Brain Ischemic Stroke - From Diagnosis to Treatment [1 ed.] 9781681083094, 9781681083100

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Frontiers in Neurosurgery Volume 3 Brain Ischemic Stroke - From

Diagnosis to Treatment Edited by Simone Peschillo Department of Neurology and Psychiatry Endovascular Neurosurgery/Interventional Neuroradiology ‘Sapienza’ University of Rome Rome Italy

Series Title: Frontiers in Neurosurgery ISSN (Online): 2405-741X ISSN (Print): 2405-7401

Volume Title: Brain Ischemic Stroke - From Diagnosis to Treatment Volume # 3 Editor: Simone Peschillo, M.D., PhD. ISBN (Online): 978-1-68108-309-4 ISBN (Print): 978-1-68108-310-0 © 2016, Bentham eBooks imprint. Published by Bentham Science Publishers – Sharjah, UAE. All Rights Reserved.

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CONTENTS FOREWORD ................................................................................................................................................................ i PREFACE .................................................................................................................................................................... v LIST OF CONTRIBUTORS .................................................................................................................................... vii CHAPTER 1 EPIDEMIOLOGY AND SOCIAL COSTS ..................................................................................... 3 6LPRQH3HVFKLOORDQG)UDQFHVFR'LDQD INTRODUCTION ................................................................................................................................................ 4 DEFINITION ........................................................................................................................................................ 4 EPIDEMIOLOGY ............................................................................................................................................... 5 Risk Factors .................................................................................................................................................... 7 Unmodifiable Risk Factors: .......................................................................................................................... 7 Modifiable Risk Factors: ................................................................................................................................ 7 PREVENTION ..................................................................................................................................................... 8 INCIDENCE, PREVALENCE AND MORTALITY ...................................................................................... 10 SOCIETAL COSTS ........................................................................................................................................... 12 ENDOVASCULAR TREATMENT AND VENOUS FIBRINOLYSIS: SOCIO-ECONOMIC COMPARISON ........................................................................................................................................ 16 WHICH ENDOVASCULAR TREATMENT TO USE? ................................................................................ 20 CONCLUSION ................................................................................................................................................... 21 CONFLICT OF INTEREST ............................................................................................................................ 21 ACKNOWLEDGEMENTS ............................................................................................................................... 21 REFERENCES ................................................................................................................................................... 21 CHAPTER 2 BRAIN ISCHEMIA AND STROKE: MECHANISMS AND OPPORTUNITIES ................... 23 )UDQFHVFR2U]LDQG%DUEDUD&DVROOD ABSOLUTE DEPENDENCE ON BLOOD FLOW ........................................................................................ HETEROGENEOUS ORGAN ......................................................................................................................... ISCHEMIC CORE ............................................................................................................................................. CYTOTOXIC AND VASOGENIC EDEMA .................................................................................................. NECROSIS AND PROGRAMMED CELL DEATHS ................................................................................... MATURATION PHENOMENON ................................................................................................................... PERINECROSIS AREAS ................................................................................................................................. MECHANISMS ASSOCIATED WITH ISCHEMIC DAMAGE .................................................................. DOUBLE SWORD PROCESS ......................................................................................................................... EVIDENCE LINKING STROKE AND INFLAMMATION ......................................................................... NOT JUST A LOCAL EVENT ......................................................................................................................... DIFFERENTIATING PRO-LIFE AND PRO-DEATH MECHANISMS .................................................... OPPORTUNITIES ............................................................................................................................................. BOXES ................................................................................................................................................................ Box 1 Theoretical Models for Measuring Cerebral Blood Flow and Metabolism ....................................... Box 2 NMDA Receptors .............................................................................................................................. Box 3 Programmed Cell Deaths ................................................................................................................... Box 4 Oxidative Stress ................................................................................................................................. Box 5 Complement, Ficolins and MBL ....................................................................................................... Box 6 Adhesion Molecules .......................................................................................................................... Box 7 Lymphocytes and Stroke ................................................................................................................... CONFLICT OF INTEREST ............................................................................................................................ ACKNOWLEDGEMENTS ...............................................................................................................................

23 25 25 27 28 29 30 32 35 36 37 38 40 41 41 43 43 46 46 48 48 49 49

REFERENCES ................................................................................................................................................... 50 CHAPTER 3 NEW IMAGING TECHNIQUES .................................................................................................. 55 (OHQD)RQWDQD$OHVVDQGUR%RHOOLV/DUD&ULVWLDQRDQG$OHVVDQGUR%R]]DR INTRODUCTION .............................................................................................................................................. PATHOPHYSIOLOGY ..................................................................................................................................... CEREBRAL VASCULAR TERRITORIES AND CLINICAL PRESENTATION .................................... IMAGING .......................................................................................................................................................... Acute Phase ................................................................................................................................................. Computed Tomography (CT) ............................................................................................................... Magnetic Resonance Imaging (MRI) ................................................................................................... Subacute Phase ............................................................................................................................................. Computed Tomography (CT) ............................................................................................................... Magnetic Resonance Imaging (MRI) ................................................................................................... Chronic Phase .............................................................................................................................................. Computed Tomography (CT) ............................................................................................................... Magnetic Resonance Imaging (MRI) .................................................................................................. VENOUS INFARCT .......................................................................................................................................... THERAPY: THE ROLE OF IMAGING ......................................................................................................... CONFLICT OF INTEREST ............................................................................................................................. ACKNOWLEDGEMENTS ............................................................................................................................... REFERENCES ...................................................................................................................................................

55 57 58 63 63 63 73 78 78 80 81 81 82 84 85 87 87 87

CHAPTER 4 MEDICAL ACUTE STROKE TREATMENT ............................................................................. 95 3DROR&DQGHODUHVLDQG$OIRQVR&LFFRQH INTRODUCTION .............................................................................................................................................. 95 GENERAL SUPPORTIVE CARE ................................................................................................................... 96 STROKE UNIT .................................................................................................................................................. 98 INTRAVENOUS THROMBOLYSIS ............................................................................................................ 100 SYMPTOMATIC HEMORRHAGIC TRANSFORMATION .................................................................... 105 INTRAVENOUS THROMBOLYSIS IN THE REAL WORLD: BEYOND CONTRAINDICATIONS? ..................................................................................................................................................................... 107 NEW THROMBOLYTIC AGENTS AND NEW MEDICAL REPERFUSION STRATEGIES ............. 113 CONCLUSION ................................................................................................................................................. 116 CONFLICT OF INTEREST ........................................................................................................................... 117 ACKNOWLEDGEMENTS ............................................................................................................................. 117 REFERENCES ................................................................................................................................................. 117 CHAPTER 5 ENDOVASCULAR STROKE THERAPY: DEVICES AND DIFFERENT APPROACHES 122 'DQLHOH*5RPDQR6DPXHOH&LRQLDQG6DQGUD%UDFFR INTRODUCTION ............................................................................................................................................ SELECTION PATIENTS FOR ENDOVASCULAR TREATMENT ......................................................... Recent Trials .............................................................................................................................................. ENDOVASCULAR RECANALIZATION STRATEGIES ......................................................................... ENDOVASCULAR MECHANICAL THROMBECTOMY ........................................................................ Mechanical Thrombectomy Devices .......................................................................................................... MERCI ................................................................................................................................................ STENT-TRIEVERS ......................................................................................................................................... Solitaire FR ................................................................................................................................................ TREVO ....................................................................................................................................................... REVIVE ............................................................................................................................................................ Tromboaspirating Devices ......................................................................................................................... PENUMBRA SYSTEM ........................................................................................................................

122 124 130 131 132 134 134 134 135 138 139 139 141

COMBINED SUCTION EMBOLECTOMY AND MECHANICAL RETRIEVAL ................................. CONFLICT OF INTEREST ........................................................................................................................... ACKNOWLEDGEMENTS ............................................................................................................................. REFERENCES .................................................................................................................................................

146 147 147 147

CHAPTER 6 MECHANICAL THROMBECTOMY FOR ACUTE ISCHEMIC STROKE: REVIEW OF THE ,WDOR/LQIDQWH EVIDENCE .............................................................................................................................................................. 152 INTRODUCTION ............................................................................................................................................ 153 SYNTHESIS-EXPANSION ............................................................................................................................. 154 Interventional Management of Stroke (IMS III) ........................................................................................ 154 The Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) ..... 155 The Solitaire FR with the Intention for Thrombectomy (SWIFT) Trial .................................................... 157 Thrombectomy REvascularization of Large Vessel Occlusions in Acute Ischemic Stroke (TREVO) ..... 158 Multicenter Randomized Clinical Trial of Endo- vascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) ................................................................................................................ 158 Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) ........................................................................ 159 Extending the Time for Thrombolysis in Emergency Neurological Deficits — Intra-Arterial (EXTEND-IA) ............................................................................................................................................................. 161 Solitaire FR With the Intention For Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME) ..................................................................................................................... 163 Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset (REVASCAT) .......................................................................................... 164 CASE EXAMPLE ............................................................................................................................................ 164 CONCLUSION ................................................................................................................................................. 166 CONFLICT OF INTEREST ........................................................................................................................... 167 ACKNOWLEDGEMENTS ............................................................................................................................. 167 REFERENCES ................................................................................................................................................. 167 CHAPTER 7 NEUROSURGERY IN BRAIN ISCHEMIC STROKE ............................................................. 170 3DROR0LVVRULDQG&ULVWLQD0DQFDUHOOD INTRODUCTION ........................................................................................................................................... Microsurgical Embolectomy ...................................................................................................................... Decompressive Craniectomy ...................................................................................................................... MOYAMOYA DISEASE ................................................................................................................................ Case Illustration .......................................................................................................................................... CONFLICT OF INTEREST ........................................................................................................................... ACKNOWLEDGEMENTS ............................................................................................................................. REFERENCES .................................................................................................................................................

170 171 173 176 178 179 179 179

CHAPTER 8 CLINICAL, PHARMACOLOGICAL AND ENDOVASCULAR MANAGEMENT OF CEREBRAL VENOUS THROMBOSIS .......................................................................................................... 185 )HGHULFR'L0DULD)ORUH%DURQQHW&KDXYHW&KDUORWWH5RVVRDQG)UHGHULF&ODUHQoRQ INTRODUCTION ............................................................................................................................................ Clinical Presentation .................................................................................................................................. Risk Factors and Clinical Work-up ............................................................................................................ Outcome and Late Complications .............................................................................................................. IMAGING DIAGNOSIS .................................................................................................................................. Computed Tomography .............................................................................................................................. Complications: Imaging Findings .............................................................................................................. CT Venography .......................................................................................................................................... Magnetic Resonance Imaging ....................................................................................................................

186 186 186 188 190 190 194 195 195

MR Venography ......................................................................................................................................... Angiographic Findings ............................................................................................................................... Predictive Factors of Clinical Deterioration ............................................................................................... CT, MRI, DSA: Comparison ...................................................................................................................... MANAGEMENT AND TREATMENT ......................................................................................................... Anticoagulation .......................................................................................................................................... Intracranial Hypertension Treatment ......................................................................................................... Specific Treatements .................................................................................................................................. Rescue Treatments ..................................................................................................................................... ENDOVASCULAR TREATMENT OF CEREBRAL VENOUS THROMBOSIS .................................... CONCLUSION ................................................................................................................................................. ACKNOWLEDGEMENTS ............................................................................................................................. CONFLICT OF INTEREST ........................................................................................................................... REFERENCES .................................................................................................................................................

198 199 200 200 201 201 202 202 203 203 209 209 209 209

CHAPTER 9 INTRACRANIAL STENOSIS: MEDICAL AND ENDOVASCULAR MANAGEMENT .... 215 $OHVVDQGUR6WHFFRDQG3DROR0DFKu INTRODUCTION ............................................................................................................................................ NEUROIMAGING OF ICAS ......................................................................................................................... MEDICAL THERAPY IN ICAS .................................................................................................................... RISK FACTORS MODIFICATION .............................................................................................................. ENDOVASCULAR THERAPY IN ICAS ...................................................................................................... Angioplasty ................................................................................................................................................ Stenting ....................................................................................................................................................... SAMMPRIS ...................................................................................................................................................... RECOMMENDED TREATMENT ................................................................................................................ NOTES .............................................................................................................................................................. CONFLICT OF INTEREST ........................................................................................................................... ACKNOWLEDGEMENTS ............................................................................................................................. REFERENCES .................................................................................................................................................

215 215 221 223 224 224 224 225 226 228 229 229 229

CHAPTER 10 UNCOMMON CAUSE OF STROKE: DIAGNOSIS AND TREATMENT (PART I) ......... 237 3DROR&HUUDWR$OHVVDQGUR3H]]LQLDQG*LRYDQQD9DXOD COLLAGEN VASCULAR DISORDERS AND OTHER NON INFLAMMATORY VASCULOPATHIES ..................................................................................................................................................................... 238 FIBROMUSCULAR DYSPLASIA ............................................................................................................... 238 Clinical Findings ........................................................................................................................................ 240 Diagnostic Assessment ............................................................................................................................... 242 Treatment ................................................................................................................................................... 243 EHLERS-DANLOS SYNDROME (EDS) ...................................................................................................... 244 Clinical Findings ........................................................................................................................................ 244 Cerebrovascular Features .......................................................................................................................... 246 Brain and Spine Structural Anomalies ...................................................................................................... 248 Treatment ................................................................................................................................................... 249 MARFAN SYNDROME .................................................................................................................................. 250 Cerebrovascular Complications ................................................................................................................. 252 Treatment .................................................................................................................................................. 253 OSTEOGENESIS IMPERFECTA ................................................................................................................. 254 Clinical Findings ........................................................................................................................................ 254 Neurological Features ............................................................................................................................... 256 Diagnosis .................................................................................................................................................... 256 NEUROFIBROMATOSIS .............................................................................................................................. 256 Cardiovascular Findings ............................................................................................................................. 257

Cerebrovascular Complications ................................................................................................................. Treatment .................................................................................................................................................. PSEUDOXANTHOMA ELASTICUM .......................................................................................................... Clinical Features ........................................................................................................................................ Vascular Complications ............................................................................................................................. Diagnosis and Treatment ............................................................................................................................ POLYCISTIC KIDNEY DISEASE ................................................................................................................ Hypertension and Cardiac Manifestations ................................................................................................. Cerebrovascular Manifestations ................................................................................................................. Treatment ................................................................................................................................................... SNEDDON SYNDROME ................................................................................................................................ Clinical Features ......................................................................................................................................... Dermatologic Manifestations ............................................................................................................. Neurological Features ....................................................................................................................... Cardiac Features ............................................................................................................................... Diagnostic Assessment ...................................................................................................................... Treatment ........................................................................................................................................... MOYA-MOYA DISEASE .............................................................................................................................. General Features and Classification .......................................................................................................... Pathogenesis ............................................................................................................................................... Clinical Features ........................................................................................................................................ Diagnosis .................................................................................................................................................... Treatment .................................................................................................................................................. CERVICAL ARTERY DISSECTION ........................................................................................................... Pathogenesis ............................................................................................................................................... Genetics of CAD ........................................................................................................................................ Clinical Manifestations .............................................................................................................................. Diagnosis .................................................................................................................................................... Ultrasound and Neuroradiological Tools .......................................................................................... Skin Biopsy and Other Advanced Diagnostic Tools ........................................................................... Treatment ................................................................................................................................................... Medical Treatment ............................................................................................................................. Interventional Procedures .................................................................................................................. Surgery ............................................................................................................................................... Prognosis ............................................................................................................................................ VASCULITIS OF THE CENTRAL NERVOUS SYSTEM ........................................................................ Primary Angiitis of the Central Nervous System (PACNS) ...................................................................... Granulomatous Angiitis of The CNS ........................................................................................................ Angiographically Defined PACNS ............................................................................................................ Cerebral Amyloid Angiopathy Related Angiitis ....................................................................................... Secondary Angiitis of The CNS ................................................................................................................. Treatment of PACNS ................................................................................................................................. REVERSIBLE CEREBRAL VASOCONSTRICTION SYNDROME ...................................................... Diagnostic Assessment in RCVS ............................................................................................................... Treatment ................................................................................................................................................... VASCULITIS IN CHILDREN ....................................................................................................................... Primary CNS vasculitis in children ............................................................................................................ Transient Cerebral Arteriopathy and Postvaricella Angiopathy in Children ............................................. GIANT CELL ARTERITIS ............................................................................................................................ Systemic Features ...................................................................................................................................... Visual Features ..........................................................................................................................................

257 259 259 260 261 262 263 264 264 266 266 267 267 267 269 270 271 271 272 273 273 274 277 278 279 283 284 286 286 288 289 289 290 291 291 291 293 295 297 297 298 300 300 304 306 307 307 307 309 310 311

Neurological and Cerebrovascular Manifestations ................................................................................... Diagnostic Assessment .............................................................................................................................. Treatment and Course ............................................................................................................................... TAKAYASU’S ARTERITIS .......................................................................................................................... Clinical Features and Differential Diagnoses ............................................................................................. Diagnostic Assessment ............................................................................................................................... Treatment ................................................................................................................................................... BEHÇET DISEASE ......................................................................................................................................... General Features ........................................................................................................................................ Neurological Features ................................................................................................................................ Diagnostic Assessment ............................................................................................................................... Neuroimaging ..................................................................................................................................... Cerebrospinal Fluid Examination ..................................................................................................... Treatment ........................................................................................................................................... SUSAC’S SYNDROME ....................................................................................................................... Clinical Findings ................................................................................................................................ Diagnostic Assessment .............................................................................................................................. Neuroradiological Features ............................................................................................................... Optical Coherence Tomography (OCT) ............................................................................................. Fluorescein Angiography of The Retina ............................................................................................ Differential Diagnosis ........................................................................................................................ Treatment ........................................................................................................................................... Course and Prognosis ........................................................................................................................ COGAN SYNDROME ..................................................................................................................................... Clinical Findings ....................................................................................................................................... Audiovestibular Manifestations ................................................................................................................. Ocular Manifestations ................................................................................................................................ Systemic Manifestations ............................................................................................................................ Neurological Manifestations ...................................................................................................................... Therapeutic Approaches ............................................................................................................................. Angiotropic Large Cell Lymphoma ........................................................................................................... Neurological Features ................................................................................................................................ Diagnostic Assessment ............................................................................................................................... Treatment ................................................................................................................................................... CLIPPERS SYNDROME ................................................................................................................................ Diagnosis .................................................................................................................................................... Treatment ................................................................................................................................................... ACKNOWLEDGEMENTS ............................................................................................................................. CONFLICT OF INTEREST ........................................................................................................................... REFERENCES .................................................................................................................................................

312 314 315 316 319 320 321 323 323 325 327 327 328 328 329 330 331 331 333 333 334 334 335 335 336 337 337 338 338 339 340 340 341 343 344 345 346 346 347 347

CHAPTER 11 UNCOMMON CAUSE OF STROKE: DIAGNOSIS AND TREATMENT (PART II) ....... 376 3DROR&HUUDWR$OHVVDQGUR3H]]LQLDQG*LRYDQQD9DXOD HEREDITARY CEREBRAL SMALL VESSELS DISEASES ................................................................... CADASIL .......................................................................................................................................................... PATHOGENESIS ............................................................................................................................................ Clinical Phenotype ..................................................................................................................................... Neuroimaging ............................................................................................................................................ COL4 A1/2 RELATED DISORDERS ............................................................................................................ Pathogenesis ............................................................................................................................................... Clinical Phenotypes .................................................................................................................................... Neuroimaging .............................................................................................................................................

377 377 378 379 380 383 383 384 387

CARASIL .......................................................................................................................................................... Clinical Phenotype ..................................................................................................................................... Neuroimaging ............................................................................................................................................. CEREBRORETINAL VASCULOPATHIES AND RELATED DISEASES ............................................. Clinical Phenotype ..................................................................................................................................... Neuroimaging ............................................................................................................................................. Pathology .................................................................................................................................................... CEREBRORETINAL MICROANGIOPATHY WITH CALCIFICATIONS AND CYSTS ................... Clinical Phenotype ..................................................................................................................................... Neuroimaging ............................................................................................................................................. STROKE AND METABOLIC DISEASES ................................................................................................... Fabry Disease ............................................................................................................................................. General Findings ........................................................................................................................................ Cerebrovascular Complications ................................................................................................................ Treatment ................................................................................................................................................... Homocystinuria .......................................................................................................................................... Clinical Findings ........................................................................................................................................ Vascular Complications ............................................................................................................................ Diagnosis .................................................................................................................................................... Treatment ................................................................................................................................................... Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS) ......... Clinical Features ......................................................................................................................................... Neurological Complications ...................................................................................................................... Radiological Features ................................................................................................................................. Metabolic and Pathological Features ......................................................................................................... Treatment ................................................................................................................................................... ISCHAEMIC STROKE AND ANTIPHOSPHOLIPID SYNDROME ....................................................... Clinical Criteria .......................................................................................................................................... Vascular Thrombosis .................................................................................................................................. Obstetric Complications ............................................................................................................................. Other Features ........................................................................................................................................... Laboratory Criteria ..................................................................................................................................... Lupus Anticoagulant .................................................................................................................................. Anticardiolipin (aCL) Antibodies .............................................................................................................. Anti β2-Glycoprotein I (aβ2GPI) Antibodies ............................................................................................. Cerebrovascular Complications ................................................................................................................ Pathology and Pathophysiology ................................................................................................................. Embolic Sources ......................................................................................................................................... Valve Abnormalities .................................................................................................................................. Intracardiac Thrombi .................................................................................................................................. Treatment .................................................................................................................................................. Primary Prevention ..................................................................................................................................... Secondary Prevention ................................................................................................................................. Catastrophic APS ....................................................................................................................................... SICKLE-CELL DISEASE .............................................................................................................................. Neurologic Complications .......................................................................................................................... Diagnostic Assessment .............................................................................................................................. Treatment ................................................................................................................................................... OTHER UNCOMMON CAUSES OF STROKE .......................................................................................... Acute Posterior Multifocal Placoid Pigment Epitheliopathy ..................................................................... Neurological Features ................................................................................................................................

387 388 389 389 390 391 392 392 393 393 394 394 394 397 399 400 402 403 404 405 406 406 407 408 409 409 410 410 410 411 411 411 412 412 412 413 414 415 415 417 417 418 418 420 420 420 422 423 426 426 427

Diagnostic Assessment ............................................................................................................................... The Differential Diagnosis ........................................................................................................................ Treatment ................................................................................................................................................... Malignant Atrophic Papulosis (Köhlmeier-Degos) ................................................................................... Clinical Findings and Neurologic Features ....................................................................................... Diagnosis and Treatment ................................................................................................................... STROKE AND MIGRAINE ........................................................................................................................... Migraine With Aura and Transient Ischemic Attack ................................................................................. Migrainous Stroke ...................................................................................................................................... Silent Cerebral Ischemic Lesion in Migraine ............................................................................................. Secondary Migraine With Aura and Ischaemic Stroke ............................................................................. Practical Implications of The Migraine–Stroke Association ..................................................................... CEREBROVASCULAR COMPLICATION OF DRUGS ABUSE ............................................................. Heroin ......................................................................................................................................................... Cocaine ...................................................................................................................................................... Cannabis ..................................................................................................................................................... Phenylpropranolamine and Ephedrine ....................................................................................................... CONFLICT OF INTEREST ........................................................................................................................... ACKNOWLEDGEMENTS ............................................................................................................................. REFERENCES .................................................................................................................................................

427 428 429 429 430 431 432 432 435 437 438 439 440 441 443 445 447 449 449 449

CHAPTER 12 ENDOVASCULAR MANAGEMENT OF ATHEROSCLEROTIC AND DISSECTED CAROTIDS ........................................................................................................................................................... 474 *XJOLHOPR3HURDQG7KHPLVWRNOLV3DSDVLOHNDV INTRODUCTION ............................................................................................................................................ INDICATIONS OF CAROTID STENTING ................................................................................................. Patient Related Factors ............................................................................................................................... Anatomy Related Factors .......................................................................................................................... ENDOVASCULAR TECHNIQUE AND MATERIALS .............................................................................. COMPLICATIONS ......................................................................................................................................... PHARMACOLOGICAL SUPPORT ............................................................................................................. CAROTID DISSECTIONS ............................................................................................................................. CONCLUSION ................................................................................................................................................. CONFLICT OF INTEREST ........................................................................................................................... ACKNOWLEDGEMENTS ............................................................................................................................. REFERENCES .................................................................................................................................................

474 476 476 476 478 486 488 490 493 494 494 494

CHAPTER 13 INTENSIVE CARE MANAGEMENT ...................................................................................... 498 )HGHULFR%LORWWD0DUWLQD1RYHOOL)LOLSSR3HFRUDULDQG*LRYDQQL5RVD INTRODUCTION ............................................................................................................................................ GENERAL SUPPORTIVE CARE AND TREATMENT OF ACUTE COMPLICATIONS ................... Ventilation and Supplement Oxygen ........................................................................................................ Sedation and Analgesia ............................................................................................................................. Blood Pressure ............................................................................................................................................ Fluid Management ...................................................................................................................................... Myocardial Complications ......................................................................................................................... Glycemic Control ...................................................................................................................................... Temperature .............................................................................................................................................. Thromboprophylaxis .................................................................................................................................. Anemia ...................................................................................................................................................... Hemorrhagic Transformation ..................................................................................................................... Cerebral Edema .......................................................................................................................................... Seizures ......................................................................................................................................................

498 499 499 500 501 502 503 503 503 504 504 504 504 505

Neuromonitoring ....................................................................................................................................... CONCLUSION ................................................................................................................................................. ACKNOWLEDGEMENTS ............................................................................................................................. CONFLICT OF INTEREST ........................................................................................................................... REFERENCES .................................................................................................................................................

506 506 506 507 507

CHAPTER 14 THE TRIALS AND TRIBULATIONS OF ISCHEMIC STROKE THERAPY ................... 511 $UDQL%RVH6RSKLD6.XR-HQQLIHU:RQJ-RKQ/RFNKDUWDQG6LX3R6LW OVERVIEW ..................................................................................................................................................... DEVICES AND CLINICAL TRIALS IN ACUTE ISCHEMIC STROKE ................................................ The Beginning of Mechanical Thrombectomy .......................................................................................... Aspiration Thrombectomy Comes of Age ................................................................................................. The Advent of Stent Retrievers .................................................................................................................. Combination Techniques Evolve ............................................................................................................... The Early Inconclusive Mechanical Thrombectomy Trials ....................................................................... Early and Rapid Reperfusion are Critical for Good Clinical Outcomes .................................................... The Benefits of Intra-Arterial Therapy are Confirmed .............................................................................. SUMMARY ....................................................................................................................................................... CONFLICT OF INTEREST ........................................................................................................................... ACKNOWLEDGEMENTS ............................................................................................................................. REFERENCES .................................................................................................................................................

511 512 512 513 514 514 516 516 517 522 524 524 525

CHAPTER 15 EVOLUTION OF DEVICES FOR ENDOVASCULAR THROMBECTOMY IN ACUTE ISCHEMIC STROKE: FROM THE BEGINNING TO THE ADAPT TECHNIQUE .................................... 529 6LPRQH3HVFKLOORDQG)UDQFHVFR'LDQD INTRODUCTION ............................................................................................................................................ PHARMACOLOGICAL INTRA-ARTERIAL THROMBOLYSIS .......................................................... CLOT-DISRUPTOR ........................................................................................................................................ Second-generation clot removers: the Penumbra aspiration system .......................................................... CLOT-CATCHER .......................................................................................................................................... STENT RETRIEVERS .................................................................................................................................... ADAPT (A DIRECT ASPIRATION FIRST PASS TECHNIQUE) ............................................................ The EKOS MicroLysUS Catheter .............................................................................................................. FUTURE PERSPECTIVES ............................................................................................................................ CONFLICT OF INTEREST ........................................................................................................................... ACKNOWLEDGEMENTS ............................................................................................................................. REFERENCES .................................................................................................................................................

529 533 534 535 537 537 538 542 542 542 542 543

SUBJECT INDEX .................................................................................................................................................... 546

i

FOREWORD I read with a lot of interest the book by Simone Peschillo and his collaborators. This book presents the current knowledge on cerebral ischaemia and its treatment. It will be for sure very useful for all those who are interested on this topic. It starts by the very concerning epidemiological and economic aspect of the disease and then it presents all the main themes of the subject. It will be a reference book that aims to be complete and it does not only present the therapeutic endo vascular techniques but also, and it is fundamental, all the medical environment and intensive care techniques which are essential. We can only admire the progresses made, even in the diagnosctic plan. I personnally began to practise neuroradiology 45 years ago … It was the time when the diagnosis of an intracerebral hemorrhage could only be made if this bleeding was voluminous enough to displace the adjacent arteries angiography ... I had the privilege in 1971 of attending the first french private presentation on CT by Ambrose who showed unrefined images made of black and white spots. It was a revolution : we were able to see directly, for the first time, the image of intracerebral blood. Nowadays, despite of MRI, CT remains a fundamental tool of decision in the field of cerebral ischaemia because it is fast and easily accessible. In the 70s, there were few interventional neuroradiologists and they were more interested in angiomas and tumors than in cerebral ischaemia. I was personnally rapidly interested in this topic and the 80s were very important for me. In 1980 I began using angioplasty to treat major supra aortic arteries, then in 1983, after Mathias [1] I started simple angioplasty in carotid arteries [2]. I described in 1984 the concept of cerebral protection [3]. After Zeumer [4], I also in 1985 performed our first cases of intra arterial thrombolysis [5]. In 1990 I dared to put in place the first carotid stent [6] and then developed this technique [7, 8]. It activated some turbulences in the vascular surgery environment… I am now delighted that this tool has become a classic in the treatment of carotid stenoses. Nevertheless let me summarize what I keep thinking on this matter: At the opposite of the other arteries, post stenting restenoses are quite rare in carotid artery because of its high flow. Long closed stents remain for us the best choice because they treat the whole pathological area and correct partially the artery tortuosity. The only real difficulty that remains is its approach on atheromatous patients. This is why we described the radial approach [9].

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I keep thinking that a cerebral protection is mandatory and that the only real protection is the temporary occlusion of the distal internal catotid artery [10]. Filters offer a protection only for big emboli and are themselves reponsible of emboli. The temporary occlusion of the common carotid artery with simultaneous occlusion of the external carotid artery, that we also have described and later abandoned, seems to be reserved for the treatment of complete occlusions of the internal carotid. Post revascularisation hemorrhage occurs in most cases on brains with previous silent infarctions. Its occurence is clearly limited by the control of blood pressure. Actually it can also be a delayed embolic hemorrhagic complication. The book presents a very detailed chapter on non atheromatous arterial lesions. It is a very interesting topic that covers several diseases. We have been early interested in the disease of Takayasu when we worked in Canada [11] and we performed endovascular treatments on similar cases. More studies will be necessary in the future to adopt a common therapeutic strategy because the reaction to endovascular techniques can be quite different from one disease to the other. In acute brain ischaemia I have to say my enthusiasm by seeing strengthening in the idea that a cerebrovascular accident is not any more a fate and that it exist therapeutic tools to treat it. After intravenous and intra arterial thrombolysis, mecanichal revascularisation technics are now available and are more and more sofisticated and effective. This book presents the various current possibilities. The time will tell us which ones are the best for each case. What is sure is that the number of necessary intervetionists will grow dramatically in the future. I am delighted at it for the whole world population. However I would like to add about this topic some personal ideas that have meant a lot to me for years: we know that it is necessary to save time and CT remains the basic emergency investigation which allows make the diagnosis of intracerebral bleeding. We dreamt of CTs in a light truck and we spoke of it for many years. It does exist presently. If we deal with an ischemic case it will allow start immediately the intravenous thrombolysis. Many lives will be saved and many brains will be less damaged. Arrived at the hospital, unless a complete clearance of the symptoms has be obtained, the patient will have an angiography. The good therapeutic decision will only be taken if the exact state of the cerebral vascularization is known. The cerebral parenchymography [12] remains for me the simplest and most adapted investigation. One single injection of contrast in the aortic arch is sufficient for confirming the arterial occlusion, its site and the exact devascularisation downstream to the occlusion. Anatomical variations are infinite and so are the individual possibilities of revascularisation. Vascularization of the cerebral parenchyma is

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the only true key point to be known In the decision of treating, occlusion of lenticulostriate arteries is for me a fundamental point. These arteries are terminal and their wall is very sensitive to ischaemia. It has been shown by Kamyjio on cat that their revasculaization after the 6er hour resulted in high purcentage of bleeding [13]. We have confirmed it [14] in showing that it was possible to eliminate post revascularization hemorrhage : intra arterial thrombolysis should not be performed on a patient after the 6th hour when the lenticulostriate arteries are occluded . On the other hand the therapeutic window can be widened if these arteries are not interested. This way of reasoning is obviously applicable also for the mechanical revascularisation. Not using these information made that the possible therapeutic window was reduced in order to limitate the hemorrhagic complications. We are convinced that these simple rules should be used by all, day and at night, and that they could save numerous lives and handicaps.

Dr. Jaques Théron Department of Endovascular and Percutaneous Therapy Hospital Nuestra Señora del Rosario Madrid Spain References [1] Mathias K. Perkutane tansluminale katheterbehandlung supraaortler arterienobstruktion. Angiology 1981; 3: 47-50. [2] Théron J, Raymond J, Casasco A, Courtheoux P. Percutaneous angioplasty of atherosclerotic and postsurgical stenosis of carotid arteries. AJNR 1987; 8: 495-500. [PMID: 2955682] [3] Théron J, Courtheoux P, Alachkar F, Maiza D. New triple coaxial catheter system for carotid angioplasty with cerebral protection. AJNR 01990; 11: 869-74. [PMID: 2145730] [4] Zeumer H, Hackle W, Ringelstein EB. Local intraarterial thrombolysis in vertebrobasilar thromboembolic disease. AJNR 1083; 4: 401-4. [5] Théron J, Courtheoux P, Casasco A, et al. The carotid territory. AJNR 1989; 10: 753-65. [PMID: 2505504] [6] Théron J, Guimaraens L, Casasco A, et al. Angioplasty of brachiocephalic vessels. In: Vinuela V, Halbach VV, Dion JE, eds. Interventional neuroradiology: endovascular therapy of the central nervous system. 1992. p. New York Raven Press. [7] Théron J, Payelle G, Coskun O, Huet H, Guymararens L. Carotid artery stenosis: treatment with protected balloon angioplasty and stent placement Radiology 1996; 201(3): 627-36. [PMID: 8939208] [8] Théron J, Guimaraens L, Casasco A, et al. “Protected” wallstenting of atheromatous stenoses at the carotid bifurcation. Interventional Neuroradiol 2003; 9: 99-126.

iv [9] Théron J, Guimaraens L, Casasco A, et al. The treatment of supraaortic arterial lesions. Interventional Neuroradiol 2007; 13: 133-44. [10] Théron J, Reul J, Venturi C, Bedogni F, Milosevic Z. Immediate and mid-term clinical outcome of patients treated with the TwinOne® cerebral protection system - multicen-tric trial : 209 Cases. Cardiovasc Interventional Radiol 2009. [11] Theron J, Tyler JL. Takayasu’s arteritis of the aortic arch: endovascular treatment and correlation with positron emission tomography. AJNR 1987; 8: 621-6. [12] Theron J, De Oliveira D, Alachkar F, Maiza D. Dynamic digitalized parenchymography. Neuroradiology 1992; 34: 361-4. [13] Kamijyo Y, Garcia JH, Cooper J. The cat. A model of hemorragic and subcortical infarction. J Neuropathol Exp Neurol 1977; 36: 338-50. [PMID: 839241] [14] Théron J, Coskun O, Huet H, Oliveira G, Toulas P, Payelle P. The carotid territory. Interventional Neuroradiology 1996; 2(2): 111-26. [PMID: 20682124]

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PREFACE Someone suffers a stroke every 40 seconds in the USA; every year over 15 million people throughout the world suffer a stroke and 5 million are left significantly disabled. Stroke is thought to be the second biggest killer worldwide, and is responsible for over 5 million deaths per year. The total economic burden of stroke is of the order of £7bilion per annum in England and Wales. Even though many efforts to treat as much as possible stroke patients have been made, many of it are still left undertreated, mainly due to the short time window and other contraindications for intravenous (i.v.) rtPA. Furthermore, much more evidence demonstrates that endovascular treatment, in selected patients, is much more resolutive. Various strategies have been developed to increase the number of treated patients: regarding the diagnosis, new neuroimaging tools allows neurologists and neurointerventionists to evaluate either the ischemic core and the vessel pattern and collateral status; regarding medical treatment, new molecules are being tested in RCTs (randomized clinical trials) with extended time windows. In this context, endovascular treatment is a new technique that allows neurointerventionists to treat patients in whom intravenous rtPA has failed and those in extended time windows, in particular in large-vessels occlusion. Regarding this novel approach, a new era has emerged with new devices (i.e. stent-retrievers and aspiration techniques), which have demonstrated in recently published RCTs higher rates of recanalization and clear superiority compared to previous devices. Several ongoing RCTs are now investigating whether bridging therapy is more effective than i.v. treatment alone, whether mechanical thrombectomy is more successful than the best medical treatment in patients ineligible for i.v. thrombolysis and which kind of endovascular treatment is much effective. The purpose of this eBook is to take stock of the latest news on the ischemic stroke treatment. In 2020, mortality will be doubled due to this serious disease; everyone, health care assistants, social assistants and politicians as well, should be first in line to fight this battle. This eBook is addressed not only to specialists in the treatment of patients with ischemic

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stroke, but also nurses, physiotherapists and finally non-medical personnel whose task is to decide on health care.

Dr. Simone Peschillo Department of Neurology and Psychiatry Endovascular Neurosurgery/Interventional Neuroradiology ‘Sapienza’ University of Rome Rome Italy

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List of Contributors Alfonso Ciccone

Department of Neurosciences, Carlo Poma Hospital, Mantua, Italy

Alessandro Boellis

NESMOS Department, University of Rome “Sapienza”. S. Andrea Hospital, Rome, Italy

Alessandro Bozzao

NESMOS Department, University of Rome “Sapienza”. S. Andrea Hospital, Rome, Italy

Alessandro Stecco

Neuroradiology Unit, Radiology Dept, Novara Maggiore Hospital, Italy

Alessandro Pezzini

Department of Clinical Science, Neurological Clinical Brescia University, Italy

Arani Bose

Penumbra Inc., Alameda, CA, USA

Barbara Casolla

Department of Neurosciences, Mental Health and Sensory Organs, University of Rome “La Sapienza”, Rome, Italy

Charlotte Rosso

APHP, Urgences Cérébro-Vasculaires, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France Facultéde Médecine, UniversitéParis 6 “Pierre et Marie Curie” (UPMC) , 75005 Paris, France

Cristina Mancarella

Department of Neurology and Psychiatry, Neurosurgery, Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy

Daniele G. Romano

Unit of Neurointerventional, Division of Neuroradiology, Department of Neurological and Neurosensorial Sciences, University Hospital of Siena, Italy

Elena Fontana

NESMOS Department, University of Rome “Sapienza”. S. Andrea Hospital, Rome, Italy

Francesco Diana

Department of Radiology, “Sapienza” University of Rome, Rome, Italy

Federico Di Maria

APHP, Service de Neuroradiologie Interventionnelle Groupe Hospitalier Pitié, Salpêtrière, 75013, Paris, France

Flore Baronnet-Chauvet

APHP, Urgences Cérébro-Vasculaires, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France

Frederic Clarençon

APHP, Service de Neuroradiologie Interventionnelle Groupe Hospitalier Pitié, Salpêtrière, 75013, Paris, France APHP, Urgences Cérébro-Vasculaires, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France

Francesco Orzi

Department of Neurosciences, Mental Health and Sensory Organs, University of Rome “La Sapienza”, Rome, Italy

Federico Bilotta

Department of Anestehsiology, Critical care and Pain medicine, “Sapienza” University of Rome, Rome, Italy

viii Filippo Pecorari

Department of Anestehsiology, Critical care and Pain medicine, “Sapienza” University of Rome, Rome, Italy

Giovanna Vaula

Stroke Unit, Department of Neuroscience, Turin University Molinette Hospital, Turin, Italy

Guglielmo Pero

Department of Neuroradiology, Niguarda Ca’ Granda Hospital, Milan, Italy

Giovanni Rosa

Department of Anestehsiology, Critical care and Pain medicine, “Sapienza” University of Rome, Rome, Italy

Italo Linfante

Miami Cardiac and Vascular Institute and Neuroscience Center Baptist Hospital, Miami, USA

Jennifer Wong

Penumbra Inc., Alameda, CA, USA

John Lockhart

Penumbra Inc., Alameda, CA, USA

Lara Cristiano

NESMOS Department, University of Rome “Sapienza”. S. Andrea Hospital, Rome, Italy

Martina Novelli

Department of Anestehsiology, Critical care and Pain medicine, “Sapienza” University of Rome, Rome, Italy

Paolo Candelaresi

Department of Emergency Medicine, San Carlo Borromeo Hospital, Milan, Ìtaly

Paolo Cerrato

Stroke Unit, Department of Neuroscience, Turin University Molinette Hospital, Turin, Italy

Paolo Machì

CHRU Montpellier, Service de Neuroradiologie, Hopital Gui de Chauliac, 80 Avenue Augustin Fliche, 34295 Montpellier Cedex 5,, Paris, France

Paolo Missori

Department of Neurology and Psychiatry, Neurosurgery, Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy

Simone Peschillo

Department of Neurology and Psychiatry, Endovascular Neurosurgery/Interventional Neuroradiology, “Sapienza” University of Rome, Rome, Italy

Samuele Cioni

Unit of Neurointerventional, Division of Neuroradiology, Department of Neurological and Neurosensorial Sciences, University Hospital of Siena, Siena, Italy

Sandra Bracco

Unit of Neurointerventional, Division of Neuroradiology, Department of Neurological and Neurosensorial Sciences, University Hospital of Siena, Siena, Italy

Siu Po Sit

Penumbra Inc., Alameda, CA, USA

Sophia S. Kuo

Penumbra Inc., Alameda, CA, USA

Themistoklis Papasilekas Department of Neuroradiology, Niguarda Ca’ Granda Hospital, Milan, Italy

Frontiers in Neurosurgery, 2016, Vol. 3, 3-22

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CHAPTER 1

Epidemiology and Social Costs Simone Peschillo1,* and Francesco Diana2 Department of Neurology and Psychiatry, Endovascular Neurosurgery/Interventional Neuroradiology, ‘Sapienza’ University of Rome, Rome, Italy 1

Department of Neurology and Psychiatry, Interventional Neuroradiology, ‘Sapienza’ University of Rome, Rome, Italy 2

Abstract: Stroke is a pathology that has a heavy socio-economic impact, considering that the annual incidence is 15 million new cases and only one-third of these has a positive clinical outcome. Stroke is the cause of 4% of all disabilities and it does, therefore, have very high indirect social costs. The purpose of this chapter is to analyse the societal costs of stroke and compare the various treatments in order to determine which gives the best results for a contained cost. Clinical outcome was analysed using the modified Rankin Scale (mRS), in which patients are allocated a score that depends on the presence of neurological symptoms and an impaired capacity to perform daily-life activities. The indirect costs related to reduced productivity were calculated through the analysis of various indices: disabilityadjusted life years (DAYLs), years of life lost (YLL) and years lived with disability (YLD). We calculated that a mRS score 10 Differences of > 10 mmHg in systolic blood pressure between arms mmHg • Bruit over subclavian arteries or Bruit audible on auscultation over 1 or both subclavian arteries or aorta abdominal aorta • Arteriogram abnormality

Stenosis or occlusion of the entire aorta, its primary branches or large arteries in the proximal upper or lower extremities, not caused by other disorders (arteriosclerosis and fibromuscular dysplasia)

  A diagnosis of Takayasu arteritis requires that at least 3 of the 6 criteria are met. Table 12. Final EULAR/PRINTO/PRES Takayasu arteritis criteria and classification definition [276]. Criterion Angiographic abnormality (mandatory criterion)

Glossary

Sensitivity (%)

Specificity (%)

AUC (%)

Angiography (conventional, CT, or MRI) of the aorta or its main branches and pulmonary arteries showing aneurysm/dilatation, narrowing, occlusion or thickened arterial wall not due to fibromuscular dysplasia, or similar causes; changes usually focal or segmental

100

99.9

99.9

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(Table ) contd.....

Criterion

Sensitivity (%)

Specificity (%)

AUC (%)

74.7

99.1

86.9

 Blood pressure (BP) Discrepancy of four limb systolic BP >10 mm discrepancy Hg difference in any limb.

63.5

99.6

81.6

 Bruits

Audible murmurs or palpable thrills over large arteries

58.8

99.8

79.3

 Hypertension

Systolic/diastolic BP greater than 95th centile for height

63.2

90.5

76.8

 Acute phase reactant Erythrocite sedimentation rate >20 mm per first hour or CRP any value above normal (according to the local laboratory)

95.0

14.1

54.6

EULAR/

100

 Pulse deficit claudication

Glossary or Lost/decreased/unequal pulse(s)

peripheral

artery

Claudication: focal muscle pain induced by physical activity

PRINTO/PRES criteria

Angiographic abnormalities of the aorta or its main branches and pulmonary arteries showing aneurysm/dilatation (mandatory criterion) plus one of the five following criteria: 1.  Pulse deficit or claudication 2.  Four limbs BP discrepancy 3.  Bruits 4.  Hypertension 5.  Acute phase reactant

  99.9

99.9

  AUC, area under the curve; CRP, C-reactive protein; c-TA, c-Takayasu arteritis; EULAR, European League Against Rheumatism; PRES, Paediatric Rheumatology European Society; PRINTO, Paediatric Rheumatology International Trials Organization

Vessel pathology of TA can be varied. Rapid disease progression may lead to aneurysm formation secondary to inadequate fibrosis or to inflammation mediated mural stress [277]. Aortic involvement in TA is typical of the disorder and is present in all patients >277–280@. The abdominal aorta is the most common site of involvement, followed by the descending thoracic aorta and aortic arch. Branch vessel disease is a common feature in TA, with the subclavian, innominate, renal, common carotid, vertebral, and mesenteric arteries most often involved. A retrospective Italian study on 104 patients showed stenosis as the most common

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lesion, ( 93% of TA patients), followed by occlusion (50% of TA patients) while dilatation and aneurysms were less common (respectively 16% and 7% of the patients) [278]. Aneurysms are common and clinically significant in the aortic root, where they can cause valvular regurgitation. Hypertension is most often caused by renal artery stenosis, but can also be associated with suprarenal aortic stenosis or a chronically damaged, rigid aorta. Clinical Features and Differential Diagnoses Other than systemic features TA patients may complained of visual symptoms due to retinopathy in up to 37% of patients, congestive cardiac failure associated with aortic regurgitation, dilated and hypertensive cardiomyopathy, neurological features secondary to hypertension and/or ischaemia, including postural dizziness, seizures, and amaurosis, an pulmonary artery stenosis. Other symptoms include dyspnoea, headaches, carotodynia, myocardial ischaemia, chest wall pain and erythema nodosum. The differential diagnoses include other causes of large vessel vasculitis such as: a) inflammatory aortitis (syphilis, tuberculosis, lupus, rheumatoid arthritis, spondyloarthropathies, Behçet’s disease, Kawasaki disease, and giant cell arteritis); b) disorders causing large vessel abnormalities such as fibromuscular dysplasia, coarctation of the aorta and Marfan syndrome and other collagen vascular disease such as neurofibromatosis. Most of these have specific features that enable diagnosis, but tuberculosis has remained an important differential and possible aetiological factor. However, tuberculous aortitis tends to cause erosion of the vessel wall with the formation of true or false aneurysms causing dissection and rupture rather than the stenosis typical of TA. Intriguingly some authors suggest that TA and giant cell arteritis are a spectrum within the same disease in which age-related factors may influence disease expression [269]. The prevalence of aortic, vertebral, and renal artery disease is similar in the two disorders but patients with TA more often had carotid,

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subclavian, and iliac artery disease, while GCA patients had a greater frequency of axillary artery involvement. Upper extremity claudication and pulselessness were reported more frequently in TA than in GCA. Blood pressure inequality between limbs was more common in TA at presentation. The prevalence of vascular bruits was comparable, with the exception of left carotid bruit, which was more frequent in TA than in GCA. The prevalence of transient ischemic attacks and stroke was comparable between the groups. Blindness (complete visual loss in at least 1 eye) occurred in 14% of GCA patients but was never reported in TA. Other authors suggest that GCA and TA although similar in some features can be differentiated on clinical ground. In a study of 280 patients, mostly with GCA found that age of 40 years at disease onset was the single most discriminatory factor. Other findings useful for the differential diagnosis between GCA an TA were ethnic background and signs of upper limb vascular insufficiency, shoulder stiffness, and scalp tenderness [281]. Diagnostic Assessment Conventional angiography is the gold standard given its sensitivity for detecting aneurysms and local areas of stenosis. Noninvasive technique such as MRI, MRA, CT angiography or ultrasonography can be used in the diagnosis (Fig. 30) [279]. One of the earliest abnormalities in TA is increased vessel wall thickness detected with duplex ultrasonography. The marked diffuse concentric thickening of the vessel wall is present with a heterogeneous appearance and has been called the “macaroni sign”. Another method of visualizing inflammation is delayed gadolinium enhanced MRI, in which TA patients will exhibit hyper enhancement in their aortic walls, particularly in the early phase. FDG-PET scans are highly sensitive for vascular inflammation revealing increased FDG uptake in areas of increased inflammation which resolved with treatment [279].

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Fig. (30). CT-angiography of a patient with Takayasu arteritis demonstrating a severely narrowed right common carotid artery in the proximal segment (thick red arrow), stenosis of the entire left common carotid artery (yellow arrows) ending at the level of the carotid bifurcation, mild stenosis at the origin of the right subclavian artery (white arrow). (Courtesy F Melis and D. Imperiale).

Treatment Both medical and surgical modalities play an important role in disease management [278]. Though corticosteroids remain mainstay, newer immunosuppressant medications have shown promise. Prednisone is typically prescribed at 0.5-1 mg/kg/day for 1-3 months, followed by a slow taper in 1-2 years. This therapy allows for 67% remission, but up to 50% treated individuals will relapse most often when daily dose of oral corticosteroid is under 20 mg. Often, relapses are treated with either increasing corticosteroid dose or the addition of a corticosteroid sparing immunosuppressant such as methotrexate. There have been several studies looking at various immunosuppressants such as cyclophosphamide, methotrexate, mycophenolate mofetil, and azathioprine. Since no cytotoxic drug has been shown to have superior efficacy the choice of the drug is related to the tolerance and the side effects [278, 279]. Recently anti-TNF therapy and Intereukin-6 receptor inhibitor (Tocilizumab) have been tried especially in patient refractory to standard therapy. Following treatment with an anti-TNF agent steroid-free remission was seen [282].

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The other important medical issues relate to the management of hypertension and the prevention and treatment of thrombosis. Hypertension can be particularly difficult, and worsened by the use of steroids with their fluid retaining side effects. The use of angiotensin converting enzyme inhibitors requires careful monitoring in view of the frequency of renal artery stenosis. Various clinical and diagnostic factors will be taken into account while monitoring the disease activity. The commonly used criteria is the physician’s global assessment and active disease definition of Kerr and coll [283]: 1) presence of clinical features and elevated acute phase reactants not attributable to another medical condition, 2) new vascular lesion(s) in previously unaffected vascular territories, 3) clinical features suggesting vascular insufficiency, and 4) biopsy of affected vessels showing inflammatory changes. A remission of at least 6 months is required to consider it sustained. Recently it has been proposed a Disease Extent Index-Takayasu, assessing only clinical findings without the requirement of imaging [284]. Endovascular therapy and other surgical options have a role but caution must be exercised as outcomes are less favorable in patients with active disease. Early surgical intervention in conjunction with institution of appropriate immunosuppressive therapy is key in the management. However, if inflammation is not in remission outcomes maybe less favorable [279]. Traditionally, hemodynamically significant areas of stenosis and occlusion have been treated surgically with either revascularization or angioplasty. The surgical intervention is advised in cases of cardiac ischemia with coronary artery involvement, moderate to severe aortic regurgitation, cerebrovascular ischemia with coronary artery involvement, ADL limiting extremity claudication, and hypertension with stenosis of the renal artery [285, 286]. If surgical intervention is well tolerated, 20 year survival rates are 73.5% [286]. Percutaneous transluminal renal angioplasty (PTRA) has been shown to have less favorable outcomes than bypass surgery. In 8 months post surgery, researchers found restenosis of 21% after PTRA. Comparing PTRA to bypass, another study found that patients in the bypass group experienced 35% restenosis over 168

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months, while patients in the angioplasty group experienced 57% restenosis over 72 months [285]. Bypass graft surgery for the thoracic aortic arch critical stenosis has been found to be a protective factor against future stroke and experts recommend that critical stenosis of the thoracic aortic arch be corrected despite presence of adequate collateral blood flow [278]. Mortality ranges from 3%-35% at 5 years follow-up depending on the severity of the disease, patient demographics, and geographical distribution. The sequelae of TA involve dysfunction of the numerous organ involved (aortic regurgitation, cardiomyopathy, left ventricular systolic dysfunction, renal failure, myocarditis, and central nervous manifestations) are the principal causes of severe morbidity and mortality. BEHÇET DISEASE Behçet disease is a multisystem inflammatory disorder with a chronic course. Its cause is still unknown, but vasculitis is the major pathologic feature. Although the neurologic involvement is less frequent than with other major presentations, it is important because it produces severe disabilities and is associated with a severe prognosis. The involvement of nervous system may be so precocious and relevant that it has been introduced the term of NeuroBehcet Disease (NBD). The mean age at onset is 20 to 35 years in different studies. In most series, Behçet disease is more common in men. It is also more severe and associated with a worse prognosis in young men. Behçet disease is characterized by exacerbations and remissions with duration of attacks ranging from a few days to a few weeks. Attacks usually end in complete remissions, but sequelae can also be found. General Features Oral ulcers are usually the first manifestation of Behçet disease and are the hallmark for the diagnosis (Fig. 31E). Oral aphthae are painful, shallow or deep, oval or round ulcers with a central whitish or yellowish necrotic base and red halo. Their size ranges from 1 to 20 mm. They are single or multiple and last several days. The most common sites of oral ulcers are the lips, buccal mucosa,

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tongue, gingiva, palate, tonsils, uvula, and pharynx [287, 288]. The genital ulcers are usually larger, deeper, more long and lasting, and more painful than oral ulcers, and they rarely occur at the onset of the disease. They usually cause scar formation. In male patients, genital ulcers typically develop on the scrotum and less frequently on the shaft of the penis. In female patients, the labia are the most common site of involvement, but vaginal and cervical ulcers can also occur [288, 289]. Cutaneous manifestations of Behçet disease include erythema nodosum-like lesions (most common), pseudofolliculitis and folliculitis (Fig. 31F), acnelike lesions, superficial thrombophlebitis, cutaneous vasculitis, and papulopustular lesions.The Pathergy reaction is a skin hypersensitivity induced by intradermal needle prick. It is performed by pricking forearm skin with a 20- or 22-gauge sterile needle. If an erythematous papule of more than 2-mm diameter develops, the test is considered positive [289]. Pulmonary involvement (recurrent hemoptysis, cough chest pain, or dyspnea) [289] cardiac involvement (pericarditis, myocarditis or endocarditis as well as coronary arteritis), gastrointestinal presentations (dysphagia, epigastric pains, colicky abdominal pain, and bloody diarrhea), and urogenital manifestations (epididymitis) are rare presentations of Behçet disease. The ocular involvement, mostly recurrent anterior uveitis (Fig. 31D) or posterior uveitis associated with retinal involvement is the most hazardous complication of Behçet disease. Inflammation of the eyes is usually episodic and resolves after a few weeks, but recurrent attacks eventually cause blindness. Joint involvement of Behçet disease presents as nondeforming, nonerosive mono-, oligo-, or polyarthritis of knees, ankles, wrists, elbows, and/or other joints. Vascular involvement includes both arterial and venous ischemic lesions. Arterial inflammatory changes can present as occlusion and/or aneurysm formation of the pulmonary, renal, subclavian, femoral, or carotid arteries. Superficial thrombophlebitis, deep-vein thrombosis (more frequently in the lower extremities), superior vena cava syndrome, Budd-Chiari syndrome, and dural

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sinus thrombosis are the main manifestations of venous involvement [288, 289]. There is no diagnostic test for Behçet disease. The erythrocyte sedimentation rate, C-reactive protein, and/or C3, C4 complement components may be elevated during the active phases of the disease. Immunoglobulins (IgA, IgM,and/or IgG) may be elevated, and immune complexes are also found in the serum of some patients [289]. In 1990, the International Study Group (ISG) proposed diagnostic criteria based on the computer analysis of clinical features from cases collected worldwide. Table 13 shows the ISG criteria for Behçet disease [290]. Table 13. International Study Group Criteria for the Diagnosis of Behçet Disease. Recurrent oral ulcerations Minor or major aphthous, or herpetifom ulceration observed by physician of patient, which recurred at least 3 times in one 12-month period Plus 2 of the following

 

• Recurrent genital ulceration Aphthous ulceration observed by physician or patient • Eyes lesions

Anterior or posterior uveitis, or cells in vitreous on slit lamp examination; or retinal vasculitis observed by ophthalmologist

• Skin lesions

Erythema nodosum observed by physician or patient, pseudofolliculitis or papulopustular lesions, or acneiform nodules observed by physician in postadolescent patients not due to steroid treatment

More recently the International Criteria for Behçet's Disease (ICBD) created in 2006 [291] vascular manifestations (VMs) such as superficial phlebitis, deep vein thrombosis, large vein thrombosis, arterial thrombosis, and aneurysm have been added to the 5 items of ISG criteria, because they are one of the characteristics of BD, and were used in many criteria before the advent of ISG. Neurological Features The frequency of neurologic involvement in Behçet disease is variable in different series (2.5% - 49%) due to geographic and ethnic factors and variable definitions of NBD [292]. In an autopsy series, 20% of patients with Behçet disease revealed pathologic signs of neurologic involvement.

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Neurologic involvement usually presents after systemic manifestations, but in the minority of patients (3% in a Turkish series) neurologic findings clearly antedated the other more common signs of the illness. The most common sites of pathologic changes are the brainstem and basal ganglia [293]. Neurologic involvement can present without orogenital ulcers, and in these cases true diagnosis of Behçet disease can be made only at autopsy. CNS manifestations of Behçet disease can be divided into 2 main groups: Parenchymal CNS involvement (NBD), which includes brainstem involvement, hemispheral manifestations, spinal cord lesions, and meningoencephalitic including aseptic meningitis. This is the most frequent form accounting of about two third of the cases. Brainstem manifestations are the most common presentation of NBD. Weakness and pyramidal signs were the most common symptoms and signs in some reports but headache was the most common symptom in other studies [292, 293]. Neurovascular-Behçet disease (nonparenchymal CNS involvement) which includes dural sinus thrombosis, arterial occlusion, and arterial aneurysms. Dural sinus thrombosis is the main features and may be responsible of focal signs as well as of intracranial hypertension (pseudotumor cerebri). The superior sagittal sinus is the most common site of thrombosis, followed by the transverse sinuses, deep cerebral veins, and cavernous sinuses, respectively [294]. Arterial involvement is a rare cause of neurovasculo-Behçet disease in comparison to venous involvement. Intracranial and extracranial arterial involvement can present as stenosis, aneurysm, or dissection of the cerebral arteries. Vasculitis of the vasa vasorum is suspected as the basis of aneurysm formation or arterial dissection. The appearance of neurologic manifestations worsens the outcome of Behçet disease. Therefore, the early diagnosis of neurologic complications is critical in planning treatment. Brainstem auditory, somatosensory, visual, and motor-evoked potentials and MRI are useful tools to find asymptomatic (or more specifically, presymptomatic) NBD patients.

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Diagnostic Assessment Neuroimaging Neuroradiologic imaging is the most helpful investigatory tool for the study of NBD. CT scan may reveal hypodense lesions usually with contrast enhancement, but it is much less sensitive than MRI [293]. MRI is the examination of choice for the study of CNS involvement in Behçet disease (Fig. 31). In acute stages of parenchymal CNS involvement, lesions appear iso- or hypointense in T1-weighted images and hyperintense in T2weighted FLAIR images [295]. In order of frequency the most common involved sites are the mesodiencephalic junction, cerebellar peduncles, pons (Fig. 31A), medulla, basal ganglia (Fig. 31B), internal capsule, cerebral hemispheres (Fig. 31C), an optic nerves. Lesions are single or more likely multiple [295] and medium-size lesions (diameter 4-10 mm) are more common than small (less than 4 mm) or large (more than 10 mm) ones [293]. In hemispheric lesions, there is no predilection for the periventricular regions in comparison to the plaques of multiple sclerosis.

Fig. (31). Images of Behcet disease. Brain MRI T2 weight shows multiple lesion involving the pons (A), the thalamus, internal capsula and basal ganglia on the right side (B) and the periventricular white matter bilaterally (C). D-F: systemic features in a patients with Bechet disease: anterior uveitis (D), lingual afta (E) and papular lesions over the trunk (F). (Courtesy MC Vigliani).

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After remission of the acute phase, lesions disappear or become smaller and/or lose their enhancing properties. Chronic lesions are iso- to hypointense in T1weighted images and slightly hyperintense in proton density and T2-weighted images and may be associated with atrophy (particularly in the brainstem) [292, 293]. Neurovascular-Behçet disease must be confirmed by neuroimaging procedures like CT angiography, magnetic resonance angiography, MRI, or conventional angiography [293]. NBD has an acute or subacute onset and a monophasic or relapsing course. As in multiple sclerosis the most frequent types of progression of NBD are relapsing-remitting and secondary progressive types [292, 293]. Cerebrospinal Fluid Examination In cases of NBD with parenchymal manifestations, neutrophilic and/or lymphocytic pleocytosis and elevated protein levels but normal glucose content are usually found, although CSF can be entirely normal. On the other hand the majority of patients with neurovascular NBD with dural sinus thrombosis, CSF is normal. In large series of NBD, oligoclonal bands were seen in a minority of patients [293]. Treatment Even if randomized trial are lacking, methylprednisolone 1 g IV daily for up to 7 days followed by prednisone 0.5 to 1 mg/kg/d is suggested for acute attacks. For the prevention of early relapses, prednisone must be tapered over 2 to 3 months [296]. There is controversy about the choice of immunosuppressant therapy as an adjuvant to corticosteroids. Various drugs have been employed successfully (chlorambucil with or without corticosteroids, low-dose methotrexate, thalidomide and cyclophosphamide) in different series. A lifelong maintenance regimen including colchicine (1–2 mg per day), aspirin, and low-dose corticosteroids has been proposed. The use of cyclosporine-A for neurologic complications of Behçet disease is discouraged by experienced authors due to adverse neurologic effects [296]. Prednisone (0.5–1 mg/kg/d) and cyclophosphamide (500–1000 mg/m2 IV monthly) with relatively good results.

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For dural sinus thrombosis associated with Behçet disease, concurrent use of corticosteroids and anticoagulants is suggested. SUSAC’S SYNDROME Susac’s Syndrome is an autoimmune disease that affects the brain, eye (retina) and inner ear and consists of the triad of encephalopathy, branch retinal artery occlusions (BRAO) and hearing loss [297, 298]. Susac's syndrome usually occurs in young women between the ages of 20 and 40. The age range in both sexes is from 16 to 58 years, and the female-to male ratio is 3:1. The clinical course is self-limited, usually ranging 2 to 4 years, after which patients will then stabilize with varying degrees of cognitive disturbance, impaired hearing, and vision loss. Although some patients recover with little or no residual disease, others are profoundly impaired with cognitive deficits, gait disturbance, and hearing loss. Usually, vision is not seriously impaired. Recurrent BRAO and hearing loss may occur in the absence of encephalopathy even if MR imaging may show “silent” white matter changes [297, 298]. The Susac’s syndrome is a disorder due to a microangiopathy of the precapillary arterioles of the brain, retina and inner ear [299, 300]. Most experts believe that this microangiopathy is due to an immune-mediated endothelial disorder that causes small vessel narrowing and occlusion, leading to microinfarctions of the brain (both white and grey matter), retina and cochlea. The endothelial barriers of the retina and cochlea are analogue to that of blood brain barrier, and these similarities can explain predilection of brain, retinal, and cochlear involvement in Susac syndrome [297 - 300]. Presence of anti-endothelial cell antibodies in some case reports is in favor of this immunologic pathophysiology, but it is not clear that these antibodies are the cause, or are produced secondarily [301]. Many other autoimmune diseases like dermatomyositis or Sjögren syndrome show similar patterns of anti-endothelial cell antibodies. The pathologic findings of brain biopsies from most of the case reports showed multiple microinfarctions of the brainstem, both grey and white matter, with the

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loss of axons, neurons and myelin in the lesions. Common findings are swollen endothelial cells, endothelial proliferation of precapillary arterioles with marked thickening of the vessel walls, and minimal non-specific periarteriolar inflammatory cell infiltration. Similar pathologic features of microvascular thrombi and mild inflammatory cell infiltration have been observed in skin and muscle biopsies from patients with Susac syndrome, suggestive of a more diffuse disease than currently is known [302] . Absence of necrosis in tissue biopsies suggests a microangiopathy, rather than vasculitis, as the leading cause. Clinical Findings The classic triad of encephalopathy, BRAO, and hearing loss is pathognomonic for Susac’s syndrome but the three elements may not all be present at the onset: 1) The encephalopathy manifests with headache, confusion, memory loss, behavioral changes and dysarthria [297 - 300]. As in cerebral vasculitis, headache, often severe and sometimes resembling migraine, is a frequent finding, may be the major presenting feature of the encephalopathy and often occurs up to six months before the onset of the other symptoms. The other symptoms of encephalopathy have a stroke-like or subacute onset, with neuropsychological deficits, bladder disturbance, long tract signs, focal neurological signs, seizures, and often vigilance impairment. 2) Hearing loss can be a dramatic and severely disabilitating feature of Susac syndrome. It often occurs overnight, may affect both ears and is frequently associated with tinnitus and vertigo. A loss of the low or middle frequencies is typical, but loss of high frequencies can also occur; like the BRAO, it may be the presenting feature or develop later. In many of the reported cases of Susac syndrome, sudden hearing loss in association with peripheral vertigo, nystagmus and tinnitus occur after the encephalopathic features [297, 298].While encephalopathic symptoms and visual disturbances may remit, hearing loss is often irreversible. 3) Visual impairment [303, 304]. The BRAO may be extensive or subtle; if the

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posterior pole of the retina is involved, patients may complain of impaired vision. As hearing loss the retinal vasculopathy is usually bilateral and may be the presenting features of the illness, or occur later in the clinical course, thus oftalmological examination should be repeated at frequent intervals. Moreover peripherally located BRAO may not result in visual symptoms, and may only be recognized by an expert ophthalmologist. Thus, MR imaging is often necessary to establish the diagnosis. In some patients, the degree of white matter change is minimal compared to the severe degree of encephalopathy [299]. On the other hand in any unexplained encephalopathy predominantly involving the white matter, but also the gray matter and leptomeninges, a neuro-ophthalmologist should evaluate the patient with a dilated funduscopic examination. Diagnostic Assessment Neuroradiological Features Cranial CT is scarcely useful and rarely detect the lesions in Susac patients while MRI is the gold standard for the diagnosis. Susac et al. reported MRI findings of 27 patients and every patient had lesions in the corpus callosum, iin periventricular areas as well as in the centrum semiovale and in subcortical regions as well as including the brainstem and the cerebellar peduncles. Parenchymal enhancement was found in 70%, and the deep grey matter such as the basal ganglia and the thalamus in 70% of the patients [305]. Leptomeningeal enhancement is an early feature being reported in 1/3 of the patients at the onset of the disease [300]. On MRI, the typical lesions are small multifocal lesions of 3–7 mm (Fig. 32C). The most important diagnostic sign, and very typical for Susac’s syndrome, are the lesion in the centre of the corpus callosum (Fig. 32A-32B) which may appear as “snowball-like” lesion. Although any part of the corpus callosum may be involved in Susac’s syndrome, the callosal lesions typically involve the central fibers with relative sparing of the periphery in contrast to the undersurface involvement of the corpus callosum founded in multiple sclerosis and acute disseminated encephalomielitis. MR images are similar to the lesions founded in multiple sclerosis or acute disseminated encephalomyelitis.

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Other typical MRI findings are series of small central holes that give the corpus callosum a riddled aspect. The snowballs result in residual holes, especially in the splenium of the corpus callosum. The linear defects of the corpus callosum reflect microinfarcts of obliquely radiating axons, the so-called “spokes”, or wedgeshaped lesions extending from the roof of the corpus callosum, the so-called “icicles”. These lesions hesitate in atrophy of the corpus callosum, the brain and the cerebellum [305] without clinical correlation between the degree of encephalopathy and the number of lesions evident on the MR image. Interestingly diffusion tensor imaging (DTI) examinations suggest that Sucas’s patients have a microstructural lesions of cerebral fibers that appear normal on conventional MRI [306].

Fig. (32). MRI T2 WI of a patient with Susac’s syndrome. The lesions are small, multiple and involve the corpus callosum in the central portion (A,B, arrows) as well as the white matter of the cerebral hemisphere (C). Courtesy F Melis and D. Imperiale.

CT angiography as well as MR angiography are normal. Even cerebral arteriography findings are almost always normal, because the involved precapillary arterioles (50) in an increasing number of families have expanded the clinical phenotype of Col4A related disorders, suggesting that they could represent the commonest hereditary small vessel disease after CADASIL. Pathogenesis Collagen type IV is a trimeric protein expressed almost exclusively in the basal membrane. In humans, it is encoded by six paralogous genes: COL4A1 to COL4A6. Each gene encodes for one of six different alpha chains, which assemble to form heterotrimers (α1α1α2; α3α4α5;α5α5α6). Alpha 1 and alpha 2 chains are ubiquitously expressed while the others are tissue or developmental time restricted. In the extracellular matrix (ECM) heterotrimers are assembled to form a bidimensional network that interacts with other ECM molecules to provide structural integrity of the basal membrane and to support cell –matrix and cell-cell communication. Mutations act in disrupting both these two functions [17]: a total of 60 mutations have been described in COL4A1 and few mutations have been reported in COL4A2, the majority of which are missense mutations involving a Gly within the Gly-X-Y repeated motif of the collagenous domain and thus affecting the triple –helical formation. A clear genotype-phenotype is absent for these mutations that were found to be associated with both adult and pediatric phenotypes. Mutations located in the initial third of the rod domain (exons 9-25, with a cluster in exons 24-25) are indeed almost exclusively associated with a distinct adult phenotype, the hereditary angiopathy with nepropathy, aneurysms and muscle

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cramps (HANAC) [18]. Although often normal on light microscopy, small vessels present marked anomalies on electromicroscopy. Focal interruptions, fragmentation, multilamination and focal thickness of vessel basement membrane are the pathological hallmarks that depict COL4A1/2 diseases as basalopathy. Clinical Phenotypes We distinguish between pediatric and adult phenotypes. Both can further be splitted in “brain restricted”; “brain and eye restricted” or “multiorgan” phenotypes. a) Pediatric brain restricted phenotypes can be considered the results of a vascular insult occurring at different times of brain development (pre and perinatal). They include extensive bilateral porencephaly resembling hydranencephaly, schizencephaly, the more frequent neonatal porencephaly and the periventricular leukomalacia with intracranial calcifications. Very few cases present porencephaly and cortical dysplasia. All these clinical manifestations variably associate with cerebral palsy, infantile hemiparesis, hydrocephalus, seizures and mental retardation. Moreover COL4A1 and COL4A2 mutations can result in perinatal or pediatric hemorragic stroke both spontaneous or trauma induced. Axenfeldt Rieger anomaly with leukoencephalopathy is the commonest brain-eye restricted pediatric phenotype. The eye involvement can vary from severe to mild anterior segment dysgenesis. Congenital cataract and glaucoma are frequent manifestations of the disease. Transient hemolytic anemia, possibly due to defective transmigration of blood progenitors cells through altered basement membranes of the bone marrow vessels, is another clinical feature of pediatric phenotype. Mutations in Col4A1 are also present in few patients with Walker Warburg syndrome that is characterized by ocular dysgenesis, defects in cortical neuronal

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migration and congenital muscular dystrophy [19]. b) Adult brain restricted phenotype is represented by familial or sporadic brain small vessel disease whose clinical manifestations range from stroke (both hemorragic, and ischemic of lacunar type) to asymptomatic or paucisymptomatic leukoencephalopathy (Fig. 3). Sporadic or recurrent cerebral haemorrages are the far more common presentation (representing the 2/3 of all strokes in these patients), with usual onset before 50 years of age (Fig. 3). Hemorragic stroke can spontaneously occur but is often triggered by minor traumas (even sneezing) and/or anticoaugulants. Early onset diffuse leukoencephalopathy (usually before 30 years of age) with microbleeds, dilated perivascular spaces and microlacunar infarcts variably associated with migraine or minor stroke is another common clinical presentation (Figs. 3 and 4). The detection of intracerebral aneurysms, almost exclusively of the carotid axis is not infrequent, although their rupture rarely occur (Fig. 3). All these phenotypes may associate with ocular anomalies such as anterior segment dysgenesis, cataract and retinal arterial tortuosity (Fig. 5).

Fig. (3). Brain MRI T2 weight image: variable degrees of white matter involvement in COL4A1 leukoencephalopathy. Some lacunar infarcts are present in the periventricular region (arrow).

The adult-multiorgan phenotype is represented by the HANAC syndrome. HANAC syndrome has a broad clinical spectrum that includes a nephropathy with

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either hematuria or bilateral renal cysts or agenesis of the kidney, a muscular involvement with elevate creatine kinase and muscle cramps, a retinal arterial tortuosity eventually leading to retinal hemorrages and a cerebral large artery disease with multiple aneurysm of the carotid axis, preferentially localized on the carotid siphon (Fig. 4C). Although cerebrovascular lesion, namely leukoencephalopathy and small vessel disease are common, they are usually asymptomatic. It has been suggested that COL4A1 mutations responsible for HANAC are associated with a lower risk of hemorragic strokes than COL4A1 mutations underlying familial porencephaly or cerebral small vessels disease [20]. Intra- and inter-familial phenotypic variability are common findings in all COL4A1- related disorders: the same mutation could be associated with different clinical presentations ranging from the absence of a neurologic phenotype to leukoencephalopathy with muscle symptoms or brain small-vessel disease and hemorragic stroke or mild infantile encephalopathy, so mimicking an apparent incomplete penetrance of these diseases. This observation together with the possibility of de novo mutations represent a challenge for genetic counselling [21].

Fig. (4). Imaging of a patients with COL4A1 disease: cranial CT showes diffuse leukoencephlopathy with extensive involvement of the frontal region, a lacunar infarction of the head of the caudate nucleus (white arrowhead) and microcalcifications (white thin arrow) (A) and a lobar hemorrhage (black arrowhead) (B); Cerebral angiography shows multiple saccular aneurism of the internal carotid artery and anterior cerebral artery in a patient with HANAC syndrome (C).

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Neuroimaging The CT and MRI document different degrees of white matter involvement, ranging from punctiform, sparse WMHs in subcortical, deep and periventricular white matter to a diffuse, symmetrical leukoencephalopathy (Fig. 3). Other radiological features are represented by lacunar infarcts, dilated perivascular spaces, microbleeds and cerebral haemorrhage (Fig. 4). The preferential sites of spontaneous haemorrages are the subcortical deep white matter, the periventricular white matter, the deep gray nuclei, the cerebellum and brainstem. Bleedings at cortical, subpial regions or cortical-subcortical junction are uncommon and differentiate COL4 related haemorrages from those in cerebral amyloid angiopathy. The angiography may document single or multiple aneurysms of the carotid axis, preferentially located at the carotid siphon (Fig. 4C).

Fig. (5). Retinal fluoroangiography: different degrees of retinal arterial tortuosity in two sisters affected by COL4A1 disease (white arrow).

CARASIL Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is the second genetic form of ischemic, non hypertensive cerebral small vessel disease in which a genetic defect was identified. The disease is caused by mutations in the HTRA gene on chromosome 10q25, coding for a high temperature requirement serine A protease1 (HTRA1) [22]. The prevalence of the disorders is currently unknow and most of the patients

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identified so far, are from Eastern countries (namely Japan and China); recently few cases have been reported from Europe [23 - 25]. The lack of a common haplotype between patients rules out a founder effect and suggests that the disease may have a wider distribution and be underdiagnosed. Males are predominantly affected (M/F ratio is approximately 3/1 in clinically definite cases). De novo mutations can be supposed, since consanguinity is present in approximately 50% of affected families. Diffuse and focal demyelination with sparing of the U fibers, small infarcts in the cerebral white matter and basal ganglia, severe atherosclerotic changes in the meningeal small arteries and arterioles including fibrous intimal proliferation, hyalinosis, splitting or thickening of the intima and of the internal elastic membrane, loss of vascular smooth muscle cells, thinning of the media and adveventitia, are the pathological findings characterizing CARASIL. Nor granular osmiophilic materials neither amylod deposition are present [26]. HTRA1 is a secreted protease involved in transforming growth factor (TGF) β activity. Mutations determine a loss of enzyme function, however the mechanism through which the dysregulation of TGFβ signaling occurs is still debated [27, 28]. Other disorders associated with TGF beta pathway dysregulation and cerebral vessels involvement include HHT (hereditary hemorragic teleangectasia) and Marfan’s syndrome. Clinical Phenotype The disoders was first described as Maeda syndrome, in young Japanese patients whose symptoms and MRI picture resembled CADASIL, who were negative for Notch3 mutations, and presented few extraneurological features such as recurrent lumbago, severe spondylosis with disk herniation and alopecia. The main clinical symptoms are recurrent lacunar strokes involving basal ganglia or brainstem and stepwise cognitive deterioration while hemorrhagic stroke is rarer and can occur either spontaneously or triggered by hypertension. The onset of neurologic symptoms is usually in the third decade, often together with severe low back pain. The patients rapidly deteriorate and became bedridden

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within 10 years from disease onset, although survival for as long as 30 years have been reported. Almost all patients develop dementia by 40 years. Alopecia is the initial symptom and develops during the second decade: it involves the entire scalp and can lack in women. The third cardinal feature of the disease is the skeletal involvement. Eighty per cent of patients presents lower back pain within 40 years with spondylosis and disk herniations usually involving the cervical and thoracolumbar spine. Ossification of intraspinal yellow ligaments and elbow and knee arthropathy could be additional features. Behavioral changes are described in CARASIL patients, including irritability and emotional incontinence: depression is not reported and differentiates this disease from CADASIL [29]. Neuroimaging CT and MRI document the early involvement of the supratentotrial white matter, together with lacunar infarcts in the basal ganglia and brainstem. MRI white matter T2 hyperintensities involve periventricular and deep white matter with sparing of the U fibers and are symmetrical and diffuse more than focal (as in CADASIL). Involvement of anterior temporal lobes is seen in the progression of the disease and is not an early radiological hallmark as in CADASIL. Cerebral angiography is usually unremarkable. CEREBRORETINAL VASCULOPATHIES AND RELATED DISEASES This group of hereditary, autosomal dominant inherited small vessel diseases include several nosological entities that variably associate retinal vasculopathy, renal involvement, white matter lesions and stroke [30]. These disorders include cerebroretinal vasculopathy (CRV), hereditary endoteliopathy with retinopathy, nephropathy and stroke (HERNS), hereditary vascular retinopathy (HVR) and later in 2007, grouped together as retinal vasculopathy and cerebral leukodystrophy (RVCL). These disorders are caused by mutations in the carboxyl-terminus of TREX1 gene coding for the major 3’ to 5’ exonuclease on chromosome 3p21. All are transmitted as autosomal dominant, fully penetrant

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diseases. The same gene has been subsequently linked to a systemic hereditary angiopathy with involvement of brain, eye, kidney, bone and liver (HSA) [31]. In RVCL most of the TREX1 mutations are frameshift mutations that lead to a premauture stop codon [32] acting as negative regulator of interferon responses to single stranded DNA (ssDNA). Mutations in the same gene are related to an early onset encephalopathy with acquired microcephaly, cerebral calcifications and leukodystrophy, the Aicardi Goutiers syndrome, familial chilblain lupus and have been found in a small percentage of sistemic lupus erithematosus. All these disorders are associated with an autoinflammatory response. While the mechanism of vascular damage remains obscure, the recent finding that microglial cells are the primary cells that express TREX1 in the brain, suggests that these small vessel disorders could recognize an immune- mediated pathogenesis. Clinical Phenotype The onset of the disease is usually in the 4th decade with visual or neurological symptoms. The disease invariably progresses and leads to death within 5-10 years from diagnosis. Visual symptoms occur at onset in 2/3 of patients. Loss of central vision is a common presentation and is sustained by retinal vessels changes with teleangectasias, microaneurysms, capillary exudation in the macula, juxtafoveolar capillary obliteration with subsequent retinal ischemia. These findings are similar to the clinical presentation of proliferative diabetic retinopathy. Capillary closure and ischemia may involve the peripheral retina too. Neovascularization of the optic disk with retinal hemorrages may occur [33]. Neurological presentation can vary from headache to psychiatric symtomps such as depression or personality changes often associated with focal deficit or seizures. The neurological onset may be abrupt and mimic a brain tumor in half of patients. In this case the symptoms are steroid responsive but tend to relapse.

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Steroid treatment does not alter the invariably progressing clinical course. Spontaneous regression of tumor like lesions is reported (Fig. 6) [34]. A progressive cognitive deterioration is common. Recently TREX1 mutation has been reported in a patient in which the risk factors profile and the clinical- neuroradiological picture (lacunar infarcts of basal ganglia and pons, mild periventricular leukoencepahlopathy) were consistent with vascular multilacunar early onset dementia [35]. Renal involvement is seen is some families, manifesting with proteinuria leading to renal failure. Cholestatic and cytolitic enzymes abnormalities may occur.

Fig. (6). CT scan of a 58 years old patient with HERNS showing a large oedematous lesion involving the left cerebral hemisphere (white arrow); other two lesions are present in the right temporal area and in the frontal region (black arrow);these lesion in the acute phase were similar to the actual lesion.

Neuroimaging The small vessels involvement may lead to two different neuroradiological presentations: leukoencephalopathy with multifocal T2 subcortical (periventricular and deep white matter) hyperintensities that tend to be confluent with disease progression and the more typical tumor like lesions sparing the

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cortex and prefer periventricular location in frontal lobes (Fig. 6). At onset, these lesions are T2 hyperintense and gadolinium enhancing, (often with ring enhancement aspect). They appear bright on DWI and dark on ADC maps and are surrounded by large oedematous reaction. The neuroradiological aspects suggest either a proliferative lesion or a tumefactive multiple sclerosis. The involvement of corpus callosum, usually spared in CRV, may help in differentiating this latter condition. As the lesion evolves, the DWI bright signal disappears, the T2 lesion volume shrinks, the oedematous reaction decreases and least, the gadolinium enhancing vanishes. Focal calcifications are another radiological feature of the disease. Pathology The common feature of this group of diseases is the presence of a thickened, multilaminated basement membrane with abnormal endothelial cells. Collagen fibrils type I and III are present in a disarranged and thicker bundles surrounding the basal laminae. The endothelial cells have a larger volume, display cytoplasmic blebs and an increased number of autophagic lysosomes. CEREBRORETINAL MICROANGIOPATHY WITH CALCIFICATIONS AND CYSTS Cerebroretinal microangiopathy with calcifications and cysts is a rare multisystem disorder characterized by the association of extensive progressive intracranial calcifications, progressive development of intracranial cysts and leukoencephalopathy. These findings may associate with retinal anomalies, namely retinal arterial teleangectasias and angiomatous retinal malformations both leading to retinal haemorrages. The disease is usually sporadic, although few familial cases have been reported with an autosomal recessive pattern of transmission. Two previously described nosological entities displays the above features: Labrune syndrome (usually classified as leukodystrophy) and Coats plus Syndrome (usually classified as vascular leukoencephalopathy).

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Recently mutations in CTC1 gene encoding the CTS telomere maintenance complex component 1 have been identified as causative at least in a subset of individuals [36]. Missense, nonsense mutations, frameshift deletion and in deletions have been described. CTC1 is a component of a trimeric complex that binds single stranded DNA and complexes with telomeres, probably preventing their degradation. The key feature of this disorder is represented by an obliterative angiopathy. Abnormal small vessels with angiomatous proliferation, calcium deposition within thickened vessel walls and parenchyma, surrounded by Rosenthal fibers are demonstrated in the affected areas of the brain. Clinical Phenotype Disease onset is usually in infancy or early childhood although several cases with adult onset are reported. The affected children display intrauterine growth retardation variably associated with spasticity, ataxia, dystonia, seizures. An obstructive hydrocephalus may develop as consequence of cyst formation and enlargement. The disease reduces the life expectancy and death may occur as consequence of cerebral haemorrhage. Raised intracranial pressure may also develop as consequence of cystic lesions. The extraneurological features include osteopenia or early onset osteoporosis with increased risk of fractures, gastrointestinal bleedings due to angiomatous/teleangectasias, portal hypertension, anemia and thrombocytopenia, alopecia and nail dystrophy. Few adult cases are reported in which the disease manifestations are brain restricted [37 - 39]. Neuroimaging The neuroradiological hallmarks of the disease are the presence of gross, bilateral, asymmetric calcifications involving the basal ganglia, the subcortical white matter

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and the cerebellum variably associated with cysts. Cysts vary in diameter (ranging from millimetric to centimetric), present an higher intensity than cerebrospinal fluid both on T1 and T2 weighted images and display a ring enhancement of the peripheral wall. The white matter around the cystic formations and calcifications looks T2-hyperintense, due to white matter oedema. STROKE AND METABOLIC DISEASES Fabry Disease FD is an X-linked, inherited disorder due to deficient lysosomal α-galactosidase A activity. Lysosomal α-galactosidase A is encoded by the GLA gene on chromosome Xq22. More than 585 pathogenic mutations have been reported in the GLA gene. FD incidence has been estimated to be 1 per 17,000 to 117,000 in the general population, but the prevalence ranges from 0.6% to 11.1%, with an average of 4.5% in men and 3.4% in women among patients with cryptogenic stroke. In FD diffuse, abnormal accumulation of glycosphingolipids occurs in all tissues, producing swelling and proliferation of endothelial cells [40 - 43]. Although FD is an X-linked disorder women tend to remain free of serious complications in the young age but most became symptomatic and often have severe complications, particularly cardiac disease and stroke [44]. General Findings The signs and symptoms of Fabry disease may be nonspecific, and if manifestations in different organs are considered in isolation, the unifying diagnosis may be missed. The classic form of FD, with no detectable αgalactosidase A presents with angiokeratomas, acroparesthesia, hypohidrosis, corneal opacity in childhood or adolescence (cornea verticillata), vascular retinopathy, tinnitus and hypoacusia, cardiac symptoms, kidneys features (proteinuria, impaired renal function), cerebrovascular accidents and silent cerebral infarction [40 - 43]. Acroparesthesia is a common symptom in pediatric patients and reflect peripheral neuropathy both episodic and chronic with acute episodes triggered by exposure to extremes of temperature, stress and emotion).

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Other common features are decreased bone mineral density, azoospermia, endocrine dysfunctions, depression or generalised anxiety (frequently reactive to neuropatic pain), slight facial dysmorphysm (periorbital fullness, prominent lobules of the ears, bushy eyebrows, recessed forehead, shallow midface, full lips, prominent nasal bridge, and coarse features among others) [40 - 43]. Progression of clinical symptoms in FD disease can be divided into three consecutive age periods (Table 1). Although the disease process begins early with evidence of storage even in the prenatal period, symptoms do not develop until early childhood. Table 1. Typical signs and symptoms of Fabry disease according to age. Typical time at onset

Signs and symptoms

Childhood and adolescence (≤16 years)

• Acroparestesia and neuropathic pain • Ophthalmological abnormalities (cornea verticillata and tortuous retinal blood vessels) • Hearing impairment • Dyshidrosis (hypohidrosis and hyperhidrosis) • Hypersensitivity to heat and cold • Gastrointestinal disturbances and abdominal pain • Lethargy and tiredness • Angiokeratomas • Onset of renal and cardiac signs, e.g. microalbuminuria, proteinuria, abnormal heart rate variability

Early adulthood (17–30 years)

• Extension of any of the above • Proteinuria and progressive renal failure • Cardiomyopathy • Transient ischaemic attacks, strokes

Later adulthood (age >30 years)

• Worsening of any of the above

Early symptoms in children (Table 1) include burning pain in the hands and feet, hypohydrosis, nausea, abdominal pain, postprandial diarrhea, poor growth, and school difficulties. Onset of symptoms in boys as young as 2 years, with an

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average age of onset of 5–6 years. Girls report first symptoms at an average age of 9 years. In FD patients involvement of kidney [45, 46], heart [47, 48] and brain has deleterious consequence in survival and clinical outcome. During the second and third decades of life, signs of renal dysfunction are hyperfiltration, microalbuminuria, proteinuria, or isosthenuria (inability to concentrate the urine). Proteinuria is present in most of male FD patients after age 20 years, although in women is less consistent. Kidney disease progresses to renal insufficiency and eventually to renal failure. The eventual development of renal failure is seen in most affected men and some patients with end stage renal disease after 40 years [45]. Nevertheless, evidence also exists that treatment might slow or prevent progression of the disease [46]. Other affected organ systems also progress, leading to life-threatening cardiac and cerebrovascular manifestations with substantial morbidity. Cardiac symptoms frequently seen include angina, dyspnoea, or palpitations [47 48]. The most common life-threatening cardiac problem in patients is arrhythmia. The earliest manifestation of abnormal rhythm is bradycardia, which is seen even in some children. Valve regurgitation is also quite common in adults but rare in children. Cardiac death is more frequent in women, and although the most frequent cause of death in men was end-stage renal failure, cardiac and cerebrovascular complications are more prevalent than previously reported. Angiokeratomas (Fig. 7A) are a common feature at presentation and will develop in about half of male adolescents with classic Fabry’s disease at a median age of onset of 14–16 years [49]. Angiokeratomas tend to increase in number and size with age, are generally located around swimming trunk regions and can bleed with trauma. Cornea verticillata, is a specific diagnostic sign, characterized by one or more lines that irradiate from a point near the centre of the cornea (Fig. 7B). It is seen in most patients, but usually do not interfere with visual acuity. Cornea verticillata is rarely visible without a slit-lamp examination. Other frequent ocular manifestations include opacities of the posterior lens and retinal vascular tortuosity [50]. The most severe but rare ophthalmological complication of FD is

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occlusion of one or more retinal vessels, which can lead to retinal infarction and permanent loss of vision. Neuropathic pain is the one major cause of morbidity during the first two decades of life and patients frequently need medication for pain even when receiving enzyme infusions [41]. Cerebrovascular Complications In the Fabry Registry which include 2446 patients stroke occurs in 6.9% of men and 4.3% of women. Of these, 87% of first strokes were found to be ischemic and 13% hemorrhagic. Analysis of the Fabry Registry has indicated that the incidence of stroke among patients with FD is higher than that observed in the general US population [51]. In men aged 35 to 45 years, the relative risk of stroke is 12.2 and 4.2 higher in male and woman respectively when compared with healthy subjects. A majority of Fabry patients experienced a first stroke between the age of 20 and 50 years, with 22% of patients having a first stroke at 70%), stroke was the first serious complication and a high proportion (50% of men and 38% of women) had, therefore, not yet been diagnosed with FD [41]. Another large-scale analysis of the Fabry Outcome Survey reported that 13.2% (15.1% men and 11.5% women) of a cohort of 688 patients with FD had either a stroke or transient ischemic attack. In the Fabry Outcome Survey, the mean age at first stroke was the 99th percentile. Positivity must be confirmed by a second test, performed 12 weeks apart. Anti β2-Glycoprotein I (aβ2GPI) Antibodies aβ2GPI antibodies, IgG and IgM isotypes, are assessed by standardized ELISA; medium-high titer is defined as > 99th percentile. As for LAC and aCL a second test, performed at least 12 weeks apart, is required for diagnosis of APS. On the basis of laboratory findings patients are classified into one of the following

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categories: I more than one laboratory criteria present (any combination); IIa LA present alone; IIb aCL antibody present alone; IIc anti-b2 glycoprotein-I antibody present alone. Cerebrovascular Complications Low title and habitually non-pathogenic aPL are found in 5–10% of healthy people [120] and may be transiently elevated after viral infections and drug exposures [121, 122]. Persistent high titre aPL antibodies are detected in less than 2% of healthy adults. aPL are found in 30% of adult and over 50% of paediatric lupus patients [123, 125]. aPL have been fairly well-established as risk factors for first juvenile ischemic stroke, but their role in recurrent stroke is less clear, and the association becomes weaker in older people [124]. Hughes suggests that up to one in five of all juvenile strokes (under 45 years) may be associated with APS [125]. Case-control and prospective studies that evaluated aPL in young adults, primarily in patients without SLE, found an increased risk for incident ischemic stroke [126 - 130]. One study evaluating the risk for recurrent stroke and aPL in young adults (age 18-44 years) found that patients with antiphospholipid antibodies had significantly more prior cerebral events, and, by survival analysis, higher probability of cerebral ischemic or systemic thrombotic events during follow-up than patients without. The Italian Project on Stroke at Young age (IPSYS) recently found aPL as an independent predictor of thrombotic recurrence in young patients (aged 1845 years) with personal history of brain ischemia [131]. Several studies have shown that strokes and transient ischemic attacks (TIAs) are the most common arterial thrombotic events in patients with APS [131 - 135]. The Euro-Phospholipid Project Group is studying the clinical and immunologic manifestations and patterns of disease expression of APS in a cohort of 1,000 patients [136] satisfying Sapporo criteria for APS [136]; at study entry stroke was

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the most common arterial thrombotic manifestation occurring in 13.1% patients, transient ischemic attack in 7.0% and amaurosis fugax in 2.8% patients. Amaurosis fugax, transient paresthesias, ataxia, motor weakness, vertigo, can all be expressions of TIAs [137]. Moreover cerebral ischemia is common in SLE patients. In 323 consecutive patients cerebrovascular disease occurred in 14.5% patients; multivariate analysis showed that aPL were independently strongly associated with cerebrovascular disease, and also with headache and seizure; LAC was independently associated with white matter hyperintensity lesions on MRI [138]. The clinical spectrum ranges from transient ischaemic attacks and focal lesions to widespread cerebral infarction, ataxia, bladder, and gait disturbance and – in extreme cases – multiinfarction dementia [129]. Stroke patients with aPL are younger and more likely to be women in comparison with stroke patients without aPL [139, 140]. Pathology and Pathophysiology Pathogenesis of cerebral ischaemia is still unclear, but many findings suggest an embolic mechanism. At autoptical examination, thrombus histology was similar in both aPL-positive and aPL-negative subjects, with no evidence of vasculitis in the aPL-positive individuals [141]. Cerebral ischaemia, often due to middle cerebral artery occlusion, may affect any cerebral arterial territory (Fig. 11A and 11B) [142]; cerebral angiography typically demonstrates intracranial branch or trunk occlusion but may be normal in about one third of patients [143]. Large artery disease is uncommon in young patients with APS and stroke. Cortical magnetic resonance imaging findings are consistent with large vessel occlusion [125, 144]. aPL patients often present small foci of high signal in the brain white matter at MRI, which are often defined as consistent with the presence of small vessel disease (Fig. 11C). Larger size and atypical topographic distribution of these lesions in aPL patients may be also consistent with demyelination and sometimes difficult to differentiate from MRI pictures in multiple sclerosis [145, 146].

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Fig. (11). A 46 year female suffered for a right side hemiparesis and expressive aphasia. Brain DWI-MR images showed a multifocal ischemic lesion in the territory of the left middle cerebral artery (A) which appeared occluded at MR angiography (B). In figure C Brain FLAIR-MRI of a 43 years old female with recurrent minor ischemic stroke showed multiple subcortical small ischemic lesions. In both the patients blood examination revealed the presence of the lupus anticoagulant factor (LAC) and high title of Ig-G aCL antibodies.

Embolic Sources Cardiac valve lesions are common in APS, and they are potential sources of emboli (Fig. 12). Transthoracic echocardiography is abnormal in one third of patients, typically demonstrating non-specific left-sided valvular (predominantly mitral) lesions characterized by valve thickening [136, 147, 148]. Such thickening is due to Libman-Sacks nonbacterial endocarditis. Lockshin et al. [149] reviewed literature about cardiac manifestation of APS. Valve Abnormalities Heart valves are frequently affected in patients with APS with or without SLE and in patients with aPL alone [150 - 152]. Echocardiographic valvular involvement is characterized by thickening of the leaflets (Libman–Sacks endocarditis) and it can be associated with valvular dysfunction; the mitral valve is more commonly involved than the aortic valve [153]. Several studies have reported high prevalence of valvular heart disease in APS (Fig. 12); there is, however, a wide variability in the reported prevalence of this phenomenon, ranging from 32%–82% [154, 155]. A prevalence of 32%–38% was reported by transthoracic echocardiography (TTE) studies [155], while higher rates (82%) were reported in a study using transesophageal echocardiography

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(TEE) [156]; such difference in result impose a TEE evaluation of APS patients affected by stroke. Valve involvement is associated with increased risk of central nervous system manifestations, mainly stroke and epilepsy. An high aCL titer (> 40 GPL) was also suggested to be a risk factor for thromboembolism [157].

Fig. (12). Images of a patient with LES and antiphospholipid syndrome Brain MRI –DW1 images showed bilateral recent ischemic lesion involving the superficial branches of middle cerebral artery on the right side (A) and left side (B) suggesting an embolic mechanism: echocardiography revealed the presence of a mitral valve vegetation (arrow) typical of Libman Sachs endocarditis (C).

Several studies on APS patients reported a strong association between valvular abnormalities and arterial thromboses, especially those involving the central nervous system [153 - 167]. Cervera et al. [156] reported that 52% of primary APS patients with valvulopathy suffered from strokes or transient ischemic attacks compared with only 15 % of patients without valvulopathy (P < 0.01). Erdogan and colleagues [158] reported valve lesions in all stroke patients and in most with other arterial or venous thrombosis. Roldan et al. [159] showed that lupus anticoagulant positivity and valvular lesions (vegetation, thickening and regurgitation) were independent predictors of MRI-proven cerebrovascular disease in lupus patients. Histologically, there is endothelial cell proliferation with focal inflammatory changes, edema or fibrosis, focal calcifications, resulting in valve thickening, rigidity and dysfunction [160]. Although the pathogenesis of the valve lesions is not clear, several studies have tried to elucidate the precipitating event that triggers the inflammatory response; deposition of aPL [161, 162] and anti-bet-

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-2GPI [163] seem to be involved in the process. The anti-beta-2GPI deposition raises the possibility that bacterial antigens induce a crossreactivity immune response leading to Libman-Sacks nonbacterial endocarditis. Qaddoura and colleagues [164] published four cases of primary APS patients with valve disease. The pathologic appearance of the valves paralleled TEE: focal, symmetric, nodular abnormalities resulting from thrombi at the coapting edges of the valve leaflets or cusps. Several studies [165 - 167] showed that these thrombi are resistant to antithrombotic or antiplatelet therapy. Although frequent, the valve lesions in aPL-positive patients rarely require surgical treatment [167]. Intracardiac Thrombi Contrary to the valve abnormalities in case of primary APS which involve the left side of the heart, intracardiac thrombi formation prevails in the right side, having an etiologic role in pulmonary embolism events [161]. Even if less common than valve abnormalities, left atrial appendage thrombus may represent a cardiac source for stroke [165], and its presence must be evaluated with TEE. The only neurological manifestation that is considered to have sufficient evidence to justify it being a part of the criteria for the diagnosis of (APS) is cerebral ischemia. Other neurological manifestations of APS are dementia and cognitive dysfunction, migraine, seizure, chorea, transverse myelopathy, optic neuropathy and multiple sclerosis [168]. Ischaemic lesions are also observed in these patients, but relation between thrombosis and such neurologic manifestation is uncertain. However, the possible effects of aPL are unlikely to be exclusively thrombotic and cross-reactivity with cerebral structures, inflammation, vasculopathy and accelerated atherosclerosis are all potential mechanisms [169]. Treatment Treatment is based on available data, and should be guided by pathogenesis of cerebral ischaemia. In transient, single test positive patients aPL can be considered as a non-specific marker of modestly increased risk of incident stroke, largely present in healthy people and without an established causative role. On the opposite side triple positivity shows an high risk condition needing treatment

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appropriate to thrombosis mechanism. Treatment must also be directed by evaluation of bleeding risk. Primary Prevention Transient aPL positivity without prior thrombosis does not require any treatment. Among 197 randomly selected blood donors, no thrombotic events were observed after 12 months of follow-up in the patients found to have aCL [170]. Neither persistent aPL positivity need treatment, although in patient with SLE low-dose aspirin can be employed, especially when other risk factors for thrombosis coexist [171, 172]. Another condition that requires a separate evaluation is occasional finding of triple positivity, although this situation is unusual, and does not constitute an APS. Secondary Prevention A systematic review of secondary thromboprophylaxis in patients with aPL was recently published by Khamashta et al. [173]. Nine cohort studies were included in this review [137, 174 - 181]. Patients included fulfilled laboratory criteria for APS, except that for two studies [180, 181]. Untreated patients had high recurrence rates (19% - 29% per year), making evident a dose-effect of oral anticoagulation, with fewer recurrent thrombotic events among patients treated with high-intensity anticoagulation (INR of 3.0 – 4.0) as compared with those with a target INR of 2.0 – 3.0. Other studies were inconclusive regarding stroke recurrence and therapy [182 - 186] including the APASS [186] a substudy of the Warfarin Aspirin Recurrent Stroke Study (WARSS) [187], a randomized doubleblind trial comparing warfarin (INR 1.4 – 2.8) and aspirin 325 mg/day for preventing recurrent stroke or death. Besides two randomized controlled trials one Canadian [188] and one European [189] compared standard anticoagulant treatment (target INR of 2.5) with highintensity anticoagulant treatment (target INR of 3.5) for the secondary prophylaxis of thrombosis in APS. Patients included fulfilled classification criteria for APS. Main APS manifestation was venous thromboembolism, present in 76% and 63%, respectively, of the individuals enrolled. Patients with recent stroke were excluded from the Canadian trial. Both studies demonstrated no advantage of high-intensity

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anticoagulation (target INR of 3.0 – 4.0) versus standard anticoagulation (target INR of 2.0 – 3.0) in terms of preventing recurrent events. These studies may underestimate the high-intensity anticoagulation considering that patients in the group frequently failed to achieve the target INR. Furthermore before instituting an anticoagulant treatment, bleeding risk should be assessed for each patient. Published data show that the frequency and severity of bleeding complications is not high in patients with APS treated with oral anticoagulation, even at target INRs >3.0 [177, 190, 191]; this may be due in part to the lower age of this population as compared with, for example, patients with chronic atrial fibrillation [192]. In presence of a thrombotic event it is essential to establish if it is part of the syndrome or not. In case of single low aPL positivity we cannot impute cerebral ischaemia to pathogenic aPL, and the stroke must be accredited to other causes, or if no cause is found classified as cryptogenic stroke and treated with aspirin as aPL negative subjects [191]. Even in presence of a single persistent high titre positivity, that realizes a middle-low risk APS, causative relation between aPL and stroke is in doubt, it is reasonable to treat patients with aspirin [193, 194] in absence of potential cardioembolic sources after complete evaluation including TEE; moderate warfarin should be considerated in presence of associated venous thrombosis or other features of APS, and when a cardioembolic source is found. By contrast a triple positivity identifies the presence of pathogenic auto-antibodies (IgG) anti-human beta 2-GPI causing LA, configuring a high risk antiphospholipid syndrome; in such contest there is a possible causative relation between aPL and stroke, through a cardioembolic mechanism. Such causative relations is reinforced by findings of embolic sources at TEE. Even if there is a general consensus about the indication of warfarin therapy in these patients, intensity of treatment is subject to debate [195 - 197]. While recurrent thromboses are exceptional with INRs >3.0, many cases have been documented within the usual therapeutic range of 2.0–3.0. However recent randomized controlled trials [198, 199] demonstrated a non-significative increased recurrent rate in patients treated with high-intensity oral anticoagulation, apparently related to management of the therapy, frequently presenting wide INR excursions in these patients.

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Therefore, specific therapy must be determined on an individual basis, taking into account the severity of the initial thrombotic event, the concurrent presence of other vascular risk factors or additional thromboses and the estimated bleeding risk according to age, bleeding history and polypharmacy [200]. Accordingly, moderate-intensity oral anticoagulation (INR range 2-3) would be justified in patients with triple positivity APS and stroke [198]. During pregnancy women must discontinue warfarin because of its teratogenic effect, and bridging treatment with heparin (LMWH) associated to aspirin is recommended. Finally, there are no data to recommend additional antithrombotic treatment such as aspirin for patients who experience recurrent events while receiving oral anticoagulants achieving a 3.0 – 4.0 target INR [173]. Finally patients with cerebral venous thrombosis have to be treated with warfarin INR 2-3 [201] Catastrophic APS This term, coined in 1972, indicates a clinical pattern characterized by small vessel thrombosis, occurring within a short time period (days or weeks), fatal in 50% cases. It can appear ‘de novo’, or following infective event, and represent about 1% of APS manifestation. The catastrophic APS can present with an acute organic brain syndrome characterized by fulminant encephalopathy [174, 202]. Microthrombotic occlusive disease of multiple small vessels (‘thrombotic microangiopathy’) has been reported in a large number of patients [203]. SICKLE-CELL DISEASE Sickle-cell disease is a multisystem disease, associated with episodes of acute illness and progressive organ damage, and is one of the most common severe monogenic disorders worldwide. A description of the complex clinical picture [204] is out of the scope of this book so we focused on cerebrovascular complications. Neurologic Complications Sickle-cell disease is one of the most common causes of stroke in children. Most

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cases are associated with vasculopathy affecting the distal internal carotid and middle cerebral arteries, although extracranial vasculopathy can also be present [204]. The pathophysiology behind focal cerebral stenosis in sickle cell disease is complex. While incompletely understood, recent research suggests a complex, causal pathway involving chronic intravascular hemolysis, release of proinflammatory mediators, activation of endothelial surface, and endothelial dysfunction [205]. Post-mortem examinations of cerebral arteries after AIS demonstrate intimal thickening with fibroblast and smooth muscle proliferation in larger arteries with resultant thrombus. Moreover children with SCD may be at increased risk of stroke due to a higher prevalence of cardiac shunting. In a single center childhood stroke cohort, children with SCD had twice the prevalence of PFO compared to children without SCD, suggesting a possible vulnerability to paradoxical embolism in additional to cerebral vasculopathy [206]. The vasculopathy seems to start in infancy, with a first-stroke incidence of 1,02 per 100 patient-years between the ages of 2 years and 5 years, and 11% of patients with sickle-cell disease have had a stroke by the age of 20 years. [204]. Typically, the stenoses affect the distal internal carotid artery, the proximal portions of the middle and anterior cerebral arteries, and can be evident with MR angiography (MRA) (Fig. 13), CT angiography and conventional angiography. Stenotic, abnormal vessel lumen can be a nidus for thrombus formation and artery to artery emboli or decrease cerebral perfusion leading to watershed ischemia. Children with severe stenosis experience recurrent transient ischemic attacks ultimately leading to ischemic stroke or, later in the disease, hemorrhage from these abnormal, delicate collateral vessels [207]. Silent cerebral infarcts have been recognized as an important clinical complication of sickle cell disease causing cognitive impairment, lower IQ, poor academic performance, and increased risk for stroke [205] The majority of silent cerebral infarcts have occurred in children with sickle cell anemia by 6 years of age with prevalence of 13 at an average age of 13.7 months, 27% in children up to 6 years of age, and 37% by 14 years of age [204 - 205] In studies in which MRI is used, up to 20% of children with sickle-cell disease have silent brain infarcts, typically involving watershed areas in the frontal lobes [205]. These pathological changes

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also seem to occur in young children [208, 209] and may be stabilized with therapy [210 - 215]. Moreover cognitive impairment also occurs in the absence of brain infarction, suggesting that this neurological deficit might be partly attributable to anaemia and hypoxia [216]. Intracranial bleeds occur in patients of all ages, but are most common between the ages of 20 years and 30 years; they are typically associated with either a moyamoya-like syndrome or cerebral aneurysms. Treatment is neurosurgical and the outcome is poor, with 26% mortality at 2 weeks. Diagnostic Assessment Brain MRI and MRA are the best diagnostic tool for the diagnosis of ischemic lesion both in symptomatic and asymptomatic SCD young patients. Vasculopathy can be detected at an early stage by use of transcranial doppler (TCD) [217, 218]. Early TCD screening and transfusion programs applied in patients with abnormal TCD really allows to significantly reduce stroke risk from 11 to less than 2% by age 18 and should be systematically done to all children with SCD [217]. TCD is recommended in children with SCD from ages 2 to 16 at least once a year. It must be performed according to a specific protocol by trained staff to obtain reliable and reproducible results. A programme of TCD screening has been established in some countries, with evidence of a decrease in stroke incidence [217, 218]. If TCD is normal, a repeat screen is recommended after 12 months; if the mean velocity of the middle cerebral artery or internal cerebral artery is between 170–200 cm/s (conditional), it should be repeated within 3 months, especially if the child is under age 6 years. In patients with mean velocity at the level of the middle cerebral artery > 200 cm/s, a second test should be repeated within 2 months and, if confirmed as pathological, enrollment in a chronic transfusion program is recommended. In patients with abnormal TCD, it is recommended to perform an MRI and MRA investigation for possible detection of brain ischemic

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lesions. If blood flow is too low (TCD  <  70 cm/s) or there is significant asymmetry between the two sides or if TCD cannot be performed, it is necessary to complete alternative neuroimaging studies, such as MRI and MRA [204 - 205].

Fig. (13). Images of patients with SCD. MR angiography in a 17 years old male showed occlusion of the left middle cerebral artery (A) and a MRI revealed ischemic lesions in the left superficial frontoparietal area (B FLAIR-images). In a 20 years old male a MR angiography revealed occlusion of intracranial carotid arteries (C) while a MRI showed multiple ischemic subcortical lesions (D T2 images).

Treatment Erythrocyte transfusion has an established role in the management of both acute and chronic complications in SCD (Table 3). Transfusion corrects anaemia, decreases the percentage of HbS, suppresses HbS synthesis, and reduces haemolysis, all of which are of potential benefit. Erythrocytes can be given as a simple additive transfusion or by exchange, in which blood is also removed. Exchange transfusion is more likely to be necessary if the initial haemoglobin concentration is high, or if there is a need for rapid decrease in HbS percentage without increasing the haematocrit and blood viscosity, typically in people with acute neurological symptoms.

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Chronic blood transfusion is inevitably associated with iron overload, although the pattern of haemosiderosis seems different to that described in thalassaemia; iron chelation is important in chronically transfused patients with SCD, mainly to avoid liver damage; desferrioxamine can be given parenterally, although the oral iron chelator deferasirox is increasingly used with evidence of benefit [204]. Table 3. Indications for blood transfusion in sickle-cell disease. Indications for acute transfusions Acute exacerbation of anaemia

Typically caused by Parvovirus B19 infection, splenic or hepatic sequestration, or severe vaso-occlusion; simple transfusion is necessary to increase haemoglobin concentrations to 80–90 g/L

Acute chest syndrome

Early simple top-up transfusion is beneficial, with exchange transfusion to reduce HbS to less than 30% if deterioration of clinical condition occurs

Stroke deficit

or

acute

neurological Urgent transfusion to increase haemoglobin concentrations to 100 g/L, and reduce HbS to less than 30%, which typically requires exchange transfusion

Multiorgan failure

HbS to less than 30% with haemoglobin concentration of 100 g/L

Preoperative management

Target HbS of less than 30% before major surgery (cardiothoracic, neurosurgery), typically requiring exchange transfusion; medium-risk or low-risk surgery might need simple transfusion to increase haemoglobin concentration to 100 g/L

Indications for regular, long-term transfusions Primary and secondary stroke Regular transfusions, either simple or exchange, to keep HbS less than prevention 30% Recurrent acute chest syndrome Regular transfusions, either simple or exchange, to keep HbS less than not helped by hydroxycarbamide 30% Progressive organ failure

Including hepatic, renal, cardiac, and pulmonary failure; little evidencebased practice and transfusion strategies vary widely

In the Stroke Prevention in Sickle Cell Anemia (STOP) study, regular blood transfusion to keep HbS below 30% reduced the risk of stroke by 90% in patients with increased TCD velocities. Exactly how chronic blood transfusion confers stroke protection is not known, but is thought to be through improvement or halting progression of large vessel cerebral arteriopathy [210]. Because chronic transfusions confer the long-term health risks of infection, iron overload and end-organ damage, alternative methods to reduce stroke risk have

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been studied. In the Stroke with Transfusions Changing to Hydroxyurea (SWiTCH) study, the efficacy of regular blood transfusions and iron chelation was compared with hydroxyurea and phlebotomy in children with sickle-cell disease and stroke. However, the study was stopped prematurely because of the high number of strokes in the hydroxyurea group; no strokes occurred in 66 children receiving blood transfusions, but seven strokes occurred in the 67 children taking hydroxyurea [214]. Additional roles for hydroxyurea in stroke prevention for children with SCA continue to be studied. A randomized clinical trial comparing hydroxyurea to chronic blood transfusions for the primary prevention of stoke in SCA is underway in the TWiTCH trial (TCD with Transfusions Changing to Hydroxyurea) [211]. Once a stroke has occurred, the risk of recurrence is more than 60%, although this risk is substantially reduced by starting a transfusion program. Some children have progressive vasculopathy, with a moyamoya-like syndrome and further strokes despite transfusion; neurosurgical revascularisation might be helpful in these circumstances [204, 212]. In patients with silent cerebral infarct the possibility of preventing progression of these infarcts with blood transfusions has been recently studied in a randomized controlled clinical trial (SIT) [213] which show that children with SCD, silent cerebral infarcts, and normal transcranial Doppler velocity will have a 58% relative risk reduction in the recurrence of infarcts while they are receiving regular blood-transfusion therapy. The benefits of blood-transfusion therapy for the secondary prevention of silent infarct recurrence in SIT [213] were lower than those in STOP which showed a relative risk reduction of 92% in patients at high risk, being selected by the presence of intracranial stenosis defined by TCD velocity [210]. However, it is not known how long transfusion should be continued in children with SCD taking into account that this therapy carries immediate and cumulative adverse effect. Therefore the reason of discontinuation is to reduce adverse effect particularly with regard to iron loading. The STOP 2 trial was stopped earlier

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because discontinuation of transfusion for the prevention of stroke in children with SCD resulted in a high rate of cerebrovascular events and abnormal bloodflow velocities on transcranial Doppler [215]. Given the problems associated with long-term transfusion , stem-cell transplantation is an intriguing and promising option for primary stroke prevention [219]. OTHER UNCOMMON CAUSES OF STROKE Acute Posterior Multifocal Placoid Pigment Epitheliopathy Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is a chorioretinal disease characterized by the presence of multiple large yellow-white placoid lesions in the retinal pigment epithelium [220]. APMPPE affects males and females equally, with striking preponderance for young adults [220, 221] and has been associated with other systemic manifestations of vasculitis and brain lesion [222, 223]. Simultaneous onset in both eyes is the most common although involvement of the second eye can be delayed for a few days or even weeks. The placoid lesions start to fade within a few days and by two weeks are replaced by areas of partly depigmented epithelium with irregular pigment clumping. The lesions are mainly at the posterior pole and never anterior to the equator. The cause is uncertain, but accumulating evidence indicates that the primary lesion is an inflammatory disorder of the small choroidal arterioles and that secondary ischemic changes produce disruption of the pigment epithelium causing the typical placoid lesions. There are evidence that viral infections, Lyme disease, postvaccination autoimmune response, collagen vascular diseases and other systemic processes, such as sarcoidosis may play a role in the etiology of APMPPE [224]. Recurrences are infrequent and usually occur in the first 6 months. Occasionally, progressive disease can lead to chorioretinal atrophy and significant visual loss [222].

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Neurological Features The common neurological findings of APMPPE are headaches and CSF pleocytosis suggesting an aseptic meningitis [221, 224]. However, some patients develop transient hearing loss [225], optic neuritis [223], meningoencephalitis [226], transient focal deficits [221], and strokes [223, 227– 229] due to vasculitic changes [230, 231]. Cerebral ischemia in patients with APMPPE is unusual and manifests clinically as strokes, or less frequently as transient ischemic attacks; these patients usually have evidence of inflammation of the CSF or aseptic meningitis [575]. There are two reported cases of death from large strokes [232, 233]. Of nine previously described cases of strokes with APMPPE, five had angiographic findings consistent with vasculitis. In one case, brain histopathology revealed focal granulomatous inflammation of medium-sized arteries [232]. Cerebral vasculitis is the presumed mechanism of injury, although angiographic evidence may be lacking. Stroke and TIA usually occurs within 4 –5 months from the onset of ocular disease, though may be concomitant [234] and involve predominantly the posterior circulation and the basal ganglia. There may be a biphasic course of the neurological illness [227], and the cerebral ischemic events can recur during the tapering of immunosuppressive drugs. APMPPE should be considered in young patients with unexplained strokes or aseptic meningitis, particularly when associated with symptoms such as scotomas or visual blurring. A detailed ophthalmologic evaluation is necessary in suspected cases: although the diagnosis can be firmly established with typical fundus and fluorescein angiography findings, the lesions are difficult to identify with direct funduscopy. Diagnostic Assessment ●

Fluorescein angiography revealed characteristic hypofluorescent lesions in the early phase of the angiogram followed by late hyperfluorescence of the same areas. If the primary lesions do not involve the fovea, the prognosis is good, with nearly complete visual function returning over several weeks (Fig. 14A).

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Cerebrospinal fluid examination may revealed a raised white cell count and protein level suggestive of CNS inflammation. Among the published cases, a lumbar puncture was performed in 17 patients: sixteen of these patients had an elevated white cell count, and 14 patients had increased protein levels. MRI, MR angiography and eventually catheter angiography should be undertaken if persistent headache, neck stiffness, or transient ischemic attack are present. Brain MRI is superior to a CT examination and is useful to detect both the symptomatic cerebrovascular lesion and new asymptomatic lesions, giving an account of the activity of the disease (Fig. 14B). No diagnostic blood test exists for APMPPE. A sedimentation rate is considered to be a good indicator of generalized inflammation, but in the published literature of APMPPE with CNS changes, it was rarely described as abnormal. Thus, a sedimentation rate is not a useful adjunctive test in the diagnosis of CNS-complicated APMPPE.

Fig. (14). Images of a patient with acute posterior multifocal placoid pigment epitheliopathy Funduscopy at the left side showed multifocal yellow-white placoid lesions at the level of the pigment epithelium and choroid of the retina (arrows); FLAIR Brain MRI image showed an ischemic lesion involving the putamen and the head of the caudate nucleus.

The Differential Diagnosis APMPPE-related CNS vasculitis should be considered in young patients with stroke when there is associated acute loss of visual acuity or history of APMPPE. Certain systemic illnesses can involve both the brain and the eyes, leading to the so-called uveoretinal-meningoencephalitis syndromes. Specific entities include Vogt Koyanagi Harada disease, sarcoidosis, Behçet’s disease, systemic lupus erythematosus, Crohn’s disease, metastatic malignancies, primary intraocular

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lymphoma, histoplasmosis, toxoplasmosis, cytomegalovirus, and syphilis. Of these disorders, Vogt Koyanagi Harada disease is a primarily ophthalmologic disease that can mimic APMPPE with initial funduscopic and angiographic findings [235] and it has been suggested that these may represent a continuum of a single disease. Treatment Once cerebral vasculitis is diagnosed, immunosuppressive treatment should be started. APMPPE should be treated aggressively, and a team effort is often required to provide optimal management of these patients. Although some patients with cerebral vasculitis improved spontaneously an aggressive treatment is reccomended, given the high risk of recurrent strokes, Combination of steroids with cyclophosphamide or azathioprine is reported to improve the outcome in primary cerebral vasculitis. The immunosuppressive agents can be stopped after 6 to 12 months, since there are no reported strokes after 5 months from the disease onset. It remains difficult to predict which patients with CSF pleocytosis and headaches will evolve to have strokes. It is necessary to follow the patients closely for neurological deterioration rather than treated with low-dose steroids. Malignant Atrophic Papulosis (Köhlmeier-Degos) Kohlmeier and Degos described a rare and potentially fatal papulosis of the skin, caused by occlusive changes in the small arteries. Subsequently Degos et al. described the condition as the "syndrome cutaneo-intestinal mortel," because the majority of patients died of multiple infarcts of the small intestine. The mean age of onset malignant atrophic papulosis (MAP) or Kohlmeier/ Degos syndrome appeared to be 35.4 ± 12.3 years. The female-to-male ratio was 1.4:1 and familial occurrence was noted in 9% of cases [236]. The etiology of MAP remains unexplained with three reasonable mechanisms consisting of vasculitis, coagulopathy and primary dysfunction of the endothelial cells [236, 237]. The simultaneous presence of various factors creating the appropriate conditions for the development of small vessel thrombosis should be

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considered. MAP may have a benign cutaneous type and a systemic, fatal variant with widespread occlusive vasculopathy of bowel as well as brain and spinal cord infarction. In the CNS, the most common abnormalities are a stenosis or occlusion of the small and middle intracerebral arteries while large extracranial arteries may show thin fibrous subendothelial plaques. Also deep vein thrombosis have been described duo to the coagulative disorder. Probably the inflammation of the vessels could have a trigger effect for the development of MAP favouring a “lymphocyte associated necrotic vasculitis” in the skin followed by deposition of mucin and aggregation of mononuclear cells in endothelial cells [236]. Finally an abnormal swelling and proliferation of the vascular endothelium could trigger cutaneous, intestinal and central nervous system thrombosis eventually triggered by viral or bacterial infection. Clinical Findings and Neurologic Features The diagnosis of MAP is based on the pathognomonic skin lesions consisting of 0.5-1 cm large papules with an erythematous rim and a-white centre and mostly occurring on the trunk and the upper extremities while palms, soles, scalp and face are rarely involved (Fig. 15). The lesions appear initially as small erythematous papules and, after a few days, the centre sinks.. Involvement of the internal organs, with multiple limited infarcts of the intestine and/or the central nervous system as well as of other organs, such as the lungs and the eyes. Unlike lupus, Degos disease does not involve the face and it does not improve with corticosteroids, it does not manifest with photosensitivity, and is universally fatal, usually within 1-2 years in the systemic form. In the past McFarland reviewed the main clinicopathological features of nine cases of MAP with neurological involvement [238]. In most of the patients the ages of onset was between 16 and 47 years, and a duration of symptoms of one to six years. Hemiparesis or hemiplegia, focal seizures, facial paresis, incoordination, dysarthria and hiccups, were the more common CNS signs; with multiple cerebral infarcts, with or without haemorrhagic changes and similar

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changes in the cerebellum or spinal cord, constituting the neuropathological findings [239, 240].

Fig. (15). Cutaneous involvement of Köhlmeier-Degos disease showing scattered lesions on the forearm (B).

The benign form of the disease is characterized by the typical skin lesions without involvement of the inner organs[241], while the malignant form is characterized by systemic manifestations with bowel perforation and peritonitis as well as thrombosis of the cerebral arteries or massive cerebral hemorrhage, meningitis, encephalitis, radiculopathy, myelitis [242] leading to lethal course in approximately in 50% of the patients within 2 to 3 years. An ocular involvement with affection of the optic nerve [243], eyelids, conjunctiva, retina, sclera and the choroid plexus, as well as the development of diplopia and ophthalmoplegia have also been described [244]. Interestingly systemic involvement can develop suddenly, even years after the occurrence of skin lesions: therefore a regular general and neurological follow-up of the patients is necessary. Diagnosis and Treatment The skin biopsy is the hallmark for the diagnosis: the tunica media is usually spared while in the adventitia it is possible to find inflammatory- like perivascular infiltration such as those found in nodous polyarteritis and thromboangioitis. Since every diagnosed MAP case can potentially develop into the systemic, lifethreatening variant, a periodic follow-up is mandatory with a skin inspection combined with additional examinations, such as MRI as well as gastroscopy and colonoscopy to assess the long-term prognosis. There is no uniformly effective

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therapy for MAP. Efforts with fibrinolytic and immunosuppressive therapy like cyclosporineA, azathioprine, cyclophosphamide and corticosteroids have been mostly unsuccessful. Besides the systemic corticosteroids have been associated with early intestinal perforation and sepsis. Eulizumab and treprostinil have been employed with conflicting results in some cases. Other therapeutic efforts with anticoagulants and compounds that facilitate blood perfusion, such as acetylosalicylic acid, pentoxifylline, dipyridamole, ticlodipine and heparin, have achieved a partial regression of the skin lesions in single cases. STROKE AND MIGRAINE Epidemiological studies have reported an association of migraine, mostly with aura, not only with ischemic stroke, but also with hemorrhagic stroke, coronary events, and even all-cause mortality [245]. The International Headache Society (IHS) [246, 247] has proposed strict diagnostic criteria for migraine and its two main types: a) migraine without aura (MO), also known as common migraine, in patients who have had only migraine without aura; b) migraine with aura (MA), also known as classical migraine, in patients who have had at least two migraine attacks with aura, regardless of how many attacks they have had without aura. Migraine With Aura and Transient Ischemic Attack MO includes the majority of people with migraine. It consists of a pulsatile lateralized headache with nausea/vomiting and/or sensitivity. The other symptoms usually begin at the same time as the headache and disappear once the headache goes. Headaches usually last between four and 72 hours. MA affects between 10 and 30 per cent of people whit migraine. Many people who have this type of migraine also have migraine attacks without aura. Attacks usually begin with an aura consisting of symptoms which develop gradually over 5-20 minutes and last less than one hour. The most frequent features are the following:

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a) Visual changes are the most common aura symptom and include flashing lights, zig-zags, sparks or dark patches. These can appear on one side or centrally and commonly expand and move across the field of vision. In other cases, scotoma without positive phenomena may occur; this is often perceived as being of acute onset but, on scrutiny, usually enlarges gradually. b) Sensations such as pins and needles and heaviness, which spread from one body part to another (i.e. from the face to the upper limb). c) loss of speech (motor aphasia) is less commonly and may follow visual changes and sensory symptoms. It is important to taking into account, to distinguish the aura from a TIA in which symptoms occur acutely, that aura symptoms usually follow one another in succession, beginning with visual, then sensory, then aphasic; but the reverse and other orders have been noted. The accepted duration for most aura symptoms is one hour, but motor symptoms may be longer lasting (migraine with prolonged aura). The aura occurs usually before the headache, but it may begin after the pain phase has started or continue into the headache phase. Visual aura is the most common type of aura, occurring in over 90% of patients with MA; when the aura includes motor weakness, the disorder should be coded as Hemiplegic Migraine or one of its subforms. Retinal migraine (monocular visual loss), hemiplegic migraine, basilar migraine, and migraine with prolonged aura prove particularly troublesome from the diagnostic standpoint. Similarly, when retinal ischemia is associated with headache as occur in oftalmic artery embolic occlusion, or with “positive” symptoms there may be a misdiagnosis of MA, particularly if the ischemia is transient. Particular interest and intriguing consequences in relation to stroke and TIA diagnosis are three type of migraine with complex aura [246] recently revised by the International Headache Society (ICHD-third edition [247]: 1) hemiplegic migraine (HM) either familiar or sporadic have motor weakness as key symptom and is classified as a separate form because of genetic and

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pathophysiological differences from migraine with typical aura [248]. Aura consisting of both of the following: a) fully reversible motor weakness, b) fully reversible visual, sensory and/or speech/language symptoms. Not infrequently may occur brainstem symptoms in addition suggesting a basilar migraine. Mutation in the neuronal voltage-gated sodium channel SCN1A have been found in this type of migraine. 2) the basilar migraine (in ICHD-3 migraine with brainstem aura) [249]: it consist of a migraine with aura symptoms clearly originating from the brainstem, without motor weakness (in this case we had to consider a familiar hemiplegic migraine). The aura consists of visual, sensory and/or speech/language symptoms, each fully reversible, but no motor or retinal symptoms. At least two of the following brainstem symptoms spreading gradually over 5 minutes and lasting 5-60 minutes has to be present: a) dysarthria, b) vertigo, c) tinnitus, d) hypacusia, e) diplopia, f) ataxia, g) decreased level of consciousness. 3) Vestibular migraine: it consist of vertigo or dizziness of moderate or severe intensity, lasting between 5 minutes and 72 hours. Considering the relevance of vertigo in the emergency setting and the differential diagnosis of vertebrobasilar stroke, vestibular migraine as defined by recent ICHS-beta is particularly relevant [250]. At least 50% of episodes are associated to headache with migrainous features (unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, photophobia and phonophobia) or visual aura. Vestibular migraine, include different subtypes: a) spontaneous vertigo including internal vertigo (a false sensation of self motion) and external vertigo (a false sensation that the visual surround is spinning or flowing); b) positional vertigo, occurring after a change of head position; c) visually induced vertigo, triggered by a complex or large moving visual stimulus; d) head motion-induced vertigo, occurring during head motion; e) head motion-induced dizziness with nausea. Duration of episodes is highly variable even if the core episode rarely exceeds 72 hours. About 30% of patients have episodes lasting minutes, 30% have attacks for hours and another 30% have attacks over several days. The remaining 10% have attacks lasting seconds only, which tend to occur repeatedly during head motion,

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visual stimulation or after changes of head position. In these patients, episode duration is defined as the total period during which short attacks recur. At the other end of the spectrum, there are patients who may take 4 weeks to recover fully from an episode [247, 250]. Both in basilar artery migraine and hemiplegic migraine motor weakness and brainstem symptoms may last several days or weeks. Headache almost always occurs being unusual the auras without headache. Patients with MA not infrequently have, in addition, attacks with aura followed by a less distinct headache or even without head pain. A number of patients have, exclusively “typical aura without headache” [247]. This can easily be mistaken for TIA but the course of the symptom are different: migraine aura symptoms develop relatively slowly and then spread and intensify, whereas the symptoms of a TIA are sudden. Migraine symptoms also tend to be ‘positive’ while in TIA they are “negative” with loss of function. Indeed there are positive symptoms (such as seeing flashing lights or having a headache), rather than losing abilities (such as losing muscle strength, vision or speech). In addition, a lack of other risk factors for stroke or TIA, a family history of migraine and previous, similar attacks would suggest migraine. Migrainous Stroke Although uncommon stroke may occur during the course of a typical attack of migraine, particularly with aura. Risk factors for migrainous stroke include female sex, mean age 35 years old, who smoke and use combined oral contraceptives. The Women’s Health Study has shown an increased risk in those migraineurs with low vascular risk profile and with high frequency of attacks. Moreover migraine is associated with subclinical brain lesions [152, 153].

Fig. (16). A 17 years old female complained of sensory impairment over her body on the left side during a prolonged attack of migraine with aura. Brain MRI showed a small lacunar lesion (arrow) of the posterior right thalamus (A: FLAIR WI coronal view;-B:T2-WI axial view); MR angiography showed a narrowing of the right posterior cerebral artery (C, arrow). Symptoms fully reverse in the following seven days whereas the posterior cerebral artery abnormalities gradually resolved in about 30 days.

A second possibility is that MA is a risk factor for some subtypes of cerebral infarction such as dissections and patent foramen ovale (PFO). In a meta-analysis of five case-control studies [254], migraine in general was twice as common in patients with dissection as in controls, with further increased risk in patients with multiple dissections. The connection between patent foramen ovale and migraine is controversial. Many observational studies showed a bidirectional association between migraine and PFO. PFO is twice as frequent in patients with MA, and MA is twice as frequent in patients with PFO, than in controls [255]. Additionally, it has been

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reported that PFO closure has beneficial effects on migraine but the scientific evidence is low; indeed results from a population-based and a clinic-based study do not confirm an association between PFO and migraine [256]. Furthermore, the first double-blind, randomized clinical trial of PFO closure for migraine [257] showed no benefit of the procedure on the primary efficacy endpoint the cessation of migraine attacks 91–180 days after the procedure [257]. The exact mechanisms by which MA might increase the risk of ischaemic stroke is unknown, but several hypotheses are plausible. A migrainous infarction can occur if the decrease in blood flow related to the aura reaches the ischaemic level according to the notion that the infarction occurs during an attack typical of previous attacks except that one or more aura symptoms persists for more than 60 minutes. A second possibility is that treatments used to acutely abort migraine attacks, particularly vasoconstrictors, increase the risk of stroke. However, although overuse of ergots has been associated with an increased prevalence of white matter abnormalities [258], neither ergots nor triptans have been consistently linked to an increased risk of stroke or other ischaemic events [259]. Silent Cerebral Ischemic Lesion in Migraine Several neuroimaging studies have shown an increased prevalence of white matter hyperintensities in people with migraine [245, 260, 261] In a meta-analysis of case-control studies, migraine was associated with a four-times increase in the risk of white matter abnormalities [252] with a positive relation with the frequency of migraine attack, suggesting a dose–response relation. However, the debate is open regarding the relationship between migraine and cerebral ischemic lesions with studies showing presence of infarct-like lesions in the posterior circulation territory , mainly in the cerebellum and the brainstem , and other reporting an association between MA and infarction lesions located outside the cerebellum [245, 253]. A population-based study in women suggests that MA also increases the risk of haemorrhagic stroke [262], particularly in elderly people. The location of small infarcts on MRI [253] and the preponderance of lacunar infarcts indicate an association of small artery diseases with MA

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A prospective study of 27.852 middle-aged women explored the association between migraine and functional outcomes after cerebral ischaemic events [263]. MA was associated with transient or benign ischaemic events without impaired functional outcomes. A misdiagnosis of stroke (e.g, in patients who have attacks of migraine with prolonged aura) is possible even if the use of neuroimaging in the diagnosis of cerebrovascular accidents reduce that risk. Moreover prolonged deficits occur mainly in a rare variety of migraine such as familial hemiplegic migraine (FHM) and basilar migraine. By contrast overdiagnosis of migraine in patients with other types of headache remains, particularly when the headache is secondary to a condition carrying a risk of stroke. Because TIA strongly increases the risk of ischaemic stroke, misclassification of TIA as an aura can lead to an overestimation of the association between MA and ischaemic stroke and induce the clinician to do an inappropriate diagnostic assessment. The differential diagnosis made according to the patient’s description is clear when symptoms are typical, with scintillations progressing gradually and lasting 15–30 min with an ensuing headache in the case of MA, and a sudden focal deficit lasting less than 1 h without headache in TIA. The interpretation of such transient focal neurological symptoms can further be challenged by the fact that in elderly patients they might be due to small focal subarachnoid hemorrhages related to cerebral amyloid angiopathy a note cause of recurrent lobar hemorrhages [264]. Secondary Migraine With Aura and Ischaemic Stroke A number of other local or systemic vascular disorders are associated with both MA and stroke. CADASIL is the best example of a cerebrovascular disease that causes MA. In the 40% of patients with CADASIL who have MA, attacks of MA are always the first symptoms, preceding the first strokes by 10–20 years. By contrast with CADASIL patients, MA is often infrequent and sometimes probably coincidental in most of the disorders detailed in Table 4 [245].

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Table 4. Disorders associated with stroke and with migraine with aura.     Disorders with brain vessel wall abnormalities  •   Brain arteriovenous malformations  •   Leptomeningeal angiomatosis (Sturge-Weber syndrome)  •   Moyamoya syndrome  •   Hereditary haemorrhagic telangiectasia  •   Sneddon syndrome  •   Mitochondrial disorders (MELAS)  •   Disorders related to COL4A1 mutations  •   Disorders related to TREX1 mutations (HERNS)  •   CADASIL (NOTCH3 mutations)   Cardiac disorders  •   Patent foramen ovale with or without atrial septum aneurysm  •   Cardiac myxoma   Blood disorders  •   Antiphospholipid antibody syndrome  •   Systemic lupus erythematosus  •   Essential thrombocythaemia  •   Polycythaemia CADASIL=cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. MA=migraine with aura. MELAS=mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes.

Practical Implications of The Migraine–Stroke Association The complex relations between migraine and stroke have important diagnostic and therapeutic implications in clinical practice. Clinicians should be very careful not to diagnose migraine in patients who have other types of headache, which can also carry a risk of stroke and require different investigations and treatment. When the diagnosis is unclear or when patients have a first scintillating scotoma after the age of 50 years, it is necessary to perform a complete ophthalmological, neurological and neuroimaging work-up. Patients who have MO, for whom there is no evidence for an increased risk of stroke, require no specific additional treatment. In patients with MA, the concern is about the detection of disorders that can cause secondary MA and eventually

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ischemic cerebrovascular disorders (Table 4). Only if other cerebral or ischaemic signs are present (i.e diffuse subcortical ischemic lesions, parenchymal calfications, abnormal vascular tortuosity of intracranial vessel), an extensive work-up is required to rule out such pathologies. However, there is a case for recommending MRI in patients who have atypical MA attacks, a late onset of MA or a recent increase in attack frequency [265]. If specific white matter abnormalities are found on MRI, genetic testing for CADASIL may be reasonable. By contrast, if MRI shows numerous silent subcortical infarcts [266] a full blood, cardiac, and cerebrovascular work-up is required. It is important to consider genetic cause of small vessel disease (see Table 4). Moreover it is reasonable to propose small doses of aspirin for cardiovascular prevention, in migraine patients with multiple vascular risk factors or evidence of large vessel atheroma since it has been shown that low-dose aspirin could have a positive effect also in migraine prevention. In young women with MA all measures of vascular prevention should be implemented encouraging patients to abstain from smoking, particularly if they also take oral contraceptives, to use progestogens only rather than oestrogen–progestogen as oral contraceptives, and to take regular physical activity. For the acute treatment of attacks with aura, triptans can be used, but because they carry the potential risk of worsening oligaemia associated with the aura, they should be taken when the aura is over. Finally triptans abuse may be a risk factor for the occurrence of reversible cerebral vasoconstriction syndrome (see paragraph “vasculitis”). CEREBROVASCULAR COMPLICATION OF DRUGS ABUSE Drug abuse has become a significant cause of both haemorrhagic and ischemic strokes, especially in young adults and adolescents, other than neuropsychiatric and systemic complication [267]. In a case–control study of over 200 patients in an urban population aged 15–44 years, drugs abuse was the most commonly identified potential predisposing condition to ischemic or haemorrhagic stroke among stroke patients less than 35 years of age [268]. In another study of 422 cases of ischaemic stroke analyzing subjects aged

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15–44 years, 4.7% had drug abuse as the probable cause of stroke [269]. It is difficult to assess the role of an individual drug in the aetiology of stroke since patients often use mixtures of drugs and do not give an honest report of their usage. The abuse of recreational drugs has to be considered in any young patient with stroke, even when other risk factors are also present and the patient denies the use of drugs. The suspected drugs include heroin, amphetamines, most often in the form of methamphetamine, cocaine including alkaloidal cocaine (crack), phencyclidine (PCP) and lysergic acid diethylamide (LSD) [270]. Heroin Among parenteral heroin users cerebrovascular complication occur as a consequence of bacterial endocarditis, particularly with Staphylococcus and Candida. Stroke may be ischemic or hemorrhagic, the latter caused by rupture of either a “micotic” aneurism or infectious vasculitis. The clinical picture in heroin endocarditis with cerebrovascular complication is often insidious and consists of minor stroke or TIA as well as symptoms of diffuse encephalopathy suggesting the presence of meningoencephalitis. Cerebral hemorrhages due to rupture of micotic aneurism may occur during the acute phase or later although aneurysm may disappear during antimicrobial treatment. Therefore it has been recommended to obtain a cerebral angiography when suspicious symptoms occur, eventually treating the aneurysm with endovascular or surgical approach, if accessible [271]. Hemorrhagic stroke in heroin users may be a consequence of hepatitis with liver failure and derange clotting or of heroin nephropathy with malignant hypertension. Moreover, ischemic stroke may be a complication of meningitis or AIDS. In some patients cerebral lesion occur after cardiac or breath arrest following an overdose or a recent injection (Fig. 17). In other patients an angiographic pattern suggesting cerebral vasculitis was found [272]. Embolization of foreign material has not been documented in heroin users but is well recognized with other agents, including opiates; indeed during the 1970s talc and cellulose crystals in both pulmonary and cerebral arteries were found at autopsy after injection of table

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crushed suspended in water of a mixture of pentazocin and tripelennamine [273].

Fig. (17). Brain MR-FLAIR WI of a heroin abuser showed a bilateral lesion of the pallidum nucleus due to a respiratory arrest. The clinical picture consisted of a bilateral rigido-akinetic parkinsonism.

Also myelopathy in heroin users may be ischemic and, in some cases, myelopathy occur on awakening from coma suggesting hypotension and borderzone infarction. Heroin placed on aluminum foil and heated with a flame produces a vapor that can be inhaled through a straw or tube to produce a high ("chasing the dragon") [274]. Chasing the dragon is an increasingly popular technique of using heroin as it avoids the risks, including HIV and hepatitis infection, associated with parenteral administration of the drug. However, a rare consequence of inhalation of heated heroin is a progressive spongiform leukoencephalopathy with marked symmetrical cerebellar white matter involvement with sparing of the dentate nuclei, posterior cerebrum, posterior limbs of the internal capsule, splenium of the corpus callosum, medial lemniscus, and lateral brainstem [275]. Clinical findings are apathy, bradyphrenia, cerebellar dysarthria and ataxia. Some patients then developed spastic hemiparesis or quadriparesis, tremor, chorea, myoclonus, pseudobulbar palsy, fever, and blindness. Cranial CT showed cerebral and cerebellar white matter hypodensities [276]. In these cases, treatment with antioxidants, including oral coenzyme Q, appear useful. Elevated lactate in brain white matter and the response to antioxidants

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suggests mitochondrial dysfunction in progressive spongiform leukoencephalopathy following inhalation of heated heroin vapor [277]. Recently a selective hippocampal ischemic lesion subsequent to acute intranasal heroine abuse, associated with cortical laminar necrosis of the left hippocampus and in absence of vascular abnormality has been described [278]. Cocaine The pathophysiological effects of cocaine include vasoconstriction, local anesthesia and central nervous system stimulation. Cocaine binds to specific receptors at pre-synaptic sites preventing the reuptake of neurotransmitters particularly of catecholamines. Sympathomimetic effects result in elevated blood pressure and heart rate, and cause symptoms of sweating, palpitations, tremor and hyperthermia. Therefore cocaine is associated with both ischemic and haemorrhagic stroke. During the 1980s, increased production of alkaloidal “crack” led to a significant increase in the number of case reports of cocainerelated stroke. The onset of symptoms is usually immediate or within 3 hours of cocaine use, and most of patients with cocaine-induced stroke have no prior cardiovascular risk factors [279, 280]. The probability of stroke is up to 14 times greater in cocaine users than in nondrug users [281, 283] and genetic factors may be involved in the death related to cocaine use. In agreement with this statistic, Silver and coworkers [282], using a urine toxicology screen, recently founded that 11% of 420 patients recruited in a single tertiary care stroke center were positive for cocaine (19% were younger than 50 years, while 9% were older; commonly black). Of these cocaine user patients with ischemic strokes, 44% were due to large-artery atherosclerosis, 11% to cardioembolism, and 22% to small-vessel occlusion. Fehnel and coworkers [281] reported that 2.2% of 4073 acute ischemic stroke patients had a history of cocaine use and/or a positive toxicology. Moreover, the authors showed that in cocaine users the most common cause of ischemic stroke was cardioembolism (43%) respect to large artery atherosclerosis (18%) and small-vessel occlusion (21%). Cocaine induces hemorrhagic and ischemic stroke, with the incidence of

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hemorrhagic stroke prevailing over ischemic stroke [279]. Active cocaine users appear to be more likely to have intracerebral hemorrhage compared with previous users (37.7% vs. 8.6%) and less likely to have ischemic stroke or transitory ischemic attack (36.1% vs. 65.7%). The use of cocaine increases blood pressure and risk of aneurysms rupturing [279], and has a close association with hemorrhagic stroke [284]. A sudden rise in systemic arterial pressure may cause haemorrhages, frequently in association with an underlying aneurysm. Vasospasm due to reversible cerebral vasoconstriction syndrome (Fig. 18), vasculitis, myocardial infarction with cardiac arrhythmias and increased platelet aggregation also may provoke infarcts [284]. Interestingly crack cocaine seems to be associated with both ischemic strokes and hemorrhage strokes, whereas cocaine hydrochloride causes mainly intracerebral and subarachnoid bleeding [285, 286].

Fig. (18). Image of a 42 years cocaine abuser male who suffered of acute “thunderclape” headache which persisted for three weeks resembling migraine (prolonged migraine or status hemicranicus). Cranial CT scan (A) and brain MRI-FLAIR image (B) showed atypical subarachnoid bleeding in the sulci of the vertex both in the left frontal and parietal area as well as and in the right fronto-parietal junction into the Rolandic sulcus. Cerebral angiography obtained two days later fail in revealing vasospasm as well as aneurysm or arteriovenous malformation. A reversible cerebral vasoconstriction syndrome (see paragraph) was suspected due to an increase in mean flow velocity of intracranial arteries at transcranial Doppler obtained seven days later but patient refused further investigation and fully recovered.

Cerebral vasculitis has been attributed to cocaine misuse and has been diagnosed based on angiography findings of arterial beading: angiographic and pathological data suggest that vasospasm with secondary thrombus formation are major causes of stroke in cocaine users [287]. Moreover, cocaine abuse may cause the clinical

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features of the reversible cerebral vasoconstriction syndrome that are intracerebral and subarachnoid haemorrhage as well as ischemic lesions due to vasospasm (see related paragraph). Amphetamines have a similar mechanism of action to cocaine by increasing the availability of catecholamines at nerve terminals, and so there may be similarities in terms of the aetiology of the vascular changes. Cerebral emboli with subsequent infarction can originate from cardiac thrombi made during a cocaine-induced myocardial infarction [288] or during cocainerelated cardiomyopathy [279]. These disease processes are established causes of cardiac arrhythmia, which may predispose to cardioembolism. Moreover, as with any substance injected intravenously, cocaine administered by this route can result in embolic vessel occlusion due to endocarditis. Stroke resulting from endocarditis may also be haemorrhagic, following rupture of a septic aneurysm [279]. Finally, a decrease in cerebral blood flow in cocaine-dependent patients has been associated with an increase in platelet aggregation and blood viscosity, while in chronic cocaine users, the release of cell growth factors by activated platelets might promote atherosclerosis, predisposing users to thrombosis and ischemia in the absence of acute intoxication, despite a young age [289]. Cannabis Cannabis sativa is the most popular illicit drug consumed in Western societies. This is, in part, because of an assumption among users that cannabis is a safe recreational drug. However, tetrahydrocannabinol, the main active component in cannabis, has been shown to induce vasoconstriction [290]. It seems clear that physiological, clinical, and epidemiological data converge on an increased stroke risk from cannabis exposure and several experts think that cannabis is a risk factor for stroke and its use should be minimized. On the other hand, given the broad exposure to cannabis in the general population, it is striking that more strokes do not occur among cannabis users. The risk of cerebrovascular events may be modulated by dose, frequency, strength (% tetrahydrocannabinol), genetic susceptibility, and other concomitant ingestants. However, it is possible that exposure is often not mentioned by patients with stroke in emergency

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departments. Two epidemiological studies have investigated this association. In a large study of hospital admissions in Texas, cannabis exposure was associated with ischemic stroke even after adjusting for alcohol and tobacco (adjusted odds ratio, 1.76; 95% confidence interval, 1.15–2.71) [291]. In a prospective case–control study with adjustment for age, sex, and ethnicity, cannabis was associated with the composite of cerebrovascular events (odds ratio, 2.30; 95% confidence interval, 1.08–5.08) [292]. Yet after further adjustment for tobacco, the association was weakened (odds ratio, 1.59; 95% confidence interval, 0.71–3.70). A recent French pharmacovigilance study of cannabis complications detected 3 cerebral complications among a pool of 35 cardiovascular-related cases of cannabis toxicity reported to a central network [293]. The 3 cerebral complications were acute cerebral angiopathy, transient cortical blindness, and spasm of the cerebral artery. Although these 3 cases recovered, an overall mortality rate of 25.6% for cardiovascular complications related to cannabis was found. A recent review includes the clinical features of stroke patient with temporal relation with cannabis assumption [294]. Most cases were men (80%) and the median age was 32 (range 15–64) years. The majority of infarctions occurred in the anterior circulation (56%); 3 cases involved both anterior and posterior circulations (5%); the remainders occurred in the posterior circulation (36%) or were not classified (3%). About a quarter of patients (22%) had recurrent stroke from subsequent re-exposure to cannabis. Half of patients (50%) had concomitant risk factors for stroke, most commonly tobacco (34%) and alcohol (11%). In the prospective cohort of Wolff and coll [295], which included 48 consecutive young cannabis users with ischemic stroke who underwent to rotational angiography and cerebrospinal fluid analysis, a specific pattern of multifocal intracranial stenosis was found in 11 (21%) patients and a focal intracranial stenosis in 10 patients. The main radiological characteristics of their angiopathy was the reversibility of vasoconstriction after cannabis withdrawal. As in previous series, the ischemic lesions were more frequent in vertebrobasilar territory,

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suggesting susceptibility of posterior circulation. Concomitant alcohol consumption or unusually high consumption of cannabis were regarded as possible precipitating factors. As in cocaine and amphetamine abusers these features may be defined as reversible cerebral vasocostrinction syndrome previously named benign angiopathy of the central nervous syndrome. In another study, the cannabis use was the most important and independent risk factor of 31 patients with intracranial ,frequently multifocal, arterial stenosis over 153 patients [296]. The authors underline two point: 1) in young stroke patients intracranial stenosis should be systematically investigated using adequate vascular imaging, even catheter angiography if there are uncertain anomalies or minimal changes on noninvasive imaging; 2) questioning about illicit drug consumption (including cannabis) or vasoactive medication use should be performed. Phenylpropranolamine and Ephedrine Phenylpropranolamine (PPA) and Pseudoephedrine are sympathomimetic amines similar to amphetamines [297] and are contained in many over-the-counter cough and cold preparations. Pseudoephedrine is also a bronchodilator and nasal vasoconstrictor, and it is generally harmless when used in recommended doses. Numerous case reports have described the occurrence of intracranial hemorrhage after the ingestion of PPA or other sympathomimetics drugs including PPA contained in appetite suppressants, and in cough and cold preparations. [298] In their Mexican study, Cantu and coll [299] found that 22 of 2500 consecutive stroke patients had a stroke, mostly hemorrhagic after using an over-the-counter cough and cold sympathomimetic drug. These drugs were implicated in 2.5% of the patients with intracerebral hemorrhage and in 8.1% of the cases with nonaneurysmal SAH. Most of them were related to PPA but stroke can also occur with the use of other sympathomimetics, particularly pseudoephedrine. In the study of Kernan et al. [298] the use of a product containing phenylpropanolamine as an appetite suppressant was associated with an increased risk of hemorrhagic stroke among women between the ages of 18 and 49 years.

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They also found an association in women with any first use of phenylpropanolamine, which involved only cough or cold remedies. Interestingly no significantly increased risk of hemorrhagic stroke was observed among men who used a cough or cold remedy that contained phenylpropanolamine. Men probably require higher doses of PPA to develop adverse cerebrovascular effects. Several mechanisms by which PPA causes cerebrovascular complications have been proposed: the development of hypertensive crisis, as a consequence of a direct vasoconstrictive action of the drugs, or the development of angiitis, which assume the features of the reversible cerebral vasoconstriction syndrome. Phenylephrine is an a1-adrenergic receptor agonist and while its use is established as a nasal decongestant it also results in an increased arterial blood pressure via vaso-constriction and cardiac stimulation and has been linked to hypertensive crisis, stroke and acute coronary syndrome. Finally, some anecdotal case reports on the cerebrovascular complications of chronic nasal sprays have been published, including 2 patients with brain infarction, apparently secondary to chronic use of the nasal decongestants oxymetazoline and fenoxazoline, and another case of retinal artery occlusion associated with excessive use of nasal spray containing oxymetazoline [300].

Fig. (19). Images of a 30 years female with triptans abuse for migraine who suffered of acute “thunderclape” headache and left side hemiplegia. Brain MRI-FLAIR (A) and SW1 images (B) showed a putaminal hematoma. MR angiography (C) revealed stenosis (vasospasm) at the level of the middle cerebral arteries bilaterally (arrows). (Courtesy GP Vaudano, G Bosco Hospital Turin).

Finally also triptans abuse may be a risk factor for the occurrence cerebral

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hemorrhages and reversible cerebral vasoconstriction syndrome (Fig. 19). CONFLICT OF INTEREST The author(s) confirm that this chapter content has no conflict of interest. ACKNOWLEDGEMENTS A. Gai, CA. Artusi, L. Caligiana, F. Dematteis, G. Zelante. REFERENCES [1]

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[255] Schwedt TJ, Demaerschalk BM, Dodick DW. Patent foramen ovale and migraine: a quantitative systematic review. Cephalalgia 2008; 28(5): 531-40. [http://dx.doi.org/10.1111/j.1468-2982.2008.01554.x] [PMID: 18355348] [256] Garg P, Servoss SJ, Wu JC, et al. Lack of association between migraine headache and patent foramen ovale: results of a case-control study. Circulation 2010; 121(12): 1406-12. [http://dx.doi.org/10.1161/CIRCULATIONAHA.109.895110] [PMID: 20231534] [257] Dowson A, Mullen MJ, Peatfield R, et al. Migraine Intervention With STARFlex Technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation 2008; 117(11): 1397-404. [http://dx.doi.org/10.1161/CIRCULATIONAHA.107.727271] [PMID: 18316488] [258] Hall GC, Brown MM, Mo J, MacRae KD. Triptans in migraine: the risks of stroke, cardiovascular disease, and death in practice. Neurology 2004; 62(4): 563-8. [http://dx.doi.org/10.1212/01.WNL.0000110312.36809.7F] [PMID: 14981171] [259] Wammes-van der Heijden EA, Rahimtoola H, Leufkens HG, Tijssen CC, Egberts AC. Risk of ischemic complications related to the intensity of triptan and ergotamine use. Neurology 2006; 67(7): 1128-34. [http://dx.doi.org/10.1212/01.wnl.0000240128.76399.fa] [PMID: 17030745] [260] Scher AI, Gudmundsson LS, Sigurdsson S, et al. Migraine headache in middle age and late-life brain infarcts. JAMA 2009; 301(24): 2563-70. [http://dx.doi.org/10.1001/jama.2009.932] [PMID: 19549973] [261] Kurth T, Mohamed S, Maillard P, et al. Headache, migraine, and structural brain lesions and function: population based Epidemiology of Vascular Ageing-MRI study. BMJ 2011; 342: c7357. [http://dx.doi.org/10.1136/bmj.c7357] [PMID: 21245119] [262] Kurth T, Kase CS, Schürks M, Tzourio C, Buring JE. Migraine and risk of haemorrhagic stroke in women: prospective cohort study. BMJ 2010; 341: c3659. [http://dx.doi.org/10.1136/bmj.c3659] [PMID: 20736268] [263] Rist PM, Buring JE, Kase CS, Schürks M, Kurth T. Migraine and functional outcome from ischemic cerebral events in women. Circulation 2010; 122(24): 2551-7. [http://dx.doi.org/10.1161/CIRCULATIONAHA.110.977306] [PMID: 21126968] [264] Izenberg A, Aviv RI, Demaerschalk BM, et al. Crescendo transient Aura attacks: a transient ischemic attack mimic caused by focal subarachnoid hemorrhage. Stroke 2009; 40(12): 3725-9. [http://dx.doi.org/10.1161/STROKEAHA.109.557009] [PMID: 19893001] [265] Detsky ME, McDonald DR, Baerlocher MO, Tomlinson GA, McCrory DC, Booth CM. Does this patient with headache have a migraine or need neuroimaging? JAMA 2006; 296(10): 1274-83. [http://dx.doi.org/10.1001/jama.296.10.1274] [PMID: 16968852] [266] Zhu YC, Dufouil C, Tzourio C, Chabriat H. Silent brain infarcts: a review of MRI diagnostic criteria. Stroke 2011; 42(4): 1140-5. [http://dx.doi.org/10.1161/STROKEAHA.110.600114] [PMID: 21393597] [267] Neiman J, Haapaniemi HM, Hillbom M. Neurological complications of drug abuse:

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pathophysiological mechanisms. Eur J Neurol 2000; 7(6): 595-606. [http://dx.doi.org/10.1046/j.1468-1331.2000.00045.x] [PMID: 11136345] [268] Kaku DA, Lowenstein DH. Emergence of recreational drug abuse as a major risk factor for stroke in young adults. Ann Intern Med 1990; 113(11): 821-7. [http://dx.doi.org/10.7326/0003-4819-113-11-821] [PMID: 2240897] [269] Sloan MA, Kittner SJ, Feeser BR, et al. Illicit drug-associated ischemic stroke in the BaltimoreWashington Young Stroke Study. Neurology 1998; 50(6): 1688-93. [http://dx.doi.org/10.1212/WNL.50.6.1688] [PMID: 9633712] [270] Levine SR, Washington JM, Jefferson MF, et al. “Crack” cocaine-associated stroke. Neurology 1987; 37(12): 1849-53. [http://dx.doi.org/10.1212/WNL.37.12.1849] [PMID: 3683875] [271] Brust JC, Dickinson PC, Hughes JE, Holtzman RN. The diagnosis and treatment of cerebral mycotic aneurysms. Ann Neurol 1990; 27(3): 238-46. [http://dx.doi.org/10.1002/ana.410270305] [PMID: 2327735] [272] Brust JC. Vasculitis owing to substance abuse. Neurol Clin 1997; 15(4): 945-57. [http://dx.doi.org/10.1016/S0733-8619(05)70357-1] [PMID: 9367974] [273] Caplan LR, Thomas C, Banks G. Central nervous system complications of addiction to “T’s and Blues”. Neurology 1982; 32(6): 623-8. [http://dx.doi.org/10.1212/WNL.32.6.623] [PMID: 7201092] [274] Gossop M, Griffiths P, Strang J. Chasing the dragon: characteristics of heroin chasers. Br J Addict 1988; 83(10): 1159-62. [http://dx.doi.org/10.1111/j.1360-0443.1988.tb03022.x] [PMID: 3191264] [275] Offiah C, Hall E. Heroin-induced leukoencephalopathy: characterization using MRI, diffusionweighted imaging, and MR spectroscopy. Clin Radiol 2008; 63(2): 146-52. [http://dx.doi.org/10.1016/j.crad.2007.07.021] [PMID: 18194689] [276] Sempere AP, Posada I, Ramo C, Cabello A. Spongiform leucoencephalopathy after inhaling heroin. Lancet 1991; 338(8762): 320. [http://dx.doi.org/10.1016/0140-6736(91)90463-Y] [PMID: 1677142] [277] Kriegstein AR, Shungu DC, Millar WS, et al. Leukoencephalopathy and raised brain lactate from heroin vapor inhalation (“chasing the dragon”). Neurology 1999; 53(8): 1765-73. [http://dx.doi.org/10.1212/WNL.53.8.1765] [PMID: 10563626] [278] Benoilid A, Collongues N, de Seze J, Blanc F. Heroin inhalation-induced unilateral complete hippocampal stroke. Neurocase 2013; 19(4): 313-5. [http://dx.doi.org/10.1080/13554794.2012.667125] [PMID: 22624985] [279] Treadwell SD, Robinson TG. Cocaine use and stroke. Postgrad Med J 2007; 83(980): 389-94. [http://dx.doi.org/10.1136/pgmj.2006.055970] [PMID: 17551070] [280] Siniscalchi A, Bonci A, Mercuri NB, et al. Cocaine dependence and stroke: pathogenesis and management. Curr Neurovasc Res 2015; 12(2): 163-72. [http://dx.doi.org/10.2174/1567202612666150305110144] [PMID: 25742568]

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[281] Petitti DB, Sidney S, Quesenberry C, Bernstein A. Stroke and cocaine or amphetamine use. Epidemiology 1998; 9(6): 596-600. [http://dx.doi.org/10.1097/00001648-199811000-00005] [PMID: 9799166] [282] Silver B, Miller D, Jankowski M, et al. Urine toxicology screening in an urban stroke and TIA population. Neurology 2013; 80(18): 1702-9. [http://dx.doi.org/10.1212/WNL.0b013e318293e2fe] [PMID: 23596074] [283] Fehnel CR, Ayres AM, Rost NS. Socioeconomic status does not predict cocaine use among ischemic stroke patients: A nested case-control study. JRSM Cardiovasc Dis 2014; 3. [http://dx.doi.org/10.1177/2048004014539666] [PMID: 25247073] [284] Daras M, Tuchman AJ, Koppel BS, Samkoff LM, Weitzner I, Marc J. Neurovascular complications of cocaine. Acta Neurol Scand 1994; 90(2): 124-9. [http://dx.doi.org/10.1111/j.1600-0404.1994.tb02691.x] [PMID: 7801738] [285] Levine SR, Brust JC, Futrell N, et al. Cerebrovascular complications of the use of the “crack” form of alkaloidal cocaine. N Engl J Med 1990; 323(11): 699-704. [http://dx.doi.org/10.1056/NEJM199009133231102] [PMID: 2388668] [286] Levine SR, Brust JC, Futrell N, et al. A comparative study of the cerebrovascular complications of cocaine: alkaloidal versus hydrochloride--a review. Neurology 1991; 41(8): 1173-7. [review]. [http://dx.doi.org/10.1212/WNL.41.8.1173] [PMID: 1866000] [287] Konzen JP, Levine SR, Garcia JH. Vasospasm and thrombus formation as possible mechanisms of stroke related to alkaloidal cocaine. Stroke 1995; 26(6): 1114-8. [http://dx.doi.org/10.1161/01.STR.26.6.1114] [PMID: 7762031] [288] Sloan MA, Mattioni TA. Concurrent myocardial and cerebral infarctions after intranasal cocaine use. Stroke 1992; 23(3): 427-30. [http://dx.doi.org/10.1161/01.STR.23.3.427] [PMID: 1542908] [289] Kolodgie FD, Virmani R, Cornhill JF, Herderick EE, Smialek J. Increase in atherosclerosis and adventitial mast cells in cocaine abusers: an alternative mechanism of cocaine-associated coronary vasospasm and thrombosis. J Am Coll Cardiol 1991; 17(7): 1553-60. [http://dx.doi.org/10.1016/0735-1097(91)90646-Q] [PMID: 2033185] [290] Ashton CH. Adverse effects of cannabis and cannabinoids. Br J Anaesth 1999; 83(4): 637-49. [http://dx.doi.org/10.1093/bja/83.4.637] [PMID: 10673884] [291] Westover AN, McBride S, Haley RW. Stroke in young adults who abuse amphetamines or cocaine: a population-based study of hospitalized patients. Arch Gen Psychiatry 2007; 64(4): 495-502. [http://dx.doi.org/10.1001/archpsyc.64.4.495] [PMID: 17404126] [292] Barber PA, Pridmore HM, Krishnamurthy V, et al. Cannabis, ischemic stroke, and transient ischemic attack: a case-control study. Stroke 2013; 44(8): 2327-9. [http://dx.doi.org/10.1161/STROKEAHA.113.001562] [PMID: 23696547] [293] Jouanjus E, Lapeyre-Mestre M, Micallef J. Cannabis use: signal of increasing risk of serious cardiovascular disorders. J Am Heart Assoc 2014; 3(2): e000638. [http://dx.doi.org/10.1161/JAHA.113.000638] [PMID: 24760961]

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[294] Hackam DG. Cannabis and stroke: systematic appraisal of case reports. Stroke 2015; 46(3): 852-6. [http://dx.doi.org/10.1161/STROKEAHA.115.008680] [PMID: 25700287] [295] Wolff V, Lauer V, Rouyer O, et al. Cannabis use, ischemic stroke, and multifocal intracranial vasoconstriction: a prospective study in 48 consecutive young patients. Stroke 2011; 42(6): 1778-80. [http://dx.doi.org/10.1161/STROKEAHA.110.610915] [PMID: 21512186] [296] Wolff V, Armspach JP, Beaujeux R, et al. High frequency of intracranial arterial stenosis and cannabis use in ischaemic stroke in the young. Cerebrovasc Dis 2014; 37(6): 438-43. [http://dx.doi.org/10.1159/000363618] [PMID: 25059999] [297] Ephedrine HCl. In: Compendium of Pharmaceuticals and Specialties. 36th ed., Ottawa, Canada: Canadian Pharmacists Association 2001. [298] Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000; 343(25): 1826-32. [http://dx.doi.org/10.1056/NEJM200012213432501] [PMID: 11117973] [299] Cantu C, Arauz A, Murillo-Bonilla LM, López M, Barinagarrementeria F. Stroke associated with sympathomimetics contained in over-the-counter cough and cold drugs. Stroke 2003; 34(7): 1667-72. [http://dx.doi.org/10.1161/01.STR.0000075293.45936.FA] [PMID: 12791938] [300] Montalbán J, Ibañez L, Rodríguez C, Lopez M, Sumalla J, Codina A. Cerebral infarction after excessive use of nasal decongestants. J Neurol Neurosurg Psychiatry 1989; 52(4): 541-3. [http://dx.doi.org/10.1136/jnnp.52.4.541] [PMID: 2738602]

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Endovascular Management of Atherosclerotic and Dissected Carotids Guglielmo Pero* and Themistoklis Papasilekas Department of Neuroradiology, Niguarda Ca’ Granda Hospital, Milan, Italy Abstract: Treatment of lesions of the extracranial internal carotid artery plays an important role in the management of ischemic stroke, particularly in the secondary prevention of further events, but sometimes also in the acute phase. The endovascular management of atherosclerotic stenosis is not just an alternative to endarterectomy but frequently is the treatment of choice. Moreover, treatment of dissections of the carotid arteries, when not exclusively medical, is in almost all cases endovascular. Experience in the neurointerventional field is necessary to correctly deal with both types of lesions of the extracranial internal carotid artery.

Keywords: Carotid stenting, Carotid dissection, Carotid atherosclerosis, Atherosclerotic plaque, Carotid stenosis, Endovascular treatment. INTRODUCTION Atherosclerotic stenosis of the extracranial internal carotid artery (ICA) is a frequent cause of stroke [1, 2]. Discovered usually only after the patient has already suffered an ischaemic event, it is nowadays clear that symptomatic carotid stenosis requires treatment. The first evidence towards this came in 1998 from two large randomized trials, the North American Symptomatic Carotid Endarterectomy Trial (NASCET) [3] and the European Carotid Surgery Trial (ECST) [4]. These studies compared endarterectomy for symptomatic stenosis to conservative management (antiplatelets), both demonstrating the superiority of Address correspondence to Guglielmo Pero: Department of Neuroradiology, Niguarda Ca’ Granda Hospital, Milan, Italy; E-mail: [email protected]. *

Simone Peschillo (Ed.) All rights reserved-© 2016 Bentham Science Publishers

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surgery in preventing new ischaemic events and death. Notably, later trials have also provided evidence in favour of surgically treating severe carotid stenosis even in asymptomatic patients, the benefit though is, in these cases, less pronounced [5, 6]. During the past couple of decades, minimally invasive therapies have been continuously gaining ground in the field of vascular diseases. In this context, carotid stenting was originally introduced as an alternative to endarterectomy for the elderly and high surgical risk patients. Although good results have been reported by several case series published in the literature [7 - 10], it has not been till recently that randomized trials were put into place to address the issue. Notably, most of these trials have failed to demonstrate any significant difference both in efficacy and safety between the two techniques [11, 12]. Studies that showed stenting associated with a higher risk profile have been largely disregarded as their results have been attributed to the limited experience of the centres involved rather than the technique itself [13, 14]. Furthermore, surgical complications such as cranial neuropathies, wound haematoma and infection have been underrated in most published studies and this is something that one should keep in mind when doing any comparisons. Despite considerable debate in the past, current guidelines advocate that best medical treatment should be generally preferred over surgery/stenting in asymptomatic patients (there are selected cases though that non-conservative treatment may still be useful) [15]. The endovascular technique of carotid stenting is, in itself, relatively easy but it requires experience in patient selection, correct choice of devices and, mainly, appropriate management of possible adverse events. The current chapter will focus on endovascular techniques applicable to carotid disease, either atherosclerotic stenosis or dissection. Carotid stenting, although rather straightforward in concept, requires careful choice of devices and appropriate perioperative management. Adverse events, even if rare, can prove devastating for the patient and should be thus readily recognized and treated.

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INDICATIONS OF CAROTID STENTING As previously stated, the NASCET and ECST trials showed, back in 1998, that symptomatic severe carotid stenosis benefits from surgical treatment [3, 4]. Most of the succeeding trials comparing standard endarterectomy to endovascular stenting found the former to be non-significantly better both in terms of safety (periprocedural stroke and death in the 30 days succeeding the treatment) and efficacy (the rate of stroke and death between 31 days and 6 months after the procedure) [11, 12]. However, further analysis revealed that there is still a place for stenting in specific patient sub-groups [11]. An in-depth analysis of all the randomized trials that have compared surgical and endovascular treatment of carotid disease is probably out of context here. Several authors have extensively reviewed the subject [11, 12, 15, 16] and identified critical factors that should be taken into consideration when choosing between surgical or endovascular treatment of carotid stenosis: Patient Related Factors ● ● ●

Age Surgical risk Comorbidities

Anatomy Related Factors ● ● ● ●

Location of the carotid bifurcation Aortic arch conformation Tortuosity of the vessels Stability of the plaque

Contra intuitively, and despite previous beliefs, clinical trials have shown by now that elderly patients do not benefit from stenting [11], probably because of the higher atherosclerotic burden on their vessels and especially in the aortic arch. Navigation through such vessels (like in ultra-octogenarian) increases the risk of embolic complications due to plaque fragmentation. Of note is that in the CREST study, the crossover between endarterectomy and stenting occurred at approximately 70 year [17, 18].

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Contrary to the elderly, patients at a high surgical risk (mainly, myocardial infarction) have been shown to benefit from endovascular treatment [12]. High surgical risk is defined by the presence of at least one of the following criteria: ● ● ● ●

NYHA class III or IV heart failure Chronic obstructive pulmonary disease More than 50% contralateral carotid artery stenosis Prior endarterectomy or stenting of the same ICA

Between comorbidities, prior neck surgery or radiation are considered to be absolute indications for carotid stenting. Surgical dissection is, in such cases, much more difficult and associated with a higher risk of cranial nerve injuries [19 - 21]. Moreover, the wall of an irradiated artery can be weaker and more difficult to manipulate. A relative contraindication for an endarterectomy is also the preexistence of a palsy of the contralateral laryngeal nerve (vocal cord paralysis) because damaging the other one can endanger airway patency [22]. In patients with impaired renal function, endarterectomy should be preferred because of the nephrotoxicity of iodinated contrast agents [21]. The only exception is patients already in need of dialysis, in which case any care to the nephrotoxic action of the iodinated contrast material is pointless [23]. Between the anatomical factors that have to be considered when choosing between available treatment modalities, the location of the carotid bifurcation is the most important one. Too high or too low bifurcations are difficult to be surgically reached and increase the complexity of the endarterectomy [19]. On the counterpart, the location of the carotid bifurcation does not influence the complexity of the endovascular treatment. Unstable plaques have a high risk of distal (intracranial) embolization during stenting procedures, mainly if an angioplasty is to be required [24]. Accurate evaluation of the plaque’s stability is difficult with ultrasonography while plaque MRI, which could help, is rarely used in everyday clinical practice [25, 26]. In our experience, risk factors include large lipidic plaques, recently symptomatic and with low echogenity. Of note is that patients with unstable plaques or rapidly progressing stenosis could benefit from non-conservative treatment even if

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asymptomatic [24 - 26]. The configuration of the aortic arch as well as vessel tortuosity are factors that need to be taken into account; though, with current catheters and guidewires, failures in accessing the common carotid arteries are extremely rare. ENDOVASCULAR TECHNIQUE AND MATERIALS During the past years, a variety of dedicated devices for carotid stenting have become available. Rapid-exchange (monorail) stents and angioplasty balloons have simplified the procedure, avoiding the need for repeated exchange manoeuvres and thus reducing both the length of the procedure as well as the risk of thromboembolism or perforation [27]. All carotid stents now are selfexpandable and pass through 6 or 7 French guiding catheters that only require simple catheterization manoeuvres to be positioned in the common carotid artery (CCA) (no need for complex “telescopic” techniques and long sheaths). A complete angiographic study of the innominate trunk, bilateral CCAs, carotid bifurcations and intracranial (anterior - posterior) circulation is mandatory before starting any stenting procedure. Studying the posterior circulation is also strongly recommended; should the carotid stenosis be haemodynamically significant, a posterior circulation angiogram will reveal collateral circulation in the affected hemisfere. We will first describe the technique and the materials for the stenting of the carotid bifurcation, and then we will move to cases in which stenting of the origin of the CCA or of the cervical/intrapetrous transition of the ICA are required. At the end of the diagnostic angiography, a guiding catheter (generally 6 French) is placed in the CCA below the stenosis. The stenosis is crossed with a 0.014 inches guidewire over which a monorail, self-expandable carotid stent is advanced and placed as to cover completely the plaque. If after releasing the stent there is still residual stenosis, gentle dilatation can be performed with an angioplasty balloon (Fig. 1). In patients with long lasting sub-occlusive stenosis, to avoid the hyper-perfusion syndrome, it is better to do this with a small, not larger than 4mm, angioplasty balloon or to leave the stent as it is (without dilatation),

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knowing that – given time – its radial force will further widen the artery.

Fig. (1). A) A right CCA injection showing a concentric post-surgical stenosis of the carotid bulb. B) The 0.014' guidewire is placed in the ICA crossing the stenosis. C) The Carotid Wallstent® 7 × 40 mm has been deployed with a slight residual stenosis. D) After an angioplasty with a 5 mm balloon. At the end of the procedure the stent and the ICA are well open with no intrastent clots. The intracranial angiogram demonstrated patency of all intracranial arteries (not shown).

Self-expanding carotid stents can be divided into closed and open cell stents, with the two types being differentiated by the number and the arrangement of the bridges connecting their different segments. In the “closed cell” stents every segment is connected to the next by the maximum number of bridges, at the angle of every cell. In the “open cell” design not all possible interconnections between the segments are used. This allows for increased flexibility of the device (i.e. better conformation in tortuous vessels and avoidance of arterial “kinks”) but also reduces the scaffolding of the plaque (Figs. 2 and 3). Note that plaque scaffolding in theory protects from embolization due to dislodgement of debris and thus a reduction of it may be associated with an increased risk for thromboembolic complications. The most widely used “closed cell” stent is the Carotid Wallstent (Boston Scientific®, Natick MA, USA). This is made of a braided wire of cobaltchromium-iron-nickel-molybdenum alloy containing a core of radiopaque tantalum that allows for improved visualization. The braided “closed cell” design

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gives optimal scaffolding of the plaque.

Fig. (2). Above, an “open cells” stent (Zilver®, Cook), note that not all possible interconnections are used between the rings of the stent. Below, a “closed cells” stent (Carotid Wallstent®, Boston Scientific) made with a mesh of metallic wire. Note the difference between the two stents in terms of area of the cells.

Fig. (3). A) CCA angiogram showing an atherosclerotic plaque at the carotid bulb with tortuosity of the ICA. B) After the stent deployment (Carotid Wallstent 7 × 40 mm) and the PTA with a 5 mm balloon, the vessel was straightened and a kink is present at the distal extremity of the stent.

“Open cell” stents are frequently made of nitinol, an alloy of nickel and titanium. Nitinol offers enhanced elasticity as well as “thermic memory” (i.e. the device, once at body temperature, tends to expand to its predefined diameter), characteristics that, in combination, confer high radial force to the stent. This

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reduces the need for balloon dilatation but it can lead sometimes to vagal stimulation as soon as the device is deployed. The latter may last for some days after the procedure and it can even go on to require medical treatment (haemodynamic support). As already mentioned, “open cell” stents are more flexible (Figs. 2 and 4) but do not have the same scaffolding potential as their “closed cell” counterparts (hence the risk of debris emboli). Moreover, the struts of “open cell” stents can damage the surface of the plaque protruding in the concave surface of the curves and further increasing the risk of embolic complications.

Fig. (4). An “open cell” stent (Zilver® 7 × 40 mm) was deployed in this sharply angulated ICA. Note how the stent is perfectly adapted to the curve of the vessel (B). Note also the irregular outward profile of the curve at the level of the plaque, due to the reduced scaffolding of the “open cells” stents. (Courtesy of Dr. Luca Quilici).

Casper (Microvention®, Tustin, CA USA) is a new “closed cell” nitinol carotid stent that has recently become available. Its mesh is much more dense than that of other available carotid stents since it follows a dual layer design with the inner layer having in fact a very high mesh density on its own (cell size area: 0.375/0.600 mm2 vs ~1 mm2 of CarotidWallstent). These characteristics reduce the chance of plaque protruding through the stent struts and giving debris emboli. The Casper stent is also more flexible than other “close cell” stents allowing for a better adaptation to tortuous vessels and therefore reducing the kinking at the

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extremities of the device. Generally, carotid stents have a cylindrical design but tapered devices are also available to accommodate for large gaps between the diameter of the CCA and the ICA. All the carotid stents now available need a 0.014 inches guidewire and almost all of them are rapid-exchange systems.

Fig. (5). A) Severe stenosis at the origin of the left CCA. B and C) The stenosis was crossed with a 0.035’ exchange guidewire and a balloon-expandable stent (Express Vascular® 8 × 17 mm, Boston Scientific) was deployed . (Courtesy of Dr. Edoardo Boccardi).

A much less frequent entity is stenosis at the origin of the CCA. We generally treat this kind of lesions using balloon-expandable stents, pre-charged on the balloon and made for peripheral use. They accept guidewires up to 0.035 inches and are “over the wire” systems requiring for an exchange manoeuvre to be brought into position. Moreover, being balloon expandable stents, they are more prone to dislodgement during the inflation of the balloon, hence great attention has to be put during the inflation to avoid movement of the device before its complete deployment. Similar procedures are used for the stenosis of subclavian arteries and those of the innominate trunk (Fig. 5). Stenosis of the distal cervical ICA is rare and often involves the transition of the vessel into the carotid canal. The proximity to the curve of the intrapetrous canal makes the procedure much more difficult because this curve is within the bone and the distal extremity of the delivery system of most stents cannot pass easily through. In most cases, some pushing against the wall of the artery is needed, this

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adds though to the risk of a dissection (Fig. 6). There are no standard endovascular devices for stenoses in this position. In our practice we use primary stenting with coronary stents (Fig. 7) or intracranial neurovascular selfexpandable stents after balloon angioplasty (Fig. 8). Each of these two approaches has its own pros and cons. Primary stenting with coronary balloon-expandable stents offers a higher chance for complete and stable resolution of the stenosis but at the same time positioning the system and engaging the curve of the carotid canal often proves challenging.

Fig. (6). A) Left ICA angiogram showing a severe stenosis of the distal cervical segment. B) A Precise® (Cordis) stent has been deployed resolving the stenosis but a dissection of the intrapetrous carotid has been caused by the delivery system of the stent. C) and D) A Neuroform® (Cordis) stent has been positioned to resolve the dissection and guarantee the patency of the artery. (Courtesy of Dr. Edoardo Boccardi).

On the other hand, angioplasty balloons and self-expandable stents are generally softer devices passing through small microcatheters but also with a lesser radial force. The risk of dissection is minimal but re-stenosis rates are higher than with coronary stents. Experience with the Casper® stent in such positions is still

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inadequate. Theoretically, it should have a softer than other systems distal end on its delivery system allowing for better trackability within the sharp curve of the carotid canal. A possible drawback is the presence of just flares and not a full dual mesh layer at both the proximal and the distal end of the stent. Keep in mind here that, in upper cervical lesions, it is frequent that only the distal end of the stent reaches to cover the stenosis. Should this be comprised of only the flares of the external Casper layer, its density and radial force may prove inadequate to provide for a good result.

Fig. (7). A) Severe stenosis of the distal cervical segment of a tortuous left ICA with a similar severe stenosis immediately proximal. B) Two coronary balloon-expandable stents were placed to correct both lesions (Liberté® 4 × 20 and 4 × 16 mm, Boston Scientific).

To close our discussion, it should be noted that coronary balloon-expandable stents can also be used in patients with severe calcific stenosis when, despite a predilatation, the delivery system of a self-expandable carotid stent cannot pass through (Fig. 9). This approach allows positioning of a 4 or 4.5 mm stent avoiding the risks due to excessive manoeuvres on the carotid plaque. Coronary balloonexpandable stents can also be used to treat stenosis of the origin of vertebral arteries (Fig. 10).

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Fig. (8). A) Severe stenosis of the distal cervical segment of the left ICA, probably due to a previous dissection. B) Control after the PTA (Gateway® 4 × 20 mm, Boston Scientific). C) Control at the end of the procedure. Placement of a neurovascular stent (Solitaire® 6 × 30 mm, EV3). (Courtesy of Dr. Luca Quilici).

Fig. (9). A) Severe ICA stenosis B) Predilation using a neurovascular PTA balloon (Gateway® 1.5 × 20, Boston Scientific). C) Post-PTA control showing immediate recoiling of the stenosis. D) Final result after the deployment of a coronary balloon expandable stent (Liberté® 4 × 20 mm, Boston Scientific).

Fig. (10). A) and C) Stenosis of both vertebral arteries in a patient who suffered an embolic ischemic event of the posterior circulation. B) and D) Both stenosis were treated with the aid of coronary balloon-expandable stents (Liberté® 3.5 × 12 on the right and 4 × 16 on the left, Boston Scientific).

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COMPLICATIONS The main risks of carotid stenting are thrombo-embolic complications and the hyper-perfusion syndrome. Other possible adverse events are injuries of the vessel wall and hypotension related to vagal baroreceptors stimulation, rarely though do these lead to clinical significant sequelae. The aim of treatment of carotid stenosis is to reduce the incidence of brain ischemia due to thrombo-embolic events. However, the main complications of both endarterectomy and stenting are associated with embolization of plaque debris (periprocedural stroke). Advances in both the techniques and the devices used for stenting as well as optimization of the periprocedural pharmacological therapy (dual antiplatelets) have significantly reduced the incidence of procedure related complications. One of the strategies proposed to reduce the risks of thromboembolic complications is trying to capture the plaque debris. Today, there are several devices out on the market designed to capture plaque debris and keeping them from embolizing intracranially. To achieve this, two different approaches have been used: distal and proximal protection. The majority of distal protection devices are filters mounted on the far end of a 0.014 inch guidewire. Once the guidewire of the protection device is advanced past the stenosis, the filter is opened and held there throughout the procedure to collect any dislodged debris. After stent deployment, a retrieval catheter is advanced over the 0.014’ wire to capture the filter. Finally, the retrieval catheter is withdrawn with the filter locked inside. Proximal protection devices block or reverse the flow in the ICA during the stenting procedure. To do that, the ECA is occluded with a balloon on a 0.014 wire (“balloon wire”) and the CCA is occluded with a 9 French balloon catheter. The guiding catheter needs to be of this size because it is used for both the balloon wire and the stent. To reverse ICA’s flow, the blood is aspirated from the guiding catheter, filtered and reintroduced in the vascular system of the patient by a venous femoral introducer.

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The efficacy of embolic protection devices is not clear. Although there are data showing a significant reduction in embolic complications [28]; randomized trials have failed to show any benefit from their use [12]. Interestingly, the Pittsburgh group published a few years back the results of a single-center randomized trial in which the rate of symptomatic stroke was similar between the two groups but the cerebral protection group had more MR-DWI proved ischemic lesions than the no cerebral protection group [29]. Given all these, and trying to keep the whole procedure as simple as possible, in our department we do not routinely use embolic protection devices for carotid stenting. Chronic reduction of the cerebral blood flow in the context of ICA stenosis induces maximal dilation of cerebral arteries in the hypo-perfused territories. This is often referred to as the “vascular reserve”. Of note is that such arteries seem to have lost their ability to rapidly return to normal caliber should the blood pressure and flow be restored. Spetzler introduced this concept in 1979 (“normal perfusion pressure break-through”) trying to explain the occurrence of haemorrhages in the normal brain surrounding the site of a resected arteriovenous malformation [30]. The capillary bed, without its normal protection system of vasoconstriction, is – according to this theory - prone to rupture leading to cerebral haemorrhages [31] (Fig. 11).

Fig. (11). A) A severe, longstanding stenosis of the right ICA was treated using a Carotid Wallstent® 7 × 50 mm (Boston Scientific) followed by two inflations of the PTA balloon. Immediately after the second inflation of the balloon, the patient became confused and upset. C) The CT scan demonstrated a big intracerebral haemorrhage which proved fatal for the patient (Courtesy of Dr. Edoardo Boccardi).

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The clinical presentation of the hyper-perfusion syndrome includes throbbing headache, focal seizures and intracranial haemorrhage (usually in the basal ganglia and less often in the subarachnoid space). Diagnosis is often delayed [31, 32]. Pre-existing hypertension, a severe degree of stenosis as well as pre-existing symptoms are all factors related to the hyper-perfusion syndrome. Its overall incidence seems to be less than 1% but it rises up to 2.7% when it comes to patients that are under treatment with glycoprotein IIb/IIIa inhibitors [33]. Hyperperfusion signs can develop anywhere from minutes to a week after the procedure and it is not unusual for symptoms to occur even some days before the actual haemorrhage [32, 34] (Fig. 12). Prognosis is poor and the mortality rate has been reported to be higher than 70% [33]. Treatment of hypertension in the days before stenting has shown to be effective in the prevention of hyper-perfusion related haemorrhages. Similarly, a firm postoperative control of the blood pressure is mandatory for at least two weeks after recanalization [35]. In patients with poor collateral circulation, the endovascular procedure should be tailored avoiding balloon dilation or under-sizing of the stent. PHARMACOLOGICAL SUPPORT In the next few paragraphs we will discuss the pharmacological treatment of patients undergoing carotid stenting focusing on the antiplatelet and anticoagulant therapy but leaving the chronic medical treatment of atheromatous patients to be discussed elsewhere. In our clinical practice, and similar to most other centres, dual antiplatelet therapy starting 5 to 7 days before the endovascular treatment is mandatory for all cases of carotid and intracranial stenting. The standard antiplatelet therapy is, in most centres, 100 mg of aspirin and 75 mg of clopidogrel daily, a scheme that generally allows for optimal control of thrombo-embolic complications [36]. However, the high rate of resistance to clopidogrel makes evaluating the individual patient’s response to it necessary. Several methods have been developed to assess the degree of platelet inhibition by

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clopidogrel. VerifyNow is by far the most frequently used one in the neurointerventional practice. Its advantages include that it is fully automated, it uses whole blood, has good reproducibility and can be used at bedside [37, 38].

Fig. (12). A and B) A patient with subclavian steal syndrome and who had the complete occlusion of the left subclavian artery and a severe stenosis of the right vertebral artery underwent in the same session to the recanalization of both the stenosis of the right vertebral artery and the occlusion of the left subclavian artery. The patient was discharged two days later asymptomatic and with good control of the blood pressure. C) He came back in hospital during the 4th post-treatment day because of headache and high blood pressure; the CT scan shown a small temporal haemorrhage and cerebellar hypodensity (not shown). A severe control of the blood pressure was established. D) and E) Three days later, in hospital, he had an hypertensive crisis and became comatose. The CT scan shown haematomas of left cerebellar hemisphere and of the left basal ganglia with intraventricular haemorrhage. The patient died during the day after. (Courtesy of Dr. Luca Valvassori).

Platelet inhibition by clopidogrel is usually assessed on the day of the procedure or, alternatively, the day before. Should an inadequate response be recorded, there are several issues, both medical and organisational, that will need to be addressed (dose adjustement or change of medication, rescheduling of the procedure etc). Ticlopidine was the first thienopyridine to be developed but its use has been limited because of uncommon but potentially serious gastrointestinal and

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haematologic side effects upon chronic use. The frequency of resistance to ticlopidine is negligible. In our center, for patients undergoing placement of an intravascular device (stent, flow diverter or other), we prefer the combination of aspirin and 250 mg of ticlopidine twice a day rather than aspirin and clopidogrel. The use of ticlopidine essentially eliminates the need for an assay to evaluate platelet inhibition while gastrointestinal and haematological side effects are negligible considering that we only prescribe it for one month after treatment [36]. During carotid stenting procedures, heparin is often administered as a precaution to reduce the risk of clot formation. The latter is associated with the intravascular presence of catheters and wires but even more so with the slowing of blood flow induced by embolic protection devices. Heparin is administered directly intravenously as well as through the flush of the guiding catheter. The intravenous dose is 70 I.U./kg while that within the flushes largely depends on each centre’s practice but generally is approximately 5,000 Units/litre of saline solution. Aim for an APTT of 250-300 sec. When embolic protection systems are not to be used, the need for systemic anticoagulation ceases and heparin in the flush bags is enough.

Fig. (13). A) and B) Left CCA angiogram in the acute phase showing an ICA dissection with slowing of the flow. C) and D) Three months follow-up angiography demonstrated a small pseudoaneurysm resulting from the previous dissection (contrast stagnation).

CAROTID DISSECTIONS Leaving the subject of atherosclerotic stenosis, we will now turn our attention to a somewhat different entity: carotid dissections. Carotid dissections represent a

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spontaneous or secondary injury of the vessel wall. They can appear as severe stenosis involving a long segment of the artery and causing haemodynamic impairment (either with or without embolic occlusion of intracranial vessels) or as pseudoaneurysmatic dilations. The cause of the stenosis is the presence of an intramural haematoma between the layers of the carotid wall that reduces the caliber of the lumen of the artery. Pseudoaneurysmatic dilations are generally the long term chronic result of dissections (Fig. 13). The site where a dissection usually starts is where the artery enters the carotid canal becoming essentially fixed in a narrow intraosseous cavity. Post-traumatic dissections due to severe direct trauma can occur at any level.

Fig. (14). A) Ischemic stroke in the acute phase; the right ICA is occluded by a dissection. B) The carotid siphon has been catheterized with a distal access catheter and the angiography shows occlusion of the carotid bifurcation and of the middle cerebral artery. C) Several thrombectomies have been performed with different stentrievers, achieving a good recanalization result (D and E). F) At the end of the procedure the dissected ICA was patent and did not require any further treatment.

In the acute phase, a dissection can be symptomatic due to haemodynamic impairment, distal spreading of emboli or a combination of both. The endovascular treatment has to be tailored according to the underlying ischemic

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mechanism. In the case of symptoms exclusively due to distal emboli, a dissected carotid, even though stenotic, seems to be haemodynamically supplemented through adequate intracranial collaterals. The goal of endovascular treatment is re-opening of the occluded intracranial vessels. Usually, access is through the dissected ICA, its patency being a secondary issue. In such situations, placing a distal access catheter beyond the dissected segment is often the safest approach since it allows for a single passage through the dissection avoiding further injuries during subsequent manoeuvres (Fig. 14). In cases that the dissection causes symptoms due to haemodynamic impairment, stenting of the dissected segment restores patency of the artery. Of outmost importance is to cover the entire dissected segment and in particular the point where the dissection originated from (Fig. 15).

Fig. (15). A) and B) A young patient suffering from recent onset (12 hours) of right hemiparesis and aphasia; she had a dissection of the left ICA with severe stenosis and poor intracranial compensation. C) and D) A long carotid stent was deployed covering all the ICA and the left hemispheric flow was immediately restored. The next day the patient was asymptomatic.

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Regarding the pseudoaneurysmatic dilatations, only a minority will require treatment. Indications include symptomatic dilatations (embolization from the sac or mass effect) as well as very large lesions (contrast stagnation inside the sac during angiography). The exact treatment modality is controversial. Good results can be achieved by placing a “close cell” stent covering the neck of the lesion. Usually, a carotid stent (e.g. Carotid Wallstent) is to be used. Remember that these are not flow related lesions and are easier to treat just by restoring a laminar flow in the parent vessel (Fig. 16).

Fig. (16). Same patient as of fig. 13. A) After 6 months of followup the pseudoaneurysm with contrast stagnation is still patent. B) A neurovascular stent (Lvis®, Microvention) was placed covering the neck of the pseudoaneurysm. C) A 6 months CTA followup show complete occlusion of the lesion.

CONCLUSION Carotid stenting is an effective alternative to endarterectomy in the management of carotid atherosclerotic stenosis; despite it is a relatively easy and rapid procedure, not all patients benefit from this kind of treatment. Patient selection is crucial to avoid complications that could prove fatal. Of outmost importance is trying to keep this procedure as easy and quick as possible. Carotid dissection is a rare entity that deserves careful consideration. Its treatment requires an experienced and well-trained endovascular team.

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CONFLICT OF INTEREST The authors confirm no conflict of interest. ACKNOWLEDGEMENTS This chapter is the result of the daily efforts of all our staff at the Neuroradiology Department of the Niguarda Ca’ Granda Hospital in Milan. My special thanks go to my wife Paola for her love and support throughout my career. REFERENCES [1]

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CHAPTER 13

Intensive Care Management Federico Bilotta*, Martina Novelli, Filippo Pecorari and Giovanni Rosa Department of Anesthesiology, Critical Care and Pain Medicine, “Sapienza” University of Rome, Rome, Italy Abstract: Acute ischemic stroke represents a leading cause of mortality and morbidity worldwide. An increasing number of patients with massive stroke require admission to ICU for neurological monitoring and management of acute complications. Medical treatment in ICU consists of sedation, analgesia, ventilator support, hemodynamic monitoring, neuromonitoring, fluid management, thromboprophylaxis and treatment of complications. Principal complications are: cerebral edema, hemorrhage, seizures, myocardial complications, hyperglycemia and fever. Severe cerebral edema after stroke represents an important complication. In this case, decompressive craniectomy successfully decreases mortality and morbidity in patients with severe cerebral edema. Therapy with mannitol is the standard treatment for intracranial hypertension. Therapeutic hypothermia may also be considered for its neuroprotective effect but its role is not demonstrated in stroke. These aspects of critical care are considered in this chapter.

Keywords: Acute ischemic stroke, Cerebral edema, Intensive care management, Intracranial hypertension, Neurocritical care, Neuromonitoring, Reperfusion therapy, Stroke units. INTRODUCTION Acute ischemic stroke (AIS) is an important cause of morbidity and mortality in the world. Despite around 15-20 % of stroke patient being admitted to the intensive care units (ICU), the evidence base guiding the intensivist managing Address correspondence to Federico Bilotta: Department of Anesthesiology, Critical Care and Pain Medicine, “Sapienza” University of Rome, Rome, Italy; E-mail: [email protected] *

Simone Peschillo (Ed.) All rights reserved-© 2016 Bentham Science Publishers

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stroke is relatively poor [1]. The purpose of this chapter is to provide our recommendations about ICU management of AIS. GENERAL SUPPORTIVE CARE AND TREATMENT OF ACUTE COMPLICATIONS Currently 4 interventions in AIS supported by class I evidence: reperfusion therapy with the use of intravenous rt-PA within 4-5 h of symptom onset, the use of aspirin within 48 h of stroke onset, decompressive craniotomy for sopratentorial hemispheric cerebral infarction and admission to a stroke unit [2]. Around 15-20% of patients require admission to an ICU to allow cares and interventions that cannot be provide on a stroke unit. There are not specific guidelines for ICU admission, but certainly the decreased conscious level , the need for mechanical ventilation and the intensive hemodynamic management, represents universal indications for admission to intensive care [3]. In the end, patients with massive stroke are admitted to ICU to facilitate organ donation in those who have expressed a wish to donate (Table 1). Table 1. Criteria for ICU admission: our recommendations. Need for intubation and/or mechanical ventilation Severe Stroke (National Institutes of Health Stroke Score > 17) Management complications of reperfusion therapy Persistent elevated blood pressure [systolic > 220 mmHg (not undergoing thrombolysis) or > 185 mmHg (undergoing thrombolysis)] or low blood pressure < 90 mmHg Management of organ support Postoperatively following decompressive craniectomy To facilitate organ donation in patients who have expressed a wish to donate

Ventilation and Supplement Oxygen Hypoxia is common after stroke. Hypoxia is determined by partial airway obstruction, aspiration, low ventilation, atelectasis and pneumonia. For these reasons, it is recommended continuous monitoring of oxygenation with pulse oximetry (SpO2) for all patients in the ICU. Although routine oxygen supplementation may seem intuitive, in literature is little know and more research is needed. In hypoxemic patients with AIS, recent AHA guidelines recommend

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O2 supplementation to rice SpO2 > 94% [4]. The choice to keep normoxia include nasal cannula, Venturi mask, non-rebreathe mask, BIPAP, CPAP and, only as last choiche, orotracheal intubation. The orotracheal intubation is indicated in patients with altered consciousness or with severe bulbar damage that causes airway compromise and the loss of protective reflexes. Others criteria are reported in the Table 2. Tracheostomy should be accomplished after 1 week of mechanical ventilation [5]. The mortality rate of intubated AIS patients was found to be between 40 and 80% and only a small percentage of patients improves after intubation [6] At last, the use of hyperventilation to decrease PaCO2 is a rapid way to reduce intracranial pressure (ICP) and may be tolerated for days in patients with severe brain edema. Indeed, hyperventilation (PaCO2 to 30-35 mmHg) cause vasoconstriction and reduce cerebral blood volume and, thus, ICP. However, in patients with brain injury, prolonged hyperventilation could cause cerebral ischemia. In conclusion, the use of extreme hyperventilation is reserved for a short time to reduce ICP and the its routine application is generally considered detrimental. In effect, hypocapnia is associated with poor prognosis. There are not evidence about use of hypercapnia to increase cerebral perfusion and to improve AIS outcomes [7]. Table 2. Criteria for mechanical ventilation: our recommendations Glasgow Coma Score ≤ 8 Critical airway compromise To prevent aspiration pneumonia Therapy for intracranial hypertension Acute respiratory failure Generalized tonic-clonic seizures or status epilepticus Apneic episodes

Sedation and Analgesia Sedation and analgesia are often necessary in patients with brain edema after stroke to manage ICP, to improve endotracheal tube tolerance and patientventilator synchrony, to reduce cerebral metabolic rate of oxygen (CMRO2), to prevent delirium [8]. In the neurological ICU, sedation and analgesia are maintained by infusion of ipnotic agents, suchs as propofol, midazolam or

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dexmedetomidine, or infusions of opioids, such as fentanyl or remifentanil. Fentanyl is very used in the ICU for its valid analgesic effect, shortage of neurotoxicity, rapid onset, and short elimination half-life. Remifentanil, an opioid chemically correlated to fentanyl, has shorter half-life than fentanyl and, thus, a lower risk of accumulation in patients with hepatic or renal failure. Furthermore, short half-time of remifentanil allows frequent wake-up tests for neurological evaluation. Propofol has hypnotic, sedative, anxiolytic, amnestic, antiemetic, and anticonvulsant properties, but not analgesic effects [9]. Important pharmacokinetic characteristics of propofol are the rapid onset and its short duration that allow frequent wake-up tests. In addition, propofol has suppressive effect on cerebral metabolism. However, propofol can cause dose-dependent respiratory depression and hypotension and, when administered at a high dose for a prolonged period ( > 4 mg/kg/h for > 48 h), may cause propofol infusion syndrome, especially in patients with acute neurological illnesses or sepsis, and receiving catecholamines and/or steroids in addition to propofol. This syndrome is characterized by various early signs including cardiac failure, rhabdomyolysis, severe metabolic acidosis, hyperkaliemia, triglyceridemia, renal failure and fatty liver degeneration [10]. Midazolam is another hypnotic agent often used for continuous infusion in the ICU for its fast onset, rapid metabolism, and short duration of action. In spite of other hypnotic agents, continuous infusion of midazolam may lead to a slow awakening. Thus, in the ICU, midazolam not allow frequent wake-up tests. Dexmedetomidine acts selectively on alpha 2-receptor. This drug has sedative, analgesic, sympatholytic and anxiolytic properties, without relevant respiratory depression. Dexmedetomidine has no anticonvulsive properties unlike propofol [11]. Dexmedetomidine is helpful in the ICU because patients are more easily stimulated and interactive than patients sedated with other agents. Bradycardia and hypotension are the most common side-effects during infusion of dexmedetomidine, especially after the loading dose. Blood Pressure Around 80% of patients are hypertensive (systolic blood pressure > 140 mmHg) during acute ischemic stroke and this may be correlated to chronic hypertension, stress, high intracranial pressure or a neuroendocrine response [12]. Theoretically, moderate hypertension might be useful to improve cerebral perfusion during AIS,

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or it could contribute to worsen cerebral edema and to convert the ischemic tissue in hemorrhagic [13]. Several hypertension contributes to encephalopathy, cardiac complications, and renal insufficiency. For this aim, regular BP monitoring should be started after AIS. It is recommended continuous BP monitoring via an arterial line in patients with unstable BP and who require mechanical ventilation. There are no data to suggest significant risks with the use of arterial lines in patients undergoing fibrinolysis [14]. Unfortunately, there are no data to guide a specific BP target during the ICU management of AIS. However, it is recommended not to lower the blood pressure unless >220/120 mmHg during the initial 24 hours of AIS. Specific blood pressure management recommendation is indicated for patients considered for fibrinolytic therapy with intravenous rt-PA. In this case, blood pressure should be lowered < 185/110 mmHg before and for at least 24 hours after fibrinolysis. First-line agents to lower BP are Labetalol ( 10-20 mg IV over 1-2 minutes, may repeat 1 time ) or Nicarpidine (5mg/h IV). Conversely, hypotension (systolic BP < 90 mmHg) should compromise cerebral perfusion and increase ischemic tissue. Hypotension should be treated with intravascular volume expansion in the first instance and with vasoactive agents such norepinephrine if unresponsive [3, 15]. Fluid Management Patients with AIS are predominantly normo volemic or hypovolemic. Hypovolemia may predispose to reduce cardiac output and hypoperfusion with concomitant increase in ischemic brain injury. Conversely, hypervolemia could worsen cerebral edema and increase stress on myocardium. Thus, maintenance of normo volemia is advised [3]. Daily fluid maintenance should be individualized based on the patient’s body weight ( 30 ml per kilogram) and fluid balance. Specific conditions, such as syndrome of inappropriate antidiuretic hormone secretion (SIADH) or fever, requires accurated monitoring of fluid management. Isotonic saline solution (NaCl 0,9%) are distributed into extracellular spaces (interstitial and intravascular) and may be useful to maintain normo volemia in patients with AIS. Hypotonic saline solutions, such as 5% dextrose or 0,45% saline, are distributed into the intracellular spaces and may increase cerebral edema, therefore should be avoided [3].

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Myocardial Complications Cardiac complications may be a trigger for the AIS (e.g. cardioembolic stroke) or a results of the stroke itself [16]. All stroke patients on ICU should receive continuous electrocardiography and repeated echocardiograms during the course of their admission. Also, cardiac troponin should be measured in patients with ECG modifications and an abnormal ventricular function on echocardiography. Hemodynamic monitoring, such as PiCCO, can be considered in patients with cardiovascular abnormalities [3]. Glycemic Control Glycemia is elevated in > 40% of patients with AIS [17]. Blood glucose elevations is associated with worse clinical outcomes, increased mortality and morbidity at 90 days, and may also attenuate the benefits of intrarterial thrombolysis [18]. Regular blood glucose monitoring is important in all AIS patients and should be accomplished on whole blood (avoid pin prick capillary measures) [19]. There is no clinical evidence about the clinical efficacy of intensive insuline therapy (ITT). Despite that, it is preferred to maintain the blood glucose between 140-180 mg/dl with continuous insulin infusion in stroke patients, monitoring routinely glucose levels [3, 20]. Temperature Approximately 50 % of patient with stroke is hyperthermic (T > 37.5 °C) [21]. Elevated temperature is associated with poor prognosis, probably due to increased of the metabolims, enhanced release of neurotransmitters and radical production [22]. The treatment is symptomatic, but it is important to exclude infective cause such as pneumonia, urinary tract infection or sepsis. Paracetamol is a first-line drug in patients with temperatures > 37.5 [23, 24]. Many studies indicate the neuroprotective role of hypothermia in the presence of global hypoxia or ischemia. Hypothermia can be obtained with rapid infusion of cold saline (4 C). The main adverse effects of hypothermia are shivering, pulmonary edema, cardiac depression, cardiac arrhythmias, hepatic dysfunction, pancreatitis, hyperglycemia, cooling diuresis, hypokalemia, hypomagnesemia, hypophosphatemia, hypocalcemia, alkalosis, hypocapnia, immunosuppression, infections, bleeding,

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and alterations in pharmacokinetics and pharmacodynamics. For these risks, hypothermia may be an indication for ICU admission and should be used by experts to prevent and manage complications [25]. Thromboprophylaxis Patients with severe stroke and elderly immobilization are at elevated risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) [3]. Prevention of thromboembolism consist of hydratation, early mobilization, the use of antithrombotics and external calf compression devices. Use of subcutaneous low molecular weight heparin (LMWH) to prevent DVT is supported by class I evidence in immobilized patients on ICU [26]. Treatment with LMWH should not be started until 24 h following fibrinolysis to reduce risk of intracranial bleeding [3]. Anemia About 97.2 % of AIS patients on the ICU presented anemia (HB < 12 g/dl in women and < 13 g/dl in men) [27]. Despite hemoglobin correction might improve oxygenation in the penumbral region of ischemic tissue and prevent tissue loss, there is currently no class I evidence supporting specific hemoglobin targets to require transfusion. Actually, aggressive transfusion approaches are not recommended and the blood transfusion is recommended for hemoglobin concentration < 7 g/dl [3]. Hemorrhagic Transformation Patients undergoing intravenous rt-Pa, intrarterial recanalization strategies and anticoagulant use presented elevated risk to occur hemorrhagic transformation [3]. There are not robust evidence about the treatment. In first instance, it is recommend to stop the rt-PA infusion, to repeat cranial imaging, and to monitor coagulation status. The routine use of cryoprecipitate, fresh frozen plasma and recombinant factor VII is not supported by robust evidence. Cerebral Edema Another important complication following AIS is the development of cerebral

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edema. Intracranial hemorrhage and cerebral edema may increase ICP. Frequent monitoring of clinical status is important in these patients because an early decompressive craniotomy might alleviate intracranial hypertension associated with cerebral edema [28]. Suspect the need for urgent surgical intervention in these patients are the developing pupillary abnormalities, a drop in the Glasgow Coma score by more than 1 point and/or a progression of edema on cranial imaging. Medical treatment interventions, such as the administration of mannitol and hypertonic saline [29], should be used as a temporizing measure prior to decompressive craniotomy and not as prophylactic use before the surgery. In literature is the use of mannitol for stroke patients is little know. Usually, this drug is administered e.v. at a dose of 0.25-2.0 g/kg every 6 hours. During therapy with mannitol, it is crucial to keep an adequate fluid balance to avoid adverse effects like dehydration, hypovolemia, hypotension, increased ICP, decreased CPP, acute kidney injury and electrolyte imbalance. Hypertonic saline is a good alternative to mannitol for osmotherapy in patiens with intracranial hypertension and, also, it may have a stronger osmotic effect of mannitol because is less able to cross the blood-brain barrier. Possible side effects of hypertonic saline are rebound cerebral edema, hyperchloremic metabolic acidosis, phlebitis, congestive heart failure, transient hypotension, hemolysis, hypokalemia, renal failure, osmotic demyelination, subdural hemorrhage, seizures, and muscle twitching. Thiopental might significantly reduce ICP in acute, but this treatment requires ICP monitoring, electroencephalography and invasive hemodynamic monitoring. Adverse effects of thiopental include hypotension, myocardial suppression, respiratory depression, infections, hepatic and renal dysfunction, thrombocytopenia, metabolic acidosis and gastric stasis. For these reasons, thiopental has used in AIS patients with cerebral edema unresponsive to others medical therapies [30]. There is not conclusive evidence that support the use of steroids in the management of cerebral edema after stroke [31]. Seizures Convulsive and nonconvulsive seizures are the result of diffuse cortical infarction [32]. Seizures are uncommon after AIS, and there are no data about prophylactic anticonvulsants. Seizures recurrence, after a first episode, should be aggressively prevented using long-acting anticonvulsant. First-line agent is phenytoin [33].

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Neuromonitoring There are not many data to support a role for neuromonitoring in AIS. ICP monitoring is not recommended but it is often used in patients with large spaceoccupying infarcts and edema. However, ICP values are often normal (< 20 mmHg) even in the presence of large infarcts volumes. ESO guidelines recommend a cerebral perfusion pressure (CPP) >70 mmHg after traumatic brain injury, but there is no evidence to support an “optimal” CPP in AIS patients on the ICU. Brain tissue oxygen tension (PtiO2) monitoring is the gold standard to evaluate cerebral oxygenation, but the evidence for its utility on the ICU is limited [34]. Near-infrared spectroscopy (NIRS) is a noninvasive monitor of cerebral oxygenation and it may have a role as a novel biomarker of cerebral autoregulation [35]. Further research is required to recommend its application in AIS patients on the ICU. Transcranial Doppler ultrasonography (TCD) is the most promising neuromonitor after AIS and it has good evidence of utility for establishing diagnosis and assessment of severity of AIS. It is able to detect acute MCA occlusion with high sensitivity and specificity, the response of arterial occlusion to thrombolysis and to assess cerebral blood flow and vasoreactivity [36]. Actually there is limited evidence to recommend multimodality monitoring in AIS. Clinical and radiological monitoring still represented the gold standard to identify deterioration after AIS. CONCLUSION Patients with AIS might be unstable –with comatose state of hemodynamic instability- and in this case might benefit of ICU care. In this subset of patients aggressive management of ventilation, cardiac function, fluid therapy and brain complications should be aggressively accomplished. Treatment of patients with AIS that need ICU by a team a neurointensivists care unit where specific treatment protocols are implemented, as compared with general ICU, is associated with reduced hospital mortality and length of stay [37]. ACKNOWLEDGEMENTS Declared none.

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CHAPTER 14

The Trials and Tribulations of Ischemic Stroke Therapy Arani Bose*, Sophia S. Kuo, Jennifer Wong, John Lockhart and Siu Po Sit Penumbra Inc, One Penumbra Place, 1351 Harbor Bay Parkway, Alameda, California, USA Abstract: In this chapter, we focus on the recently published randomized controlled trials examining combined endovascular therapy with IV tPA versus IV tPA alone. In October 2014, the first evidence was presented from a randomized clinical trial conducted in the Netherlands showing the benefit of endovascular therapy in acute ischemic stroke secondary to emergent large vessel occlusion in the anterior circulation. Four randomized controlled trials later confirmed these results. The advances in techniques and devices which enabled these positive findings for intraarterial therapy, including aspiration thrombectomy, stent retrievers, and combination strategies will be discussed herein. We will also consider where opportunities remain to maximize favorable outcomes while minimizing costs as these recent trial results are translated into clinical practice.

Keywords: Acute ischemic stroke, Endovascular therapy, Intra-arterial therapy, Mechanical thrombectomy, Randomized clinical trial, Reperfusion catheter, Stent retriever. OVERVIEW Excellent reviews of historical acute ischemic stroke trials have been published, for example see Nogueira et al. [1], which also cover the introduction of intravenous fibrinolytic agents and intra-arterial therapy. In early 2014, a review article accurately described the evolution of intra-arterial approaches and tools for acute stroke therapy [2]. Thus, we will dwell in this chapter upon the more recent Address correspondence to Arani Bose: Penumbra Inc, One Penumbra Place, 1351 Harbor Bay Parkway, Alameda, California, USA; E-mail: [email protected] *

Simone Peschillo (Ed.) All rights reserved-© 2016 Bentham Science Publishers

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studies, in particular those randomized clinical trials (RCT) comparing combined intra-arterial therapy (IAT) with IV tPA to standard medical management alone [3 - 9]. Endovascular approaches to stroke treatment have been available as a promising option for patients ineligible or refractory to IV thrombolytic therapy since 2004. Finally in late 2014, a watershed event in the acute ischemic stroke field was achieved when a large randomized controlled trial definitively demonstrated the benefit of IAT in acute stroke patients with evidence of proximal artery occlusion in the anterior cerebral circulation [3]. These findings were subsequently confirmed by four published randomized controlled trials, which were halted early due to lack of equipoise [4 - 7]. Two additional positive RCTs have been presented publicly as of this writing [8, 9]. DEVICES AND CLINICAL TRIALS IN ACUTE ISCHEMIC STROKE The Beginning of Mechanical Thrombectomy Acute stroke thrombectomy is ushering in the future of neurointervention. Around 87% of stroke is ischemic due to in-situ thrombosis, extracranial embolus, or other origins. Only 3-5% of stroke is a result of hemorrhage in the subarachnoid space due to aneurysm rupture. Although current neurointerventional treatment of stroke is restricted to large clot burdens, located within the proximal vessels of the Circle of Willis, and treated within eight hours of symptom onset, this subgroup still represents at least a ten-fold larger group than the whole of the treated aneurysm population. Ischemic stroke thrombectomy remains by far the largest opportunity for expansion in neuroendovascular research and development, as well as for positive impact on patients’ survival and quality of life. Mechanical thrombectomy of occlusions causing an acute ischemic event has been an accepted procedure since catheters were first placed in the neurovasculature. Catheter-based suction thrombectomy was first described by Gerhard Schroth as early as the late 1980’s. Direct aspiration would remain central to neurointerventional thrombectomy from that time forward. By 2004, the first FDA-approved product specifically intended for thrombectomy in acute stroke patients was launched, called the Merci Retriever (Concentric Medical/Stryker Neurovascular). The first generation ‘X’ devices resembled a

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wire with the shape of a corkscrew, which was placed inside the clot in an effort to engage it and retrieve out of the body. A balloon-tipped guide catheter would be delivered in the proximal internal carotid and inflated prior to fully withdrawing the Merci under “flow arrest” conditions. Aspiration was then applied on the balloon guide to capture residual emboli and thrombus not collected by the Merci. Later generations, including the “L” and “K-mini” devices, modified the configuration of the grabber wire, some adding suture strands to assist in retaining the thrombus. The Merci device was only moderately successful in the clinic because of challenges in realizing consistent success. Complete or mostly complete intracranial vessel reperfusion (TICI 2A-3 or TIMI 2/3) was achieved only 48% of the time in a major study [10]. Aspiration Thrombectomy Comes of Age Four years later, in December 2007, the Penumbra System (Penumbra, Inc.) gained approval in the United States for use in revascularization of acute stroke patients. The Penumbra System used aspiration as its primary method of action. A flexible, large bore microcatheter was deployed to the site of occlusion and aspiration applied directly on the lesion itself. However, the early Penumbra System catheters, the largest of which was 0.041 in internal diameter, were not quite wide enough to avoid becoming obstructed by the thrombus and so another component, a Separator, was introduced to clear the catheter lumen and to continually break up the thrombus ingested under aspiration. Without a Separator, the early microcatheters could clog, at times necessitating removal and re-access, prolonging procedural times. Thus by using a Separator, direct aspiration and clot capture were combined to facilitate continuous thrombectomy. The Penumbra System increased the rate of successful reperfusion to 82% in the Pivotal trial for FDA approval [11], and improving further to 87% in the real-world POST study [12]. A stent-like three-dimensional (3D) binary nitinol device known as the Separator 3D was launched in Europe in January 2012 as an additional component of this system. The Separator 3D was designed to engage a thrombus in a third radial dimension, as the open body of the 3D is compressed and then retrieved into a Reperfusion Catheter positioned at the proximal margin of the primary occlusion [13, 14].

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Further advancements in the Penumbra System line consisted of the Reperfusion Catheter 054, a larger width version of the 041, including a mid-shaft taper that enlarged to 0.064 inches proximally, further boosting aspiration efficiency over the distal tip [15]. Next came an enhancement in the entire family of Penumbra System catheters called MAX. This technology consisted of more pliable polymers, greater nitinol reinforcement, and a larger number of stiffness transitions to enable smoother navigation to the occlusion site [16]. The Advent of Stent Retrievers In March and August of 2012, two Stent Retrievers were introduced in the US including the Solitaire FR (Covidien/Medtronic) and the Trevo (Concentric Medical/Stryker Neurovascular). Stent Retrievers built upon the mode of action of the MERCI Retriever but are hypothesized to immediately restore blood flow as the non-implantable stent is deployed within the thrombus, and the circumferential wall pushes the clot aside. The mesh of the device then insinuates itself within the thrombus over the next several minutes and subsequent retraction retrieves the clot into a proximal balloon guide under flow arrest. These devices performed significantly better in RCTs than their predecessor, the MERCI Retriever, successfully removing thrombus 68.5% of the time for Solitaire [17] and 86% of the time for Trevo [18]. NASA was a post-marketing retrospective multicenter registry examining the real-world clinical outcome and reperfusion using the Solitaire [19]. In NASA, the 90-day mRS 0-2 rate was 42% compared to 37% in SWIFT and 40% in TREVO 2, the pre-market Pivotal trials for the Solitaire and Trevo, respectively. Combination Techniques Evolve The use of a proximal balloon-tipped guide to recover the stent retrievers under flow arrest has disadvantages, however, including risks of damage to the carotid artery (dissection or perforation) and vasospasm. Also, the balloon inflation lumen restricts the internal diameter for stent and clot recapture. Therefore, by late 2012, use of the stent-retriever-local-aspiration, (SRLA) or “Solumbra” technique (a combination of “Solitaire” and “Penumbra”) without flow arrest, grew. The combination of stent and aspiration thrombectomy represented the next major

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development in therapeutic options [20, 21]. As the model of a distal retriever placed in the clot combined with proximal balloon guide aspiration experienced a renaissance with the introduction of stent retrievers, a novel concept was put forth by Turk and colleagues called ADAPT: A Direct Aspiration first Pass Technique [22, 23]. ADAPT is a straightforward approach to treating large vessel occlusion in the brain whereby a large bore aspiration catheter, usually the 5MAX (Penumbra, Inc.) is advanced to the occlusion site and the clot is suctioned without any adjunctive device, such as a Separator. The thrombus is usually ingested deep within the catheter en bloc, retaining the clot’s integrity and allowing complete clearance without distal emboli by fully suctioning the clot from the body. Or, the thrombus may be secured at the distal tip of the catheter and withdrawn under continuous aspiration. If pure aspiration fails as a first pass, access is maintained with the ADAPT technique and other modalities may be attempted next, including stent retrievers deployed through the same large bore aspiration catheter, in a “Solumbra”-type maneuver. The investigators described 97% successful reperfusion to TICI 2B/3 [24] and an unprecedented 65% rate of complete revascularization (TICI 3). This pursuit of the ideal revascularization, TICI 3, became the new benchmark. The clinical outcomes reported previously, and used historically in the field to represent “successful” revascularization, included TICI 2A or TIMI 2. This meant that one half of the middle cerebral artery (MCA) territory could remain occluded and still be tallied as “successful.” This measure may have been considered helpful in the comparison of clinical trials, but the patient would not have found the outcome to be satisfactory. The novel ADAPT innovation has potential advantages of simplicity and lower cost [25, 21]. Tools and techniques were now available which allowed quick, straightforward, and complete clot removal to become commonplace. Within a few months of publication on the ADAPT technique, another significant advance was introduced, the ACE catheter (Penumbra, Inc.). Now with a 0.060 inch distal internal diameter, and building on the polymer and reinforcement technology innovations of the MAX line, the ACE catheter could easily access the MCA territory over a microcatheter, and had the aspiration capacity to often fully ingest and remove a thrombus from the body without further manipulation or

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retraction of the catheter. This means that a large lumen catheter is still available at the site of occlusion to deliver any back-up or adjunctive devices if they were to be required after use of ACE alone. As reported at the ABC-WIN meeting in Val d’Isere, France in 2014, ACE achieved TICI 2B/3 (not including TICI 2A) in 96% of cases, while complete reperfusion, TICI 3, remained very high at 66% [26 28]. The Early Inconclusive Mechanical Thrombectomy Trials Three large RCTs published simultaneously in 2013, IMS III, SYNTHESIS Expansion, and MR RESCUE were the first to compare endovascular therapy (EVT) with IV tPA to IV tPA alone and reported similar findings of safety and functional independence [29, 30, 31]. In IMS III, pre-specified subgroup analysis of subjects with large vessel occlusion (LVO) documented at baseline CT angiography, however, found a highly significant benefit with the combination of IA and IV treatment over standard IV tPA alone [32]. Terminal and tandem occlusions of the internal carotid artery (ICA) and M1 MCA segment demonstrated a trend towards better 90-day outcomes after combined IA-IV therapy. Most interventionalists would agree that IAT would not be expected to benefit patients lacking a LVO. In addition to a lack of requirement for angiographically confirmed LVO as an inclusion criterion for patient selection (IMS III, SYNTHESIS), other contributing factors to the finding of neutrality included the predominant use of older thrombectomy devices such as the Merci Retriever instead of contemporary methodology such as stent retrievers, ADAPT, and “Solumbra”, and delay in initiation of IAT after symptom onset [33, 34]. Early and Rapid Reperfusion are Critical for Good Clinical Outcomes Revascularization is associated with better clinical outcomes and decreased mortality as numerous publications support the hypothesis that removal of the occlusion and achieving reperfusion of the target vessel is a strong predictor of improved 90-day good outcomes in ischemic stroke patients. In the IMS III trial, for example, 90-day good outcome was 18% when TICI 0-1, and 42% when TICI 2A-3 was achieved [29]. In Nourollahzadeh’s meta-analysis of 140 studies published from 1985 to 2011, subjects with successful revascularization had a

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five-fold higher likelihood of being functionally independent at 90 days [35]. Furthermore, mortality rate was three times higher in patients with closed vs. open vessels. In Rha and Saver’s meta-analysis, 90-day good outcome was 25% at TIMI 0-1 and 58% when TIMI 2-3 or TIBI 2-5 was achieved [36]. Likewise, mortality was 42% when vessels were closed and 14% when open. In addition, shorter time to angiographic reperfusion (TTR) has been shown to be the key for better clinical outcomes in the IMS pilot trials, the RECANALISE registry, and, most recently, the IMS III trial. In a post-hoc analysis of pooled data from the IMS pilot trials (IMS I and II), longer TTR after IV-IA tPA therapy was associated with a lower likelihood of mRS score ≤2 at 90 days [37]. In fact, the probability of functional independence decreased by 20% for each 30-min delay in reperfusion. MCA and distal internal carotid artery (ICA-T) occlusions with successful reperfusion to TICI 2–3 were included in their analysis. Similarly, the RECANALISE prospective registry study reported that a 30-min decrease in TTR after IV-IA tPA treatment and, if required, thrombectomy, significantly increased the probability of 90-day good clinical outcome after adjustment for admission NIHSS and age [38]. Further, an analysis of pooled data from IMS I and II plus five prospective observational studies reported favorable clinical outcomes decreased with each 30-min delay in reperfusion after IV-IA therapy [39]. In a preplanned analysis of data from the IMS III trial, delays in TTR were also found to be associated with a reduced likelihood of good clinical outcome in patients after moderate to severe stroke [40]. Thus, a number of publications suggest that rapid treatment should be emphasized regardless of the reperfusion modality chosen. The Benefits of Intra-Arterial Therapy are Confirmed Almost 20 years after the groundbreaking NINDS trial resulting in the approval of IV tPA to treat stroke, recent results from the randomized, concurrent controlled trials, MR CLEAN [3], ESCAPE [4], and EXTEND-IA [5] confirmed that intraarterial therapy in acute ischemic stroke patients with a LVO in the anterior circulation is safe and effective within 6 hours after symptom onset. The open label MR CLEAN trial randomized 500 patients to IV tPA vs. IV tPA + IA therapy. Key patient inclusion criteria included anterior circulation LVO

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confirmed by CTA and IA treatment initiated within 6 hours from onset (Table 1). Procedural times, symptomatic intracranial hemorrhage, and mortality rates are shown in Figs. (1 - 3). The adjusted odds ratio (OR) for ordinal 90-day mRS was 1.66 (95% confidence interval [CI] 1.21 to 2.28) (Fig. 4). The rate of functional independence favored IAT (33% vs 19%, OR 2.05, 95% CI 1.36 to 3.09). (a)

(b)

(c)

Fig. (1). Procedure times: stroke onset to IV tPA (min), median and IQR; (a) IA + IV and (b) IV alone. Time from symptom onset to mTICI 2B/3 reperfusion (min), median and IQR (c)*. *ESCAPE to first reperfusion; SWIFT PRIME to first deployment of thrombectomy device.

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Furthermore, subjects over the age of 80 also derived benefit from endovascular treatment (3.24 OR, 95% CI 1.22 to 8.62). As technology advanced, clinical outcomes supplanted reperfusion as the primary endpoint. Moreover, a metaanalysis of all prospective RCTs completed on or before November 4, 2014, demonstrated superior outcomes in patients randomized to EVT compared to medical management [41].

Fig. (2). Symptomatic intracranial hemorrhage.

Fig. (3). Mortality. For ESCAPE, adjusted analysis comparing the two arms was significant, p