber layer thinning was apparent funduscopically. Of note, optical coherence tomography (OCT), though not performed in this case, is an important diagnostic tool with great sensitivity in detecting and quantifying optic atrophy. This pattern of retinal ganglion axonal loss often matches the dense cecocentral scotomas on perimetric testing. Chronic and dense cecocentral visual loss with temporal pallor and excavation of the optic disc in an otherwise healthy young patient is most consistent with an inherited optic neuropathy. Possibilities include dominant optic atrophy (DOA), Leber hereditary optic neuropathy (LHON), Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, deafness), and others [1]. The patient’s history of symptom onset does not definitively support the insidious progressive visual loss of DOA nor the acute-subacute and sequential loss associated with LHON. In this case, the family history is somewhat ambiguous and does not definitively support a familial disorder. However, variable expressivity, incomplete penetrance, and the possibility of de novo mutations may contribute to the lack of contributing family history in confirmed cases of inherited optic neuropathy [2]. Thus, family history can be helpful if clearly positive, but should not dissuade the clini-

cian if negative. The pattern of inheritance in this case is also ambiguous and could be consistent with DOA (autosomal dominant) and LHON (maternal/mitochondrial). Examination of family members accompanying the patient should always be performed at the time of examination or arranged on follow-up as part of the evaluation, since subclinical findings can be informative. Genetic testing should be pursued in cases of bilateral, primary optic atrophy with a high suspicion for a genetic/ inherited etiology once other obligatory conditions have been excluded (see below). Available methods for genetic testing have evolved considerably over the last decade. The current standard is to sequence panels of genes associated with a group of conditions (in this case, general eye disease, or optic neuropathy more specifically). Negative results can be carried forward to whole exome or genome sequencing, along with samples from family members to determine segregation with disease for uncovered, candidate variants. The technology and clinical standard for genetic testing is ever-­ changing, so patients who are tested by a method at one point in time may benefit from retesting using more updated or advanced methods at regular intervals (typically on the order of years). Optic disc pallor and excavation along with temporal perimetric defects should raise concern for a compressive etiology. Suprasellar tumors including those of the pituitary may present with bitemporal visual field defects. Compression of the posterior portion of the optic chiasm preferentially affects central retinal fibers and can mimic cecocentral-like defects. The patient denied headache or symptoms that might suggest an endocrinologic disturbance, but these features are

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only helpful if supportive. Any patient presenting with optic atrophy of unclear etiology must undergo neuroimaging (magnetic resonance imaging of the brain and orbit, without and with gadolinium) to evaluate for a compressive lesion. There are no historical data in this patient to support nutritional or toxic causes, but again, absence of these features does not exclude these possibilities. Nutritional deficiencies may initially present with sequelae such as visual loss. Potential mechanisms may include dietary restriction (intentional or unintentional) or malabsorption (e.g., Celiac disease, Crohn disease, post-bariatric surgery, short-gut syndrome). Markers for nutritional optic neuropathy include serum levels of vitamin A, thiamine (B1), riboflavin (B2), pyridoxine (B6), cobalamin (B12), folate, copper, homocysteine, and methylmalonic acid. Even if the suspicion for toxic or nutritional optic neuropathies is low, the clinician should exclude these as potentially contributing to the clinical picture, because visual loss will often progress if these entities are unrecognized. In addition, nutritional deficiencies and toxins carry implications for systemic disease, and may be reversible with treatment. Normal (or low) tension glaucoma is another consideration, but the perimetric pattern and clear predilection of this condition for the temporal retinal nerve fibers along with dyschromatopsia make this possibility less likely. Cone dystrophy could also be considered in this case, presenting with central visual loss with dyschromatopsia. Though the prominence of the optic atrophy is more suggestive of a primary optic neuropathy, one might consider multifocal electroretinography to evaluate macular photoreceptor function.

a

Fig. 18.3  Magnetic resonance imaging (MRI) of the brain and orbits. Coronal T2-weighted, fat-suppressed images depict small and T2-hyperintense orbital portions of the optic nerves (a; yellow arrows)

E. D. Gaier

Summary of testing considered in cases of suspected inherited optic atrophy: 1. Magnetic resonance imaging of the brain and orbits with contrast to rule out a compressive lesion and demyelinating lesions. 2. Vitamin levels—vitamin A, vitamin B2, vitamin B6, vitamin B12, folate, copper, homocysteine, methylmalonic acid; complete blood count. 3. Genetic testing including sequencing of OPA1, ideally including assessment of copy number variants. Next-­ generation testing through diagnostic panels should also include mitochondrial genomic sequencing to assess for LHON mutations and sequencing of other nuclear optic atrophy genes such as OPA3, WFS1, etc. 4. Examination of parents and other family members. 5. Careful neurologic examination looking for peripheral neuropathy and abnormal reflexes. Consider audiology testing. 6. Consider heavy metal and lead screens, inflammatory, and infectious markers. The patient had neuroimaging as suggested above, and no compressive lesion was identified. The optic nerves were noted to be small in diameter and T2-hyperintense (Fig. 18.3) without evidence of enhancement after intravenous injection of gadolinium. Laboratory testing results included normal cobalamin (B12) levels, and targeted testing for the three most common LHON mutations (m.3460, m.11,778, m.14,484) was

b

and a thinned optic chiasm without evidence of a mass or external compression (b; blue arrow).

18  Dominant Optic Atrophy: A Teenager with Progressive Painless Vision Loss

107

Normalized Copy number (wrt REF)

1.0

0.5

E1 I1 E2 E3 E4 E5 E6 E7 E8 E9 E10 E11 E12 E13 E14 E15 I16 E18 E19 E20 E21 E22 E23 E24 E25 E26 E27 E27 E28 I29 E30 E31 REF REF REF REF REF REF REF REF REF REF

0.0

Probe (E, Exon; I, Intron)

Fig. 18.4  OPA1 Multiplex Ligation-dependent Probe Amplification (MLPA) results in the index case showing a heterozygous deletion involving exons 26–28 (MRC Holland [P229 OPA1 probemix,

Amsterdam, the Netherlands]). Copy number is normalized to mean levels across reference probes (right); bars depict standard error of the mean across 3 independent runs. Adapted and modified from [2].

negative. Sanger sequencing of the OPA1 gene (performed prior to the availability of next generation sequencing) revealed no causative variants. Subsequent Multiplex Ligation-dependent Probe Amplification (MLPA) of OPA1 showed a large heterozygous deletion involving exons 26–28 (Fig. 18.4). In this case, the genetic testing result is unambiguous and positive for disease-causing disruption of the OPA1 gene, supporting the diagnosis of dominant optic atrophy (DOA). MLPA is sensitive to copy number variations (including large genomic deletions and duplications) that are pathogenic but may be missed on traditional Sanger and next-­ generation sequencing.

founder effect. The most classic presentation of DOA is of bilateral, highly symmetric loss of central visual acuity, dyschromatopsia (particularly in the blue-yellow axis; tritanopia), and cecocentral scotomas on perimetric testing. Loss tends to be insidious and very slowly progressive. The optic nerve appears pale, most prominently in the temporal sector, with excavation. Between individuals, there is considerable variability in each of these clinical features, but often, there is clinical correlation between features within patients; patients with more severe clinical optic atrophy and disc excavation have more profound visual loss. Perimetric field loss can depict a range of patterns, possibly mimicking bitemporal loss as in our case, and may be confounded by eccentric and unstable fixation [2]. Our current understanding of DOA is informed primarily by cross-sectional studies that depict a wide range of clinical severity [1, 2]. Variable expressivity (clinical severity) and incomplete penetrance (not all patients with the same genetic mutation exhibiting the clinical phenotype) are also appreciated among individuals within a family who harbor the same mutation. The source of this variation is unclear but may relate to other genetic modifiers and/or environmental factors. In particular, mitochondrial stressors including smoking and alcohol use are theoretical risk factors for progression, and avoidance of these stressors is advised for patients with DOA. The true timing, nature, and factors driving progression in DOA remain unknown.

Final Diagnosis OPA1-related dominant optic atrophy

Clinical Discussion Treatment and Prognosis Dominant Optic Atrophy (OMIM #165500) was first described by Dr. Poul Kjer in Denmark, where there is a relatively high prevalence (~1/30,000 vs ~1/50,000) due to a

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The natural history of DOA is poorly understood. Our patient reports wearing glasses in the first decade of life but notes a significant decline in visual function in the early second decade. Anecdotally, it is common among patients with DOA to experience a decline in visual function early in life that plateaus over time. Unlike LHON, there is no recovery of visual function aside from day-to-day variance dependent on testing conditions and fixation. Visual acuity among DOA patients ranges from normal to the level of legal blindness, but typically does not progress beyond ~20/200 (Snellen). Our patient was on the severe end of this spectrum. Aside from visual loss, a subset of patients with DOA exhibit systemic and/or efferent neuro-ophthalmologic dysfunction. Cases of so-called DOA-plus phenotypes comprise approximately 15% of cases (OMIM #125250) [3]. The most common clinical manifestations of DOA-plus include sensorineural hearing loss, ataxia, myopathy, peripheral neuropathy, and progressive external ophthalmoplegia. Spastic paraplegia and multiple sclerosis-like illnesses have also been described [3]. Patients with DOA-plus phenotypes tend to have worse visual outcomes as compared with DOA patients with isolated afferent neuro-ophthalmologic disease. Sensorineural hearing loss is the most common systemic manifestation of DOA and can be mild or even subclinical. As such, referral of DOA suspects for audiology testing may be of diagnostic and/or prognostic use in some clinical circumstances. Disease-causing variants in the OPA1 gene are found in ~60% of definitive cases of DOA [2, 4]. To date, >500 distinct, disease-causing OPA1 variants have been identified (https://databases.lovd.nl/shared/genes/OPA1). OPA1 protein is nuclear-encoded, ubiquitously expressed, and localizes to the inner mitochondrial membrane. OPA1 protein plays multiple essential roles in mitochondrial function including stabilization of mitochondrial networks via fusion, promotion of cellular energy production by supporting components of the electron transport chain, sequestration of pro-­apoptotic cytochrome c, and maintenance of mitochondrial DNA [5]. There are no definite OPA1 variants that portend a better or worse visual prognosis. Missense variants and variants within the region encoding the guanosine triphosphatase domain of OPA1 carry an increased rate of systemic phenotypic expression [3]. This effect is hypothesized to result from a dominant-negative (as opposed to haploinsufficiency) mechanism. Patients with OPA1 dysfunction also accumulate mitochondrial DNA deletions. The burden of mitochondrial genetic disruption may account at least in part for some of the variable phenotypic expression of OPA1-related disease.

Important Aspects of the Diagnosis The final diagnosis in this case is definitive, but genetic testing results are not always as clear. Sequencing of OPA1 and

E. D. Gaier

other genes causing primary optic atrophy can identify one or more variants of unclear clinical significance. Depending on the location and nature of the resulting change, the pathogenicity of a given variant can be estimated and even modeled in silico. Ambiguous genetic testing results should always be interpreted and communicated to the patient/family with the aid of a geneticist or licensed genetic counselor. In this way, an appropriate degree of certainty (or uncertainty) and implications for family planning can be delivered with accuracy. The patient described in this chapter was referred to a low vision specialist, who prescribed optimal refractive correction, performed microperimetric testing (Fig.  18.5), counseled the patient and family on adaptive strategies and tools, and registered the patient with the state commission for the blind. Establishing care with a low vision specialist is critically important for patients with hereditary optic neuropathies, as it is for any patients with functionally limiting, irreversible visual loss. Low vision specialists are best equipped and trained to provide patients with necessary resources and provide school and workplaces effective recommendations/guidance on necessary accommodations to allow patients with low vision to develop and maintain independence and productivity. Summary of treatment/management of confirmed case of DOA: 1. Referral for genetic counseling to help interpret genetic testing results (whether positive or negative). 2. Establish care with a low vision specialist. 3. Registration with the state commission for the blind as per guidelines and on an individual basis. 4. Arrange for examination of siblings and family members, especially children. 5. Follow-up of neuro-ophthalmologic care on an annual-­ biannual basis.

Novel Insights In our case, the genetic testing result was determined 3 years after the patient’s initial evaluation. This exemplifies another important consideration in the diagnostic workup of inherited optic atrophy syndromes—the constant evolution of genetic diagnostic testing means that answers to some suspect cases may be revealed with time. A negative genetic testing result in cases with a high clinical suspicion should not be considered mutation-negative, but rather secondary to a yet-to-be determined, suspected genetic cause. Thus, maintenance of care is important to provide periodic updates in diagnostic technology, recognize interval development of diagnostic clues by monitoring the natural history of a given individual’s disease, and educate patients and their families

18  Dominant Optic Atrophy: A Teenager with Progressive Painless Vision Loss

a

Fig. 18.5  Microperimetric (Nidek MP-1) performance demonstrating eccentric fixation and foveal/perifoveal loss of sensitivity. Fundus images for the right (a) and left (b) eyes with superimposed sensitivities to focally presented stimuli; red indicates failure, green indicates pass.

on the current state of treatment including current clinical trials when and where available. There are currently no effective treatments to prevent or slow the progression of visual loss in DOA. Mitochondrial function is critically important for retinal ganglion cell health and maintenance, as exemplified in DOA, LHON, and other inherited, nutritional, and toxic optic neuropathies [5]. The observation that disease-causing genetic variants are systemically present, yet only manifest as optic neuropathy, demonstrates the susceptibility of retinal ganglion cells above other neurons to mitochondrial dysfunction. While the metabolic demand of retinal ganglion cells is high (contributed at least in part by obligatorily unmyelinated intraocular axonal segments), insufficient cellular energy production cannot completely account for the phenotypic expression of optic atrophy. The multiple roles that mitochondria play in retinal ganglion cell health and disease are under active investigation with implications for multiple optic neuropathies (not just inherited optic neuropathies) [5]. Genetic therapies comprise a promising avenue, but they face several crucial hurdles in addition to the challenges that come with studying any intervention for a rare, very slowly progressive, and highly variable disease. Thus, there is an ongoing need for progress in scientific and clinical research in this area.

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b

Retinal fixation points are depicted by yellow cross marks, and the anatomic fovea are designated by blue arrows. Relative positions of the anatomic foveae and retinal fixation points are consistent with superior displacement of cecocentral scotomata on perimetric testing (Fig. 18.1).

Clinical Pearls

• Cases of bilateral optic atrophy must be evaluated by neuroimaging and laboratory testing to exclude potentially treatable and/or malignant causes of optic atrophy. • DOA causes symmetric, insidious central visual loss and dyschromatopsia that manifests in the context of (temporal) optic disc pallor and possibly in association with systemic deficits such as sensorineural hearing loss, ataxia, myopathy, peripheral neuropathy, and progressive external ophthalmoplegia. • Patients with inherited optic atrophy syndromes do not always report a clear family history, so genetic testing should be considered in cases with a high clinical suspicion. • Our current understanding of inherited optic neuropathies, including the diagnosis and management, is evolving. Though there are currently no efficacious therapies, maintenance of ophthalmic care (including with a low vision specialist) provides ongoing availability of important resources (both diagnostic and therapeutic) for patients and families.

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References 1. Yu-Wai-Man P, et al. Inherited mitochondrial optic neuropathies. J Med Genet. 2009;46:145–58. 2. Gaier ED, et al. Diagnostic genetic testing for patients with bilateral optic neuropathy and comparison of clinical features according to OPA1 mutation status. Mol Vis. 2017;23:548–60.

E. D. Gaier 3. Yu-Wai-Man P, et al. Multi-system neurological disease is common in patients with OPA1 mutations. Brain. 2010;133:771–86. 4. Yu-Wai-Man P, et al. The prevalence and natural history of dominant optic atrophy due to OPA1 mutations. Ophthalmology. 2010;117(1538–46):1546.e1. 5. Olichon A, et  al. Mitochondrial dynamics and disease, OPA1. Biochim Biophys Acta. 2006;1763:500–9.

Leber Hereditary Optic Neuropathy: A Teenager with Painless Sequential Vision Loss

19

Aubrey L. Gilbert

Case Presentation A 16-year-old boy with no significant past medical or ophthalmologic history, and no family history of ophthalmologic or neurologic disease, presented to an optometric clinic reporting painless, subacute worsening of central vision during the prior 2–3 months. He said the right eye had vision loss first and then, around a month later, he developed vision loss in the left eye. His best corrected distance visual acuity at that time measured 20/400 in the right eye and 20/150 in the left eye. The examination was documented to be unremarkable, and he was referred to a general ophthalmologist for further evaluation. In the ophthalmology clinic, no abnormality was observed on ophthalmologic examination. Magnetic resonance imaging (MRI) of the brain and orbits with and without contrast was performed and was unremarkable. He was then evaluated by a retina specialist who noted no retinal abnormalities. Optical coherence tomography (OCT) of the macula was unremarkable. Corneal topography showed no significant abnormality to account for his reduced vision. He was subsequently referred for neuro-ophthalmologic evaluation for nonorganic vision loss. In the Neuro-­ Ophthalmology clinic, 2 months after his initial presentation to Optometry, he reported continued worsening of central visual impairment bilaterally. His best corrected distance visual acuity measured 20/400 for each eye. He was unable

to see the control color plates. Pupillary responses were brisk and symmetric, and there was no relative afferent pupillary defect. Intraocular pressures were normal. Humphrey visual field testing demonstrated dense central/cecocentral depression bilaterally, worse in the right than the left eye (Fig. 19.1). Ocular motility was unremarkable, as was the anterior segment examination. The posterior segment examination was notable for bilateral optic disc hyperemia and mild elevation, with very subtle telangiectatic vessels (Fig. 19.2). There was mild tortuosity of the retinal vessels. OCT of the peripapillary retinal nerve fiber layer (RNFL) revealed thinning temporally, and minimally supranormal thicknesses superiorly and inferiorly in each eye (Fig. 19.3). Macular scans showed diffuse thinning of the ganglion cell-inner plexiform layer (GC-IPL) in each eye. In the absence of retinal disease, further workup for an underlying optic neuropathy was pursued.

Differential Diagnosis

• • • • • •

Toxic optic neuropathy Nutritional optic neuropathy Hereditary optic neuropathy Infiltrative or inflammatory optic neuropathy Compressive optic neuropathy Ischemic optic neuropathy

A. L. Gilbert (*) Department of Ophthalmology, Kaiser Permanente Northern California, Vallejo, CA, USA e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_19

111

112

A. L. Gilbert

Fig. 19.1  Humphrey 30-2 visual field testing showing dense central/cecocentral depression affecting the right>left eye. OD: right eye; OS: left eye.

Fig. 19.2  Fundus photographs demonstrating bilateral optic disc hyperemia. Mild elevation and subtle telangiectatic vessels were also evident on direct examination. (Right eye is shown on the left and the left eye on the right).

19  Leber Hereditary Optic Neuropathy: A Teenager with Painless Sequential Vision Loss

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Fig. 19.3  Optical coherence tomography testing demonstrating thinning of the peripapillary retinal nerve fiber layer temporally and minimally supranormal thickness superiorly and inferiorly in each eye. OD: right eye; OS: left eye.

114

Diagnostic Workup Review of the previous contrast-enhanced MRI of the brain and orbits showed no compressive lesion or signs of inflammation and was also otherwise unremarkable. Screening labs for nutritional and toxic etiologies were normal. Genetic testing identified a homoplasmic m.11778 G > A pathogenic point mutation in the mitochondrial MT-ND4 gene, one of the three most common mutations associated with Leber hereditary optic neuropathy.

Final Diagnosis Leber hereditary optic neuropathy (LHON) associated with the 11778 mutation

Clinical Discussion Treatment and Prognosis LHON is one of the most common diseases of mitochondrial origin, with a prevalence of 1 in between 30,000 to 50,000 individuals [1]. LHON is maternally inherited, but clinical symptoms more frequently occur in young men. However, many patients do not report a family history of vision loss, the age range of affected patients is broad (3–70 years), and women may also be affected, but at lower rates. The vast majority of cases are attributable to one of three point mutations: 11778/ND4, as present in this patient, 14484/ND6, or 3460/ND1. About 5% of cases are from other mutations [2]. Classically, patients present similarly to our patient, with acute or subacute, painless, severe, central vision loss that occurs in each eye sequentially, usually over days to weeks, but vision loss can also occur simultaneously in both eyes, or with longer intervening delay between eyes, even up to years. Vision usually stabilizes after a year, and most patients remain severely impaired, often with vision in the range of legal blindness, although some do have partial recovery. Younger age at onset and presence of the 14484/ND6 mutation, which often manifests with more mild vision loss from the onset, are associated with greater potential for visual improvement [3–6]. The classic fundus appearance in LHON is disc edema with peripapillary telangiectasias, tortuosity of the retinal vessels, and no leakage on fluorescein angiography. However, the fundus changes can be subtle or absent, and pupillary responses usually appear grossly normal. Providers who do not frequently see cases of LHON may misdiagnose patients as nonorganic at initial presentation. Eventually optic atrophy becomes apparent.

A. L. Gilbert

Currently, the only authorized treatment for LHON is idebenone, an analogue of ubiquinone thought to support mitochondrial electron transport, and that is approved in Europe but not available by prescription in the United States. Patients in the United States can order idebenone without a prescription from various internet sites. Recently, gene therapy trials have been undertaken, and long-term outcomes from these trials are still being analyzed. This patient and his family received additional genetic counseling and he was enrolled in a gene therapy trial that was available at the time. His vision remained stable and his optic discs developed progressive atrophy that remained most profound in the papillomacular bundle, with resultant temporal pallor evident on examination. He underwent Low Vision evaluation and received necessary accommodations for school. Due to the association of some LHON cases with additional neurologic symptoms and/or cardiac arrhythmias, so-called “LHON Plus,” he had a neurologic examination and a screening electrocardiogram that were normal.

Important Aspects of the Diagnosis In addition to the clinical history, OCT can be helpful in identifying cases, since mitochondrial disease often manifests with a distinct pattern of RNFL and GC-IPL changes. Increased retinal nerve fiber layer thickness can be detected on OCT as much as 6 months prior to clinical manifestations, peaking at the time of symptoms, and then decreasing to plateau below normal, with most pronounced RNFL thinning affecting the papillomacular bundle. There is often significant longitudinal presymptomatic thinning of the GC-IPL that starts in the inner nasal region and then extends in a spiral and centrifugal pattern [7]. Cranial neuroimaging of patients with LHON is often unremarkable. However, MRI may show subtle optic nerve and chiasmal thickening, enhancement, and T2 hyperintensity in some patients [8, 9]. Optic tract thickening and T2 hyperintensity on MRI has been reported as well. The presence of one of the mitochondrial point mutations listed above is thought to be contributory but not sufficient to result in clinical manifestations of LHON, as it is known that there are many asymptomatic carriers. About half of those male individuals, and about a tenth of those female individuals, with a mutation go on to develop vision loss [6, 10]. Potential proposed contributors to clinical conversion have included environmental issues such as toxic exposures and infections, hormonal influences, and other specific genetic factors [11, 12]. When questioned, some patients will endorse precipitating metabolic stressors, although in many cases, none are identified. Patients should be advised to avoid metabolic stressors, in particular, any tobacco or smoke exposure,

19  Leber Hereditary Optic Neuropathy: A Teenager with Painless Sequential Vision Loss

heavy alcohol use, and any drugs that may cause mitochondrial dysfunction. Genetic testing of at-risk family members can be considered, although it is not possible to predict which patients who carry a mutation will become symptomatic. It can still be helpful to know the genetic status, however, since avoidance of stressors may help to prevent clinical manifestations.

Novel Insights Regarding treatment, there is currently no cure for LHON, although many therapies have been tried. The largest, double-­ blind, randomized, placebo-controlled study of a medication for treatment of LHON was RHODOS, (Rescue of Hereditary Optic Disease Outpatient Study,) which included 85 patients with one of the three main mutations, and with symptom onset within 5 years, who were randomized to receive placebo or idebenone at 300 mg three times a day for 24 weeks. The study did not reach the primary endpoint of best recovery in visual acuity, but post hoc analysis suggested some visual acuity improvement with idebenone treatment, particularly in participants with 11778 or 3460 mutations, and in participants with a difference in vision between the two eyes [13]. There was an international consensus statement on the management of LHON published in 2017 based on a conference, notably sponsored by Santhera Pharmaceuticals, the company that makes idebenone [14]. Recommendations from that publication include initiation of idebenone at a dose of 900 mg/day in patients who present within a year of onset, and continuation of that treatment for at least 1 year. A publication in 2020 on an open-label, multicenter, retrospective, noncontrolled analysis of long-term visual acuity and safety in 111 LHON patients treated with idebenone suggested that treatment be initiated early and maintained for more than 24  months [15]. The most recent treatment approach that has been studied is gene therapy, with viral targeted introduction of exogenous DNA into the mitochondrial genome. With advances in the field of gene therapy, diseases with known genetic mutations such as LHON are being targeted for treatment. Recently, two phase-3 multicenter clinical trials with rAAV2/2-ND4 gene therapy (RESCUE and REVERSE trials) showed sustained bilateral improvement of best-­ corrected visual acuity following unilateral injection compared to an external control group of untreated ND4-­ LHON patients [16–18]. These results suggest more effective genetic therapies may be available for LHON patients in the near future.

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Clinical Pearls

• Leber’s hereditary optic neuropathy classically presents in young men with painless, subacute, sequential, central vision loss and disc edema with peripapillary telangiectasias. However, some cases occur with vision loss in both eyes simultaneously, in women, in younger or older individuals, frequently in the absence of any family history of visual loss, and with a normal fundus appearance. Therefore, LHON should be in the differential diagnosis of any optic neuropathy without an apparent alternative etiology. • Ophthalmologic examination in the early phase of Leber’s hereditary optic neuropathy may be notable for telangiectatic microangiopathy with pseudoedema of the optic disc and can reveal temporal disc pallor later on, but can also appear normal on clinical examination at presentation or in the interim. OCT often shows peripapillary RNFL increased thickness many months in advance of vision loss, and GC-IPL thinning may also be evident before symptom onset. • Visual prognosis is variable and treatment of Leber’s hereditary optic neuropathy remains challenging, currently with idebenone as the only authorized treatment (in Europe), but clinical trials have been undertaken to explore gene therapy, with longterm results pending. Patients should be advised to avoid metabolic stressors, and consideration can be given to genetic testing for family members.

References 1. Puomila A, Hamalainen P, Kivioja S, Savontaus M, Koivumaki S, et al. Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland. Eur J Hum Genet. 2007;15:1079–89. 2. Riordan-Eva P, Sanders M, Govan G, Sweeney M, Da Costa J, et al. The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain. 1995;118:319–37. 3. Johns D, Heher K, Miller N, Smith K.  Leber’s hereditary optic neuropathy. Clinical manifestations of the 14484 mutation. Arch Ophthalmol. 1993;111:495–8. 4. Nagai A, Nakamura M, Kusuhara S, Kanamori A, Negi A. Unilateral manifestation of Leber’s hereditary optic neuropathy after blunt ocular trauma. Jpn J Ophthalmol. 2005;49:65–667. 5. Smith J, Hoyt W, Susac J. Ocular fundus in acute Leber optic neuropathy. Arch Ophthalmol. 1973;90:349–54. 6. Yen M, Wang A, Wei Y. Leber’s hereditary optic neuropathy: a multifactorial disease. Prog Retin Eye Res. 2006;25:381–96.

116 7. Balducci N, Savini G, Cascavilla ML, et  al. Macular nerve fibre and ganglion cell layer changes in acute Leber’s hereditary optic neuropathy. Br J Ophthalmol. 2016;100:1232–7. 8. Phillips PH, Vaphiades M, Glasier CM, Gray LG, Lee AG. Chiasmal enlargement and optic nerve enhancement on magnetic resonance imaging in Leber hereditary optic neuropathy. Arch Ophthalmol. 2003;121:577–9. 9. Blanc C, Heran F, Habas C, Bejot Y, Sahel J, Vignal-Clermont C. MRI of the optic nerves and chiasm in patients with Leber hereditary optic neuropathy. J Neuro-ophth. 2018;38:434–7. 10. Fraser J, Biousse V, Newman N. The neuro-ophthalmology of mitochondrial disease. Surv Ophthalmol. 2010;55:299–334. 11. Sadun A, Carelli V, Salomao S, et al. Extensive investigation of a large Brazilian pedigree of 11778/haplogroup J Leber hereditary optic neuropathy. Am J Ophthalmol. 2003;136:231–8. 12. Hudson G, Carelli V, Spruijt L, et al. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-­ haplogroup background. Am J Hum Genet. 2007;81:228–33. 13. Klopstock T, Yu-Wai-Man P, Dimitriadis K, et  al. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. 2011;134(Pt 9):2677–86. 14. Carelli V, Carbonelli M, de Coo IF, Kawasaki A, Klopstock T, Lagreze WA, La Morgia C, Newman NJ, Orssaud C, Pott JWR,

A. L. Gilbert Sadun AA, van Everdingen J, Vignal-Clermont C, Votruba M, Yu-Wai-Man P, Barboni P. International consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy. J Neuro-ophth. 2017;37:371–81. 15. Catarino CB, von Livonius B, Priglinger C, et al. Real-world clinical experience with idebenone in the treatment of Leber hereditary optic neuropathy. J Neuro-ophth. 2020;40:558–65. 16. Newman N.  Assessment of rAAV2/2-ND4 gene therapy efficacy in LHON using an external control group. North American Neuro-­Ophthalmology Society Annual Meeting, February 2021. Virtual. 17. Biousse V, Newman NJ, Yu-Wai-Man P, Carelli V, Moster ML, Vignal-Clermont C, Klopstock T, Sadun AA, Sergott RC, Hage R, Esposti S, La Morgia C, Priglinger C, Karanja R, Blouin L, Taiel M, Sahel JA, LHON Study Group. Long-term follow-up after unilateral intravitreal gene therapy for Leber hereditary optic neuropathy: the RESTORE study. J Neuroophthalmol. 2021;41:309–15. 18. Newman NJ, Yu-Wai-Man P, Carelli V, et  al. Efficacy and safety of intravitreal gene therapy for Leber hereditary optic neuropathy treated within 6 months of disease onset. Ophthalmology. 2021;128:649–60.

Nutritional Optic Neuropathy from Vitamin A Deficiency: A Boy with Autism and Decreased Vision

20

Stacy L. Pineles

Case Presentation A 9-year-old boy presented with gradual loss of vision over the past 6 months. The patient was nonverbal due to severe autism, but prior to symptom onset, he always had seemingly normal vision. Over the past 6 months, he had been bumping into walls, tripping over large objects, and groping at objects that he wished to grab. His mother had noticed that he seemed to exhibit more light sensitivity recently. His past medical history was significant for autism and nonverbal status. At 5 years of age, he had a normal magnetic resonance imaging (MRI) of the brain as part of his autism workup. He had no other medical problems and did not currently take any medications. Family history was negative for ophthalmologic and

neurologic diseases. Review of systems was significant for hypotonia but otherwise was noncontributory. On examination, the child was able to fix and follow large bright objects; however, he did not track very small objects. His visual fields appeared constricted in all quadrants based on confrontation with brightly colored toys. His pupils were bilaterally sluggish without a relative afferent pupillary defect. There was no light-near dissociation. Intraocular pressures were 17 mmHg right eye and 17 mmHg left eye. The slit-lamp examination revealed diffuse punctate epithelial erosions, but was otherwise normal. A dilated fundus examination revealed bilateral temporal optic nerve atrophy (Fig. 20.1). The patient was not able to cooperate with any other ancillary testing.

Fig. 20.1  Fundus photographs demonstrating temporal optic nerve pallor of the right optic nerve (shown on the left) and temporal optic nerve pallor of the left optic nerve (shown on the right).

S. L. Pineles (*) Department of Ophthalmology, University of California, Los Angeles, Los Angeles, CA, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_20

117

118

In the setting of decreased visual function and bilateral optic nerve pallor, further workup was pursued for a presumed optic neuropathy.

Differential Diagnosis

• Toxic optic neuropathy • Nutritional optic neuropathy –– B12 deficiency –– Vitamin A deficiency –– Thiamine deficiency –– Copper deficiency • Inherited optic neuropathy –– Dominant optic atrophy –– Leber hereditary optic neuropathy • Compressive optic neuropathy • Neurodegenerative diseases with optic atrophy • Glaucoma • Retinal dystrophy with secondary optic atrophy

Diagnostic Workup Since the optic nerve atrophy was symmetric, subacute or chronic, and most prominent in the temporal quadrant, the leading diagnosis was a “mitochondrial optic neuropathy,” which includes toxic, nutritional, and inherited etiologies. In this case, given the history of autism, it was important to specifically ask the family about diet and potential toxic exposures for this patient. Children with autism frequently have selective eating patterns in which they will only eat foods of certain colors or textures, which can lead to a multitude of vitamin deficiencies [1]. In addition, they may be placed on a specialized diet by a parent in attempts to treat symptoms related to their autism. The presentation of mitochondrial optic neuropathies and specifically nutritional optic neuropathies is classically a bilateral, painless, slowly insidious onset of vision loss. Any level of visual acuity is possible at presentation; however, severe vision loss such as “no light perception” would be exceedingly rare. In children with vitamin deficiency optic neuropathies, the color vision is always affected early, and the visual field is always abnormal with either a cecocentral or central scotoma most commonly present. Depending on the timing of presentation, the optic nerves can look normal, pale (especially in the temporal quadrant), or edematous. The patient’s parents described a self-imposed highly restricted diet in which the patient only ate bagels and French fries. They were not aware of any family history of eye diseases or toxic exposures.

S. L. Pineles

The following tests were ordered and are recommended in a patient with progressive symmetric optic atrophy: 1. Vitamin levels—vitamin A, vitamin B2, vitamin B6, vitamin B12, folate, copper, homocysteine, methylmalonic acid: (a) An important pearl in the diagnosis of vitamin deficiency optic neuropathy is the difference between serum and tissue levels of vitamin B12. Although laboratory assays test the serum level of Vitamin B12, there may be a functional deficiency at the tissue level that is not reflected by serum tests. In these cases, serum vitamin B12 levels may be low-normal despite the presence of vitamin B12 deficiency optic neuropathy. If a functional deficiency of vitamin B12 is suspected at the tissue level, serum homocysteine and urine methylmalonic acid should be measured—an elevation of these tests would be indicative of functional B12 deficiency and should be treated similarly with vitamin supplementation [2]. 2. Complete blood count. 3. Heavy metal and lead screen. 4. Magnetic resonance imaging (MRI) of the brain and orbits to rule out a compressive lesion and demyelinating lesions. 5. Careful neurologic examination to detect peripheral neuropathy and abnormal reflexes. 6. Consider inflammatory and infectious markers such as angiotensin-converting enzyme, antinuclear antibody, and erythrocyte sedimentation rate in certain circumstances In this case, the vitamin A level was undetectable on both the initial test and confirmatory retesting. The patient also had low-normal levels of vitamin B12 with normal homocysteine and methylmalonic acid. The heavy metal and lead screens were normal as was the complete blood count and cranial MRI.

Final Diagnosis Nutritional optic neuropathy from Vitamin A deficiency

Clinical Discussion Treatment and Prognosis Vitamin deficiency optic neuropathy presents similarly regardless of the underlying vitamin that is deficient; however, the comorbidities that occur are different. The most common vitamin deficiency that is associated with optic neu-

20  Nutritional Optic Neuropathy from Vitamin A Deficiency: A Boy with Autism and Decreased Vision

ropathy is vitamin B12 or folate deficiency. Vitamin B12 is found in foods such as fortified cereals, fish, eggs, and milk. Folate can be ingested in foods such as fortified cereals, lentils, spinach, eggs, avocados, corn, and peas. In addition to optic neuropathy, B12 deficiency is associated with macrocytic anemia, thrombocytopenia, neutropenia, myelopathy, and subacute combined degeneration, as well as neuropsychiatric abnormalities. Vitamin A deficiency is a rare cause of optic neuropathy and is more frequently associated with xerophthalmia and retinopathy. Although vitamin A deficiency is uncommon in the developed world, it can be deficient in children with limited diets or gastrointestinal disease [3], especially in those who avoid foods with high levels of vitamin A, such as carrots, broccoli, sweet potatoes, and meats such as chicken, pork, or beef. Perhaps, the rarest cause of vitamin-deficiency-associated optic neuropathy is copper deficiency. Copper deficiency presents similarly to vitamin B12 deficiency with optic neuropathy, macrocytic anemia, and subacute combined degeneration. The prognosis of vitamin deficiency optic neuropathy is dependent on the duration of the vitamin deficiency and amount of optic atrophy present upon presentation [4]. All patients suspected of vitamin deficiency should undergo a gastrointestinal evaluation to determine whether there are any anatomic or systemic etiologies such as malabsorption. Vitamin supplementation should be commenced under the supervision of a pediatrician. If diagnosed and treated early, patients may enjoy an almost complete recovery within a month of nutritional supplementation. However, in children, disease typically presents late when there is already atrophy of the optic nerve. In cases with late presentation and severe optic atrophy at the time of presentation, visual recovery may be poor and patients should be counseled on the guarded prognosis. It is also important for patients with nutritional optic neuropathies to avoid other toxins that might worsen their condition (see below). The final diagnosis was vitamin A deficiency, which caused an optic neuropathy as well as the corneal surface disease that was observed on the initial examination of the anterior segment. This patient was treated with supplementation of both vitamin A and vitamin B12. In addition, he underwent a full gastrointestinal evaluation to ensure that the vitamin deficiencies were strictly diet related and not a result of malabsorption. He was later diagnosed with vitamin C and vitamin D deficiencies as well.

Important Aspects of the Diagnosis Although nutritional optic neuropathy is more common in the developing world, it is also frequently observed worldwide in specific circumstances such as in patients with a history of bariatric surgery, alcoholism, gastrointestinal

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disease such as irritable bowel syndrome, or psychiatric disorders such as anorexia nervosa. Much of our modern understanding of the disorder results from historical epidemics of optic neuropathy, which most recently involved an epidemic of optic neuropathy in Cuba, affecting 0.5% of the country’s population. Although nutritional optic neuropathy can frequently be attributed to a deficiency of a single micronutrient, the epidemic in Cuba was attributed to a coalescence of a nationwide shortage of food, resulting in a widespread lack of dietary variety including insufficient animal protein and vegetable intake, and a high level of alcohol and tobacco usage [4]. Micronutrients that were implicated in this epidemic included Vitamins B1, B2, B12, and folate. In any patient with an optic neuropathy, it is important to take a careful history regarding diet and gastrointestinal symptoms, as well as toxic exposures. The laboratory evaluation should include serum Vitamins B1, B2, B6, B12 levels, folate, homocysteine, and copper levels, as well as a urine methylmalonic acid level. In addition, patients who have undergone gastrointestinal surgery may be deficient in zinc and magnesium, and children with restricted dietary intake may also be deficient in vitamin A, D, C, zinc, and selenium. The timing of symptom onset may be related to the affected micronutrient, with Vitamin B1 (thiamine) deficiency symptoms occurring weeks to months after the nutritional deficiency begins, and vitamin B12 optic neuropathy typically occurring months to years after onset of the nutritional deficiency. Copper deficiency may be the most well-­ tolerated deficiency that ultimately results in optic neuropathy, often presenting years after the nutritional deficit began [4]. The earliest symptoms and signs of nutritional optic neuropathy typically include dyschromatopsia, loss of contrast sensitivity, and visual field defects. Later, optic nerve pallor and loss of visual acuity manifest. Once diagnosed, the management of nutritional optic neuropathy must consist of eliminating the underlying cause, replenishing nutrients in conjunction with the patient’s medical team, and counseling to avoid toxins (see below). The visual outcome of this disease is directly related to the rapidity with which the diagnosis was determined and treatment initiated. If the disorder is treated quickly after onset, visual acuity frequently improves first within weeks, followed by color vision, and visual field. In the Cuban epidemic, the majority of patients (90%) had markedly improved visual acuity after treatment despite persistent optic atrophy. The severity of optic atrophy is related to visual outcome, as the Cuban patients with severe and permanent vision loss were those with the most severe cases of optic atrophy [4]. A follow-­up regimen of 1–2 weeks after treatment initiation followed by 4–6  weeks if there is improvement has been suggested [4].

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Novel Insights In spite of nutritional repletion, patients with nutritional optic neuropathy are at continued risk for optic neuropathy if they are exposed to toxins. The presence of cyanide in tobacco products is implicated in the pathogenesis of nutritional optic neuropathy due to vitamin B12’s role in the detoxification of cyanide. Similarly, alcohol indirectly potentiates symptoms of nutritional optic neuropathy due to its negative effect on liver function, which is crucial for micronutrient absorption. Through various mechanisms, other toxins may potentiate nutritional optic neuropathy in children and adults—these include lead, other heavy metals, methanol, and medications such as ethambutol, amiodarone, and isoniazid. The final common pathway in the pathogenesis for most nutritional optic neuropathies is a disruption of mitochondrial function resulting in increased oxidative stress, especially in the metabolically active papillomacular bundle. However, the pathogenesis of vitamin A deficiency–related optic neuropathy is less defined. Vitamin A is essential for epithelial function, and its deficiency is more typically related to conjunctival xerosis, keratomalacia, fleck retinopathy, and loss of visual function due to retinopathy. However, recent authors have proposed that vitamin A may also have a role in neural maintenance, due to experiments involving rats with diabetic neuropathy, who have improvements in neuropathic symptoms after treatment with vitamin A [5]. Despite these findings, there is still much work to be done to improve our understanding of the pathogenesis of vitamin A deficiency optic neuropathy.

S. L. Pineles

Clinical Pearls

• Vitamin deficiency is a cause of bilateral, symmetric, chronic optic neuropathy in children. • Autistic children are frequently at risk for vitamin deficiency due to highly restricted eating patterns. Other causes of vitamin deficiency in children include gastrointestinal disease, gastrointestinal surgery including bariatric surgery, fad diets, food allergies, and eating disorders such as anorexia nervosa. • Bilateral optic neuropathy in a child should prompt an evaluation that includes neuroimaging and a directed laboratory evaluation based on the past medical history, dietary history, family history, and social history.

References 1. Pineles SL, Avery RA, Liu GT.  Vitamin B12 optic neuropathy in autism. Pediatrics. 2010;126:967–70. 2. Grzybowski A. Low serum vit. B12 level does not mean vit. B12 deficiency—problems related to the diagnosis of vitamin B12 deficiency. Curr Eye Res. 2014;39:425–6. 3. Simkin SK, Tuck K, Garrett J, Dai S.  Vitamin A deficiency—an unexpected cause of visual loss. Lancet. 2016;387:93–4. 4. Jefferis JM, Hickman SJ.  Treatment and outcomes in nutritional optic neuropathy. Curr Treat Options Neurol. 2019;21:5–10. 5. Farrell MC, Weiss SJ, Goodrich C, Martinez Lehmann MP, Delarato N. Food aversion leading to nutritional optic neuropathy in a child with severe vitamin A deficiency. J Neuroophthalmol. 2021;41:e718–9.

Part V Strabismus and Disorders of the Extraocular Muscles

Congenital Fibrosis of the Extraocular Muscles (CFEOM): A Baby with Poor Tracking and Exotropia

21

Mary C. Whitman and Elizabeth C. Engle

Case Presentation A baby boy presented to the ophthalmology clinic at age 2  months of age with poor visual behavior. His parents reported that he did not seem to fix and follow objects, or to respond to lights being turned on or off. The birth history was significant for a full-term birth following an uneventful pregnancy. He was noted at birth to have microphallus and cryptorchidism, but was otherwise healthy. On initial ophthalmologic examination, he was unable to fix and follow objects. He had a large (>50∆) exotropia, and no adduction of either eye. Vertical eye movements also appeared limited. Left upper eyelid jaw winking was noted with sucking. The pupils were equal, round, with an equal response to light. He had lower lid entropion, worse in the left eye. The anterior segment was otherwise normal. The dilated funduscopic examination revealed normal optic nerves, vessels, and maculae. On examination at age 4 months, he still did not fix and follow, but vision measured by visually evoked potential (VEP) testing  showed 20/134 with both eyes viewing. His exotropia was estimated to be 70–80∆. On general examination, the baby’s head circumference was at the second percentile and he had low-set posteriorly rotated ears, epicanthal folds, and narrow palpebral fissures. The neurological examination revealed mild facial weakness with inability to smile, and axial and proximal appendicular weakness. At age 6 months, he was noted to have global developmental delay.

At age 1.5  years, he was evaluated specifically for the management of strabismus. He had an 80∆ exotropia, inability to adduct either eye past the midline, limitation of elevation, and limitation of depression, although the resting position of the eyes was in slight down-gaze (Fig. 21.1). His visual behavior was improved. He adopted a left head turn when viewing with his right eye and a right head turn when viewing with the left eye. He had bilateral ptosis, but the lids cleared the visual axis. There were intermittent nystagmoid movements of each eye. To treat his strabismus, he had bilateral lateral rectus recessions of 14 mm and bilateral inferior rectus recessions of 11  mm. Five weeks after that surgery, there was improvement of the head position and motility, but he had a residual exotropia of 40∆ (Fig. 21.1).

Differential Diagnosis

• CFEOM (congenital fibrosis of the extraocular muscles) • Third nerve palsy • Moebius syndrome • Prader Willi syndrome • Smith Lemli Optiz syndrome

M. C. Whitman (*) Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA e-mail: [email protected] E. C. Engle Departments of Neurology and Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Howard Hughes Medical Institute, Chevy Chase, MD, USA © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_21

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Fig. 21.1  External photographs documenting the eye position in primary gaze. Eye position before any strabismus surgery (top left). Neither eye could adduct, and there were minimal vertical movements. There was improvement in the alignment immediately after the supra-

M. C. Whitman and E. C. Engle

maximal recessions of the lateral rectus and inferior rectus bilaterally (top right), but the exotropia recurred quickly (bottom left). At age 16, despite multiple surgeries, he has a large angle exotropia with minimal eye movements.

Diagnostic Workup Initial diagnostic workup at age 2 months included an electroretinogram (ERG), which showed normal responses, and magnetic resonance imaging (MRI) of the brain, which was reported as normal for age. Plasma amino acid and urine organic acid screens were normal. 7-Dehydrocholesterol level was normal and therefore did not confirm Smith Lemli Optiz syndrome. Chromosome analysis revealed 46XY.  Fluorescence in situ hybridization (FISH), ­subtelomeric FISH, and methylation 15 studies were normal and therefore not consistent with Prader Willi syndrome. Repeat MRI at 7 years of age revealed small extraocular muscles, anterior commissure and mild corpus callosum hypoplasia, absent olfactory sulci, and hypoplasia of the left olfactory bulb (Fig.  21.2). The latter two imaging findings are consistent with Kallmann syndrome (anosmia with hypogonadotropic hypogonadism). His parents reported that he was not able to smell. Re-review of his earlier MRI scans at that time did show absence of the olfactory sulci. Genetic testing at age 7  years revealed a TUBB3 c.1228G > A missense mutation, resulting in a E410K amino acid substitution. Parental DNA analysis revealed that this mutation arose de novo. This genetic variant results in the “TUBB3 E410K syndrome.” [1].

Fig. 21.2  Coronal MRI at age 7 shows lack of olfactory sulci (white arrow). Note also the medialized position of the optic nerve (black arrow), caused by the large exotropia, and the small extraocular muscles.

21  Congenital Fibrosis of the Extraocular Muscles (CFEOM): A Baby with Poor Tracking and Exotropia

Final Diagnosis Congenital Fibrosis of the Extraocular Muscles, Type 3: TUBB3 E410K syndrome

Clinical Discussion Treatment and Prognosis Ophthalmologic treatment of CFEOM aims to maximize functional vision, minimize abnormal head posture, and improve eye alignment and appearance. It is not possible to restore full eye movements; a reasonable goal is cosmetically acceptable alignment in primary position, which can require multiple strabismus surgeries. In patients with the TUBB3 E410K syndrome, the exotropia is often very severe, and supramaximal strabismus surgery is usually required, potentially including removing the lateral rectus from the globe and sewing it to the orbital wall. To improve the chin­up head position, large inferior rectus recessions, often coupled with ptosis surgery, are required. Care should be taken not to lift the lids too high; a final marginal reflex distance of 1–2 mm should be the goal. CFEOM patients are at high risk for corneal exposure due to limitations in upgaze and lack of Bell’s reflex, and possibly also due to decreased corneal sensation. Corneal exposure can be successfully treated with scleral lenses, such as the Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) contact lens. To maximize vision, careful attention to refractive error and treatment of any amblyopia are required. Individuals with the TUBB3 E410K syndrome require care by multiple specialists in addition to ophthalmology. Patients are born with facial weakness, Kallmann syndrome (anosmia and hypogonadotropic hypogonadism), and, in some cases, vocal cord paralysis. Males are often treated with testosterone at birth for microphallus and cryptorchidism; both males and females need hormonal treatment to induce puberty. Patients develop intellectual and social disabilities, and all reported patients have required special education services. Patients develop a progressive axonal peripheral polyneuropathy, typically in the second decade of life. Finally, some patients have cyclic vomiting, and this may respond to prophylactic valproic acid [1]. Our patient underwent multiple strabismus surgeries to address his marked strabismus. Following his initial supramaximal recessions of both lateral rectus and inferior rectus muscles at age 1.5, he had a residual exotropia of greater than 40∆. He then had the right lateral rectus disinserted from the eye and attached to the periosteum at age 2.5. This did not improve the alignment. He then had Botox to both lateral rectus and both inferior rectus muscles, twice, which did not

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substantially improve the alignment. At age 4, the lateral rectus muscle was resected, and the muscle stump was sutured to the orbital rim to deactivate the muscle; this slightly improved the exotropia (Fig. 21.1). His parents have elected not to pursue further strabismus surgery. Corneal exposure was first noted in both eyes at age 2.5  years, which progressively worsened. He was initially treated with lubrication and intermittent erythromycin ointment. At age 5, he had repair of epiblepharon, with everting sutures on the right and a Weiss procedure on the left. He has not required ptosis surgery. At age 10, he began wearing PROSE lenses to treat the corneal exposure. He has done well with the PROSE lenses. Vision at age 16 was 20/25-2 in the right eye and 20/40-2 in the left eye. To treat his hypogonadotropic hypogonadism, a short course of testosterone was given at age 14  months, which caused normalization of penile size and descent of his testes. At age 13, he was started on HCG to induce puberty and then transitioned to testosterone injections, which he remains on. Neurologically, he had global developmental delay, including gross motor, fine motor, speech, and cognition. He began walking at 25 months of age and showed significant speech delay. Developmental assessment at age 3 showed a Mental Development Index (roughly equivalent to IQ) score of 65. Neuropsychological assessment at age 12 showed IQ subscales that ranged from extremely low to average; given these discrepancies between composite scores, a full-scale IQ could not be reported. He has required special education services throughout his education, in a substantially separate classroom, but is able to read, write, and speak fluently. He developed seizures at the age of 3, which were managed with medications. EMG (electromyography) at age 9.5 showed mild, generalized sensorimotor polyneuropathy, but he remains ambulatory.

Important Aspects of the Diagnosis Three subtypes of CFEOM were originally defined clinically, but are now defined genetically. CFEOM1 is an isolated eye movement disorder consisting of ptosis, inability to elevate the eyes above midline, and variable deficits in horizontal eye movements. It results from missense mutations in KIF21A, a kinesin motor protein that transports molecular cargos along microtubules [2]. These mutations are usually inherited in an autosomal-dominant fashion. CFEOM2 is an isolated eye movement disorder consisting of ptosis, exotropia, and very limited vertical and horizontal eye movements. Pupils are small and minimally reactive. It results from homozygous loss-of-function mutations in PHOX2A, a transcription factor important in neuronal specification of the motor neurons in the oculomotor and trochlear nuclei [3]. It is inherited in

M. C. Whitman and E. C. Engle

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an autosomal-recessive manner. CFEOM3 has the most variable clinical presentation, and is caused by missense mutations in TUBB3, a neuron-specific tubulin monomer and a component of microtubules [4]. There is exquisite genotypephenotype correlation between specific TUBB3 missense mutations and clinical presentation. Certain amino acid substitutions, most commonly the R262C substitution, cause an isolated eye movement disorder consisting of limited vertical eye movements with or without ptosis, which can be unilateral or bilateral. Those cases are usually inherited autosomal dominantly. Other amino acid substitutions, including E410K and R262H, cause a complex neurological syndrome including severe limitations of vertical and horizontal eye movements, exotropia, ptosis, facial weakness, intellectual disability, peripheral neuropathy, and other features associated with particular mutations. These syndromic cases usually result from de novo mutations. Cases of ­syndromic CFEOM have also been reported with missense variants in two other tubulin monomers, TUBB2B and TUBA1A. Patients with syndromic CFEOM are often initially misdiagnosed with Moebius syndrome due to the combination of restricted eye movements and facial palsy, but there are important clinical distinctions. Moebius syndrome involves facial palsy with limitations of abduction, due to maldevelopment of cranial nerves six and seven. Moebius patients have esotropia or orthotropia in primary position. By contrast, syndromic CFEOM3 patients are exotropic and have limited adduction and vertical eye movements, due to involvement of cranial nerve three. Thus, a new definition for Moebius syndrome has been proposed: facial palsy, limitation of abduction, and normal vertical eye movements without ptosis.

Novel Insights The syndrome was named “congenital fibrosis of the extraocular muscles,” because it was assumed to be a primary extraocular muscle disorder. We now know that the primary pathology is neurogenic due to errors in cranial motor neuron or axon development, and the fibrosis of the muscles is secondary to missing innervation. PHOX2A mutations lead to defects of neuronal specification; Phox2a knock-out mice lack oculomotor and trochlear nuclei and MRI of CFEOM2 patients reveals hypoplastic or absent cranial nerves 3 and 4. KIF21A and TUBB3 mutations lead to abnormalities of peripheral axon guidance. Mice harboring the equivalent of the most common human Kif21a missense variant show misrouting of the oculomotor nerve, especially the superior branch, which innervates the superior rectus and levator muscles [5]. Similarly, mice harboring a Tubb3 human missense mutation display misrouting of the oculomotor nerve

[4]. It is particularly interesting that specific mutations in KIF21A and TUBB3 involving microtubules and a microtubule-­ associated protein cause similar phenotypes. For both these genes, the phenotype is not caused by loss of function, but rather the specific mutations alter the function of the encoded protein. For KIF21A, CFEOM-causing mutations disrupt autoinhibition of the protein, leading to unregulated overactivity. Most CFEOM-causing mutations in TUBB3 are in the region of the molecule that interacts with microtubule-associated proteins. Mutant tubulin monomers are incorporated into microtubules, and, counterintuitively, tubulin monomers with the mutations that cause the most severe phenotypes are incorporated more highly than those with mutations that cause less severe phenotypes. This indicates that the presence of the mutant tubulin within the microtubule disrupts microtubule function. Consistent with this, Tubb3 knockout mice that do not manufacture mutant tubulin have normal neuronal development. Both KIF21A and TUBB3 are widely expressed throughout the nervous system, and it remains unclear why the ocular motor nerves are specifically vulnerable to these particular mutations. The study of CFEOM has shown the important role that microtubules play in controlling axon guidance.

Clinical Pearls

• Facial weakness with exotropia and vertical gaze limitations is not Moebius syndrome, but instead is most likely a TUBB3 syndrome. • CFEOM patients are at high risk for corneal exposure: ptosis repair must be very conservative and PROSE lenses can be vision-saving. • Syndromic CFEOM requires referral to other specialties, particularly endocrinology to assess for and treat Kallmann syndrome.

References 1. Chew S, Balasubramanian R, Chan WM, et al. A novel syndrome caused by the E410K amino acid substitution in the neuronal beta-­ tubulin isotype 3. Brain. 2013;136(Pt 2):522–35. 2. Yamada K, Andrews C, Chan WM, et al. Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Nat Genet. 2003;35:318–21. 3. Nakano M, Yamada K, Fain J, et  al. Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nat Genet. 2001;29:315–20. 4. Tischfield MA, Baris HN, Wu C, et al. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell. 2010;140:74–87. 5. Cheng L, Desai J, Miranda CJ, et al. Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling. Neuron. 2014;82:334–49.

Duane Syndrome: An Infant with Crossed Eyes

22

Lauren C. Ditta

Case Presentation

Diagnostic Workup

A 10-month-old healthy Caucasian boy was referred from the pediatrician to evaluate inward crossing of the eyes, which the parents had noted for the past several months. The birth, medical, and family history was unremarkable, and the child was meeting all developmental milestones. There had been no report of an antecedent viral illness or trauma. On clinical examination, the child’s visual behavior was normal for age. Teller visual acuity preferential looking tests measured 4.8 cy/cm both eyes, and he objected equally to occlusion with either eye. On the sensorimotor examination, he did not appear to have an obvious esotropia in the primary position. However, there was moderate −3 limitation to abduction of the right eye. He had appropriate, symmetric facial animation, and there appeared to be no torticollis. His anterior and posterior segment examinations were unremarkable. The cycloplegic refraction revealed hyperopia of +1.00 diopter in each eye. The recommendation was made to observe the child closely, without any further treatment or diagnostic testing at this time. The family agreed with the plan and was amenable to close follow-up.

The patient was re-examined every 3–4  months during the following 2 years. He maintained normal, equal vision and continued to have a −3 limitation of abduction in the right eye with an esotropia of 25∆ in right gaze only. Other cranial neuropathies or new neurologic signs were not observed. At 2 years of age, he started to develop a head turn of approximately 20° to the right (Fig.  22.1). At 3  years old, there was a measurable right esotropia of 15–20∆ in primary position with left eye fixation preference (Fig. 22.2), and an increasingly larger head turn to the right. The horizontally incomitant deviation with limited abduction of the right eye is not consistent with an infantile or accommodative esotropia. Given the very early onset of the deviation without accompanying neurological findings and the absence of a marked esotropia in primary position, the interpretation was that this presentation was more consistent with a static, congenital oculomotor condition of Duane syndrome rather than an acquired cranial nerve VI palsy.

Differential Diagnosis

• • • •

Infantile esotropia Accommodative esotropia Duane retraction syndrome of the right eye Cranial nerve VI/abducens nerve palsy of the right eye

L. C. Ditta (*) Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA Le Bonheur Neuroscience Institute, Le Bonheur Children’s Hospital, Memphis, TN, USA St. Jude Children’s Research Hospital, Memphis, TN, USA e-mail: [email protected]

Fig. 22.1  An external photograph showing the child’s natural head position on routine visual acuity testing in the clinic. Note that there is a slight right head turn. By Hirshberg light reflex, the eyes appear to be aligned with this head posture.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_22

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Fig. 22.2  External photograph demonstrating that in forced primary head position, there is a slight deviation of the light reflex temporally in the right eye, consistent with a right, small-angle esotropia.

Final Diagnosis Duane retraction syndrome of the right eye

Clinical Discussion Treatment and Prognosis Duane syndrome or Duane retraction syndrome (DRS) is a congenital ocular movement disorder primarily caused by failed innervation to the lateral rectus muscle by the abducens nerve, along with aberrant innervation by the oculomotor nerve branches. Most cases of DRS are sporadic, unilateral, and occur more frequently in left eyes. Three types of DRS are commonly described; type 1, characterized by limited abduction and esotropia (most common), type 2 characterized by limited adduction and exotropia, and type 3 characterized by limited adduction and abduction. Although DRS generally presents as an isolated disorder, all types may accompany other syndromes such as Klippel-Feil, Goldenhar, hemifacial microsomia, and velocardiofacial syndrome [1]. The clinical features of type 1 DRS include abnormal horizontal eye movements, notably, a deficiency of abduction with esotropia in primary position, mimicking a sixth nerve palsy. There is palpebral fissure widening on abduction, possible mild reduction of adduction, and globe retraction on adduction, best identified by narrowing of the palpebral fissure due to cocontraction of the medial and lateral recti. Patients with type 1 esotropic DRS often manifest an esotropia when looking straight-ahead. However, the esotropic deviation is relatively small (particularly in unilateral cases)

L. C. Ditta

relative to the marked limitation of abduction. To maintain ocular alignment, patients often adopt a head turn toward the DRS eye. Children with DRS rarely complain of diplopia, often maintain good binocular vision with the slight head position, and usually do not develop amblyopia. Many patients do well and do not need surgery. Observation is preferred if the eyes are aligned with a mild head turn, especially in young children. A cycloplegic refraction should be performed on all children with esotropia to identify an accommodative component, which may partially correct residual esotropia. Indications for surgery include a large compensatory head posture or a manifest deviation that reduces binocular fusion or causes amblyopia. Additional considerations are large up-shoots (upward deviation of the eye) or down-shoots (downward deviation of the eye) or unacceptable globe retraction, which typically worsen over time. Specific surgical recommendations are beyond the scope of this chapter but include medial rectus recessions, vertical rectus muscle transpositions, or both [2, 3]. At 3.5 years of age, our patient underwent a right medial rectus recession of 6.5  mm for a persistent right head turn and an esotropia of 20∆. Intraoperatively, the medial and lateral rectus appeared anatomically normal. There was mild limitation to abduction in the right eye during forced duction testing. Postoperatively, the child maintained central, steady fixation with each eye, the head position improved, he was orthotropic, and he had excellent fusion. The patient and family have remained pleased with the outcome of surgery. As expected, he continued to have a −2 to −3 limitation of abduction and globe retraction with adduction of the right eye (Figs. 22.3, 22.4, and 22.5).

Fig. 22.3  External photograph of the patient 10 years following strabismus surgery demonstrating the stability of his alignment as orthotropic in primary position with improved torticollis.

22  Duane Syndrome: An Infant with Crossed Eyes

Fig. 22.4  An external photograph showing mild palpebral fissure narrowing with adduction of the right eye, which was more difficult to discern when he was an infant.

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In DRS, there is often marked limitation to abduction. However, patients may be orthotropic or have only a small strabismic deviation (usually an esotropia 30Δ) in primary position. Of course, ocular misalignment from Duane Syndrome should be present at birth although this may not be observed by the parents who mistakenly believe the deviation is acquired. Another consideration in these cases is that the abduction deficit may occur from medial rectus muscle restriction. A forced duction test should be considered to evaluate muscle restriction. The evaluation should assess for findings of trauma as well as elevated intracranial pressure. Physical examination should specifically address papilledema and hemispheric or posterior fossa neurological signs such as ataxia, nystagmus, or facial palsy. Neuroimaging, specifically an MRI of the brain with and without contrast, should be obtained. Based on the clinical findings, a lumbar puncture should be considered with measurement of opening pressure and hematological/infectious studies. The diagnosis of a benign complete sixth nerve palsy should be a diagnosis of exclusion and is characterized by acute onset, history of antecedent febrile viral illness or vaccination, absence of other cranial nerve dysfunction, absence of other neurological deficits, and absence of signs of intracranial hypertension. Patients with presumed benign sixth nerve palsy should be closely monitored for signs of underlying neurological disease.

Novel Insights Surgical treatment is considered when the underlying condition is addressed and there is a stable angle of deviation with no improvement for more than 6 months. It is important to analyze if there is residual lateral rectus function. In cases of residual lateral rectus function, the options include ipsilateral medial rectus recession plus lateral rectus resection. If there

C. M. Salgado and D. I. Paredes

is no residual function, vertical rectus muscle transposition can be performed [2]. The main purpose of vertical transpositions is to provide abduction tone to improve alignment. If there is some degree of residual function of the lateral rectus muscle, resection of that muscle will have fewer complications in comparison to transposition procedures [3]. The use of botulinum toxin in paralytic strabismus may result in a shorter recovery period, diminished contracture of the antagonist muscle, and correction of small chronic ­deviations. Botulinum injections of the medial rectus may be useful during surgical treatment of sixth nerve palsy with vertical transposition procedures in order to reduce the contracture of the ipsilateral medial rectus and avoid a three muscle incisional procedure [4]. A relatively new treatment under research is the use of bupivacaine in the paretic muscle. Bupivacaine selectively damages striated muscle, releasing growth factors that may play a role in new muscle fiber formation [5]. However, the results with this approach have been unpredictable.

Clinical Pearls

• An acquired sixth nerve palsy in the pediatric population should be considered an ominous sign of serious pathology such as neoplasia, intracranial hypertension, and head trauma until proven otherwise. In these circumstances, neuroimaging is essential toward identifying life-threatening etiologies. • Patching therapy and botulinum toxin injection are tools that treat amblyopia and medial rectus contracture respectively in the affected eye. • After the underlying neurological etiology is addressed, strabismus surgery with or without botulinum toxin may be performed with acceptable long-term results.

References 1. Park KA, Oh SY, Min JH, Kim BJ, Kim Y. Acquired onset of third, fourth, and sixth cranial nerve palsies in children and adolescents. Eye. 2019;33:965–73. 2. Liu Y, Wen W, Zou L, Wu S, Wang S, Liu R, et  al. Application of SRT plus MR recession in supra-maximal esotropia from chronic sixth nerve palsy. Graefes Arch Clin Exp Ophthalmol. 2019;257:199–205. 3. Gunton KB.  Vertical rectus transpositions in sixth nerve palsies. Curr Opin Ophthalmol. 2015;26:366–70. 4. Gómez de Liaño R. The use of botulinum toxin in strabismus treatment. J Binocul Vis Ocul Motil. 2019;69:51–60. 5. Scott AB, Miller JM, Shieh KR. Bupivacaine injection of the lateral rectus muscle to treat esotropia. J AAPOS. 2009;13:119–22.

Acute Acquired Comitant Esotropia: A Teenager with Acute-Onset Diplopia

27

Ryan R. House and Timothy W. Winter

Case Presentation A 13-year-old Hispanic female presented with approximately 4 months of symptomatic diplopia. She noticed sudden-­onset double vision one morning while her mother was driving her to school. The double vision seemed to come and go throughout the day, usually lasting for a few seconds to a few minutes; the only relief came with closing either eye. A review of the outside records from her optometrist indicated a history of mild myopic refractive error with no strabismus. The patient was referred to pediatric neuro-­ ophthalmology for further evaluation. There was no significant medical history and the review of systems was negative for headaches, head tilt, weakness, ptosis, or family history of strabismus. Best corrected visual acuity was 20/20-1  in each eye at distance and J1+ in each eye at near. The pupils were briskly reactive without afferent pupillary defect or anisocoria. Visual fields by confrontation were full in both eyes. Ishihara plate testing showed no color vision deficit. The anterior and posterior segment examination was unremarkable in each eye, with no optic nerve edema and a cup-to-disc ratio of 0.1. Although prior records indicated mild myopia, the cycloplegic refraction was plano in each eye. Extraocular motility was full in each eye. Stereo acuity was noted to be 5/10 circles corresponding to 250 seconds of arc. On Worth 4 Dot testing, the patient had diplopia at distance and fused at near. On the sensorimotor exam, there was an 18Δ esotropia (ET) in all cardinal gazes at distance on alternate prism cover testing (APCT) and 14Δ intermittent esotropia on APCT at near. A trial of prism adaptation was performed with 9Δ base out Fresnel prisms over each eye. With this in place, she had binocular single vision at distance and at near. R. R. House · T. W. Winter (*) Loma Linda University Eye Institute, Loma Linda University, Loma Linda, CA, USA e-mail: [email protected]

Differential Diagnosis

• Acquired, intermittent, alternating, nonaccommodative esotropia –– Primary, isolated form –– Secondary form related to intracranial pathology • Masked sixth nerve palsy • Neuromuscular disease such as Myasthenia Gravis, Lambert Eaton syndrome, or Miller Fisher variant of Guillain–Barre • Spasm of near reflex • Thyroid eye disease • Divergence insufficiency esotropia • Nonrefractive, accommodative esotropia (high accommodative convergence to accommodation ratio)

Diagnostic Workup Given the concern for possible intracranial pathology and/or neuromuscular disease, an extensive workup was conducted including magnetic resonance imaging (MRI) of the brain and serologic workup. MRI brain with and without gadolinium showed a simple retrocerebellar arachnoid cyst measuring 2.2 × 1.4 × 2.5 cm, and was otherwise normal (Fig. 27.1). Basic metabolic panel, acetylcholine-receptor-binding, acetylcholine-receptor-modulating, and acetylcholine-­ receptor-­ blocking antibodies, anti-MUSK antibody, anti-­ striational muscle antibody, antilipoprotein-receptor-related protein 4 (LRP4) antibody, antivoltage-gated calcium channel antibody, antiganglioside antibody panel, thyroid-­ stimulating hormone, free T4, thyroid-stimulating immunoglobulin, antithyroglobulin antibody, antithyrotropin receptor antibody, and antithyroperoxidase antibody were all within normal limits. Given normal neuroimaging, there is no evidence of compressive etiology of her strabismus. Standard results from an exhaustive serologic evalua-

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_27

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Fig. 27.1  T2-weighted axial MRI image demonstrating retrocerebellar arachnoid cyst.

tion and full motility of both eyes with comitance in all directions are not consistent with restrictive, paralytic, or neuromuscular disease. Comitance of the deviation at distance and near fixation is not consistent with divergence insufficiency or a high accommodative convergence to accommodation ratio. It was finally determined that the patient had a primary, acute, acquired, comitant, intermittent, alternating, nonaccommodative esotropia.

Final Diagnosis Acute acquired comitant esotropia (AACE)

Clinical Discussion Treatment and Prognosis Acute acquired comitant esotropia (AACE) is a form of nonaccommodative esotropia that develops after 6 months of age. Typical presentation is in older children and young adults [1], and has traditionally been subdivided into separate categories. The Swan type occurs as a result of disruption of fusion such as monocular occlusion, the Franceschetti type occurs in mildly hyperopic patients after illness or psychological stress, and the Bielschowsky type occurs in patients with a large degree of myopia and with a greater degree of deviation at distance than near [2]. Some authors have recommended reclassifying the Bielschowsky type as a form of divergence insufficiency [3]. This patient does not fit

neatly into any of these categories. There are reports that have described AACE as a sign of intracranial pathologies, including posterior fossa tumors and Chiari I malformations [3]. Additional studies have shown an association of AACE with excessive near work and smartphone use [3, 4]. Treatment and prognosis for AACE is varied with prisms, strabismus surgery, and botulinum toxin A all having been used successfully. Patients with Chiari I malformation should be evaluated and treated by neurosurgery prior to considering surgical correction of AACE, as the degree of deviation has been reported to change in some cases after decompression [3]. Many studies have shown recurrence of the esotropia after primary surgical repair [1, 5, 6], and therefore, several authors have suggested using prism adaptation prior to surgical planning [5, 6]. The role of botulinum toxin A to one or both medial rectus muscles has been increasing in popularity, with multiple studies showing successful results near or approaching traditional surgical correction of AACE [1, 3]. In this case, after a thorough diagnostic workup, which was normal, the patient underwent bilateral medial rectus recessions of 3.5 mm. The arachnoid cyst was interpreted to be an incidental finding. Postoperative measurements at 3 months showed fusion at near and distance with A (p.Arg1640Gln)

heterozygous

PATHOGENIC

ABCA4

c.5312+3A>T (Intronic)

heterozygous

PATHOGENIC

CLCC1

c.1600G>A (p.Ala534Thr)

heterozygous

Uncertain Significance

KIAA1549

c.899C>T (p.Pro300Leu)

heterozygous

Uncertain Significance

PEX2

c.635A>G (p.Asn212Ser)

heterozygous

Uncertain Significance

About this test This diagnostic test evaluates 293 gene(s) for variants (genetic changes) that are associated with generic disorders. Diagnostic genetic testing, when combined with family history and other medical results, may provide information to clarify individual risk, support a clinical diagnosis, and assist with development of a personalized treatment and management strategy.

Fig. 36.4  Inherited retinal dystrophy panel revealing two pathogenic heterozygous mutations of the ABCA4 gene (c.4919G > A, c.5312 + 3A > T).

Final Diagnosis Genetically confirmed Stargardt macular dystrophy with acquired neurosensory nystagmus

Clinical Discussion

Our patient was referred to Low Vision Services for a complete evaluation. She was prescribed a 6X handheld monocular telescope for distance visual demands, and she was coached through setting up the accessibility features on her tablet computer and smartphone. She and her family were also provided with educational resources about her condition and how to advocate for her in school and her extracurricular activities.

Treatment and Prognosis Stargardt macular dystrophy is the most common form of juvenile macular dystrophy. It is characterized by mutations in the ABCA4 gene, which encodes a transmembrane transport protein in photoreceptor outer segments [1]. ­ Malfunction in this protein results in accumulation of the lipofuscin-like material at the level of the retinal pigment epithelium cells resulting in a cascade of photoreceptor death and progressive central vision loss beginning in the first or second decade of life, deteriorating rapidly during teenage years, and plateauing with final visual acuity between 20/200 and 20/400 in adulthood [2]. Treatment for Stargardt macular dystrophy is limited and remains controversial, though there are novel adenovirus-associated vector-targeted gene therapies that may be available in the near future. Meanwhile, management of patients has focused on limiting exposure to bright light to reduce retinal damage (by reducing the rate of formation of all-trans retinol in photoreceptors), avoiding smoking tobacco, and maximizing the patient’s visual experience through low vision aids.

Important Aspects of the Diagnosis This case helps illustrate the diagnostic value of detecting acquired nystagmus in cases of vision loss. In cases of early-­ onset inherited retinal dystrophy or other anterior visual pathway pathology with subtle or absent fundus changes, the finding of acquired nystagmus is of critical diagnostic value. Visual system disorders generate nystagmus either because the loss of visual inputs to the fixation system leads to an inability to detect and correct ocular drift, or because the loss of visual signals degrades the long-term tuning of the ocular motor system responsible for maintaining stability. In the first mechanism—the mechanism more likely associated with our patient’s acquired nystagmus—an increase in latency of the visually mediated eye movements beyond 70 ms outpaces the brain’s capacity to generate compensatory stabilizing movements and creates a compounding retinal error. In the latter mechanism, the ongoing degraded retinal image from a progressively compromised visual sys-

36  Nystagmus Associated with a Retinal Dystrophy: A Teenager with Vision Loss and Eye Shaking

197

tem deprives the cerebellum of the necessary feedback to continuously calibrate and optimize eye movements [3]. Disorders of the anterior visual pathway eventually reach a nadir of visual acuity, and regardless of the mechanism of acquired nystagmus thereafter, there is an impetus to minimize the further propagation of the retinal error through mitigation of the residual nystagmus. This residual acquired nystagmus can be managed in three ways: with optical correction, medical therapy, or surgical intervention. The primary benefit of optical correction with spectacles is to minimize retinal blur and maximize visual acuity during periods of foveation. In cases of acquired nystagmus that have a null point or damp with convergence, a secondary benefit of spectacle correction is realized by introducing prism correction to compensate for anomalous head position associated with a null point or to induce convergence to damp nystagmus. Spectacle correction can also be used in combination with contact lens correction, which has been independently shown to modulate nystagmus through biofeedback mechanisms. A combination of high plus spectacle correction to induce myopia with high-minus contact lens to neutralize the induced myopia can negate a significant portion of the negative visual effects of eye movements [4]. Surgical intervention can be a useful adjunct in the management of acquired nystagmus once visual deterioration has stabilized, and especially in cases that demonstrate anomalous head posture or nystagmus that damps with convergence. In the former, the Anderson–Kestenbaum four-muscle technique, involving recession and resection of the horizontal rectus muscles, is used to broaden the null zone (total area where nystagmus’s oscillations are most damped or minimized with resultant increased foveation time and best vision) and minimize the head turn. In the latter, the medial rectus muscles are recessed to generate some divergence and stimulate convergence with the aim of damping the nystagmus. More recently, theories on the role of proprioceptive feedback from extraocular muscles on nystagmus waveforms have led to the use of tenotomy/reattachment procedures to disrupt the feedback loop and mitigate nystagmus [4].

competitive N-methyl-d-aspartate (NMDA) antagonists like memantine (Namenda), and anticonvulsants like vigabatrin (Sabril) have all been reported to improve acquired nystagmus as well but must be used judiciously in children due to the risk of severe and potentially debilitating side effects ranging from drowsiness and somnolence to ataxia, confusion, and behavioral problems [4, 5]. In the absence of large-scale clinical trials demonstrating efficacy of any of these treatments, the use of medical therapy for the primary indication of nystagmus in children remains controversial. Gene therapy is an emerging avenue for medical therapy in cases of acquired nystagmus secondary to heritable retinal dystrophies like Leber congenital amaurosis. Treatment of the underlying dystrophy has produced improvement in nystagmus along with improvement in vision [5].

Novel Insights

References

While medical therapy is NOT indicated for the primary treatment of acquired nystagmus in the pediatric population, there are medications that have been reported to improve other types of nystagmus. Agonists of the neurotransmitter γ-aminobutyric acid (GABA) like clonazepam, gabapentin, and baclofen have been reported to improve both up- and downbeat nystagmus, though a double-masked trial comparing the latter two did not demonstrate this consistently. Anticholinergic drugs like trihexyphenidyl (Artane), potassium channel blockers like dalfampridine (Ampyra), non-­

1. Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH. Insights into the function of Rim protein in photoreceptors and etiology of Stargardt’s disease from the phenotype in abcr knockout mice. Cell. 1999;98:13–23. 2. Sullivan JM, Birch DG, Spencer R.  Chapter 11: Pediatric hereditary macular degenerations. In: Reynolds JD, Olitsky SE, editors. Pediatric retina. Berlin: Springer-Verlag; 2011. p. 245–95. 3. Stahl JS, Averbuch-Heller L, Leigh RJ. Acquired nystagmus. Arch Ophthalmol. 2000;118:544–9. 4. Thurtell MJ, Leigh RJ. Treatment of nystagmus. Curr Treat Options Neurol. 2012;14:60–72. 5. Rucker JC. An update on acquired nystagmus. Semin Ophthalmol. 2008;23:91–7.

Clinical Pearls

• Pediatric acquired nystagmus with vision loss should prompt a comprehensive investigation with a detailed funduscopic examination and when possible or necessary, ancillary testing, including fundus autofluorescence, optical coherence tomography, electrophysiology, and neuroimaging. • Upon visual stabilization, acquired nystagmus due to retinal dystrophy can be treated with optical aids, medical therapy, and/or surgical therapy to minimize the propagation of retinal error and improve visual experience. • Stargardt macular dystrophy is the most common form of juvenile macular degeneration, clinically characterized by progressive central vision loss beginning in the first or second decade of life and ending with a final visual acuity ranging between 20/200 and 20/400 in adulthood. Though treatment options are currently limited, there are novel gene therapies on the horizon.

Downbeat Nystagmus: A Teenager with Downbeat Nystagmus

37

Loulwah Mukharesh and Joseph F. Rizzo

Case Presentation A 17-year-old woman presented for a routine eye exam and was found to have asymptomatic downbeat nystagmus that did not prompt a diagnostic evaluation. Seven years later, she developed constant vertical oscillopsia, which caused difficulty with depth perception, impaired sense of balance, and inability to see clearly. She also developed occasional frontal headaches. Her past medical history included anxiety and obsessive-compulsive disorder, which were well controlled using sertraline. The past ocular history was notable for a right esotropia that was treated with bifocal glasses and patching at 2 years of age, and then strabismus surgery at 5 years of age with a good surgical and clinical outcome. Her family history was negative for ophthalmologic and neurologic diseases. Her review of systems was otherwise non-contributory. The neuro-ophthalmic examination revealed best corrected visual acuities of 20/30 + 1 right eye and 20/60 left eye. Ishihara color vision testing was normal in both eyes. There was physiologic anisocoria. The left pupil was 0.5 mm larger than the right pupil in both light and dark. Pupils were briskly reactive with no relative afferent pupillary defect. Automated visual field testing was within normal limits. The ocular motility examination revealed full ductions. The eye movements were characterized by a binocular, conjugate, downbeat nystagmus that was present in primary position and became more prominent in all directions of gaze, especially on downgaze obliquely to the right or left (Video

37.1). The sensorimotor examination revealed a comitant exotropia of 4Δ in all directions of gaze at distance and on primary gaze at near. Worth-4-dot testing demonstrated left eye suppression at distance and near. Dilated funduscopy revealed normal bilateral optic nerve heads and retina. An abbreviated neurological examination revealed right-sided hyperreflexia, right-sided clonus of the foot, and an extensor plantar reflex on the right. Further workup was pursued to evaluate the etiology of her downbeat nystagmus and right-sided long tract signs of corticospinal damage.

Differential Diagnosis

• Idiopathic • Structural central nervous system lesions (e.g., cervicomedullary junction due to Arnold-Chiari malformation, platybasia, basilar impression) • Inflammatory/infectious (e.g., demyelination, brainstem encephalitis, cerebellitis) • Ischemic • Neoplastic/paraneoplastic (e.g., anti-glutamic acid decarboxylase GAD-65 associated diseases) • Neurodegenerative (e.g., spinocerebellar ataxia, episodic ataxia type 2, multiple system atrophy) • Nutritional (e.g., thiamine deficiency leading to Wernicke encephalopathy, magnesium deficiency) • Toxins (e.g., alcohol, recreational drugs) or medications (e.g., lithium, anticonvulsants)

Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/978-­3-­031-­16147-­6_37.

L. Mukharesh · J. F. Rizzo (*) Neuro-Ophthalmology Service, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear, Boston, MA, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_37

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L. Mukharesh and J. F. Rizzo

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Diagnostic Workup

2. Vitamin levels such as thiamine. 3. Blood alcohol or medication levels, especially lithium and antiepileptic drugs, depending on the clinical context. 4. Magnesium levels. 5. Paraneoplastic panel and/or anti-glutamic acid decarboxylase-­65 (GAD-65) antibodies (under plausibly relevant circumstances).

Since this patient developed symptoms secondary to downbeat nystagmus and had right-sided long tract signs of corticospinal damage, prompt magnetic resonance imaging (MRI) of the brain, with and without contrast, was obtained. The neuroimaging (Fig. 37.1) showed a 26-mm downward displacement of the cerebellar tonsils, with significant crowding at the foramen magnum and compression of the dorsal aspect of the cervicomedullary junction (Arnold-­ Chiari malformation), without hydrocephalus. Following neurosurgical consultation, a suboccipital craniectomy with posterior decompression of the C1 and C2 vertebrae was performed. A repeat cervical MRI 1  month after surgery (Fig. 37.2) showed reduced mass effect on the posterior margin of the cervicomedullary junction and proximal cervical spinal cord. After surgery, there was gradual reduction in nystagmus and oscillopsia, and by 12  months after surgery, the nystagmus was no longer evident, and the patient did not report oscillopsia. MRI must be performed in all cases with downbeat nystagmus. In this case, MRI was performed promptly because of her progressive course of symptoms and the finding of long-tract (i.e., corticospinal) signs. A more extensive diagnostic investigation is not needed if a structural cause is found on neuroimaging. If neuroimaging does not identify an etiology, the more Fig. 37.2  Sagittal T2 STIR-weighted MRI of the cervical spine showextensive workup could include: 1. Careful neurologic examination looking for subtle focal neurologic deficits that might guide the workup for underlying etiology.

a

ing postsurgical appearance following the suboccipital craniectomy and posterior decompression of C1 and C2 vertebrae. The surgery removed the mass effect on the posterior aspect of the cervicomedullary junction and proximal cervical spinal cord. There was evidence of a small pseudomeningocele at the site of the suboccipital craniectomy (red arrow).

b

Fig. 37.1  Sagittal T1-weighted MRI of the brain with gadolinium contrast depicting a 26-mm cerebellar tonsillar herniation through the foramen magnum (a, yellow rectangle). There is indentation of the dorsal cervical spinal cord (b, red arrows) by the cerebellar tonsils.

37  Downbeat Nystagmus: A Teenager with Downbeat Nystagmus

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6. Cerebrospinal fluid (when suspecting brainstem encephalitis or paraneoplastic etiologies). 7. Full body computed tomography (CT), testicular ultrasound, and/or positron emission tomography (PET/CT) if a paraneoplastic etiology is suspected. 8. Genetic testing in consideration of spinocerebellar degeneration.

treatment of DBN in the setting of anti-glutamic acid decarboxylase (GAD) antibodies. After 6 months of neurosurgical intervention, her visual acuities improved to 20/20–2 each eye. The downbeat nystagmus was no longer evident on primary gaze, and there was a subtle oblique nystagmus on downgaze which was best appreciated through slit lamp examination.

Final Diagnosis

Important Aspects of the Diagnosis

Downbeat nystagmus secondary to an Arnold-Chiari malformation

The majority of cases of downbeat nystagmus have an identifiable etiology, the most common of which (20% of the time) is a cerebellar degeneration (usually spinocerebellar ataxia, although multisystem atrophy and sporadic adult-­ onset ataxia can present similarly). Vascular lesions and an Arnold-Chiari malformation account for roughly 10% of cases each. Notably, around 40% of cases remain idiopathic, although this number depends on the extent of diagnostic evaluation [2]. A normal brain MRI with CSF pleocytosis and elevated protein may lead to the suspicion of a paraneoplastic etiology, especially in the setting of a prior history of malignancy [3]. Typical paraneoplastic antibodies include anti-Hu (also known as ANNA-1), but a novel antibody (i.e., Kelch-like protein-11 (KLHL11) antibody) associated with occult germ-cell tumors has been reported to cause sensorineural hearing loss, ataxia, and DBN [3]. In cases where there is no identifiable pathology on high-­ quality MRI including sagittal images, diagnostic testing is often negative [1, 4]. One study of 50 patients with presumed idiopathic DBN included 23 patients who also had ataxia on their neurological examination; in these DBN patients, 12 were found to have cerebellar degeneration, one patient had a cervicomedullary cavernoma, and one had a supratentorial infarct, while the remainder had normal neuroimaging [4]. Serological testing for antibodies in these same patients revealed eight (16%) with positive GAD-65 antibodies [4]. Paraneoplastic panel testing revealed only one patient with P/Q-type voltage-gated calcium channels, and one patient with anti-striational muscle antibodies [4]. In conclusion, it may be more cost-effective to defer paraneoplastic panel testing in patients with idiopathic downbeat nystagmus, but one may consider sending for GAD-65 antibodies. The mechanism of DBN is believed to be reduced activity of the Purkinje cells (PCs) of the cerebellum, which leads to symmetric hypofunction of the flocculus or paraflocculus, which results in a conjugate slow upward drift of the eyes followed by fast corrective downward saccades [2]. The main visual consequence of downbeat nystagmus is oscillopsia and inability to maintain foveal fixation. The latter often causes subnormal visual acuities. The management depends on the etiology, with discontinuation of any possible offending agents, repletion of potential vitamin deficiencies, surgical intervention if a structural etiology is present, or

Clinical Discussion Treatment and Prognosis Downbeat nystagmus (DBN) is a relatively uncommon form of “jerk” nystagmus in which the fast phase is directed downwardly [1]. DBN is either “primary” (i.e., idiopathic), or “secondary” to an identifiable pathology [1, 2]. DBN presents with gait imbalance in approximately 80% of cases, and oscillopsia in about 40% of cases [2]. Patients may also present with diplopia and “blurred vision,” even though most patients have normal central visual acuity. Higher amplitude nystagmus, however, often degrades acuity. The prognosis of DBN is variable and dependent on the etiology. Discontinuation of any offending agents, such as alcohol, lithium, or anti-epileptics, may be effective in reducing or eliminating symptoms although some cases of lithium toxicity are notoriously persistent. When an anti-epileptic medication is causative, a therapeutic balance must be sought between seizure control and mitigation of oscillopsia while transitioning to some other anti-seizure medication. Thiamine supplementation is mandatory for patients presenting with ophthalmoplegia, ataxia, and confusion in the context of Wernicke’s encephalopathy. Surgical decompression for structural causes that are potentially correctable such as ArnoldChiari malformation is usually curative, such as in our case. Decompression surgery generally is not performed for relatively small (i.e., < 8 mm) tonsillar herniations. Other structural causes that are not amenable to surgical intervention such as cerebellar/brainstem strokes or hemorrhages have a poorer prognosis. Identification of a paraneoplastic etiology must direct therapeutic strategies to the primary tumor. Given that most patients with DBN are symptomatic, use of potentially beneficial medical intervention should be considered. Medications such as 4-aminopyridine and 3,4-­ diaminopyridine are generally the most effective. However, other medications that should be considered include clonazepam, baclofen, and gabapentin. Intravenous immunoglobulin (IVIG) infusions can also be considered for

202

medical treatment including 4-aminopyridine (which is a potassium channel blocker that alleviates DBN by increasing the inhibitory output of the floccular Purkinje cells on the vestibular nuclei) [2].

Novel Insights Novel treatments that have not been substantiated by more than one group include noninvasive techniques and targeted local injections. Examples of non-invasive therapeutic techniques include using real-time computer-based visual feedback or resting in a dark environment for 2  hours, which resulted in improved visual acuity in 50% of patients and 33% of patients, respectively [5]. Unconventional surgical techniques that aim to fixate the globe and therefore reduce the nystagmus amplitude, and hence oscillations, include inserting an oculomotor prosthesis or implanting a titanium T-plate securely into the lateral orbital rim while maintaining alignment with the inferior rectus muscle insertion [5]. Retrobulbar botulinum-toxin A injections have also been demonstrated to help improve nystagmus and oscillopsia [5].

Clinical Pearls

• A careful history and detailed neurologic and ophthalmologic examination can alter the diagnostic pathway using a tier-based approach in testing, which can ultimately reduce unnecessary testing, patient inconvenience, and financial burden. • Downbeat nystagmus due to medications can occur in cases of supratherapeutic levels (e.g., oxcarbazepine) or therapeutic doses (e.g., pregabalin and lithium). • Treatment of DBN depends on the etiology and ranges from medical treatment with oral medications (such as 4-aminopyridine), immune-­ modulation (such as IVIG), and surgical treatments (such as posterior decompression in Arnold-Chiari malformation).

L. Mukharesh and J. F. Rizzo

References 1. Cogan DG.  Down-beat nystagmus. Arch Ophthalmol. 1968;80:757–68. 2. Wagner JN, Glaser M, Brandt T, Strupp M. Downbeat nystagmus: etiology and comorbidity in 117 patients. J Neurol Neurosurg Psychiatry. 2008;79:672–7. 3. Kattah JC, Eggers SD, Bach SE, Dubey D, McKeon AB.  Paraneoplastic progressive downbeat nystagmus, ataxia and sensorineural hearing loss due to the ANTI-Kelch-11 protein antibody. J Neuroophthalmol. 2021;41(2):261–5. Epub ahead of print. PMID: 33630775. 4. Abbasi B, Gupta AS, Stephen CD, Bouffard MA, Schmahmann JD, Chwalisz BK.  Diagnostic evaluation of downbeat nystagmus: an update. Poster presented at the North American Neuro-­ Ophthalmology Society 2021 Annual Meeting. 5. Tarnutzer AA, Straumann D.  Nystagmus. Curr Opin Neurol. 2018;31:74–80.

Opsoclonus Myoclonus Syndrome: A Child with “Jumping Vision”

38

James O’Brien and R. Michael Siatkowski

Case Presentation A previously healthy 12-year-old girl presented to the emergency department due to her vision “jumping” while trying to focus or read for the past 2 weeks. Six weeks before, she experienced fever and sore throat, followed by generalized seizures, and she was evaluated in the emergency department by the neurology service. Magnetic resonance imaging (MRI) of the brain demonstrated broad areas of increased T2 signal in the left frontal, parietal, and occipital lobes with diffusion restriction. A lumbar puncture revealed lymphocytic pleocytosis, elevated protein, elevated IgG synthesis rate, and elevated opening pressure. She was ultimately diagnosed with aseptic meningoencephalitis and discharged from the hospital on a regimen of levetiracetam and acyclovir with follow-up in the neurology outpatient clinic. At her follow-up appointment with neurology, she reported that although she no longer had any seizures, she had subsequently developed involuntary muscle contractions and leg weakness, and she reported falling several times. In addition, her visual symptoms persisted and were worsening. For this reason, she was re-admitted for additional work-up and evaluation, and the Pediatric Neuro-Ophthalmology service was consulted at this time. On examination, the visual acuity was 20/20 in each eye without correction. The motility examination revealed normal ductions and versions. However, there were intermittent bursts of shimmering binocular, conjugate saccadic eye movements, which were multidirectional and seemingly random, consistent with opsoclonus (Video 38.1). Pupils, color Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/978-­3-­031-­16147-­6_38.

plates, confrontation visual fields, intraocular pressures, ocular alignment, anterior segment, and dilated fundus examinations were all normal.

Differential Diagnosis

• Opsoclonus myoclonus syndrome –– Paraneoplastic syndrome secondary to: Neuroblastoma Small cell lung carcinoma Other malignancies (e.g., breast, gastric, renal, gynecologic) –– Post-infectious/post-vaccination inflammatory syndrome • Demyelinating disease –– Acute disseminated encephalomyelitis (ADEM) –– Multiple sclerosis –– Neuromyelitis optica –– Anti-MOG antibody syndrome • Meningitis/encephalitis –– Viral (e.g., West Nile virus, varicella zoster virus, cytomegalovirus, human herpes virus 6, HIV, hepatitis C virus, influenza) –– Bacterial (e.g., mycoplasma, salmonella) • Toxic/metabolic disease –– Lithium toxicity –– Phenytoin toxicity –– Cocaine intoxication –– Diabetic hyperosmolar syndrome • Traumatic (e.g., diffuse axonal injury) • Idiopathic • Volitional ocular flutter

J. O’Brien (*) · R. M. Siatkowski Department of Ophthalmology, Dean McGee Eye Institute/ University of Oklahoma College of Medicine, Oklahoma City, OK, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_38

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Diagnostic Workup The patient underwent repeat MRI of the brain and MRI of the spine, which re-demonstrated the broad areas of abnormal T2 signal and diffusion restriction in the left frontal, parietal, and occipital lobes with slight interval increase in size, as well as patchy enhancement within the cervical spinal cord extending from C3 to T1. Repeat lumbar puncture again revealed elevated CSF WBCs (106) with lymphocytic predominance (90%), elevated IgG synthesis, and an elevated opening pressure of 35  cm H2O.  There were no oligoclonal bands, the viral encephalitis PCR panel was normal, and viral and bacterial cultures were negative. Due to concern for a paraneoplastic syndrome, MRI of the chest, abdomen, and pelvis was performed. A pelvic exam, Pap smear, and fecal occult blood test were also performed. All results were normal. A serum paraneoplastic panel was ordered and was negative (including anti-neuronal antibody, Purkinje cell antibody, collapsin response mediator protein (CRMP-5), anti-glial nuclear antibody (AGNA-1), calcium channel antibodies, and potassium channel antibodies). Extensive additional testing was performed to assess for underlying autoimmune or infectious disease, including aquaporin-4 antibody, ANCA, ACE, ANA, serum protein electrophoresis, Hepatitis B virus (HBV), Hepatitis C virus (HCV), C3, C4, rheumatoid factor, urinalysis, and urine protein electrophoresis. All test results were normal.

Final Diagnosis Opsoclonus myoclonus syndrome in the setting of acute disseminated encephalomyelitis (ADEM)

Clinical Discussion Treatment and Prognosis Treatment of opsoclonus myoclonus syndrome, regardless of etiology, consists of immunosuppression to address the underlying immune-mediated pathophysiology. Treatment of an underlying malignancy, when present, is also necessary. However, it is notable that treatment of neuroblastoma alone does not consistently improve the neurologic outcomes of patients with associated opsoclonus myoclonus syndrome, and immunosuppression is usually necessary to treat the latter. Traditionally, medical treatment for opsoclonus myoclonus syndrome included corticosteroids or corticotropin (ACTH). More recently, treatment strategies have expanded to include intravenous immunoglobulin (IVIg), rituximab,

J. O’Brien and R. M. Siatkowski

cyclophosphamide, azathioprine, and plasma exchange. There is evidence that a multi-modal approach has better neurologic outcomes than monotherapy with corticotropin or corticosteroid-based treatments alone. Patients may follow either a mono- or multi-phasic disease course, with the latter group having a poorer prognosis in terms of neurologic function. Long-term neurologic sequelae may include motor, speech, cognitive, sleep, developmental, or behavioral disturbances. Patients frequently require multi-disciplinary rehabilitative care with physical, occupational, and/or speech therapists. For patients with neuroblastoma, the presence of opsoclonus myoclonus is associated with a better survival prognosis and a greater likelihood of localized, lower-grade tumors with more favorable genetic and histologic profiles. The paraneoplastic autoimmune reaction that induces the opsoclonus may also attack the tumor, resulting in the improved survival prognosis. In contrast, neuroblastoma patients without opsoclonus myoclonus syndrome are more likely to have metastatic disease at diagnosis and have a poorer 3-year survival rate. While approximately half of pediatric patients with opsoclonus myoclonus have an underlying neuroblastoma, only a small minority (approximately 2%) of patients with neuroblastoma will develop opsoclonus myoclonus syndrome. In this case, during the patient’s admission, she received intravenous methylprednisolone (1000  mg per day for 5 days) and experienced improvement in her symptoms. She was discharged home on an oral prednisone taper, with planned follow-up with neurology and ophthalmology. At follow-up in our clinic 6 weeks later, her visual symptoms were minimal, with only mild, infrequent oscillopsia and improvement of her opsoclonus. She did not experience any recurrence of her other symptoms.

Important Aspects of the Diagnosis Opsoclonus myoclonus syndrome is a rare disorder affecting approximately 1/1,000,000 persons, with an annual incidence of approximately 1/5,000,000. Patients present with the subacute onset of ataxia, which is usually followed by myoclonic jerking of the limbs, and opsoclonus. Sleep or behavioral disturbances are also frequently seen. These symptoms are frequently preceded by a viral-like prodrome. When opsoclonus is not initially present, there may be a delay in timely diagnosis, and patients are often initially misdiagnosed (acute cerebellitis and Guillain-Barre syndrome are common initial diagnoses), which may delay timely treatment initiation [1]. There are no specific diagnostic tests for opsoclonus myoclonus syndrome, and it remains a clinical diagnosis. However, patients with opsoclonus myoclonus syndrome

38  Opsoclonus Myoclonus Syndrome: A Child with “Jumping Vision”

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require thorough testing to investigate for a potential underlying paraneoplastic syndrome and malignancy, after first excluding a primary central nervous system disorder. In children, especially those between ages 1 and 3 years, the chief concern is an associated neuroblastoma; adults may have an associated small cell lung carcinoma, breast adenocarcinoma, or ovarian teratoma. Children with opsoclonus myoclonus should undergo magnetic resonance imaging of the brain, spine, neck, thorax, abdomen, and pelvis to evaluate for demyelinating disease and to assess the sympathetic pathway and adrenal glands for evidence of neoplasia. Metaiodobenzylguanidine (MIBG) scintigraphy is another testing modality which can be helpful when first-line modalities are equivocal for the presence of a catecholamine-­ secreting tumor such as neuroblastoma. Lumbar puncture with cerebrospinal fluid analysis may reveal B-cell pleocytosis and can be helpful to exclude the presence of a central nervous system infection. The catecholamine metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA) are present in the urine of neuroblastoma patients in as many as 95% of cases, making these tests helpful for confirmation of a neuroblastic tumor. Not all tumors may produce these metabolites, however, and therefore these assays should not be relied on alone for diagnostic purposes due to the potential for false negative results. Lastly, there are no specific, reliable, or clinically useful serologic markers for opsoclonus myoclonus syndrome; however, there are reports of associated anti-Purkinje, anti-­ neuronal, and anti-Hu antibodies in some patients. Opsoclonus is arguably the most distinctive and prominent feature of opsoclonus myoclonus syndrome and must be distinguished from other eye movement disorders such as nystagmus or other varieties of saccadic intrusion. Nystagmus, by definition, is characterized by an initial slow movement away from fixation, which may be followed by either a rapid re-fixation saccade (jerk nystagmus) or another slow phase (pendular nystagmus). Opsoclonus and the other saccadic intrusions, alternatively, do not contain any slow phases and consist entirely of rapid saccadic eye movements. Square-wave jerks are a type of saccadic intrusion which only consist of horizontal movements away from and back to fixation with a brief intervening pause (intersaccadic interval). In contrast, ocular flutter consists of horizontal movements but lacks an intersaccadic interval. Eye movements similar to ocular flutter may be consciously produced and are termed volitional “nystagmus” (a misnomer due to the lack of a slow phase, but still commonly in use). Lastly, opsoclonus is multi-directional and may contain horizontal, vertical, and torsional vectors. The multi-directionality sets it apart from the other saccadic intrusions. It should be noted that ocular flutter and opsoclonus may fall along a spectrum, and ocular flutter may need to be monitored for progression to

opsoclonus in the appropriate context. Square wave jerks have not been reported to date as a precursor to the opsoclonus myoclonus paraneoplastic syndrome.

Novel Insights Opsoclonus myoclonus syndrome is thought to be an immune-mediated reaction targeting central nervous system tissues in the cerebellum and/or brainstem. An imbalance between omnipause and burst cell activity is the underlying pathophysiology of opsoclonus. This may occur via disinhibition of ocular motor neurons due to dysfunction of Purkinje cells in the cerebellar vermis and cerebellar caudal fastigial nucleus. The Purkinje cells normally provide inhibitory input to the cells of the caudal fastigial nucleus, the latter being responsible for the initiation of saccadic eye movements by projecting to pontine burst neurons. Therefore, this disinhibition ultimately manifests as the involuntary saccadic movement of opsoclonus. Conversely, the brainstem burst neurons may become disinhibited due to dysfunction of their respective inhibitory omnipause cells. Omnipause cells receive excitatory and inhibitory input from the superior colliculus, and it is postulated that dysfunction of the omnipause cells causes disinhibition of saccadic burst neurons. Functional neuroimaging provides further evidence that there is dysfunction of these regions of the ocular motor pathways. One study found that there is substantially increased glucose metabolism in the cerebellar tonsils and fastigial nuclei on FDG-PET imaging in the setting of opsoclonus myoclonus, which could suggest that this is the origin of the abnormal saccades. Alternatively, the authors speculate that this increased activity could be an effort to suppress the involuntary movements via the cerebellar oculomotor pathways [2]. An immune-mediated pathophysiology is supported by evidence that patients will frequently have B-cell pleocytosis on cerebrospinal fluid analysis. Furthermore, some patients with opsoclonus myoclonus syndrome demonstrate positivity for anti-neuronal, anti-Purkinje, or anti-Hu autoantibodies, although it should be noted that not all patients are seropositive for such antibodies. For example, one series found that 81% of patients with neuroblastoma-related opsoclonus myoclonus had anti-neuronal IgG antibodies, whereas only 25% of neuroblastoma patients without opsoclonus myoclonus were positive for such antibodies. Rates of positivity for anti-neuronal IgM antibodies were lower for both groups, 19% and 23%, respectively. Anti-Hu antibodies were detected in only 25% of the patients with paraneoplastic opsoclonus myoclonus [3]. Ultimately, future studies to identify areas of neurologic dysfunction or biomarkers of opsoclonus myoclonus will help better define its exact pathophysiology.

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In the setting of neuroblastoma, opsoclonus myoclonus syndrome is associated with lower grade tumors and a more favorable survival prognosis. One study found that 90% of neuroblastoma patients with opsoclonus myoclonus syndrome had localized or non-metastatic tumors, while those without the syndrome had non-metastatic disease only 35% of the time [4]. Patients with opsoclonus myoclonus syndrome had a 3-year survival rate of 100% in the study, whereas those without opsoclonus myoclonus syndrome had a less favorable survival rate of 77% [4]. Additionally, the same group found that patients with opsoclonus myoclonus syndrome and neuroblastoma tend to have tumors with more favorable genetic and histologic characteristics when compared to those without the syndrome [5]. Despite having a favorable survival prognosis, opsoclonus myoclonus syndrome does have a more guarded neurologic prognosis. Patients are likely to have long-term problems with motor, cognitive, speech, sleep, or behavioral functions, and there should be involvement of physical, occupational, and speech therapists as well as special educators in their care. There is evidence that multimodal medical treatment of opsoclonus myoclonus syndrome has more favorable neurologic outcomes when compared to corticosteroids or corticotropin alone. Patients will likely require chronic treatment to help prevent relapses. Future clinical trials will be helpful for determining a “gold standard” treatment algorithm. A randomized, prospective, multi-center trial found that patients with opsoclonus myoclonus syndrome and neuroblastoma, when treated with IVIG in addition to prednisolone and chemotherapy, had greater therapeutic response, according to a standardized severity score, than patients treated without the addition of IVIG (80.8% versus 40.7%, respectively). This suggests that a combination immunosuppressive treatment approach is likely of greater benefit to patients [6]. Another study compared the neurologic outcomes between a cohort of 15 new (nine of whom had opsoclonus in the setting of neuroblastoma) and 23 previously reported patients with comparable clinical profiles [7]. They found that longterm neurologic assessment scores were superior in the 15 patients treated more recently with more aggressive immunosuppression (using agents such as rituximab, cyclophosphamide, or azathioprine in addition to corticotropin-­ based therapies and IVIg) when compared to the 23 patients who were treated with corticotropin or steroids and IVIg without additional agents [7]. The authors specifically mention that rituximab was used at a significantly higher rate in patients with the better outcomes, and its B-cell depleting mechanism of action is attractive as a therapeutic option given the suspected humoral immune-mediated pathophysiology of opsoclonus myoclonus syndrome. Notably, no patients in the more recent and more aggressively treated cohort had spontaneous, observable opsoclonus at their follow-­ up

J. O’Brien and R. M. Siatkowski

assessment, indicating a favorable recovery profile for this aspect of the syndrome. Patients who responded to treatment demonstrated improvement at a median of 5  weeks after initiation (range 1  day–8  weeks). The same research group performed an earlier longitudinal follow-up study of neurologic, behavioral, and cognitive functioning of a cohort of 19 patients between 2 and 4  years following their initial diagnosis [8]. The patients showed improvement over time in terms of these variables; however, there were greater improvements in patients without disease relapse. Unfortunately, most patients (74%) followed a relapsing, multi-phasic course, with relapses usually occurring during tapering of corticotropin or corticosteroids, or when an additional subsequent illness occurred such as a respiratory infection. Only a minority of patients experienced a more favorable monophasic course. Most patients in this latter group were observed at an age-appropriate level in terms of neurologic, cognitive, and academic assessments at follow-­up. This suggests that relapses are an important long-term negative prognostic factor. There were no identifiable predictors of disease relapse, including the severity of the presenting illness, and this remains an area of interest for future studies.

Clinical Pearls

• Opsoclonus myoclonus syndrome is an immune-­ mediated disorder, which, in about half of pediatric cases, can be attributed to a paraneoplastic syndrome related to neuroblastoma. • Patients with opsoclonus myoclonus syndrome related to neuroblastoma have a more favorable survival prognosis but a more guarded neurologic prognosis. Regardless of etiology, patients may have long-term motor, speech, cognitive, or behavioral deficits requiring ongoing rehabilitative care. • Opsoclonus myoclonus syndrome requires multi-­ modal immunosuppressive therapy in addition to the relevant associated oncologic treatments. Chronic or relapsing disease carries a more guarded neurologic prognosis. This may be mitigated by early, aggressive immunosuppressive treatment.

References 1. Tate ED, Allison TJ, Pranzatelli MR, et  al. Neuroepidemiologic trends in 105 US cases of pediatric opsoclonus-myoclonus syndrome. J Pediatr Oncol Nurs. 2005;22:8–19. 2. Oh SY, Boegle R, Zu Eulenburg P, et al. Longitudinal multi-modal neuroimaging in opsoclonus-myoclonus syndrome. J Neurol. 2017;264:512–9. 3. Antunes NL, Khakoo Y, Matthay K, et  al. Antineuronal antibodies in patients with neuroblastoma and paraneoplastic opsoclonus-­ myoclonus. J Pediatr Hematol Oncol. 2000;22:315–20.

38  Opsoclonus Myoclonus Syndrome: A Child with “Jumping Vision” 4. Rudnick E, Khakoo Y, Antunes NL, et al. Opsoclonus-myoclonus-­ ataxia syndrome in neuroblastoma: clinical outcome and antineuronal antibodies—a report from the children’s cancer group study. Med Pediatr Oncol. 2001;36:612–22. 5. Cooper R, Khakoo Y, Matthay KK, et al. Opsoclonus-myoclonus-­ ataxia syndrome in neuroblastoma: histopathologic features— a report from the children’s cancer group. Med Pediatr Oncol. 2001;36:623–9. 6. de Alarcon PA, Matthay KK, London WB, et al. Intravenous immunoglobulin with prednisone and risk-adapted chemotherapy for

207 children with opsoclonus myoclonus ataxia syndrome with neuroblastoma (ANBL00P3): a randomized, open-label, phase 3 trial. Lancet Child Adolesc Health. 2018;2:25–34. 7. Mitchell WG, Wooten AA, O’Neil SH, et  al. Effect of increased immunosuppression on developmental outcome of opsoclonus myoclonus syndrome (OMS). J Child Neurol. 2015;30:976–82. 8. Mitchell WG, Brumm VL, Azen CG, et al. Longitudinal neurodevelopmental evaluation of children with Opsoclonus-ataxia. Pediatrics. 2005;116:901–7.

Part VII Pupillary Abnormalities

Horner Syndrome: A Baby with Anisocoria

39

Seema Emami and Michael J. Wan

Case Presentation A 12-month-old baby girl was referred for assessment of anisocoria since early infancy. The parents were uncertain of the exact onset but believed that this finding was not present at birth. The parents also noted intermittent “puffiness” around the left eye but no definite drooping of the eyelid. The child was born at term via uncomplicated caesarean section delivery. To date, development and health have been normal. On examination, the child demonstrated good visual behavior with equal fixation in each eye. The pupil examination showed anisocoria, left pupil smaller than the right, with a difference in pupil size of approximately 0.5  mm in the light (Right 1.5 mm, Left 1.0 mm), increasing to 1.0 mm in the dark (Right 5 mm, Left 4 mm). There was a subtle asymmetry of the eyelids, with mild ptosis of the left upper eyelid but no reverse ptosis of the left lower eyelid (Fig. 39.1). The anterior segment was unremarkable with no iris heterochromia, although there was a small lesion in the superior left iris, consistent with an iris nevus. The sensorimotor examination was normal with full versions and orthotropia in all fields of gaze. Dilated fundus examination was normal.

Fig. 39.1  External photograph showing anisocoria (left pupil smaller) with subtle left upper eyelid ptosis.

Differential Diagnosis

• • • • • • • •

Horner syndrome Physiologic anisocoria Ocular trauma Anterior uveitis Anterior segment dysgenesis or malformation Iris tumors Medication-induced anisocoria Aberrant regeneration in the setting of an oculomotor nerve palsy

S. Emami · M. J. Wan (*) Department of Ophthalmology and Vision Sciences, The University of Toronto and The Hospital for Sick Children, Toronto, ON, Canada e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_39

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Diagnostic Workup Given the presence of ipsilateral miosis and ptosis, a cocaine test was performed. One hour after instillation of cocaine 4% eye drops to both eyes, there was increased anisocoria. The left pupil dilated modestly to 3 mm, whereas the right pupil dilated to 5 mm, confirming the diagnosis of left Horner syndrome. Subsequent spot urinary catecholamine assays did

Fig. 39.2  MRI showing a focal paraspinal soft tissue lesion extending from T1 to T3 on the left side. The lesion is bright on T2-weighted imaging (T2), with avid heterogeneous enhancement on T1-weighted

S. Emami and M. J. Wan

not demonstrate elevated levels of homovanillic acid (HVA) or vanillylmandelic acid (VMA), and a chest-X-ray and abdominal ultrasound were unremarkable. Magnetic resonance imaging (MRI) of the brain, neck, and chest was performed 3  weeks after presentation and identified a left paraspinal mass (Fig.  39.2). She underwent thoracoscopic resection of the mass, and pathology was consistent with low-grade neuroblastoma.

imaging post gadolinium injection (T1Gado), and restricted diffusion on diffusion-weighted imaging (DWI).

39  Horner Syndrome: A Baby with Anisocoria

Final Diagnosis Horner syndrome from low-grade neuroblastoma

Clinical Discussion Treatment and Prognosis Neuroblastoma is the most common pediatric extracranial solid tumor and the most common cancer diagnosis in the first year of life [1]. The presentation of neuroblastoma in children is highly variable, ranging from a localized mass (as in our patient) to widely disseminated disease. Based on several features, neuroblastoma is categorized as low, intermediate, or high-risk, which guides treatment and prognosis [1]. Patients with high risk disease undergo intensive chemotherapy, surgery, and external beam radiotherapy and have a survival rate of 40–50%. Patients with intermediate risk disease undergo chemotherapy and surgery and have a survival rate of 90–95%. For patients with low-risk disease, such as our patient, surgery is generally curative and the survival rate is >98%. The clinical features of Horner syndrome may persist despite the resolution of the causative lesion. Close follow-up for amblyopia is important in all cases of Horner syndrome regardless of the cause. This is typically secondary to refractive amblyopia from an induced astigmatism since the ptosis is typically 1–2  mm and does not obscure the visual axis. Surgical ptosis repair is often unnecessary but may be warranted if there are psychosocial concerns. In our case, the patient had complete resection of the neuroblastoma with no systemic treatment. No recurrence or metastatic disease was detected on repeat MRI with long-­term follow-up. The left upper eyelid ptosis became more severe, and reverse ptosis became apparent immediately following surgery (Fig. 39.3a). Over time, the ptosis a

b

Fig. 39.3  External photographs showing worsening of left upper eyelid ptosis and reverse ptosis immediately after surgery (a), with gradual improvement shown 2 years after surgery (b).

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returned to baseline without treatment (Fig. 39.3b). There was delayed development of impaired left-sided facial flushing noted approximately 2  years following presentation.

Important Aspects of the Diagnosis Pediatric Horner syndrome has several potential causes including birth trauma, head and neck surgery, vascular malformation, infection, congenital dysgenesis of the oculosympathetic pathway, mass lesions, and idiopathic occurrence. Diagnostic confirmation of Horner syndrome is important because oculosympathetic disruption may arise secondary to occult lesions along its pathway. The presence of isolated Horner syndrome appears to have variable specificity for the diagnosis of neuroblastoma or other malignant compressive entities. A systematic review reported that, amongst 152 patients combined over eight separate studies, approximately 15% of new Horner syndrome cases were associated with a new diagnosis of occult space-occupying lesion following detailed radiographic imaging [2]. Of these patients, 60% resulted in a new neuroblastoma diagnosis. However, the rate of neuroblastoma identified in children with isolated Horner syndrome ranges widely from 0% to 27% in the literature [2–5].

Novel Insights There is currently no standardized algorithm for the evaluation of children with Horner syndrome. At present, high-­ resolution radiography of the head, neck, and chest using magnetic resonance imaging (MRI) is recommended in all children with Horner syndrome to identify compressive, vascular, or infiltrative etiologies. MRI is preferred in young children due to its lack of radiation exposure, but computed tomography (CT) may provide adequate resolution of mass lesions should timely MRI be unavailable [2]. Urine catecholamine studies are more commonly positive in children with large neuroblastoma lesions, whereas localized tumors are more likely to be associated with normal urine tests [3]. Nevertheless, urinary testing for VMA and HMA is recommended as a non-invasive and relatively inexpensive adjunct screen for neuroblastoma. The utility of imaging the entire oculosympathetic pathway in all isolated Horner syndrome cases is an active area of study. Some studies have found a low yield for mass lesions in otherwise healthy children and have questioned the need to expose all children with isolated Horner syndrome to prolonged anesthesia (for a sedated MRI) or radiation (for a CT) [4]. A recent review found that all cases of

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mass lesions presenting as isolated Horner syndrome have been located in the neck or upper chest, suggesting that imaging of the head and orbit may be unnecessary if there are no associated findings [5]. The optimal diagnostic pathway for isolated Horner syndrome in children continues to be an active area of research, although complete imaging of the oculosympathetic pathway remains the standard of care at present.

Clinical Pearls

• Horner syndrome arises from the disruption of the oculosympathetic pathway and classically presents with ipsilateral miosis (greater in the dark), dilation lag, ptosis (with reverse ptosis), and anhidrosis, although the signs can be subtle and not all signs are present in all cases. • Children with Horner syndrome of unknown etiology require high-resolution imaging (preferably MRI) of the head, neck, and chest to evaluate for causative space-occupying lesions along the oculosympathetic pathway. • Neuroblastoma is a relatively uncommon but potentially fatal cause of Horner syndrome in children, and prompt diagnosis is important since the prognosis is favorable if the tumor is still localized when detected and treated.

S. Emami and M. J. Wan

References 1. Maris JM.  Recent advances in neuroblastoma. N Engl J Med. 2010;362:2202–11. 2. Braungart S, Craigie RJ, Farrelly P, Losty PD. Paediatric Horner’s syndrome: is investigation for underlying malignancy always required? Arch Dis Child. 2019;104:984–7. 3. Mahoney NR, Liu GT, Menacker SJ, Wilson MC, Hogarty MD, Maris JM. Pediatric horner syndrome: etiologies and roles of imaging and urine studies to detect neuroblastoma and other responsible mass lesions. Am J Ophthalmol. 2006;142:651–9. 4. Smith SJ, Diehl N, Leavitt JA, Mohney BG. Incidence of pediatric Horner syndrome and the risk of neuroblastoma: a population-based study. Arch Ophthalmol. 2010;128:324–9. 5. Graef S, Chiu HH, Wan MJ. The risk of a serious etiology in pediatric Horner syndrome: indications for a workup and which investigations to perform. J AAPOS. 2020;24:143 e141–6.

Anisocoria from a Third Nerve Palsy: A Child with Abnormal Pupils

40

Gad Dotan

Case Presentation A 3-year-old child was referred to the ophthalmology clinic for evaluation of anisocoria that was incidentally noticed by his pediatrician on a routine physical examination. There was no history of trauma or ocular pain, and there were no other abnormal systemic findings. The child was previously healthy and developmentally normal, with a normal birth and delivery. On ophthalmologic examination, the visual acuity was 20/25 in each eye. The right pupil diameter was larger than the left pupil diameter, with a greater difference noticed under bright light illumination (6 mm right versus 3 mm left) compared with dim light illumination (7 mm right versus 5 mm left, Fig. 40.1). The external examination showed no ptosis or proptosis. The sensorimotor examination was normal with no strabismus and full versions. A slit lamp examination did not reveal any obvious abnormalities of the pupil or anterior segment. A dilated fundus examination was normal. On review of prior photos, anisocoria was not present and therefore this was interpreted to be a new finding.

Differential Diagnosis

• Isolated internal ophthalmoplegia (Adie’s tonic pupil) • Traumatic mydriasis • Third nerve palsy/cranial nerve (CN) III palsy/oculomotor nerve palsy • Pharmacologic pupil dilation • Tonic pupil in the setting of infection (e.g., syphilis Argyll Robertson pupil, herpes zoster associated third cranial nerve palsy) • Tonic pupil in the setting of Miller Fisher syndrome • Dysautonomia with associated pupillary abnormalities

G. Dotan (*) Pediatric Ophthalmology Unit, Schneider Children’s Medical Center, Tel Aviv University, Petah Tikva, Israel e-mail: [email protected]

Fig. 40.1  Anisocoria greater under bright light illumination. The top photo was taken with an active flash and the room lights turned on. The bottom photo was taken without a flash and dimmed room lights.

Diagnostic Workup When evaluating anisocoria, there are several questions which should be considered to guide the differential diagnosis and further diagnostic testing. First, does the pupil size vary depending on different lighting conditions? Pupil size is recorded under bright and dim conditions. Anisocoria greater in bright light indicates that the larger pupil is abnormal due to poor contraction of the iris sphincter muscle, innervated by the autonomic parasympathetic system. Anisocoria greater in dim light illumination indicates that the smaller pupil is abnormal from impairment in the sympathetic system. Anisocoria may not vary with lighting conditions and this likely reflects physiologic anisocoria. Simple or physiologic anisocoria is clinically noticeable when the interpupillary diameter difference is at least 0.4 mm. This finding can be found in up to 20% of people, with approximately 2% having a difference greater than 1 mm, which is typically about the same under light and dark illumination [1]. Second, is the anisocoria isolated or is it associated with other neurological and/or ophthalmologic abnormalities including ptosis, extraocular motility disturbances, strabismus, decreased corneal sensitivity, facial asymmetry, and decreased tendon reflexes. In this regard, conditions such as

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_40

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cranial nerve III palsy, Horner syndrome, Miller Fisher syndrome, and herpes zoster infection are typically associated with other neurological disturbances (e.g., ptosis or ophthalmoplegia). Finally, is the onset acute or long standing? A review of old photographs may lend information. Additional details in the medical history may include a history of trauma (e.g., traumatic mydriasis) or inadvertent use of a dilating substance (e.g., pharmacologic anisocoria). In this case, the anisocoria appeared to be worse in bright light, suggesting that the affected pupil was the larger right pupil. Pharmacologic testing to differentiate between conditions associated with this abnormality is performed using dilute (0.125%) pilocarpine, a muscarinic agonist agent a­ cting at the neuromuscular junction of the iris sphincter muscle to cause miosis. A robust reaction to dilute pilocarpine suggests a denervation hypersensitivity response and is consistent with an Adie’s tonic pupil. Pupils that do not constrict following both dilute and non-dilute pilocarpine are typically pharmacologically dilated. Thirty minutes after installing dilute (0.125%) pilocarpine in both eyes, the right pupil constricted more exten-

G. Dotan

sively with the reversal of the anisocoria, with the right pupil becoming smaller in diameter (Fig. 40.2). Since this child’s neurological examination was normal without ptosis or ophthalmoplegia, the patient was diagnosed with a right Adie’s tonic pupil. In this condition, a careful neurologic examination to evaluate for abnormal reflexes would be indicated. This child’s reflexes were normal. Magnetic resonance imaging (MRI) of the brain was read as normal, consistent with the diagnosis of the right Adie’s tonic pupil. The child was followed annually without developing any other ophthalmological or neurological abnormalities, until the age of 6 years (3 years after his initial presentation) when he developed a new right eye elevation limitation that was greater in adduction (Fig. 40.3). In the setting of this limitation of extraocular motility, a follow-up MRI scan of the brain and orbits was performed, which demonstrated an enlarged right cavernous sinus from a schwannoma of the right third cranial nerve (Fig. 40.4). When the original MRI was rereviewed, mild asymmetry of the right cavernous sinus was appreciated which during the original evaluation was considered to be an insignificant finding. The final interpretation was that this was anisocoria from a right third cranial nerve schwannoma with an initial presentation, which mimicked an Adie’s tonic pupil.

Fig. 40.2  Thirty minutes after installing dilute pilocarpine in both eyes (bottom photo), there was anisocoria reversal, with the right pupil becoming smaller in diameter, compared with pre-installment top photo.

Fig. 40.3  Upward eye movements demonstrating right eye elevation limitation that is greater in adduction.

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Fig. 40.4  Axial brain MRI demonstrating right cavernous sinus enlargement.

Final Diagnosis

Important Aspects of the Diagnosis

Anisocoria from a Third Nerve Palsy

Schwannomas are usually benign peripheral nerve sheath tumors arising from Schwann cells, which wrap around peripheral nerves’ axons. They are more common in children with neurofibromatosis type 2 disease. Schwannomas of the ocular motor cranial nerves have been described, including in children, more frequently involving the third cranial nerve compared with the fourth (trochlear) and sixth (abducens) cranial nerves. These are typically slow growing tumors that lead to progressively worsening cranial neuropathies.

Clinical Discussion Treatment and Prognosis Adie’s tonic pupil is rare in childhood [2]. Dilute pilocarpine may be utilized to evaluate patients when this condition is suspected. More typically, this condition occurs with an age of onset in the third to fourth decade and affects women more than men [3]. Anisocoria mimicking an Adie’s tonic pupil can be the initial presentation of a third cranial nerve lesion, including an endodermal cyst or schwannoma of the oculomotor nerve [4]. In these cases, the pupillary abnormality may precede other features of third cranial nerve palsy by a time period ranging from weeks to years. Constriction of the pupil in the setting of dilute (0.125%) pilocarpine is thought to occur from a denervation hypersensitivity response. However, there are reports that the pupil in a third cranial nerve palsy may also have denervation hypersensitivity and react to dilute pilocarpine, making this test less specific for an Adie’s tonic pupil [5].

Novel Insights Recent reports found that approximately 1% of slowly progressive acquired extraocular muscle palsies are caused by occult schwannomas that are often missed unless a high index of suspicion is maintained by performing 1–2  mm MRI orbit cuts [6]. A third cranial nerve palsy that develops after a mild trauma such as a blow to the head, can be a sign of an occult compressive lesion such as a third cranial nerve schwannoma. Treatment options include observation, surgical tumor removal, and stereotactic radiosurgery. Surgical tumor resection usually results in palsy worsening; however, recent studies report that gamma-knife radiosurgery can halt tumor progression and improve the third cranial nerve palsy

218

[7, 8]. Regarding strabismus, since schwannomas may progress, non-surgical treatments such as prisms may be considered until stability of the examination is established for more definitive strabismus surgery.

Clinical Pearls

• Pediatric acquired isolated anisocoria greater in lighted illumination from a presumed Adie’s tonic pupil can rarely be the first presentation of a third cranial nerve palsy and should be followed routinely for the development of ptosis or ophthalmoplegia that may be observed after weeks to years. • A dilute pilocarpine test is often performed to confirm clinical suspicion of a postganglionic parasympathetic lesion. However, pupil constriction from dilute pilocarpine indicating a denervation hypersensitivity response cannot accurately distinguish an Adie’s tonic pupil from a preganglionic third cranial nerve lesion. • Beware of “normal” MRI scans. Occult abnormalities may be missed on initial interpretation and become apparent on subsequent imaging. If possible, it is always better to review the scans with a neuroradiologist, directing attention to the primary area of possible pathology.

G. Dotan

References 1. Silbert J, Matta N, Tian J, Singman E, Silbert DI.  Pupil size and anisocoria in children measured by the plusoptiX photoscreener. J AAPOS. 2013;17:609–11. 2. Phillips PH, Newman NJ.  Tonic pupil in a child. J Pediatr Ophthalmol Strabismus. 1996;33:331–2. 3. Thompson HS.  Adie’s syndrome: some new observations. Trans Am Ophthalmol Soc. 1977;75:587–626. 4. Werner M, Bhatti MT, Vaishnav H, Pincus DW, Eskin T, Yachnis AT.  Isolated anisocoria from an endodermal cyst of the third cranial nerve mimicking an Adie’s tonic pupil. J Pediatr Ophthalmol Strabismus. 2005;42:176–9. 5. Jacobson DM. Pupillary responses to dilute pilocarpine in preganglionic 3rd nerve disorders. Neurology. 1990;40(5):804–8. 6. Yulek F, Demer JL.  Isolated schwannoma involving extraocular muscles. J AAPOS. 2016;20:343–7. 7. Langlois AM, Iorio-Morin C, Faramand A, et  al. Outcomes after stereotactic radiosurgery for schwannomas of the oculomotor, trochlear, and abducens nerves. J Neurosurg. 2021:1–7. https://doi. org/10.3171/2020.8.JNS20887. 8. Yang SS, Li ZJ, Liu X, Li Y, Li SF, Zhang HD. Pediatric isolated oculomotor nerve schwannoma: a new case report and literature review. Pediatr Neurol. 2013;48:321–4.

Part VIII Neurologic Diseases with Neuro-Ophthalmic Manifestations

Craniopharyngioma: A Teenager with Decreased Vision, Peripheral Visual Field Defects, and Diplopia

41

Mehdi Tavakoli

Case Presentation

each eye. Automated perimetry was performed, which confirmed a bitemporal hemianopia (Fig. 41.2). The dilated funA 14-year-old African American boy presented to the neuro-­ dus examination showed optic atrophy in both eyes with an ophthalmology service with a complaint of blurry vision and otherwise normal posterior segment (Fig.  41.3). Optical difficulty with peripheral vision. Four  months prior to coherence tomography (OCT) showed thinning of the retinal presentation, he had developed new onset headaches and nerve fiber layer and the ganglion cell layer in both eyes subsequently, blurred vision with diplopia. A local (Fig.  41.4). The sensorimotor examination showed full ophthalmologist diagnosed bilateral disc edema and bilateral motility. There was no strabismus at distance or at near and abducens nerve palsy. Magnetic resonance imaging (MRI) of no residua of the abducens palsy in either eye. the brain had revealed a suprasellar tumor (Fig. 41.1), which was treated surgically. Postoperatively, the diplopia resolved, but he was referred to neuro-ophthalmology for evaluation of Differential Diagnosis persistent poor vision and changes in peripheral vision. • Craniopharyngioma On examination, the best corrected vision was 20/400 • Chiasmal glioma right eye and 20/200 left eye with a mild myopic correction. • Germ cell tumor The pupillary examination was normal with no relative affer• Arachnoid cyst ent pupillary defect. There was dyschromatopsia in both eyes • Pituitary adenoma on Ishihara color plates. Visual fields by confrontation revealed decreased responses in the temporal periphery of a

b

c

Fig. 41.1  MRI scans of the brain in axial (a), coronal (b), and sagittal (c) views demonstrate the suprasellar lesion with mixed solid and cystic components. Mild ventriculomegaly (b, arrow) and optic chiasm compression and displacement are evident (c, arrow). M. Tavakoli (*) Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Callahan Eye Hospital, Birmingham, AL, USA Ophthalmology Department, George Washington University School of Medicine and Health Sciences, Washington, DC, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_41

221

222

M. Tavakoli

Left Eye

Right Eye

Fig. 41.2  Automated humphrey perimetry of the right and left eyes demonstrates an asymmetric bitemporal hemianopia.

Fig. 41.3  Fundus photos of the right and left eye with optic atrophy in both eyes (right eye shown on the left and left eye shown on the right).

41  Craniopharyngioma: A Teenager with Decreased Vision, Peripheral Visual Field Defects, and Diplopia

223

a

b

Fig. 41.4  OCT of the peripapillary retinal nerve fiber layer (rNFL) reveals bilateral temporal and nasal loss with relative preservation of the superior and inferior rNFL (right eye shown on the left and left eye

shown on the right) (a). Macular ganglion cell layer OCT reveals a binasal loss corresponding to the bitemporal visual field loss (b). OD: right eye; OS: left eye.

Diagnostic Workup

with craniopharyngioma. Review of the pre-operative MRI in this patient revealed a complex multicystic suprasellar mass with compression of the optic chiasm and associated hydrocephalus with enlarged lateral ventricles (Fig.  41.1b). Histologic examination of the resected tumor revealed cystic changes, calcification, and squamoid lining cells consistent with adamantinomatous type craniopharyngioma. The Humphrey visual field in this patient, as presented in Fig.  41.2, showed a classic bitemporal hemianopia. Bitemporal hemianopia is the most common pattern of visual field defect in patients with craniopharyngioma. This tumor often impacts the eyes asymmetrically. In suprasellar tumors such as craniopharyngioma that compress the chiasm superiorly, the visual field defect will be denser inferiorly, as seen in this patient. Bitemporal hemianopia is characteristically associated with a “bow-tie” or band optic atrophy. The ­damaged crossing nasal fibers originate from (1) nasal macula (these fibers are also called papillomacular

Reduced visual acuity, dyschromatopsia, and optic atrophy are all signs of optic neuropathy in this patient. The bitemporal hemianopia in the visual field test localizes the pathology to the optic chiasm and raises the possibility of a variety of sellar and suprasellar lesions. An associated bilateral sixth nerve palsy indicates a large lesion that either has increased the intracranial pressure due to compression of the third ventricle and subsequent hydrocephalus (which is more likely in this case given the MRI findings) or extension of the tumor to the cavernous sinus. MRI of the brain with and without gadolinium contrast is the best neuroimaging modality in cases with bitemporal hemianopia because it can visualize the anatomy of the retro-orbital visual pathways including the optic chiasm. A computed tomography (CT) scan is not the first choice in children because of radiation exposure; however, it can show the characteristic calcification in patients

224

M. Tavakoli

fibers and project to the temporal portion of the disc) and (2) nasal retina (which project to the nasal portion of the disc). Although it is hard to appreciate band optic atrophy in our patient, OCT showed the temporal and nasal peripapillary RNFL loss (Fig. 41.4a). The reduced density of the ganglion cell layer at the nasal half of the macula is demonstrated by the macular GCL OCT (Fig. 41.4b). Moreover, the relative preservation of the superior and inferior peripapillary RNFL corresponds to the relatively intact fibers emerging from the temporal retina.

corrected the obstructive hydrocephalus and relieved the intracranial pressure. He was referred to the low vision service to provide support and recommendations for accommodations given the profound central vision loss and peripheral vision loss which he experienced. Follow up neuro-ophthalmology visits were scheduled at regular intervals to ensure that no further vision loss occurs from the recurrent tumor.

Final Diagnosis

Neuroimaging is diagnostic. The tumor has a combination of solid and cystic components best demonstrated by both computed tomography (CT) scan and MRI. While the CT scan is valuable to show the craniopharyngioma’s characteristic calcifications, MRI with and without gadolinium injection is the modality of choice to delineate the tumor extension and its relation to the nearby structures such as the optic chiasm [1]. The common etiologies of suprasellar tumors in children are different from those in adults and include:

Craniopharyngioma with compressive optic neuropathy

Clinical Discussion Treatment and Prognosis Craniopharyngioma is a rare, benign, and slow-growing suprasellar or intrasellar tumor. It is believed to arise from the embryonic remnants of the Rathke’s pouch along with the craniopharyngeal duct. Its incidence is 0.5–2 per million person per year with a bimodal age distribution in children (50 years) [1]. Craniopharyngioma has two histologic subtypes: adamantinomatous and squamous papillary. The adamantinomatous type is more prevalent in childhood craniopharyngioma and tends to adhere to the surrounding structures. This feature results in a higher risk of tumor recurrence after surgical resection as complete removal of tumor may not be possible. The clinical course is typically insidious often with a delay between the onset of symptoms and the diagnosis. Clinical manifestations are usually a combination of symptoms and signs related to increased intracranial pressure (ICP), visual impairment due to papilledema and/or compression of the chiasmatic visual pathways, and endocrinopathies due to disruption of the hypothalamus-pituitary axis. Headache is the most common initial symptom followed by visual symptoms. The associated endocrine manifestations include obesity, delayed growth and puberty, and diabetes insipidus [1, 2]. Neurosurgery is the mainstay of treatment. Pediatric craniopharyngiomas typically adhere to adjacent vital structures, which often make total surgical resection challenging. If the post-operative MRI reveals residual tumor, adjuvant radiation is warranted to prevent recurrence. Treatment of endocrinopathies and visual rehabilitation are other essential parts of the management as undertaken in this patient [1, 2]. When we saw the patient several weeks after the surgery, papilledema and the sixth nerve palsies were no longer present, as surgical resection of the tumor subsequently

Important Aspects of the Diagnosis

• Craniopharyngioma: Craniopharyngioma is the most common etiology of pediatric sellar and suprasellar tumors [3]. • Chiasmal glioma: This is the second most common sellar mass in children after craniopharyngioma. Chiasmal gliomas usually present before the age of 5 years and similar to craniopharyngioma, can cause optic nerve edema/atrophy and endocrine abnormalities. Neuroimaging can often differentiate chiasmal gliomas from craniopharyngiomas. Chiasmal glioma can be associated with neurofibromatosis type 1 [3]. • Germ cell tumors: This includes a variety of entities including germinoma and non-germinomatous tumors. The suprasellar area and the pineal gland are the two common regions affected by germ cell tumors in the central nervous system. • Arachnoid cyst: Arachnoid cysts most often present in childhood and when they involve the suprasellar area, can cause hydrocephalus and papilledema. • Pituitary adenoma: In contrast to adults, pediatric adenoma is an uncommon etiology of pediatric suprasellar tumors.

Novel Insights Several studies have evaluated visual prognosis in the setting of craniopharyngioma. A recent systematic review of visual function in children with craniopharyngioma reports a high rate of visual impairment at diagnosis (50.3%) [4]. In a retrospective study of 59 patients with pediatric craniopharyngioma with 5 years of follow-up, 31% of patients had severe

41  Craniopharyngioma: A Teenager with Decreased Vision, Peripheral Visual Field Defects, and Diplopia

vision loss at presentation. At the final follow-up visit, 58% of the patients had visual impairment in at least one eye (i.e., visual acuity of 20/50 to 20/150 or at least 50% loss of visual field, but more than 20° of visual field intact). Only 10% were legally blind in both eyes in this series (visual acuity 20/200 or worse or  6 g/L, is indicated for all patients with severe immunoglobulin G deficiency [6]. Since patients with ataxia-telangiectasia have an increased risk for secondary malignancy, avoiding excess exposure to ionizing radiation may help to prevent the development of cancer, especially hematologic malignancies during childhood. Furthermore, the lifetime risk of breast cancer in a female carrier of the ATM pathogenic mutation is greater than 25%;

• Various causes of hereditary ataxia are accompanied by several ophthalmological abnormalities such as eye movement disorders, optic atrophy, cone dystrophy, or thickening of the retinal nerve fiber layers. • Dilated conjunctival vessels become apparent with age in ataxia-telangiectasia. Therefore, checking for the dilated conjunctival vessels with slit lamp examination is an important clue for diagnosis in children with ataxia but is often overlooked. • Avoiding excess exposure to radiation is necessary to reduce the development of malignancy in patients with ataxia-telangiectasia. In addition, frequent breast examinations are recommended for female patients as well as for mothers of patients who are ATM mutation carriers.

45  Ataxia Telangiectasia: A Child with Abnormal Eye Movements and Ataxia

References 1. Jayadev S, Bird TD.  Hereditary ataxias: overview. Genet Med. 2013;15:673–83. 2. Brodsky MC. Neuro-ophthalmologic manifestation of systemic and intracranial disease. Pediatric neuro-ophthalmology. 3rd ed. New York: Springer; 2016. p. 673–5. 3. Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. Orphanet J Rare Dis. 2016;11:159.

247

4. Zannolli R, Buoni S, Betti G, Salvucci S, Plebani A, Soresina A, et  al. A randomized trial of oral betamethasone to reduce ataxia symptoms in ataxia telangiectasia. Mov Disord. 2012;27:1312–6. 5. Gazulla J, Benavente I, Sarasa M.  New therapies for ataxia-­ telangiectasia. Arch Neurol. 2007;64:607–8; author reply 8-9. 6. van Os NJH, Haaxma CA, van der Flier M, Merkus P, van Deuren M, de Groot IJM, et al. Ataxia-telangiectasia: recommendations for multidisciplinary treatment. Dev Med Child Neurol. 2017;59:680–9.

Neuronal Ceroid Lipofuscinosis: A Boy with Seizures and a Change in Visual Behavior

46

Steven F. Stasheff

Case Presentation A 7-year-old boy with a 2-year history of seizures presented 8  months after his parents noticed that he would not look directly at people, TV, books, or toys unless they were within 1–2 ft of his face. They noted that he adopted an anomalous head posture that he adjusted frequently to improve his view with eccentric fixation. These symptoms gradually worsened over the 8 months, with more trouble reading and writing in dim light, but he still recognized letters and sight words. No changes in ocular alignment or nystagmus were noted, and yearly optometry examinations had been normal over the preceding 2 years. Amblyopia was diagnosed by the optometrist 4 months after his parents first noticed his changes in visual behavior. Subsequently, two different pediatric ophthalmologists found a normal exam except for visual acuity which could not be corrected to better than 20/200–20/400 with both eyes viewing. There was no associated illness, trauma, or environmental exposure. His birth history was unremarkable. He achieved normal early childhood developmental milestones, without recognized loss of developmental skills at the time of seizure onset or during the period of visual loss. However, his parents described him as “already behind in reading” after progress seemed to halt in first grade, when visual changes first were noted. Other language and developmental skills remained normal. There was no family history of known neurologic, developmental, and/or ophthalmologic disorders.

Two years prior to presentation, complex partial seizures had occurred several times over a 5-month period before he was treated with Trileptal. He was then switched to Keppra after generalized seizures began, and he was seizure-free for over 9 months on monotherapy. On examination, visual acuity was measured at 20/380 right eye and 20/130 left eye by preferential looking testing. With LEA matching, he was able to achieve 20/200 vision with binocular viewing at distance and 20/50 with binocular viewing at near. His pupils were sluggishly reactive with normal accommodation, no paradoxical responses, and no relative afferent pupillary defect. There was evidence of dyschromatopsia in each eye as he was only able to see the control plate with Ishihara testing. By confrontation, a relative central scotoma was noted in both eyes. The sensorimotor examination was normal with full motility, no strabismus, and no nystagmus. He had 3000 arc seconds of stereopsis. Dilated fundus examination revealed normal optic nerves. His maculae had a subtle irregular pigment pattern and blunted foveal reflex more prominent in the right eye with surrounding mild pigmentary mottling in mid-macular to -peripheral regions. There was moderate attenuation of the perimacular retinal arterioles (Fig. 46.1). His neurologic examination was remarkable only for inattention and high activity, mild-moderate expressive language delays, and moderate diffuse hypotonia.

S. F. Stasheff (*) Pediatric Neurology and Neuro-Ophthalmology, Center for Neuroscience and Behavioral Medicine, Gilbert Family Neurofibromatosis Institute, Children’s National Hospital, Washington, DC, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_46

249

S. F. Stasheff

250

a

b

Fig. 46.1  Fundus photos of the subject in the case presentation at the first neuro-ophthalmology visit. (a) Foveal and parafoveal views of the right eye (left panel) and left eye (right panel). (b) Mid-peripheral views

Differential Diagnosis

• • • •

• • • • • • •

Vitamin deficiency (vit. A, E, B6, B12/folate) Inherited retinal dystrophy/degeneration (IRD) Neuronal ceroid lipofuscinosis Other lysosomal storage disease (e.g., Gaucher, Niemann–Pick, Fabry’s, Tay–Sachs, Sandhoff disease) Joubert syndrome or other nephronophthisis (NPHP)/ciliopathy Peroxisomal disorder Mucopolysaccharidoses, mucolipidosis, or sialidosis Mitochondrial disease Leukodystrophy (e.g., Krabbé, metachromatic) Para-infectious, paraneoplastic, or other autoimmune disorder Epileptic encephalopathy

of the fundus. Note subtle mottled pigmentary appearance and attenuated arterioles (right eye, left panel; left eye, right panel).

Diagnostic Workup Extensive blood work was normal including vitamins A, E, B6, B12/folate levels, CBC with differential, basic metabolic panel, lactate, pyruvate, ammonia, thyroid stimulating hormone (TSH), and very long-chain fatty acids (VLCFA). Genetic testing of the mitochondrial genome and nuclear genes influencing mitochondrial function identified several variants of unknown significance (VUSs), including one heterozygous mutation not matching phenotype. One month later, a retinologist concurred with the findings noted above, and optical coherence tomography (OCT) showed “significant thinning of the retina and loss of outer retinal elements” in both eyes. Four months later, Ophthalmic Genetics evaluation revealed that the visual acuity had declined further to 20/640 right eye and 20/500 left eye. There was evidence of dyschromatopsia on the Cambridge

46  Neuronal Ceroid Lipofuscinosis: A Boy with Seizures and a Change in Visual Behavior

a

251

c

b

Fig. 46.2  Fundus autofluorescence of the subject 1 month after initial neuro-ophthalmology visit (a) and 1 year later (b). Subtle mottling of RPE autofluorescence becomes more distinct over this interval, taking on a “bulls’ eye” appearance (right eye shown on the left and left eye

shown on the right). Optical coherence tomography (OCT) in (c) demonstrates loss of photoreceptor signal intensity and loss of readily recognizable laminar structure of the outer retina.

Color Test. Fundus autofluorescence (FAF) revealed subtle mottled changes, which progressed with time (Fig. 46.2a, b). OCT showed diffuse, severe photoreceptor disorganization and loss (Fig. 46.2c). Whole exome sequencing (WES) subsequently revealed a homozygous out-of-frame duplication of at least exons 10–14 in CLN3, due to maternal uniparental disomy (UPD).

and CLN2, for which enzyme replacement therapy (ERT) received FDA and European approval in 2017, and for which widespread neonatal electroencephalography (EEG) screening has been promoted to assure early diagnosis and potentially life-changing treatment [3, 4]. The NCLs share a common pathophysiology: lysosomal dysfunction in neurons and, in some forms, in cells of other organs. Where identified, the mutated gene results in either a primary enzyme deficit or a deficit in one of the co-active proteins or membrane transporters, leading to the accumulation of autofluorescent lipopigments (ceroids) that form intracellular inclusions whose morphology varies among NCL types. While they sometimes can be appreciated on light microscopy, electron microscopy (EM) is most sensitive and is the basis for their descriptive names: granular osmiophilic deposits (GRODs); curvilinear, fingerprint, or rectilinear complex (or “condensed forms”) profiles (CLP, FPP, RLC, respectively), or vacuoles in select cell types in a few NCLs. Each of these deposits has been shown to contain, in various proportions, subunit C of mitochondrial ATP synthase, saposins (SAP) A and D, and/or β-amyloid proteins; other components are likely to be discovered. In some NCL types, there is differential accumulation of lipopigments in some structures more than others (e.g., the substantia nigra in CLN3; spiny versus non-spiny neurons of the striatum; dendrites versus soma/axons, and photoreceptors prior to retinal ganglion cells [RGCs] in the retina [but RGCs first in CLN 5]). The role of inflammation (e.g., microglia and astrocyte activation) and possible autoimmune mechanisms has been recognized more recently [1, 2, 5]. Common phenotypic features of the NCLs include (1) progressive cerebral and/or cerebellar atrophy, often of posterior more than anterior regions; (2) especially with more severe or advanced disease, atrophy of subcortical gray

Final Diagnosis Neuronal ceroid lipofuscinosis with a genetically confirmed CLN3 mutation

Clinical Discussion Treatment and Prognosis Collectively, the neuronal ceroid lipofuscinoses (NCLs) comprise the most common pediatric neurodegenerative disorders, with an incidence ranging from 1.6/100,000  in the United States to 7/100,000 in Iceland, comprising to date 13 specifically identified types (Table 46.1) [1–3] (For detailed resources, see https://www.ucl.ac.uk/ncl-­disease/ and https:// www.ucl.ac.uk/drupal/site_ncl-­d isease/mutation-­a nd-­ patient-­database). Among these, the causative genes are named identically, with a few exceptions due to recent changes in nomenclature as genetic etiology and pathophysiology have been better defined (e.g., CLN 3, 4, 5, and 9). In addition, “Batten disease” has come to refer more broadly to NCLs as a group [2, 3]. Here, we highlight the most common form, CLN3, since its ophthalmologic presentation is dramatic and often the initial indicator of the correct diagnosis;

CLN3

CLN3—# 204200

81

129

CLN2/ TPPT1

CLN2—# 204500

Pathology (EM/ light microscopy) Cytoplasmic autofluorescent (ceroid) inclusions: GRODs >est yield: skin, lymphocytes

Lysosomal transmembrane protein

Ceroid inclusions: CLP in phRs & RGCs, glia, RPE, conjunctivae, skin fibroblasts; FPP in RGCs >est yield: lymphocytes, rectum

Soluble Ceroid lysosomal protein inclusions: TPPT1 CLP; > est yield: skin

# mutations Protein 69 Soluble lysosomal protein PPT1

NCL form/ OMIM # Gene CLN1—# CLN1/ 256730 PPT1

Sz (multiple types: tonic, clonic, tonic-­clonic, myoclonic, atonic, absence), cognitive & motor skill regression, myoclonus, ataxia, speech d/o

Sz, cognitive & motor skill regression, myoclonus, ataxia, speech disorders

By 2–4 yo: refractory Sz, ataxia, myoclonus, cognitive (esp. language) & motor regression EEG: photoparoxysmal response at 1–3 Hz

Precipitous ↓ VA as initial symptom at 4–8 yo; ocular inflammation

Diagnostic key(s) At  est yield: skin

Transmembrane Ceroid protein in the ER inclusions: FPP > GRODs

Late infantile phenotype, onset at 18 mo-8 yo OR Adult onset

↓ VA up to blindness, OA, rarefaction of retinal vessels, retinal degeneration with peripheral bone spicules, macular edema

Late infantile phenotype, onset at 2–7 yo, Northern epilepsy (variant), onset 5–10 yo

SCT—pre-clinical only: bone marrow transplantation Rx—pre-clinical only: ZK-187638, retigabine, IGF-1

Gene tx—phase I/II trial: AAV9 i-thecal; pre-clinical Rx—pre-clinical: flupirtine, retigabine, minocycline, curcumin, docosahexaenoic acid (DHA) Gene tx—single ↓ VA up to blindness, may Late infantile phenotype, onset patient: tailored be initial symptom, antisense bull’s-eye maculopathy, OA at 2–7 yo oligonucleotide

↓ VA up to blindness, central retinal atrophy, +/− cherry-­red spot

(continued)

Turkish variant Northern epilepsy

Kufs disease type A (Lake-­ cavanagh) Indian variant

Finnish variant Gene tx—pre-­ ↓ VA up to blindness within Late infantile phenotype, onset clinical: Lentivirus, 7–10 yo, retinal at 3–7 yo AAV9; trial pending degeneration

Parry disease

Sz, cognitive & motor skill regression, myoclonus, ataxia, speech disorders Sz, cognitive & motor skill regression, myoclonus, ataxia, speech disorders

None Adult phenotype, onset ~30 yo, slowly progressive

NONE recognized

Sz, cognitive & motor skill regression, myoclonus, ataxia, tremors, speech disorders

Sz, cognitive & motor skill regression, myoclonus, ataxia, speech disorders EPMR: progressive Sz first, slower progression visual epilepsy, cognitive decline; Sz, loss late progressive ataxia, psychomotor degradation, myoclonus

Autosomal Soluble dominant membrane-­ associated lysosomal protein, a pre-synaptic co-chaperone: “cysteine string protein alpha” (CSPα)—cf. CLN1 Soluble Ceroid lysosomal protein inclusions: CLP, FPP

46  Neuronal Ceroid Lipofuscinosis: A Boy with Seizures and a Change in Visual Behavior 253

1

11

1

CLN12—# CLN12/ 610513 ATP13A2

CLN13—# CLN13/ 615362 CTSF

CLN14—# CLN14/ 611725 KCTD7

Soluble lysosomal protein, cysteine protease cathepsin-F Soluble membrane-­ associated lysosomal protein, K-channel tetramerization domain KCTD7

Lysosomal transmembrane protein, may regulate ion homeostasis

Soluble, extracellular protein progranulin

Onset in 20’s, rapid retinal dystrophy progression

Cognitive & motor skill regression, progressive dementia, Sz, dysarthria, cerebellar ataxia & atrophy Parkinson’s-like Parkinson’s-like symptoms symptoms: progressive myoclonus, akinesia, ataxia, rigor, ↓ mood, speech disorders, dementia, bulbar syndrome Cognitive & motor ↓ Memory, skill regression, behavioral disturbance before progressive dementia, Sz, facial bradykinesia, dyskinesias rigidity Mental retardation, Myoclonic Sz microcephaly, before progressive developmental regression, visual myoclonic epilepsy (EPM3), ataxia loss

Neurologic manifestations Congenital phenotype: early epilepsy, microcephaly, v rapid decline Later onset forms: ataxia, cognitive decline, speech disorders

Presentation age/Systemic manifestations Congenital phenotype: ↓ fetal growth, respiratory failure, spontaneous abortion, stillbirth, death within a few days-weeks of birth Later onset forms: chiefly neurologic manifestations Adult phenotype

None Adult phenotype, onset ~30 yo

None Infantile phenotype, onset at birth-2 yo

↓ VA, OA

None

Gene tx—pre-­ clinical only: AAV1, −4, −9; overexpression may be cytotoxic

Treatment Gene tx—pre-­ clinical only: AAV i-ventric, i-parenchymal

Unknown

↓ VA up to blindness in young adulthood, possibly initial symptom, phR degeneration, OA, vascular scarring, pigment epithelial alteration Unknown Juvenile phenotype, Parkinson’s-like symptoms, onset 13–16 yo

Ophthalmologic manifestations Congenital phenotype: unclear Later onset forms: retinitis pigmentosa-­like retinal atrophy

Kufs disease type B

Juvenile parkinsonism-­ NCL

Eponym (historic)

Ab antibody, AC anterior chamber, CLP curvilinear profile, ERT enzyme replacement therapy, FPP fingerprint profile, Gene tx gene therapy, GROD granular osmiophilic deposit, OA optic atrophy, phR photoreceptor, RLC rectilinear complex, RGC retinal ganglion cell, SCT stem cell therapy, Sz seizure(s), VA visual acuity, yo years old

3

Pathology (EM/ light # microscopy) Diagnostic key(s) mutations Protein Microcephaly; in 10 Soluble utero Sz lysosomal protein cathepsin D

CLN11—# CLN11/ 614706 GRN

NCL form/ OMIM # Gene CLN10—# CLN10/ 610127 CTSD

Table 46.1 (continued)

254 S. F. Stasheff

46  Neuronal Ceroid Lipofuscinosis: A Boy with Seizures and a Change in Visual Behavior

255

Dark Adaptation

Light Adaptation Right Eye

Ambient light: 3 cd/m2

Start: 11:56 AM, Duration: 36 min

Left Eye

Dim flash 2

Flash: 0.010 cd.s/m , Chromaticity (0.33, 0.33) at 0.5 Hz

Bright flash

Background: 0.0 cd/m

2

Right Eye

µV

bwave ms

µV

Trial

a-wave ms

µV

NM

NM

31.3

–4.5

40.3

4.4

1

13.5

4.6

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Fig. 46.3  Full field flash electroretinography (ERG) yields only extremely low amplitude and delayed responses, just discernible for light-adapted bright flash and 30-Hz flicker stimuli, representing cone photoreceptor signals.

structures; and (3) degeneration of the retina +/− the optic nerve (usually later in the disease course, in some types only secondary to the retinal degeneration). In several NCLs, degeneration and lipopigment accumulation occur in organs outside the nervous system: skeletal muscle, the cardiac conduction system and muscle, vascular walls, and lymphocytes (particularly in CLN3) [1–3, 5]. In this case, in the year following genetic diagnosis, there was further progression of granular changes, and new scattered areas of discrete atrophy were evident (“bull’s eye” maculopathy, Fig. 46.2b), and full field electroretinography (ERG) showed that only some low-amplitude cone-flicker responses were maintained (Fig. 46.3).

Important Aspects of the Diagnosis The various NCLs are most clearly differentiated clinically based on the chronological order and relative severity with which various features appear in the different neuronal and non-neuronal sites (Table 46.1). A precipitous decline in visual acuity (VA) beginning between the ages of ~4 and 8 years, as

in the case presented here, is pathognomonic for mutations in CLN3. Visual loss is often the initial presentation of CLN3 disease, and its recognition is essential for making an accurate early diagnosis. In retrospect, mild developmental delays and a moderate seizure disorder were the earliest features present in this patient, but since these are relatively common and non-specific features of a large variety of pediatric neurologic conditions, the precipitous visual loss provided the key diagnostic clue redirecting his diagnostic investigations and clinical care [3]. The characteristic pigmentary changes in the macula and mid-peripheral retina (“bull’s eye” maculopathy in ~20%) (Fig.  46.2) may not appear until after ERG responses are minimal (Fig. 46.3), with vascular attenuation and optic atrophy (in ~75%) progressing to gliosis still later. Also, note that this patient’s visual decline was initially attributed by his pediatric neurologist to occipital seizures, based on focal EEG activity. Similarly, behavioral changes were attributed to adverse effects of Keppra but in retrospect were likely common manifestations of CLN3 that include behavioral/personality changes and cognitive decline [3]. His ultimate molecular diagnosis highlights another intriguing point: uniparental disomy is an unusual genetic mecha-

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nism for NCL and, akin to compound heterozygous mutations, might well present with a less “classic,” archetypal phenotype. As the disease progresses, speech and motor skills decline, 50% develop cardiac conduction defects, and an inflammatory/autoimmune component increases before death occurs within three decades [1–3, 5]. In contrast to CLN3, CLN2 typically begins in infancy or toddler years, with rapidly progressive, intractable epilepsy (polymorphic: tonic, tonic-clonic, myoclonic, atonic, absence), cognitive regression—especially language, myoclonus, and ataxia. Retinal degeneration develops later and is less prominent. Progression may be assessed with one of the several scales (Hamburg, Weill Cornell; for clinical trials, the CLN2 Disease Clinical Rating Scale emphasizes motor, language, visual function, and seizures). As in the CLN3 case presented here, the non-specific nature of early symptoms often delays diagnosis by ~2 years [1, 2, 5]. Especially since the 2017 FDA and European approval of enzyme replacement therapy (ERT) with intraventricular cerliponase alpha, early recognition and treatment of CLN2 disease can significantly slow its progression (though typically not halting progression or reversing deficits, and retinal degeneration, in particular, progresses essentially unchanged—presumably since ERT is not delivered directly to the eye) [4]. Hence, some advocate that EEG and genetic testing be obtained as soon as rapidly progressive seizures and language regression are recognized in the typical age range. EEG is characterized by a paroxysmal response to low frequency (1–3 Hz) photic stimulation. In treating refractory seizures, carbamazepine and phenytoin should be avoided since they may precipitate adverse events [2]. Overlap with CLN1 is also worth considering, but CLN1 usually presents at a considerably younger age with substantially more severe seizures and rapid degeneration. Several other NCL types, although less common, are characterized by one or several particular features that may narrow the differential diagnosis (Table 46.1). In the absence of highly specific features, other neurodegenerative disorders—especially those with retinal degeneration—must be ruled out through general laboratory screening and/or imaging of other organs (e.g., renal dysfunction in Joubert syndrome, neurodegeneration with brain iron accumulation (NBIAs), liver/spleen/kidneys in other lysosomal storage disorders such as Gaucher, Niemann–Pick, Fabry’s, Tay–Sachs, Sandhoff, or Krabbé disease, metachromatic leukodystrophy, mucopolysaccharidoses, mucolipidosis, or sialidosis) [1–4].

Novel Insights For definitive diagnosis of the NCLs, the historical standard was tissue biopsy with electron microscopy (EM) identify-

S. F. Stasheff

ing characteristic patterns of intracellular inclusions; tissues with the highest biopsy yields were conjunctiva or rectum, and in some forms peripheral lymphocytes (CLN3) or skin (CLN2, -3, -11). However, among NCL types, the overlap of inclusion patterns, gene products, storage compounds, and their roles in cellular physiology substantially limits the precision of this method [5]. In contrast, genetic testing has advanced to the point that it now usually supersedes EM and other diagnostic approaches and provides definitive identification of each patient’s molecular deficit(s). Critically, this provides for early diagnosis and treatment (if available), more accurate prognoses to prepare in advance for management of secondary complications, a means for accurately monitoring disease progression and response to treatment(s), and valuable knowledge for family planning [1]. Thus, to optimize current and future care of patients with NCL, clinicians must remain vigilant for characteristic signs and symptoms and obtain genetic testing as soon as a diagnosis of NCL is suspected. Several commercial panels are available to screen for mutations in all or most NCL genes, or testing can be directed to one or several suspected NCL genes (Gene Test Registry—https://www.ncbi.nlm.nih.gov/gtr/). Finally, although currently CLN2 disease is the only NCL for which directed therapy is available, there has been a recent acceleration in pre-clinical research and several ongoing or pending clinical trials for the treatment for multiple other forms of NCL [4] (Table  46.1; https:// clinicaltrials.gov/).

Clinical Pearls

• The neuronal ceroid lipofuscinoses (NCLs) are a group of lysosomal disorders (13 types) characterized by neurodegeneration leading to progressive visual loss, epilepsy, motor dysfunction, and cognitive and behavioral decline. • Two types are especially salient for pediatric neuro-ophthalmologists: –– CLN3, distinctly characterized by precipitous visual loss (normal → ~20/200 over ~6 months). –– CLN2, the only type currently treatable with gene therapy. • Diagnostic testing, to distinguish NCLs from other classes of neurodegenerative disorders with similar features, ranges from neuroimaging and electrophysiology (EEG, ERG) to tissue biopsy, but when there is suspicion for NCL, early confirmatory genetic testing identifies the specific form of NCL, facilitating optimal treatment and anticipation of subsequent patient needs.

46  Neuronal Ceroid Lipofuscinosis: A Boy with Seizures and a Change in Visual Behavior

References 1. Aungaroon G, Hallinan B, Jain P, Horn PS, Spaeth C, Arya R. Correlation among genotype, phenotype, and histology in neuronal ceroid lipofuscinoses: an individual patient data meta-analysis. Pediatr Neurol. 2016;60:42–48.e44. 2. Dragos AN, Sara EM, Berge AM. Neuronal ceroid lipofuscinoses. Epileptic Disord. 2016;18:73–88.

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3. Ouseph MM, Kleinman ME, Wang QJ. Vision loss in juvenile neuronal ceroid lipofuscinosis (CLN3 disease). Ann N Y Acad Sci. 2016;1371:55–67. 4. Specchio N, Ferretti A, Trivisano M, Pietrafusa N, Pepi C, Calabrese C, Livadiotti S, Simonetti A, Rossi P, Curatolo P, Vigevano F.  Neuronal ceroid lipofuscinosis: potential for targeted therapy. Drugs. 2021;81:101–23. 5. Radke J, Stenzel W, Goebel HH.  Human NCL neuropathology. Biochim Biophys Acta (BBA) Mol Basis Dis. 2015;1852:2262–6.

47

Adrenoleukodystrophy: A Child with Progressive Vision Loss Marc Dinkin

Case Presentation A 3-year-old boy with X-linked adrenoleukodystrophy (C-ALD) presented with vision loss in both eyes. Routine newborn screening had found him to be positive for elevated plasma very-long-chain fatty acid (VLCFA). Subsequent genetic testing confirmed the diagnosis of adrenoleukodystrophy with a mutation in the ABCD1 gene p.ARG660Trp c.1978 C > T in exon 9. Magnetic resonance imaging (MRI) a

b

e

f

Fig. 47.1  T1 axial post-contrast MRI prior to bone marrow transplant demonstrated enhancement of the splenium of the corpus callosum (a) and brainstem corticospinal tract (b, yellow arrows) and subtly along the optic chiasm (b, white arrowhead). (c) T2 Axial FLAIR revealed hyperintensities along the splenium and optic radiations. (d) Coronal T1 post-contrast MRI showed subtle optic tract enhancement. (e) Axial

of the brain at 12 months was entirely normal. At age 2, he developed skin hyperpigmentation and was found to be Addisonian. Replacement hydrocortisone was started. An MRI of the brain at 36 months revealed an enhancing splenial lesion (Fig.  47.1a) with bilateral T2 hyperintense and enhancing lesions extending from the brainstem corticospinal tracts (Fig. 47.1b) into the posterior limbs of the internal capsules bilaterally, as well as small punctate bilateral anterior temporal subcortical white matter hyperintensities, and c

g

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T1 MRI obtained after vision loss demonstrated thin optic tracts. (f) Ongoing T2 hyperintensity is observed along midbrain corticospinal tracts. (g) New T2 hyperintensity was also observed extending along the middle cerebellar peduncles bilaterally. (h) Fundus photo of the left eye 3 months after vision loss was first recognized demonstrating optic nerve pallor.

M. Dinkin (*) Departments of Ophthalmology and Neurology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Heidary, P. H. Phillips (eds.), Fundamentals of Pediatric Neuro-Ophthalmology, https://doi.org/10.1007/978-3-031-16147-6_47

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subtle hyperintensities along the optic radiations (Fig. 47.1c). The MRI findings were consistent with a Loes Score of 4. That week, he began walking funny, dragging his right foot, and drifting to the left. He began having bouts of urinary incontinence at home. He was found to be hyperreflexic in the right lower extremity. He, therefore, underwent a rapid transplant with unrelated 7/8 umbilical cord using clofarabine, fludarabine, busulfan, anti-thymocyte globulin, and rituximab. He was engrafted and transfusion independent and immune reconstituted by day 100. His course was complicated by ileus and an engraftment syndrome. Three months after the transplant, he developed increased spasticity requiring baclofen and gabapentin. The medical course was further complicated by skin graft versus host disease which responded to topical steroids, and a BK hemorrhagic cystitis. He developed a right eye conjunctivitis and upper respiratory symptoms, and a nasal swab was positive for adenovirus. At the same time, he started biting his blanket and picking. He spiked a fever, and blood cultures revealed adenovirus in the blood. He developed hemolytic uremic syndrome with anemia and hemoglobin to 6.4 for which he received high dose IV steroids and rituximab. Six months after the transplant, he began dropping things, moving his mouth without speaking, yawning, and picking with his hands in the air. He developed opsoclonus, and an EEG was negative. At this time, his mother noted that he was no longer looking at his toys or books. On neuro-­ ophthalmological examination, visual acuity was no light perception in both eyes. There were saccadic movements without an apparent inter saccadic interval of both eyes in all directions consistent with opsoclonus. Both pupils were completely unresponsive. The optic discs were normal. Repeat MRI showed an increase in white matter hyperintensities, now consistent with a Loes Score of 9.

Differential Diagnosis

• Cortical vision loss related to ALD • Optic pathway dysmyelination related to ALD • Autoimmune optic neuropathy in the setting of a suspected parainfectious cerebellitis • Bilateral posterior ischemic optic neuropathy in the setting of severe anemia • Nutritional optic neuropathy

M. Dinkin

Diagnostic Workup In retrospect, the pre-transplant MRI suggested a subtle optic tract enhancement (Fig. 47.1d). The new MRI revealed mild atrophy of both optic tracts (Fig. 47.1e), and T2 hyperintensity along the brainstem corticospinal tracts (Fig. 47.1f). A lumbar puncture was unrevealing. The presence of omnidirectional saccadic movements in both eyes consistent with opsoclonus suggested an acute cerebellitis, which may rarely occur in the setting of adenovirus. An autoimmune optic neuropathy was also considered, although anti-CRMP antibodies were negative. To treat the suspected cerebellitis and any inflammatory contribution to the vision loss, steroids were continued, and he received IVIG.  Ultimately, the opsoclonus was attributed to new demyelination observed in the bilateral middle cerebellar peduncle (Fig. 47.1g). Opsoclonus is not typically observed in C-ALD, but downbeat nystagmus with prominent middle cerebellar peduncle involvement has been reported [1]. At follow-up 3 months later, the opsoclonus had subsided, but he appeared to remain no light perception in both eyes. Funduscopy now revealed optic nerve pallor in both eyes (Fig. 47.1h). The lack of improvement of vision despite IVIg argued strongly against an autoimmune etiology. Progression of disease on MRI, albeit mild, was most consistent with vision loss resulting from ALD-associated dysmyelination of the optic radiations, and based on the complete loss of pupillary function, of the pregeniculate optic pathways as well. The development of multi-directional saccadic movements suggestive of opsoclonus at the time of vision loss led to a search for an autoimmune cerebellopathy, and in turn raised the possibility of concomitant autoimmune optic neuropathies. In this case, the involuntary eye movements may have been a result of the progressive vision loss. Blindness frequently results in nystagmus with both pendular and jerk features, typically in the horizontal plane. Nystagmus with simultaneous searching saccades in our patient may have simulated opsoclonus. Demyelination along the middle cerebellar peduncles may also have been contributory.

Final Diagnosis Progression of X-linked adrenoleukodystrophy

47  Adrenoleukodystrophy: A Child with Progressive Vision Loss

Clinical Discussion Treatment and Prognosis X-linked cerebral adrenoleukodystrophy (C-ALD) is a rare, potentially fatal disease of cerebral demyelination due to a mutation in the ABCD1 gene, which encodes the transport protein X-linked adrenoleukodystrophy protein (ALDP) [2]. This mutation results in the abnormal transport of very long chain fatty acids (VLCFA), specifically hexacosanoic (C26:0) and tetracosanoic acid (C24:0) into the peroxisome, the organelle responsible for their metabolism. As a consequence, VLCFA accumulate in certain tissues, including the adrenal gland, testicles, and brain. In most patients with this mutation, adrenal insufficiency occurs, manifesting as hypoglycemia, hypotension, fatigue, weight loss, and skin pigmentation. In approximately 35% of the affected males, the accumulation of VLCFA in the subcortical white matter results in a progressive demyelinating disease, childhood cerebral ALD, beginning between ages 3 and 10. This results initially in behavioral problems and learning disabilities, and the regression of neurological milestones as the disease progresses. Cognitive dysfunction, vision and hearing loss, spastic ataxia, seizures, coma, and death ensue within 3 years in untreated cases. In 20% of the affected males, cerebral ALD presents in the third decade of life, while 10% are spared cerebral disease and only experience adrenal insufficiency. In most other affected males, the disease is characterized by a spastic paraparesis and peripheral neuropathy that develops in their 20s, known as adrenomyeloneuropathy (AMN). The pathology of C-ALD is characterized by a mostly symmetrical demyelination, especially in the corpus callosum, and the posterior white matter, the latter resulting in cortical vision loss [2]. While the accumulation of VLCFA may cause direct toxicity to oligodendrocytes and myelin, the presence of macrophages, some of which bear lamellar inclusions, supports the concept of a secondary inflammatory demyelinating process. The clinical course of C-ALD can be assessed and followed using the neurological function scale (NFS), which is a 25-point scale developed in 2000 [3]. The score is increased by 1–3 points for various neurological deficits including hearing loss, visual impairment, tube feeding, and aphasia. The burden of disease on MRI may also be quantified using the Loes score, a 34-point system that adds a point for any signal change (T1, T2 or enhancement) within various anatomic regions of the brain [4]. For the visual system, a point is added for the involvement of the optic tract, lateral geniculate nucleus, Meyer’s loop, and/or the optic radiations. The administration of a concoction of glyceryl-trioleate and glyceryl-trierucate (also known as Lorenzo’s Oil) may

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slow or prevent disease progression in asymptomatic patients with C-ALD [5] but requires the simultaneous limitation of dietary fat intake. More recently, allogeneic hematopoietic stem cell transplantation (HSCT) has emerged as a therapy which may prevent the progression of disease in boys with radiological evidence of demyelination without neurological symptoms. However, HSCT does not treat associated Addison’s disease, and since it is only effective when given early in the disease course, newborn screening and MRI surveillance of effective individuals are essential means of identifying candidates and ensuring proper timing of treatment. A 2019 multicenter, retrospective study demonstrated a 78% overall 5-year survival among 65 C-ALD patients undergoing HSCT vs. 55% in 72 patients who did not receive treatment [6]. Even for patients with gadolinium-enhancing disease at baseline, the 2-year survival without major functional disability rate was 89% among transplanted patients vs. 29% for untreated patients. However, adverse events after HSCT include infection (29%), graft versus host disease (38%), and engraftment failure (18%), and 18% died at 1 year. Unfortunately, our patient experienced infection, graft versus host disease, and progression of disease following HSCT.

Important Aspects of the Diagnosis Vision loss in C-ALD most commonly results from cortical vision loss but may also reflect pre-geniculate demyelination [2]. In fact, in a study of 15 children with C-ALD in 1987, optic disc pallor was observed in seven, optic dysplasia in one, and macular pigmentary mottling in two [7]. The post-­ mortem pathology of a 10-year-old boy who had light perception vision and optic atrophy at his last examination revealed loss of macular ganglion cells and the corresponding retinal nerve fibers temporal to the disc [8]. The cross section of the optic nerves showed demyelination, glial cells with cytoplasmic inclusions, and macrophages containing lipid vacuoles. In vivo assessment of retinal nerve fiber layer thickness using optical coherence tomography (OCT) in children with C-ALD may demonstrate atrophy, including cases with tract-­related homonymous hemianopia [9]. While some authors have attributed a loss of RNFL and GCL to retrograde trans-synaptic degeneration (RTSD) as a consequence of optic radiation demyelination [10], the presence of significant optic pallor in such cases (which typically would be absent in RTSD) suggests primary atrophy of the pre-­geniculate pathways as well. In our case, both the loss of pupillary function and eventual optic atrophy confirmed degeneration of anterior pathways. A recent small study evaluated OCT findings in 11 patients with adult

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C-ALD or AMN [11]. Not surprisingly, RNFL thinning was more prominent in the C-ALD group than in the AMN group and was more likely to spare the inferior RNFL, likely a reflection of the penchant of C-ALD demyelination for the superior parieto-occipital cortex, which would lead to superior RNFL loss through RTSD.  As such, OCT is a logical choice as a potential non-invasive biomarker of disease for use in clinical trials in C-ALD, although the latency between cortical demyelination and secondary RNFL atrophy is an important limitation. Large OCT studies are lacking in children, and in fact, clinical use of OCT is less common in the pediatric population, since the majority would have to be sedated for the study, without a clear change in management predicated on the results. As demonstrated by our case, vision loss may still occur following stem cell transplantation, especially in the first year. A review of 94 boys who received HSCT between 1982 and 1999 showed an 8-year survival rate of 56%. Fourteen patients who survived 100 days or more underwent a pre and post HSCT ophthalmological examination [12]. Among these children, the range of visual acuity loss following HSCT was 0–1.90 logMAR units, with a median loss of 0.36 (the equivalent of a drop from 20/20 to 20/45 on the Snellen chart). Factors that predicted a more significant loss of acuity following transplant were a pretransplant MRI severity score >11, a pretransplant performance IQ score