Danoushka Tememe, MD Vasculopathy and Vasculitis • Fibromuscular Dysplasia • Moyamoya • Snedden’s Syndrome Overview • Susac’s Syndrome • Systemic Vasculitis • Primary angiitis of the CNS Fibromuscular Dysplasia • FMD is a noninflammatory, nonatherosclerotic arterial disease of the medium-sized arteries throughout the body, which could lead to arterial stenosis, occlusion, aneurysm, and dissection.

• The renal and carotid/vertebral arteries are most frequently affected • Iliac, mesenteric, subclavian arteries Fibromuscular Dysplasia • Often multifocal and bilateral.

• Usually involves the mid segment of the vessels and spares origins

• Age 25 to 50 years and affects women more often than men (3:1). Hypertension TIA/Stroke Spontaneous dissection Presentation Neck pain Pulsatile tinnitus Horner’s syndrome Vessel wall layers Typical string-of-beads pattern with alternating regions of lumen narrowing and vessel dilatation over a length of 3 – 5 cm FMD “String of beads” Extreme tortuosity “S curve” • There is no standard protocol to treat FMD

• Aim of treatment is to improve blood flow and depends on which arteries are affected and the severity • Balloon angioplasty +/- stent

Treatment • The carotid arteries should be imaged if FMD is found elsewhere in the body

• Aspirin daily

• Smoking cessation Moyamoya • Moyamoya disease is a progressive occlusive arteriopathy of the bilateral supraclinoid internal carotid arteries • Moyamoya syndrome: Down syndrome, neurofibromatosis type 1, sickle cell • Moyamoya-like vasculopathy: radiation, meningitis Moyamoya • Abnormal network of fine collateral vessels

• Additional collaterals may develop: • Leptomeningeal collaterals from the posterior cerebral artery • Transdural collaterals from the external carotid artery • Can present with TIA/stroke (50-75%) or intracranial hemorrhage (IPH or SAH). • Seizures, headache

• Fragile collaterals are prone to hemorrhage and Presentation hemodynamic failure.

• Symptomatic episodes of ischemia may be triggered by exercise, crying, coughing, straining, fever, hyperventilation, dehydration, hypotension (e.g., general anesthesia for minor procedures). Smooth Muscle Proliferation and Intraluminal Thrombi Suzuki Grading System Moyamoya Stage 3/4 Stage 4/5

Ivy Sign: Sulcal flair hyperintensities representing slow flow from leptomeningeal collaterals

Indicates decreased CVR Brush Sign Brush Sign on SWI Correlates with Severity of Moyamoya Steal Phenomenon

• Administration of a vasodilator such as Diamox can assess cerebral reserve by observing cerebrovascular reactivity to hemodynamic stress. Post-op MRA showing STA-MCA bypass as high signal intensity

SPECT seven days after left STA-MCA bypass demonstrating marked improvement in CBF Post- • Moyamoya vessels start regressing 1 month after bypass surgery. treatment changes • STA caliber increases 3 months after surgery. following STA- • ICAT steno-occlusion quickly progresses after MCA bypass surgery. Sneddon Syndrome • Progressive disorder affecting small- and medium-sized blood vessels. • Cerebral, ocular, renal, and cardiac involvement

• Characterized by livedo racemosa (net-like patterns of Sneddon Syndrome discoloration on the skin) and neurological abnormalities.

• More common in women • Onset of neuro symptoms in the 3rd to 4th decade • The livedo generally occurs up to 10 years earlier Livedo Racemosa

• Persistent, erythematous or violaceous discoloration of the skin, in a broken, branched, discontinuous and irregular pattern.

• Located on limbs (100%), trunk (84–89%), buttocks (68–74%), or the hands or feet (53–59%)

• Results from persistent impairment of peripheral blood flow caused by occlusion of small or medium-sized arteries • Does not disappear with rewarming • vs livedo reticularis, which is caused by temporary vasoconstriction • Skin biopsy: occlusion without inflammation of the small to medium-sized arteries at the border between dermis and subcutis. • May reveal thrombosis of subcutaneous arterioles and compensatory capillary dilation with blood stagnation. • Can also see intimal endothelial proliferation and proliferation of medial smooth muscle cells Diagnosis • Blood tests: check for antiphospholipid antibodies (40-50% of patients are aPL+) and rule out other autoimmune conditions (including lupus)

• CECR1 gene implicated given its role in producing adenosine deaminase 2, which is an enzyme that helps support the lining of blood vessel walls. Intra-capillary (thin arrow) and mural (thick arrow) Skin Biopsy widespread thrombosis Biopsy

• Biopsy site should be in the center of the lesions, where the skin seems to be untouched. • Multiple biopsies increase the diagnostic yield.

• The goal of a biopsy is to obtain samples of the medium vessel found in the deep reticular dermis and subcutaneous fat, which may require a wedge or large punch biopsy for increased yield. Cerebral Angiogram

• Shows peripheral small-vessel and medium-vessel vasculopathy resulting in pruning of the distal cortical vessels and tortuous irregular distal collaterals. • No specific treatment for underlying condition

• Antiplatelet therapy • Can use anticoagulants if +antiphospholipid antibodies

Treatment • ACE inhibitors may reduce endothelial proliferation

• Nifedipine may reduce skin symptoms • No effect on cerebrovascular complications

• Smoking cessation and avoidance of estrogen oral contraceptives Susac’s Syndrome • Autoimmune disease characterized by retinal, cochlear, and brain microangiopathy

• Clinical triad of subacute encephalopathy, Susac’s Syndrome branched retinal artery occlusion, and sensorineural hearing loss

• More common in women • Age of onset between 20-50 years of age "snowball“ infarcts of the central fibers of the corpus callosum with relative preservation of the peripheral fibers Classic infarcts in the internal capsule with a “string of pearls” pattern Vasculitides • Characterized by inflammation and necrosis of the blood vessel wall

• Primary CNS vasculitis vs systemic vasculitis with involvement of the CNS

• Systemic vasculitis can be separated into 3 main groups based on if they affect predominantly large-sized vessels, medium-sized, or small-sized vessels • Large vessels including the aorta are affected in giant-cell arteritis Vasculitides • Medium-size arteries in classic polyarteritis nodosa • The small-vessel vasculitides are separated in those with antineutrophil cytoplasm antibodies (ANCA) and those without.

• Primary angiitis of the central nervous system (PACNS) affect both medium- and small-sized vessels

• Major symptoms of cerebral vasculitis are stroke, headache and encephalopathy Classification of primary vasculitides.

Classification of primary vasculitides

Vessel size Granulomatous Nongranulomatous Large Giant cell arteritis Takayasu arteritis

Medium Polyarteritis nodosa Kawasaki disease Small (with ANCA) Granulomatosis with polyangiitis Microscopic polyarteritis Churg–Strauss syndrome Small (with immune complexes) Cryoglobulinemic vasculitis Behçet syndrome • Major symptoms of cerebral angiitis are stroke, headache, and encephalopathy. • Other symptoms include seizures, cranial nerve palsies, or myelopathies.

• Elevated ESR/CRP is seen in systemic vasculitis • May include anemia, thrombocytosis, elevated liver Symptoms enzymes, and low complement • Complement consumption is seen in vasculitis with immune complexes.

• In PACNS, serum findings usually are normal, but CSF studies reveal inflammatory findings (ie mild lymphomonocytic pleocytosis or protein elevation) - ESR/CRP - CBC w/ diff - CMP (Cr, LFTs) - Coags - SPEP/UPEP - CK Lab tests in - ACE - Cryoglobulins - TSH, thyroid antibodies, suspected - ANA, ds-DNA, RF, histone antibodies, complement (C3/4), SSA/B, ANCA, BCx - RPR, HIV, Hep B/C

vasculitis - Urine examination (ie hematuria, protein, UPEP, utox)

- CSF: cell count in tube 1 and 4, gram stain, CSF culture, VZV ab, CMV PCR, EBV PCR DSA

Carotid doppler

Imaging CTA

MRA

18-FDG PET is very sensitive in revealing inflamed vessels Diagnostic criteria for the diagnosis of Primary Angiitis of the CNS

1 Acquired neurological deficit unexplained after complete evaluation

2 Diagnostic cerebral angiogram with narrowing of vessels, areas of dilation and/or beaded vessel appearance, displacement of vessels or vessel occlusions

3 No evidence of systemic vasculitis or any other condition that could mimic the angiogram findings • PACNS is more common in males (2:1)

• Onset most often occurs after 40 years of age

• ESR not helpful Primary Angiitis of

the CNS • CSF inflammation is observed in ~90% of patients

• Histological findings are characterized by infiltrations of the vascular walls with mononuclear cells including lymphocytes, macrophages, and histiocytes Temporal Arteritis Takayasu Arteritis Large vessel vasculitides Diagnostic criteria of temporal arteritis

Three of the five diagnostic criteria 1 Age 50 years or more 2 New headache 3 Tenderness of the superficial temporal artery 4 Elevated sedimentation rate, at least 50 mm/h 5 Giant cell arteritis in a biopsy specimen from the temporal artery Criteria for the diagnosis of Takayasu’s arteritis

Takayasu’s arteritis may be diagnosed when at least three of these six criteria are present (sensitivity of 90.5% and a specificity of 97.8%) 1 Age at disease onset <50 years 2 Claudication of extremities 3 Decreased brachial artery pulse 4 Blood pressure [systolic] difference > 10mmHg between arms 5 Bruit over subclavian arteries or abdominal aorta 6 Arteriographic narrowing or occlusion of the aorta, its primary branches or large arteries (not due to arteriosclerosis, fibromuscular dysplasia or similar causes) Medium vessel Polyarteritis nodosa Vasculitides Classification of polyarteritis nodosa

PAN may be diagnosed with three of these ten criteria (82% sensitivity, 86% specificity), if other vasculitides are excluded 1 Loss of weight >4 kg 2 Livedo reticularis 3 Testicular pain 4 Myalgias 5 Mononeuritis or polyneuritis 6 Blood pressure elevation >90 mmHg 7 Creatinine >1.5 mg/dl 8 Hepatitis B or C virus antibodies 9 Pathologic arteriography (aneurysm, occlusions) 10 Typical histology finding Granulomatosis with polyangiitis Small vessel vasculitides Churg–Strauss syndrome Granulomatosis with polyangiitis

Diagnosis with two of four criteria possible (sensitivity 85%, specificity 92%)

1 Necrotizing ulcerating inflammation of nose, sinuses, mouth, or pharynx

2 Irregular lung infiltrates

3 Nephritis

4 Granulomatous vascular and perivascular inflammation • Multisystem, chronic-relapsing vasculitis • Recurrent oral ulcerations must be present with at least two of the following: • recurrent genital ulceration, eye lesions (uveitis, cells in the vitreous on slit lamp examination or retinal vasculitis), erythema nodosum Behçet’s disease • Diagnosis is purely clinical • Recurrent oral and genital ulcers are frequently the only symptoms at the onset of the disease. • CNS involvement (Neuro–Behçet) occurs in about 30% of patients after an average of 5 years. • Brainstem is predominantly involved • Stroke, CN, and headache