Disclosures/Conflicts

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1 42nd Annual Recent Advances in Neurology Thursday, February 12, 2009 Cerebral Vasculitis (Primary CNS Vasculitis) Disclosures/Conflicts None J. Donald Easton Department of Clinical Neurosciences Alpert Medical School of Brown University and Rhode Island Hospital Providence, Rhode Island Why select this arcane topic? MR: Overlap of imaging features Because it is frequently mentioned in brain imaging reports and neuroradiology conferences, and rarely diagnosed Findings compatible with small vessel ischemic disease, demyelination, or vasculitis. Clinical correlation suggested Vasculitis Demyelinating disease (ADEM) Cyclosporine leukoencephalopathy CNS Lyme Page 1

2 Primary and Secondary Vasculitides Primary Large vessel involvement (the aorta and its major tributaries, which supply the extremities, head & neck) Giant cell arteritis Takayasu s arteritis Medium (main visceral arteries and branches) & small vessel involvement Polyarteritis nodosa Cutaneous polyangiitis Wegener s granulomatosis Churg-Strauss syndrome Microscopic polyangiitis Buerger s disease Primary and Secondary Vasculitides Continued Medium and small vessel involvement (continued) Cryoglobulinemia Kawasaki disease Behçet s syndrome Primary angiitis of the CNS Cogan s syndrome Small vessel involvement (vessels smaller than arteries eg, arterioles, venules, and capillaries) Cutaneous leukocytoclastic vasculitis Urticarial vasculitis Henoch-Schönlein purpura Secondary Vasculitides & Mimics Secondary Vasculitides & Mimics Continued Infections Subacute bacterial endocarditis Syphilis Hepatitis B Hepatitis C CMV EBV HIV Meningococcemia Tuberculosis Brucella Salmonella Rocky Mountain spotted fever Medications Beta-lactams Sulfonamides Quinolones Macrolides Thiazides Loop diuretics Beta blockers Phenytoin Propylthiouracil Selective serotonin reuptake inhibitors NSAIDs Medications continued Anti-tumor necrosis factor antibodies Colony stimulating factors (GM-CSF, G-GSF) Drugs Cocaine Amphetamines Heroin Connective tissue diseases Rheumatoid arthritis Systemic lupus erythematosus Sjögren's syndrome Polymyositis Dermatomyositis Other Malignancy Thrombotic thrombocytopenic purpura Cardiac myxoma Cholesterol emboli syndrome Atherosclerosis Calciphylaxis Amyloidosis Moyamoya disease Ehlers-Danlos syndrome Fibromuscular dysplasia Antiphospholipid antibody syndrome Page 2

3 Primary Angiitis of the CNS Terminology Why is CNS Vasculitis often Mentioned? Granulomatous angiitis Isolated angiitis of the CNS CNS Vasculitis Primary Angiitis of the CNS Initial presentation is non-specific and includes stroke, a common disease There are no pathognomonic symptoms or signs Affects both sexes and all ages MRI and angiographic mimics abound Why is CNS Vasculitis Rarely Diagnosed? Clinical features of biopsy-proven PACNS It is rare There are no tests with 100% sensitivity The most sensitive tests (MRI, LP) are non-specific The most specific tests (angiography, brain biopsy) carry risk and have poor sensitivity Occurs at all ages (mean age: 46) 70% are male Duration to diagnosis: 5 months Acute presentations of PACNS are very unusual Treatment can be life saving Page 3

4 Key features of PACNS Symptoms of PACNS Clinical Variable onset but most frequently a prolonged prodrome of 3-6 or more months Mixture of focal and non-focal neurologic signs CSF analysis abnormal in 90% (aseptic meningitis findings) Blood tests are normal Radiographic Neuroimaging reveals signs of multifocal ischemia of varying ages Variable presence of leptomeningeal enhancement Angiography normal in approximately 40%; high probability in 40% Pathology Vasculitis of small and medium vessels of leptomeninges and underlying cortex with variable degrees of granulomatous changes Giant cells may or may not be present Headache 55-90% Impaired Cognition 83% Encephalopathy 70% Seizure 30% Ischemic stroke 15% Cerebral hemorrhage 11% MRI: multiple ischemic lesions of variable age and meningeal enhancement (enhances biopsy site) MRI: acute and chronic hemorrhage ICH occurs in about 10-15% of patients MRI (GRE) may reveal acute, subacute or chronic ICH Coexisting ICH and variable-age ischemic lesions are suggestive Page 4

5 Spinal Fluid in PACNS Angiography in PACNS: insensitive and non-specific Abnormal in 90% of biopsy-proven cases Mean protein: 177mg/dL Mean cell count: 77/mm 3 CSF useful to exclude infection, neoplasm Classic : alternating stenoses and ectasia Normal in 40% of bx proven PACNS Of abnormal angiograms in PACNS, 30% do not show beading Example - PACNS Severe small vessel vasculitis Note severe pruning and occlusion of distal vessels with irregular appearance Page 5

6 Beware of angiographically-diagnosed PACNS PACNS: only brain biopsy is definitive Angiography may be normal in PACNS Angiography may show beading in other diseases (e.g., reversible vasoconstriction) Differentiating vasculitis from other non-inflammatory vasculopathies by angiogram alone is impossible Diagnosis by brain biopsy is the gold standard Biopsy of PACNS Brain biopsy in PACNS False negative rate: 25% (lesions are patchy) Sampling brain + meninges, recent lesion, increases yield May show granulomatous angiitis, necrotizing vasculitis, or both Required to differentiate PACNS from other inflammatory & non-inflammatory vasculopathies PACNS showing granulomatous infiltrate within a recent hemorrhagic infarction Page 6

7 Classic PACNS Treatment of PACNS (without biopsy only in typical cases) 45 year old man Subacute headache, behavior change Encephalopathy & focal signs Multiple acute, subacute infarcts on MRI Inflammatory spinal fluid Abnormal angiogram +/- brain biopsy Treatment is empirical Prednisone 1 mg/kg Cytotoxic therapy (cyclophosphamide) Monitor patients clinically, CSF, MRI Maintenance therapy to keep clinical activity, CSF, MRI stable for 6 months to 1 year Relapse has been described Mortality about 5% So, CSF & MRI are usually abnormal The combination of normal MRI & normal CSF rules it out What is and isn t CNS Vasculitis Conditions resembling PACNS excluded by the preliminary diagnostic criteria (adapted from Calabrese 1995) (1 of 3) What is CNS Vasculitis? A subacute, progressive, multifocal encephalopathy due to inflammation in the arteries of the CNS What isn t CNS Vasculitis? Systemic vasculitides Polyarteritis nodosa Allergic granulomatosis Hypersensitivity vasculitis (cutaneous leukocytoclastic vasculitis) and related disorders Vasculitis of connective tissue disorders Wegener s granulomatosis Giant cell arteritis Takayasu s arteritis Behçet s syndrome Lymphomatoid granulomatosis Cogan s syndrome Infections Viral Bacterial Fungal Rickettsial Neoplasms Angioimmunoproliferative disorders Carcinomatous meningitis Infiltrating glioma Malignant angioendotheliomatosis Page 7

8 Conditions resembling PACNS (2 of 3) Conditions resembling PACNS (3 of 3) Drug Use Amphetamines Ephedrine Phenylpropanolamine Cocaine Ergotamine etc Vasospastic disorders Postpartum angiopathy Eclampsia Pheochromocytoma Subarachnoid hemorrhage Migraine and exertional headache Reversible Cerebral Vasoconstrictive Syndrome (RCVS) Other vasculopathies and mimicking conditions Fibromuscular dysplasia Moyamoya disease Thrombotic thrombocytopenic purpura Sickle cell anemia Neurofibromatosis Cerebrovascular atherosclerosis Demyelinating disease Sarcoidosis Emboli (subacute bacterial endocarditis, cardiac myxoma, paradoxical emboli) Acute posterior placoid pigment epitheliopathy and cerebral vasculitis Other vasculopathies and mimicking conditions (continued) Antiphospholipid antibody syndrome Susac s syndrome (encephalopathy, branch retinal artery occlusions and sensorineural hearing loss) MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) Reversible Cerebral Vasoconstrictive Syndrome (RCVS) It has many names Call Syndrome Call-Fleming Syndrome Thunderclap headache with reversible vasospasm Migrainous vasospasm Benign angiopathy of the CNS Postpartum angiopathy Drug induced cerebral angiopathy OFTEN CONFUSED WITH CNS VASCULITIS Pathophysiology unknown Reversible Cerebral Vasoconstrictive Syndrome (RCVS) A diagnosis requires all of the following criteria: 1. Acute, severe and recurring headaches with or without neurologic symptoms and signs 2. No evidence of aneurysmal subarachnoid hemorrhage 3. Normal or near normal cerebrospinal fluid a. Protein <70 mg% b. White blood cell count <20 cells per/mm 3 c. Normal glucose 4. Reversible cerebral segmental vasoconstriction involving arteries of Circle of Willis documented by serial angiography, CT, or MR angiography or flow-related vascular technique (transcranial Doppler) within 12 weeks after onset Page 8

9 Causes (partial list) Idiopathic RCVS in a 10 year old boy Iatrogenic Phenylpropranolamine Pseudoephedrine Ergotamine tartrate Methergine Bromocryptine Lisuride SSRIs Sumatriptan Isometheptine Cocaine Ecstasy Amphetamines LSD Tacrolimus Cyclophosphamide IVIG RBC transfusions/erythropoetin Other Pregnancy Head Trauma Pheochromocytoma Spinal subdural hematoma Neurosurgical procedures Coughing, coitus, valsalva Before verapamil After verapamil Idiopathic RCVS in a 10 year old boy Reversible Cerebral Vasoconstriction Syndrome Symptom Onset ACA 12 weeks later ACA Was taking sertraline (SSRI) & then trazodone (SSRI & 5-HT 2A antagonist) On day 16 developed thunderclap headache and multiple infarcts MCA MCA MCA MCA SSRI stopped, symptoms improved Follow-up angiogram normal VA VA Page 9

10 Reversible Cerebral Vasoconstriction Syndrome Angio: Decongestant Vasculopathy Angio 3 months following cessation of agent Comparison of PACNS and RCVS Treatment of RCVS PACNS RCVS Sex predominance Male 3:2 Female 2:1 Onset Long prodrome Acute minutes to days 3-6 months, progressive thunderclap Symptoms and signs Chronic headache, focal Acute headache + signs and encephalopathy focal signs CSF analysis Chronic meningitis findingsnormal Angiogram Normal in 40%; high High probability probability in 50% >95% Biopsy Arteritis in leptomeninges and/or cortex in 75-80% Short course (4-6 weeks) calcium channel blocker (+ prednisone) If no resolution, re-evaluate the diagnosis Severe cases: induced hypertension, angioplasty Page 10

11 Summary: CNS Vasculopathy CNS vasculopathy is a spectrum of inflammatory and noninflammatory processes Imaging findings are non-specific with considerable overlap Angiographic findings need to be interpreted alongside clinical history and other imaging findings Catheter-based angiography remains the gold standard for small artery disease Primary CNS Angiitis is a specific disease entity with a typical clinical course and CSF, angiogram and biopsy findings Reversible Cerebral Vasoconstriction Syndrome is a disease entity with a typical clinical presentation and course, and angiogram, but a diverse array of causes Page 11