Vasculitis and nervous system

Dr. Parag MoonSenior resident,

Dept. of Neurology,GMC, Kota.

Spectrum of clinicopathological disorders characterized by inflammation of blood vessels, including arteries and veins of varying caliber

Result in variety of clinical neurological manifestations related to ischemic injury of central nervous system (CNS) and peripheral nervous system (PNS).

Definition

Systemic necrotizing arteritis◦ Polyarteritis nodosa◦ Churg–Strauss syndrome◦ Microscopic polyangiitis

Hypersensitivity vasculitis◦ Henoch–Schonlein purpura◦ Hypocomplementemic vasculitis◦ Cryoglobulinemia

Systemic granulomatous vasculitis◦ Wegener granulomatosis◦ Lymphomatoid granulomatosis◦ Lethal midline granuloma

Giant cell arteritis◦ Temporal arteritis◦ Takayasu arteritis

Connective tissue disorders associated with vasculitis◦ Systemic lupus erythematosus◦ Scleroderma◦ Rheumatoid arthritis◦ Sjogren syndrome◦ Mixed connective tissue disease◦ Behcet disease

Inflammatory diabetic vasculopathy

Isolated peripheral nervous system vasculitis

Granulomatous angiitis of the nervous system

Classification of vasculities that affect the nervous system

Vasculitis associated with infection◦ Varicella zoster virus◦ Spirochetes◦ Treponema pallidum◦ Borrelia burgdorferi◦ Fungi◦ Rickettsia◦ Bacterial meningitis◦ Mycobacterium tuberculosis◦ HIV-1

Central nervous system vasculitis associated with amphetamine abuse

Paraneoplastic vasculitis

Classification of vasculities that affect the nervous system

Polyarteritis nodosa Necrotizing arteritis and nodules in small-

and medium-sized vessels of heart, liver, kidney, pancreas, testicles, brain, nerves, skeletal muscles sparing lungs and spleen.

Dominant neurological picture-peripheral neuritis with predilection for legs in 50 %

Three quarters-lesions in arteriae nervorum in post mortem studies.

Clinically apparent brain infarcts-10%

Systemic Necrotizing Arteritis

Histological lesions-mononuclear cell infiltration, necrosis of internal and external elastic lamina of media, fibrin deposition, perivascular inflammation of adventitia, and intimal proliferation ->narrowing of arterial lumina.

Focal deposition of perivascular connective tissue, vascular necrosis, and denuding of endothelium occur

Followed by vascular thrombosis, ischemia, aneurysm formation, rupture, and hemorrhage.

Multiple small cortical and subcorticalregions of increased signal-infarcts indistribution of small arteries.

Third, or proliferative-chronic inflammatory cells replacing neutrophils of second phase; evidence of necrosis of media, early intimal proliferation (arrowheads), and fibrosis. Lumen isalmost completely occluded.

Microscopic polyangiitis Differs from PAN in affliction of small arterioles,

capillaries, and venules of lungs and kidney with necrotizing glomerulonephritis.

Circulating antinuclear cytoplasmic autoantibodies (ANCA), usually myeloperoxidase or perinuclear ANCA (p-ANCA)-80%

Epineurial arteries involvement-polyneuropathy mononeuritis multiplex (MNM) type in 1/4th

Skin nodules and purpura in majority.

Churg-Strauss syndrome Syndrome of asthma, eosinophilia, extravascular

granulomas, and necrotizing vasculitis of small and medium arteries, arterioles, capillaries, and veins.

Angiitis and extravascular necrotizing granulomas with eosinophilic infiltrates.

Granulomas located near small arteries and veins Characterized by palisading epithelioid

histiocytes arranged around central necrotic zones in which eosinophils predominate.

Three phases. 1. Prodromal period of constitutional symptoms

(rhinitis and asthma). 2. Peripheral blood and tissue eosinophilia3. Systemic vasculitis

Three fourths have neurological involvement similar to PAN

Typically peripheral neuropathy of MNM type, stroke, and hemorrhage.

Laboratory diagnosis-myeloperoxidase or p-ANCA seropositivity, and tissue biopsy.

Unique predilection for dermis Inflammatory infiltrates-extravasation of

erythrocytes, pronounced endothelial swelling, andinfiltration by PMN and later mononuclear cells, with resultant fibrosis.

Involves arterioles, capillaries and postcapillary venules.

Resultant nuclear fragments or leukocytoclasia and fibrinoid necrosis (termed leukocytoclastic vasculitis [LCV]) and circulating immune complexes deposit in skin and vasculitic lesions.

Lesions-same stage of evolution.

Hypersensitivity Vasculitis

Leucocytoclastic vasculitis- Entire vessel and perivascular tissue are infiltrated with polymorphonuclear leukocytes and some chronic inflammatory cells with necrosis and nuclear debris with vascular lumen nearly obliterated

Drug-related vasculitis 20% of dermal vasculitis cases. Clinical spectrum varies from urticaria,

wheezing, and rhinitis; variable serum sickness to laryngeal edema; and hypotension.

Rash mostly maculopapular or vesicular—less often palpable purpura— along arms and legs

More severe drug reactions-multiple organ involvement.

Results from focal deposition of immune complexes developed from covalent binding of offending drug or its metabolites with native or foreign proteins to produce hapten molecules.

Serum sickness Varying degrees of infiltration of arterioles,

capillaries, and venules with interstitial inflammation by PMN cells, eosinophils, and mononuclear cells.

Urticaria followed by erythematous or maculopapular rash, petechiae, palpable purpura, and lymphadenopathy

Accompanied by arthralgia, edema, headache, and lethargy.

Nervous system-◦ brachial plexus neuritis, ◦ mononeuritis simplex and multiplex,◦ Guillain-Barre´ syndrome, ◦ cranial nerve palsies, ◦ blurring of vision, ◦ retinal and palpebral hemorrhages,◦ meningismus, ◦ stroke,◦ myelopathy.

Immune complex disease

Henoch-Schonlein purpura Nonthrombocytopenic purpura, arthralgia,

abdominal pain, leukocytoclastic vasculitis of skin lesions

Affected child-fever, headache, anorexia. Palpable purpuric lesions-extensor surfaces

of lower extremities and buttocks Associated with migratory angioneurotic

edema of hands, scalp, face, lower legs, and genitalia.

Deposits of immunoglobulins particularly IgA and C3-kidney and blood vessel walls

Hypocomplementemic vasculitis Urticaria, migratory arthralgia, and

persistent or intermittent hypocomplementemia.

Sometimes severe angioneurotic edema and life-threatening laryngeal edema

Conjunctivitis, episcleritis, uveitis, mild renal disease, pericarditis, abdominal pain, splenomegaly.

Pseudotumor cerebri-most common neurological manifestation.

Immunological-binding of IgG antibody to C1q along basement membranes with complement activation.

Cryoglobulinemia Reversibly precipitate at below 37degree Composed of IgG and IgM, complement,

lipoprotein and antigenic protein moieties.◦ Type I-single monoclonal IgM or IgG antibody◦ Type II-mixed, has monoclonal IgM possessing

activity against polyclonal IgG◦ Type III-mixed polyclonal and non-immunoglobulin

Types I and II-lymphoproliferative diseases, particularly multiple myeloma and Waldenstrom macroglobulinemia.

Type III-infection and collagen vascular diseases

Four vascular lesions (1) occlusion of small and large vessels in type I or II; (2) bland thrombosis of small arteries and arterioles (3) endothelial swelling, proliferation, and basement

membrane thickening (4) LCV.

Peripheral nerves-chronic axonopathy of large myelinated fibers.

Dermatitis, palpable purpura heralded by a sharp or burning sensation.

PNS and CNS-more common with types II and III.

Cryoprecipitation-cause of ischemia of arterioles and capillaries due to hyperviscosity and direct plugging of small vessels.

CNS manifestations-vascular occlusion with or without vasculitis.

Peripheral neuropathy-epineurial vasculitis, cryoprecipitate deposition, microvascular ischemia with resultant secondary axonopathy.

Inflammatory cell infiltrate-mainly T cell with lesser numbers of B lymphocytes

Isolation of HCV RNA in peripheral nerve biopsies-unsuccessful.

Presence of cryoglobulinemia, bone marrow studies, nerve biopsy, studies for HCV, HIV, occult cancer, infection, plasma cell dyscrasia, CVD

Wegener granulomatosis. Triad-necrotizing granulomatous lesions of

sinuses and lower respiratory tract, systemic necrotizing vasculitis of small arteries and veins, and glomerulonephritis

WG lesions begin as minute foci of granular necrosis and fibrinoid degeneration with PMN cells followed by histiocytes and giant cells along margins of granulomas

Systemic GranulomatousVasculitis

One fourth- CNS involvement Direct destruction of nerve or brain tissue

by necrotizing granulomas Necrotizing arteritis of cerebral and arteriae

nervorum of peripheral nerves. Multifocal pain, sensory loss, and weakness

due to MNM Circulating c-ANCA directed against

proteinase 3.

Stroke, intracerebral and subarachnoid hemorrhage, optic neuritis

Contiguous extension from nasal and paranasal sinus cavity granulomas-pseudotumor with exophthalmos, extraocular muscles, optic nerve involvement

Extension through temporal bone-middle ear.

Muscular artery nearly completely destroyed. A large confluent area of fibrinoiddegradation is surrounded by neutrophils, palisading histiocytes, lymphocytes, plasma cells, and some giant cells

Lymphomatoid granulomatosis. Malignant lymphoreticular disorder with

strong predilection for CNS. Present with constitutional symptoms and

skin lesions resembling erythema nodosum. Focal neurological-MNM, unilateral cranial

nerve palsies, hemiparesis, ataxia, seizures, spinal and radicular syndromes, myopathy.

CNS-invasion of unifocal and multifocal necrotizing angiocentric and angiodestructive lesions of small- and medium-sized muscular arteries and their endothelia by masses of T cells, plasma cells, histiocytes, and atypical lymphoreticular cells

Immunoblast formation-cerebrum, brain stem, cerebellar parenchyma, meninges

Lethal midline granuloma. Relentlessly invasive necrotizing process of

nose and palate that causes destruction of sinuses and all major midline structures of head

Producing grotesque facial mutilation and ultimately death.

CNS complications-direct invasion of orbit and face, jugular vein, and sigmoid and cavernous sinuses leading to vascular thrombosis, sepsis, meningitis.

Temporal arteritis-older adult whites of either gender and involves medium and large arteries.

Headache, scalp tenderness, thickened nodular and pulseless superficial temporal artery, unilateral visual loss, jaw claudication

Along branches of external carotid artery and arteritis of vertebral and carotid arteries typically at end points of dural investment.

Biopsy of temporal artery

Giant Cell Arteritis

Takayasu arteritis-aorta and its branches in young Asian women.

Obliterative lesions in large arteries such aorta and its major branches.

Dizziness, syncope, subclavian steal, carotid sinus syndrome, stroke, amaurosis fugax, corneal opacification, cataracts, claudication and gangrene of limbs, chest and abdomen angina.

A, Early lesion of a arge muscular artery, necrosis, inflammation, and giant cell formation (single arrow) seen immediately adjacent to internal elastic lamina (arrowhead), which is undergoing degenerative changes, some intimal proliferation (double arrows) B, More advanced lesion-complete segmental destruction of internal elastic lamina and virtually the entire media (arrows). Marked intimal proliferation has nearly occluded lumen, and few inflammatory cells remain.

Granulomatous angiitis of the nervous system Nearly exclusive neurological manifestations Headache, mental change, pleocytosis and elevated

protein content in CSF with signs of angiographic beading that precede focal seizure and stroke

Untreated-coma and death. Can occur in association with cell arteritis,

sarcoidosis, varicella-zoster virus, lymphoma, amyloid angiopathy,HIV infection.

Diagnostic biopsy of brain and overlying meninges From named cerebral vessels to medium and small

leptomeningeal vessels

A, Media and adventitia of this small leptomeningeal artery completely replaced by multinucleated giant cells (arrowheads). Intimal proliferation with obliteration of vascular lumen and a dense, perivascular, mononuclear inflammatory infiltrate B, Larger leptomeningeal vessel-necrosis of media and internal elastic lamina with multinucleated giant cell formation (arrows), intimal proliferation (arrowhead), lymphocytic infiltration of the adventitia and neighboring meninges

Systemic lupus erythematosus. True vasculitis-present in only 10% Atinuclear antibody (ANA) screen-

homogenous pattern in majority Antibodies to native double- stranded DNA

(anti-dsDNA) and reactivity to the Smith (Sm) and ribonucleoprotein (RNP)

Antiphospholipid antibodies (APA) (lupus anticoagulant (LAC) and anticardiolipin (aCL) antibody)-prothrombotic events

Collagen Vascular Diseases

Small vessel within brain parenchyma-largely necrotic. Abundant fibrin (darkly stained) is evident in vessel walls and surrounding tissues. A fewchronic inflammatory cells indicate the presence of vasculitis

Scleroderma. Diffuse fibrosis affecting firstskin and later systemic

organs and nervous system. Vascular lesions-

increased collagen deposition sclerosis, and hyalinization proliferation of endothelium, fibrosis of adventitia and intima,

and duplication and fraying of internal elastic membrane progressive luminal obliteration

Associated with HLA-DQb1 & mediated by three autoantibodies (anticentromere, anti-SCL-70 or topoisomerase, anti-RNA polymerase III)

CREST syndrome

Digital artery-severe intimal hyperplasia and greater than 90% luminal narrowing. Severe adventitial fibrosis and marked telangiectasia of vasa vasorum is seen, media and internal elastic lamina are relatively spared

Rheumatoid arthritis. Three forms of vasculitis occur

1. Proliferative endarteritis of few organs, notably heart, skeletal muscle, and nerves characterized by inflammatory infiltration of all layers of small arteries and arterioles, with intimal proliferation, necrosis, and thrombosis.

2. Fulminant vasculitis indistinguishable from PAN3. LCV with palpable purpura, arthritis, cryoglobulinemia,

and low complement levels. Nonvasculitis spinal and epidural involvement-

vertebral collapse, subluxation, and direct narrowing of spinal canal due to rheumatoid pannus.

Sjogren syndrome Keratoconjunctivitis sicca and xerostomia. Two types of vasculitis

1. LCV of skin with palpable purpura, urticaria, erythematous macules, and papules

2. Resembles PAN with muscle, nerve, CNS, visceral vascular involvement without aneurysm formation.

Associated with extractable RNA proteins Ro or SS-A and intranuclear RNA-associated antigen La or SS-B.

Mixed connective tissue disease. Clinical and histopathological features of SLE,

scleroderma, and polymyositis Proliferative vascular changes, capillary

involvement, and mild tissue fibrosis. Behcet’s disease. Triad of oral and genital ulcers, uveitis, and

vasculitis Cutaneous, retinal, and CNS vasculitis. Direct inflammation of neuraxis-focal brain stem

meningoencephalitis.

Purulent bacterial meningitis Mycobacterial Treponema pallidum Borrelia burgdorferi Varicella zoster Fungal-Aspergillus, Candida, Coccidioides,

mucormycosis HIV-associated granulomatous angiitis of

brain, eosinophilic temporal arteritis, vasculitic meningoencephalitis, MNM resembling PAN

Infection-Associated Vasculitis

Parenteral drug use Necrotizing arteritis of polyarteritis type Amphetamine, cocaine,

phenypropanolamine and opioids, alone or in combination.

Substance Abuse

Paraneoplastic encephalomyelitis, sensory neuronopathy, high anti-Hu antibody titers

Transmural inflammation of epimysial and epineurial vessels on muscle and nerve biopsy

Mostly seen with cancer of lung, kidney, prostate, lymphoma.

Paraneoplastic Vasculitis

Blood Studies Complete blood count Erythrocyte sedimentation rate Chemistry panel-creatine phosphokinase Antinuclear antibody Complement levels Rheumatoid factor

Diagnosis-Laboratory investigation

Cryoglobulins Immunofixation electrophoresis Quantitative immunoglobulins Antibodies (selectively) to: Ro (Sjogren

syndrome [SS]-A), La (SS-B), Smith (Sm), SCL-70, hepatitis B and C virus, human immunodeficiency virus type 1, Borrelia burgdorferi (ELISA, Western blot), c-ANCA, p-ANCA

Electroencephalography Electromyography and nerve conduction

studies Cerebrospinal fluid analysis: protein,

glucose, cell count, immunoglobulin G level, cytology, VDRL, gram stain, culture, India ink; viral antigens, Lyme Ab, PCR (as indicated)

Neurodiagnostic

MRI Multiple bilateral cortical and deep white matter

signal abnormalities and enhancement of meninges after gadolinium.

MR angiography-useful in evaluation of medium and large-vessel disease but misses fine-vessel contours

DSA-Beading of vessels-found only in 1/3rd with histologically proven CNS vasculitis, as well as in CNS infection, atherosclerosis, cerebral embolism, and vasospasm of diverse causes.

Multiple microaneurysms-rare in CNS vessels.

Imaging

Ectasia and beading in M1 segment and lack of flow in the A1 segment of the right anterior cerebral artery (arrow).

(a) MRangiography showing basilar artery narrowing with irregularity (long arrow) and abrupt cut off of the right vertebral artery (shortarrow)..

(b) Angiogram showing narrowed left internal carotid artery.

Muscle and nerve biopsy Temporal artery biopsy Meningeal and cortex Skin Systemic organs Lymph nodes

Histopathological

Immunomodulating agents◦ IvIg

Immunosuppresants◦ Corticisteroids◦ Cyclophosphamide◦ Azathioprine

Treatment

Physical therapy and orthosis-to maintain range of motion and strength, to improve function status, and to maintain ambulation.

Effective pain management- tricyclic antidepressants, gabapentin, mexiletine, opioids, clonazepam, and topical anesthetic creams

Limit ischemic enhancing effects of other conditions,

such as diabetes mellitus, hypertension and hyperlipidemia

Cessation of cigarette smoking.

Supportive Therapy

THANK YOU

NEUROVASCULITIS; Younger, David S;CONTINUUM: Lifelong Learning in Neurology:; Feb 2005:Vol11 - Issue 1:11-42

Central nervous system vasculitis; Rula A. Hajj-Alia, Leonard H. Calabrese: Current Opinion in Rheumatology 2009, 21:10–18

Central nervous system vasculitis:Neil J. Scolding: Semin Immunopathol (2009) 31:527–536

Vasculitis of the nervous system: David S. Younger: Current Opinion in Neurology 2004, 17:317–336

References