vasculitis

Central Nervous System Vasculitis

Introduction The vasculitidies is a heterogeneous group of

disorders in which inflammation of the blood vessels is the main pathological finding.

Vasculitis is a descriptive histopathiological term referring to

Intramural inflammation of the blood vessels Perivascular changes Necrosis of the blood vessels

Inflammation involves arteries with variable involvement of capillaries and veins

Classification: A. Primary Vasculitis Large artery vasculitis

– Giant cell arterities– Takayasau arteritis

Medium artery vasculitis– Classical polyarteritis

nodosa– Kawasaki syndrome

Medium artery vasculitis1.Necrotizing vasculitis:

Wegner's granulomatosis Churg Strauss syndrome Microscopic polyangitis

2.Collagen vascular disease SLE Rheumatoid arthiritis Sjogren syndrome Scleroderma Overlap syndrome

Small Vessel vasculitis Henoch Schonlien purpra Essential cryoglobulinemia Cutaneous leucoclastic vasculitis

Classification: B. Secondary Vasculitis

May affect large, medium or small vessels Causes include

Infections: e.g. syphilis, hepatitis B, HIV, herpes Drugs Systemic disorders e.g. ulcerative collitis Sarcoidosis Chemical exposure Radiation induced Hypersensitivity reactions

Classification

Some forms of vasculitis do not fit well with this classification including

Primary CNS vasculitis Relapsing polychondritis Susac syndrome Behcet disease

Mechanism of tissue damage1. Immune complex deposition

Mechanism of tissue damage2. Other antibody mediated mechanisms

ANCA mediated vasculitis: These antibodies play a direct role in generating and

maintaining vascular inflammation Two types are known

Cytoplasmic ANCA: Targets proteinase 3 Associated with nearly 95% specificity with

Wegner's granulomatosis Perinuclear ANCA

Dilated at myeloperoxidase Associated with microscopic polyangiitis and Churg

Strauss disease Direct antibody damage

Mechanism of tissue damage3. Cell mediated

Cell mediated mechanisms are important in some forms of vasculitis including primary CNS vasculitis and giant cell arteritis

In all forms of vasculitis lead to obstruction of blood vessels through

Obstruction of the lumen Endothelial change promoting coagulation Alterations in vascular tone Damage to vessel wall leading to haemorrhage or

microaneurysm formation

Neurological manifestations of vasculitis

Course: variable Central manifestations:

Headache Seizures Stroke like episodes Cognitive or behavioural changes Aseptic meningitis Optic neuritis Sinus thrombosis Myelitis

Neurological manifestations of vasculitis

Peripheral manifestations Peripheral neuropathy Myositis

Complications of systemic disease e.g.uremic encephalopathy

Complications of treatment e.g. opportunistic infections due to immune suppression

Investigations

No single investigation confirm diagnosis of cerebral vasculitis

Blood tests: CBC: anemia,leucocytosis ESR and C reactive protein Serology

Specificity variable for different diseases May be affected by disease activity Some forms of vasculitis are negative for all

serological markers

Investigations

Lumbar puncture: Features of inflammation Oligoclonal bands: variable during the course of

disease MRI:

Shows outcome of vasculitis on parenchyma e.g infarctions, meningitis inflammation

MRA is useful in large and medium artery disease but not small vessel disease

Investigations Contrast angiography: Negative 30-40% Abnormalities include:

Segmental narrowing

Localized dilatation and beading

Biopsy: From brain, meningies,

muscle Brain biopsy may be

unhelpful in 25% of cases

Principles of treatment

Main lines of therapy are Immune suppressants

Steroids Cyclophosphamide Other durgs immune suppressants IVIG, plasmapharesis Monoclonal antibodies

Symptomatic management e.g antiepileptics Anticoagulants or antiplatlets Rehabilitation Patient education

1. Large Vessel Arteritis: Temporal Arteritis

Chronic inflammatory disorder targeting large and medium sized vessels

Onset usually above the age of 55 Women twice affected as men Most commonly affects

Branches of the external carotid Ophthalmic artery Vertebral artery


Granulomatous angitis Confined to internal

elastic lamina Inflammatory infiltrate

formed of mononuclear and giant cells

Activated T cells predominate


Clinical picture:– Headaches

– Visual manifestations

– Jaw claudications

– Stroke or TIAs

– Polymyalgia rheumatica

– Other neurological manifestations (PN)

– Enlarged temporal artery

1. Large Vessel Arteritis: Temporal arteritis

Investigations ESR CBC:

normocytic anemia raised platelets: risk factor for visual loss

Biopsy 2 cm long Should not delay steroid therapy Can be positive up to 14 days after treatment

IL-6: promising for follow up Mild elevated liver functions is common


Treatment

– Steroids: 60-80mg prednisolone for 1-2 weeks followed by gradual withdrawal guided by ESR

– Headache and systemic manifestations respond within 24-48 hours

– Therapy need to be continued for at least one year with most patients needing 2-4 years of therapy

– Azathioprine can be used as steroid sparing or in the rare steroid dependent patient

1. Large vessel arteritis: Takayasau arteritis

Chronic inflammatory arteriopathy of aorta and its major branches and pulmonary artery of unknown cause.

Prevalent in young women of Asian ancestry Pathology

Identical to giant cell arteritis Early: granulomatous changes in media and

adventia Late: intimal hyperplasia, medial degeneration and

adventital fibrosis

Takayasu Arteritis: Clinical picture

Insidious onset Acute or pulseless phase

Skin rashes Fever Myalgia Arthirits Pleuritis Carotydins Elevated ESR

Temporal Arteritis: Clinical picture

Late or occlusive stage: Appear months or years later Multiple arterial occlusions that manifest by

Cervical bruits Absent carotid or radial pulse Assymetrical blood pressure recordings Arterial hypertension

Neurological manifestations Visual disturbances commonly bilateral Syncope occurs in 50% of cases Strokes


Other manifestations of head and neck ischemia

Jaw claudications Ischaemic

occulopathy Ischaemic necrosis

of lips, nasal septum and palate

Investigations: Arteriography MRA


Treatment:

– Active phase• Oral steroids

• Cyclophosphamide

• Azathioprines

• Methotrexate

– Chronic phase• Angioplasty or bypass of severely stenotic vessels

2. Medium Vessel Arteritis: Classical polyarteris nodosa

An unusual disorder with inflammation of medium sized arteries in various organs charactarized by formation of aneurysms

About 20-30% have heapatitis B antigen or antibody in serum

Systemic manifestations– Constitutional symptoms– Renal failure: presenting feature in 80% of cases– GIT: perforation and haemorrhage– Skin: purpra up to gangrene– Myocardial infarction– Arthralgia


Neurological manifestations (50% of cases)

– Peripheral neuropathy (most common)• Painful subacute mononeuritis

• Mononeuritis multiplex

• Radiculopathy

• Symmetrical distal neuropathy

– Cerbrovascular complications• Ischemia or hemorrhage

• Affects brain, spinal cord or optic nerve


Investigations– Laboratory:

• CBC: Esinophilia, anemia, leucocytosis

• Hematuria• Positive ANCA

– Biopsy: from kidney or peripheral nerves

– Visceral angiography– Uremia– Low complement

Treatment– Steroids– Cyclophposphamide

2. Medium vessel arteritis: Kawasaki Syndrome

Systemic vasculitis of acute onset mainly affecting infants and children

Clinical picture– Fever– Cervical lymph adenopathy– Mucocutaneous manifestations

• Conjuctival injection• Fissuring of lips• Rash

– Cardiac:• The most common manifestation

• Coronary artery aneurysms causing infarctions

2. Medium vessel arteritis: Kawasaki Syndrome

Neurological manifestations

– Aseptic meningitis is the most common

– Encephalopathy

– Hemiplegic strokes

– Facial palsy

– Epileptic seizures Treatment

– Corticosteroids

– Other immune suppressants

3. ANCA Associated Vascultis: Pathogenesis

A subtype of vasculitis charactarized by necrotizing inflammation of small vessels and antibodies to neutrophil constituents

Include: WG, CSS and MPA ANCA ( Antineutrophil cytoplasmic antibody) has a

direct role in pathogenesis leading to activation of neutrophils

Neutrophils need to be first “primed” by another factor such as an infectious agent, and attached to the vessel wall

Granulomatous lesions in WG include activation of T lymphocytes, with excess involvement of Th17 type

Neutrophils are primed by cytokines, resulting in expression of ANCA antigens at the cell surface.

Primed neutrophils adhere to the endothelium and ANCAs interact with their antigens, resulting in neutrophil activation.

ANCA-activated neutrophils release factors that can directly damage the endothelium but also activate the alternative complement pathway with generation of the powerful neutrophil chemoattractant C5a.

C5a and the neutrophil C5aR may compose an amplification loop for ANCA-mediated neutrophil activation, eventually culminating in severe necrotizing inflammation of the vessel wall

3. ANCA associated vasculitis: Microscopic Angitis

A multisystem small vessel vasculitis with severe renal involvement

Renal failure is the most common finding Neurological manifestations include;

– Mononeuritis multiplex in 55% of cases

– CNS involvement in only 10% of cases GUT, skin and joints may be affected Treatment: steroids

3. ANCA associated vascultis: Churg Strauss syndrome

Systemic vasculitis associated with granuloma formation in people with recently developed atopy

Clinical manifestations:

– Chest: asthma, pulmonary infiltrates

– Skin: rashes, articaria, subcutaneous nodules

– Glomerulonephritis

– GIT involvements


Neurological manifestations

– Peripheral • Mononeuritis multiplex

• Symmetrical polyneuropathy

• Radiculopathy

• Trigeminal neuropathy

– Central• Seen in only 7% of cases

• Ischaemic stroke

• Ischaemic optic neuropathy

• Encephalopathy: confusion, behavioral changes


Investigations:

– ANCA: cANCA (50%), pANCA (25%), negative (25%)

– Esinophilia

– Nerve conduction studies: often abnormal with no clinical evidence of neuropathy

– Brain MRI: often normal

– EEG: slowing

– Angiography: may not show vasculopathy Treatment: corticosteroids, cyclophosphamide pulse

3. ANCA associated vascultis: Wegner's granulomatosis

Small vessel systemic vasculitis with granuloma formation

Clinical features– Respiratory tract affection: charactarestic

• Subacute or chronic sinusitis• Nasal ulcerations• Ottitis media• Tracheal stenosis• Hemoptysis• Pneumonitis

– Renal disease: occur in 80% of cases

– Eye and orbit affections


Neurological manifestations:Occur in 50% of cases– Peripheral

• Mononeuritis multiplex• Less commonly symmetrical polyneuropathy

– CNS affection• Brain may be affected direclty or through extension of

granuloma from upper respiratory tract• Basal meningitis• Temporal lobe dysfunctiom• Cranial neuropathies: 2,6,and 7• Cerbral infarctions• Orbital pseudotumor• Sinus thrombois• Seizures


Investigations

– cANCA

– Biopsy: necrotizing granulomatus vasculitis

– Contrast MRI: meningial thickening and infiltration

– Esinophilia Treatment:

– Steroid and cyclophposphamide

– Other immune supressants

4. Vasculitis associated with collagen disease Systemic Lupus Erythrematosis

Chronic autoimmune multi-system disease characterized by high risk of thrombosis and relapsing remitting course.

Epidemiology

– Prevelance: 130 per 100000 in US

– Mostly affects young adults but may start in childhood

– Females 9 times more commonly affected than men The most common vasculitis to present with

neurological manifestations

4. Systemic Lupus ErythromatosisNeuropathology

Pathological findings reveal a wide range of abnormalities including

– Cortical atrophy– Vascular lesions: micro-infarcts and haemorrhages– Patchy demyelination: MS like or ischaemic

Correlation between pathological changes and symptoms is poor

Microvasculopathy– Most common finding– Caused by complement activation with or without

immune complex deposition– SPECT and MRS studies suggest that cerebral atrophy

and cognitive dysfunction are caused by ischemia secondary to microvasculopathy

4. Systemic Lupus Erythromatosis Neuropathology

Blood brain barrier dysfunction;– Pro-inflammatory cytokines or auto-antibodies up-

regulate expression of adhesion molecules on endothelial cells. This facilitate entry of inflammatory cells into the brain

The role of auto-antibodies:– No direct role for ANA – No deposition of Abs in choroid plexus– Anti-glutamate receptor antibodies may play a role

in cognitive dysfunction and psychiatric disease– Anti NR2: subset of antiDNA that may induce

neuronal apoptosis– Antiphospholipid Abs play a direct role if associated

4. Systemic Lupus Erythromatosis: Clinical manifestations

Systemic:– Skin lesions– Renal involvement– Joints: non deforming

arthiritis– Cardiac:

• Pericarditis

• Endocarditis

– Lung: pleurisy, infiltrates

– Hematological: • Anemia

• Leucocytosis

4. Systemic Lupus Erythromatosis: Clinical manifestations

Neurological manifestations– Seen in up to 75% of cases– The presenting symptom in 3% of cases, but present

with other manifestations in up to 30% of cases– May occur in absence of systemic manifestations or

serological activity– All are manifestations are non specific– Central and peripheral nervous system are involved– Associated with poor outcome due to accumulated

disability– The third commonest cause of mortality after renal

disease and iatrogenic

4. SLE: Neurological manifestations

Strokes and TIA– Small vessel disease is the most common – Embolization from endocarditis can occur– Associated with antiphospholipid antibodies– Hemorrhages are less common and are due to

hypertension from renal disease and/or platelet dysfunction

Acute confusional state/encephalopathy– Headache– Clouding of consciousness– Focal neurological features– Epileptic seizures– Raised CSF cells– Diffuse EEG slowing

SLE:Neurological manifestations

Seizures: common and may be– Isolated: focal or generalized– Part of acute encephalopathy– Secondary to stroke– Acute symptomatic seizures due to metabolic

abnormalities– Secondary to CNS infection

Movement disorders :– Rare– Chorea is the most common– Usually associated with aPL Abs– No structural changes in basal ganglia

SLE: neurological manifestations Aseptic meningitis (rare)

– Presents with subacute or chronic headache and fever

– CSF: lympohcytosis with normal glucose Migraine like headaches Intracranial sinus thrombosis Psychiatric manifestations

– Schizophrenia like psychosis– Mood disorders– Anxiety

Cognitive problems:– Clinically evident in 5% of patients– Detected in up to 40% by neuropsychology

SLE: Neurological manifestations

Myelitis: may be extensive Peripheral neuropathy

– Radiculopathy :axonal or demyelinating– Polyneuropathy– Autonomic neuropathy

• Polymyositis• Associated Myasthenia Gravis• Cranial neuropathies (2%)

– Acute or chronic hearing loss– Optic neuropathy– Other cranial neuropathies

SLE:Investigations Raised ESR CRP: not raised CBC

– Anemia: normocytic normochromic, hemolytic– Leucopenia, lymphocytopenia– Thrombocytopenia

Low C3 and C4 Serology

– ANA: senstive but not specific– Anti DNA; more specific but positive in 50% of

cases– Anti-SM Abs: present in less than 50% of cases– Antiphospholipid Ab– Anti ribosomal Abs: linked to neuropsychiatric SLE

SLE: MRI

Small focal periventricular and cortical white matter lesions (40 to 80%)

Diffuse brain atrophy: correlated with cognitive decline and duration Diffuse white matter lesions Gross infarction

SLE :Investigations CT PET:

– 40 to 80% of patients with neuropsychiatric SLE show bilateral parietooccipital white matter hypometabolism in absence of MRI abnormalites

MRS:– Detect neurometabolic abnormalities in apparently

normal white and gray matter CSF:

– Raised protein level– Neutrophil or lymphocyte pleocytosis– Oligoclonal bands in 50% of cases

Biopsies: skin, renal

SLE: Treatment

Immune suppression

– IV prednisolone followed by oral therapy

– IV cyclophosphamide

– Azathiprine

– Others• Mycophenolate mofitil

• Hydroxychloroquine

• Rituximab

• Plasmapharesis

• IVIG

SLE Treatment

Symptomatic treatment for

– Seizures

– Psychiatric manifestations Prevention of stroke

– Moderate to high doses of warfarin

Antiphospholipid syndrome

Antiphospholipid Abs include

– Lupus anticoagualnts

– Anticardiolipin : • IgG, IgM

• β2-GP1 component is associated with strokes and myocardial infarctions

– Antiphosphatidyl letholamine

– Antiphosphatidyl serine

– Antiphosphatidyl choline

– Responsible for falsely negative syphilis serology


Defined as an episode of arterial or venous thrombosis leading to tissue ischemia or recurrent foetal loss in the presence of moderate to high titre of aPL or lupus anticoagulant on at least two occasions at least 12 weeks apart

Other laboratory findings

– Prolonged PTT

– Thrombocytopenia


Primary antiphospholipid syndrome In association with other vasculitis esp SLE Other secondary causes

– Infections e.g.HIV

– Inflammatory bowel disease

– Drugs: hydralazine, phenytoin, valproate, phenothiazides

– Liver transplantation

– Paraproteinemias May be rarely seen in normal individuals


Direct role on pathogenesis through interactions with platelets, endothelium and coagulation proteins

Bind to phospholipid components on various cells Stimulate intracellular signaling of P38 mitogen

activated protein kinase. This event is probably important in intiating thrombotic events

Two hit hypothesis

– aPL induce a prothrombotic state

– Thrombosis is triggered by second local trigger

Antiphospholipid syndrome: Clinical manifestations

Neurological– Ischaemic stroke– Cognitive abnormalitis– Headaches– Multiple sclerosis like episodes– Transverse myelitis (rare)– Seizures: direct block of GABA receptors in animals– Acute ischaemic encephalopathy:

• Confusion

• Spastic quadripareis which is usually asymmetrical

– Chorea


Systemic:

– Repeated abortions

– Endocarditis

– Deep venous thrombosis

– Arterial thrombosis in any organ

– Livedo reticularis


Catastrophic antiphospholipid syndrome

– Rapid onset of severe multiorgan failure

– Adult respiratory distress syndrome

– Abdominal pain

– Fulminant encephalopathy

Antiphospholipid Disease

Investigations: Laboratory MRI:

– Small focci of high signal in subcortical white matter scattered throughout the brain

Treatment:

– Cerebral ischemia: aspirin for primary prevention, warfarin for secondary prevention

– During pregnancy: steroids plus low dose aspirin

– Special precautions needed in perioperative period

Sneddon Syndrome

• A disorder characterized by association of extensive livedo reticularis and cerebrovascular disease due to non inflammatory arteriopathy involving smal to medium sized arteries

• Clinical manifestations:– Livideo reticularis and livedeo racemosa– Strokes: mainly affecting small vessels– Hypertension and cardiac valve disease may be seen

• aPL Abs positive in 45% of cases

• Some cases progress to SLE

• Some cases are hereditary

Rheumatoid Arthritis

A systemic inflammatory disease characterized by a polyarthiritis due to chronic deforming synovial inflammation.

Mainly affect females in child bearing age Pathogenesis :

– Rheumatic factor

– Circulating immune complexes leading to vasculitis

– Formation of rheumatoid nodules

– Release of inflammatory mediators

Rheumatoid Arthritis: systemic manifestations

Constitutional symptoms– Fever, fatigue,

weight loss, night sweats

Arthritis– Symmetrical– Deforming– Affecting small

hand joints– others joints may

be affected – Morning stiffness

Rheumatoid Arthritis: Systemic Manifestations

Skin: – Subcuatneos nodules– Vasculitis

Eyes– Episcleritis– Scleritis– Sicca syndrome

Rheumatoid Arthritis: systemic manifestations

Raynaud's phenomenon Spleen and lymph node enlargement (Felty

syndrome) Heart: pericarditis, myocarditis, aortitis, Conduction

defects Blood changes: anaemia, thrombocytosis (marker of

activity) Respiratory : cricoid arthiritis, diffuse interstitial

fibrosis, bronchiolitis, nodules Renal : no direct affection but may be secondary to

medication or amyloidosis

Rheumatoid Arthritis: Neurological Manifestations

Entrapment Neuropathies:– Due to compression of peripheral nerves by

hypertrophied synovium or joint deformity

– Carpal tunnel syndrome is the most common

– Other forms• Ulnar nerve compression at the elbow

• Lateral popliteal nerve at the head of fibula

• Tarsal tunnel syndrome

• Posterior interosseous neuropathy

• Digital nerve compressiom


Vasculitic Neuropathy– Due to: necrotizing vasculitis of the vasa nervosa– Manifests as:

• Mononeuritis multiplex• Polyneuropathy: distal, symmetrical,

predominantly sensory

Left: nerve bundle with vasa nervosum in the centre. Right necrotizing vasculitis of the vasa nervosum with obliteration of the lumen and inflamatory cell infiltration


Cervical cord complications– Due to damage of articular structures in the cervical

spine with compression of nervous structures Atlanto-axial sublaxation:

– Pathology: Erosion of the transverse ligament of the atlanto-odontoid joint leading to posterior movement of the peg on neck flexion with indentation of the cord

– Clinical manifestations• Often asymptomatic

• Pain: involve the head and may radiate anteriorly into fronto-temporal region

• Parasthesia or electric like pain in the arms

Rheumatoid Arthritis: Altantoaxial sublaxation

Cervical myelopathy:– Mild spastic

quadriparesis– Atrophy in the

hands: difficult to elicit in patients with severe deformities

– Sensory loss in hands and upper cervical dermatomes

Investigations:– Plain X-ray – MRI

Increased distance between the anterior border of the dens and the posterior border of the anterior tubercle of C1 (blue line) The "pre-dentate space," should be less than 3 mm in the adult. The red line above should smoothly connect all of the spinolaminar white lines of each vertebral body but clearly is directed posterior to the spinolaminar white line of C1 (green arrow) since C1 is subluxed forward on C2.

Rheumatoid Arthritis: Neurological complications

Subaxial Sublaxation– Due to cervical facet joint

involvement below the atlantoaxial joint

– Most common in C2-C3, C3-C4– Multiple partial sublaxation lead

to staircase spine

Basilar invagination– Due to destruction of the lateral

masses of C2– Results in descent of the skull into

the cervical spinal with upward migration of odontoid process

– Lead to lower cranial neuropathy, pontine or medullary dysfunction


Rheumatoid meningitis;– Due to direct involvement of the meninges by

rheumatoid inflammatory process– Typically affects the dura but leptomeningitis may

occur– May occur at any stage of the illness– Clinical manifestations:

• Headaches

• Seizures

• Cranial neuropathies

• Focal neurological symptoms

Rheumatoid Arthritis: Neurological Manifestations Other rare complications

– Encephalopathy: diffuse vasculitis– Polymyositis– Rheumatoid nodules in brain and spinal cord

Complications of treatment– Gold: peripheral neuropathy, may resemble GBS– D-penillamine: drug induced myasthenia gravis,

myopathy, taste disturbances– Methotrexate: Rarely cause leucoencephalopathy in

doses used for RA– TNF inhibitors (e.g etanrecept, influximab), increased

liability to infection, activation of TB, rare MS like demyelination, neuropathy

– Chloroquine: neuropathy, myopathy or both– Leflunoamide: axonal neuropathy

Rheumatoid Arthritis: Investigations

Serological marker– Rheumatoid factor: more important as a marker of

activity

– ANA positive in 20% of cases Markers of inflammation:

– ↑ESR, ↑CRP, thrombocytosis, normal complement According to presentation

– Cervical imaging

– Meningitis: CSF and meningeal biopsy

– Neuropathy: Neurophysiology, nerve biopsy

Rheumatoid Arthritis: Treatment

Close co-operation with rheumatologist for management Cervical disease:

– Conservative: soft collar, physiotherapy, avoid hyperextension

– Surgical:indicated in • Myelopathy• brainstem compression• Severe spinal stenois• Spinal instability• intractable pain

Meningitis: no etablished treatment, but steroids, cyclophpsphamide and TNF inhibitors were used

Neuropathy: immune suppressants

Sjogren Syndrome

Systemic autoimmune disorder characterized clinically by sicca syndrome and pathologically by lymphocytic infiltration of exocrine glands

Subtypes– Primary Sjogren syndrome

– Scondary Sjogren syndrome: in association with other autoimmune disorders such as

• SLE

• Systemic sclerosis

• Polymyositis

• Primary biliary cirrhosis

Sjogren Syndrome: Clinical manifestations

• Glandular manifestations:– Dry eyes– Dry mouth– Parotid gland enlargement– Kerato-conjunctivitis sicca: damage to the cornea

and conjunctiva as a consequence of xeropthalmia• Extra-glandular manifestations:

– The presenting manifestations in one third of patients

– Joint problems

– Constitutional symptoms

– Renal disease

Sjogren Syndrome: Neurological Manifestations

• Peripheral neuropathy: Seen in 30-60% of cases• Ataxic sensroy neuronopathy

– Due to lymphocytic infiltration of the dorsal root ganglion with neuronal degeneration and neuronal loss

– Subacute or chronic onset– Severe proprioceptive sensory loss leading to sensory

ataxia, positive rombergism and pseudoathetosis– Lost reflexes

• Trigeminal sensory neuropathy– Sensory ganglionopathy of the trigeminal nerve is

suspected– Numbness, parasthesia and diminished pain

sensation in one or both trigeminal nerves– No motor dysfunction


• Painful sensory neuropathy– Chronic small fibre neuropathy– Presents with distal painful dysthesias with distal

sensory loss– Deep tendon reflexes are preserved– No ataxia– Normal nerve conduction studies– Reduced epidermal nerve fibre density

• Autonomic neuropathy– Rarely isolated – Aidie's pupil– Orthostatic hypotension– Hypohydrosis


• Mononeuritis multiplex:

• Multiple cranial neuropathies

• Radiculoneuropathies

– Chronic sensory motor radiculoneuropathy

– Elevated spinal fluid protein

– F-wave latency prolongation

– Gadoloniumenhancement of spinal roots in cauda equina


• CNS manifestations– Link to cognitive deficits, behavioural changes and

MS like picture is not well established

– Co-occurrence with neuromyelitis optica is better documented

– Myelopathy may take the form of• Extensive longitudinal myelitis

• Acute transverse myelitis

• Chronic myelopathy

• Intraspinal haemorrhage

– Focal cerebral ischemia: uncommon

Sjogren Syndrome: Management

• Investigations– Serology:

• Anti Ro/ Anti La:positive in 60% of cases• RF and ANA may be positive• α Fodrin Antibody: organ specific antibody against

salivary gland antigen, diagnsotic validity still uncertain

– Tests for peripheral neuropathy• Treatment of neurological complications:

– Not fully agreed– Corticosteroids – Other immune modualtors: Azathipoprime,

cyclophoshpamide– IVIG and influximable tried in neuropathy with little

improvement

Systemic Sclerosis

• A disorder characterized by wide spread and slowly progressive fibrous sclerosis affecting skin, lung, kidney, gut and heart

• Subtypes;

– Systemic sclerosis: limited or diffuse

– CREST syndrome (Calcinosis, Raunaud's phenomenon, Sclerodactly, Esophegeal stricture, Telangectasia)

– Localized sclereoderma

Systemic Sclerois: General Manifestations

• Skin• Lungs: progressive

fibrosis, pulmonary hypertension

• Renal • GIT: reflux, stomach

outlet obstruction, intestinal pseudo-obstruction

• Joint

• Cardiac

Systemic Sclerosis: Neurological manifestations

• The least likely collagen disorder to cause neurological complications

• Manifestations include

– Peripheral neuropathy

– Myelopathy

– Entrapment neuropathy

– Cerebral arteritis

– Painful trigeminal neuropathy

– Intracerberal small vessel disease

– Myopathy

Mixed Connective Tissue Disorder

• Characterized by mixed features of scelroderma, polymyositis and SLE

• High Antibody levels of ANA, Anti-ribonuclease

• Neurological Presentations:

– Trigeminal neuropathy

– Sensory neuropathy

– Polymyisitis

Seronegative Arthritis

Ankylosing spondylitis:• Neurological

manifestations reflect severe spinal disease

Reiter's disease• Triad of Seronegative

arthropathy, urethritis, conjunctivitis

• Neurological manifestations in 25% of cases

• Aseptic meningitis, seizures and psychiatric manifestations are most common, but wide range described

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Other forms of Vasculitis: Isolated CNS Vasculitis

• A rare form of vasculitis of unknown etiology confined to the brain and spinal cord

• Pathology:

– Chronic granulomatous inflammation of the vessel wall

– Mainly affects smal arteries and veins (less than 200μm)

– Mainly affects leptomeningies – Affection is segmental and focal– Pathological subtypes: granulomatous, necrotizing,

lymphocytic

Isolated CNS vasculitis: Clinical picture

• Most common in males above the age of 50• Encephalopathic form: Progressive cumulative

multifocal neurologica dysfunction resembling• Stroke like presentation: Ischaemic or

hemaorrhagic lesions with evidence of more widespread affection

• Headache• Focal neurological deficits: hemiparesis, ataxia,

aphasia, seizures• Non specific visula complaints: in 15% of patients• Systemic sympotms are generally absent

Primary CNS angitis: Investigations

• Lab results are usually unremarkable• ESR; mildly elvated in 30% of cases• EEG: non specific slowing• CT: multiple focal areas of low intensity nad/or

hemorrhages• MRI: non specific

– Wide spread T2 hyperintensities – Linear and punctate pattern of leptomeningeal

enhancement• MRA: does not usually show vasculopathy• CSF: increased protein and lymphocytes• Angiography: may be normal

Primary CNS angitis: Management

• Brain biopsy: – the most reliable diagnostic technique– Best yield when: taken from lesion and involving

leptomeingies– If no accessible lesion: non dominant frontal lobe

• Treatment: high dose steroids• Prognosis: may not always be poor

Susac syndrome

• A non inflammatory microangiopathy of unknown cause characterized by a triad of deafness, retinal microinfarction and encephalopathy

• Affects mainly young adult females• Course: recurrent attacks variably including one or more of

ocular, cochlear or cerebral manifestation• Investigations:

– No peripheral markers of inflammation– CSF: normal or show mild inflammatory response– MRI: multifocal microinfarcts in both white matter and grey

matter– Ovoid ischaemic lesions of the ocrpus callosum are the

morphological finger print of Susac syndrome• Treatment:

– Corticosteroids or other immune suppressant– Anticoagulants

Susac syndrome

Fundus shows two area of retinal infarction from occlusion of both superior and inferior branch retinal arterioles.MRI of the brain showing typical corpus callosum changes in Susac syndrome

Relapsing polychondritis

• Very rare disorder characterized by recurrent inflammatory episodes affecting cartilage often associated with inflammation of other organs

• Systemic manifestations:– Eyes: Episcleritis or conjunctivitis– Joint inflamation– Deafness and vertigo: of peripheral origin– Constitutional symptoms: fever, malaise– Inflammation of cartilage:

• Ear, nose , ear larynx• Attacks last for 1- 4 weeks and may resolve

spontaneously

Relapsing polychondritis

• Neurological manifestations– Global encepahlopathy– Seizures– Strokes– Cranial neuropathies esp.

facial and optic– Subacute aseptic meningitis– Aortic arch syndrome

• Investigations:– Elevated ESR– 50% show ABS against type

2 collagen• Treatment: coricosteroids

Other Rare CNS vasculopathies

• Cogan syndrome:– Recurrent episodes of interstitial keratitis, vestibular

auditory symptoms with central or peripheral nervous system involvement

• Eale's disease:– Isolated retinal vasculitis causing visual loss.

Neurological complication rare

• Kohler Degos Syndrome:– Rare non inflammatory occlusive vasculopathy

involving skin (papular lesions), GIT (peritonitis, gut perforation) and CNS (Hemorhages)

Behcet disease

• A multi system disease of unknown cause charactarized by perivascular inflamation leading to oral and genital ulcers, uveitis and recurrent venous thrombosis.

• Epidemiology– Incidence varies from 7/10000 in Europe to

42/10000 in Turkey

– Geographical distribution follows the old Silk Route

– Men more commonly affected than women

– Age of onset 20-40 but may occur in childhood

– Diagnosis unlikely after the age of 50

Behcet disease:Aetiology

• Not completely understood• Does not show typical features of autoimmune

diseases• Genetic factors:

– Association with HLA B51 is the best established, seen in 55 to 75% of cases

• Environmental factors– Infectious agents might trigger an immune response

through antigenic mimicry– Best evidence for a role of oral streptococcal

infections, with improvements in oral hygiene improving prognosis

– Other viral and fungal agents implicated

Behcet disease:Pathogenesis

• It involves arteries and veins of all sizes• The inflamation may be vascular or perivascular• Injury to vascular wall is seen with

– Oral and genital ulcers– Skin lesions– Uveitis– Major vein occlusion

• No injury to vessel wall in acne and brain lesions• Neurtrophilic hyperfunction plays a pivotal role in

inflamation and underlies pethergy reaction• Role of B and T lymphocytes is less clear• Thrombotic tendency caused by a combination of

disordered coagulation and endothelial dysfunction

Behcet disease: Systemic manifestations• Mucocutaneous manifestations

– Oral ulcers– Genital ulcers– Erythema nodosum like – Acne– Pathergy reaction

• Eye manifestations:– Seen in 50% patients– Anterior uveitis– Posterior uveitis

• Joint disease:– Non deforming arthiritis

or arthralgia– Knee most commonly

affected– Back pain is uncommon

Behcet disease: Systemic manifestations

• Major vessel involvement– Thrombophlebitis– DVT of large veins– Arterial aneurysms– Pulmonary artery

aneurysms• Gastrointestinal

involvement:– Mucosal ulceration– Colicky abdominal

pain – diarrhea – Common in far east

Behcet Disease:Neurological manifestation

• Appearance of neurological symptoms in a patient with Behcet disease that are compatible with neurological syndromes known to arises in the disease after other causes have been ruled out

• Usually develop 3-6 years after onset• The first manifestation in 6% of cases• Classified into

– Central nervous system manifestations• Parenchymal• Non-parynchmal

– Peripheral manifestations– Other uncommon syndromes

Behcet Disease: Parenchymal invovlement

• Subacute meningioencephalitis– 75% of cases– Often associated with exacerbation of systemic disease– Brain stem involvement

• Ocular abnormalities• Other cranial nerve involvement• Cerebellar dysfunction• Pyramidal manifestations

– Cerebral hemisphere involvement:• Encephalopathy• Hemiparesis• Seizures• Dysphasia• Cognitive dysfunction

Behcet Disease: Parenchymal involvement

• Spinal cord involvement• Progressive subcortical demntia

– Usually accompanied by ataxia– Accounts for 10% of cases

• Asymptomatic parenchymal involvement– Diagnosed in patients with neurological signs on

examination but no neurological symptoms– May be associated with MRI abnormalities

• Stroke– Stroke like presentation is usually due to parencymal

affection– Ischemic stroke occurs in only 1.5 % of cases

• Epilepsy– Occur in 2-5% of cases– Mostly generalized

Behcet Disease: Parenchymal involvement

• Tumor like presentation– Very rare– Large lesion involving

diencephalon or brainstem– Most patients were known

to have Behcet diseae– Biopsy was needed for

diagnosis in the majority– Good response to

coricosteroids• Acute meningitis

– Relatively common with parenchymal disease

– Rare in isolation

Behcet Disease: Parenchymal Complications

• Other rare Parenchymal manifestations– Movement disorders– Optic neuropathy (0.4%) – Isolated transverse myelitis

• Behcet Disease: Non Parenchymal Complications

• Due to involvement of major blood vessels• Affects one fifth of patients• Include

– Venous sinus thrombosis

– Intracranial aneurysms (exceedingly rare)

Behcet Disease: Other manifestations

• Mixed parenchymal and vascular disease (20%)• Psychiatric manifestations

– Anxiety and depression– Most likely reaction to illness

• Cognitive impairment– Usually associated with other manifestations– Manifestations of subcortical dementia

• Headache:– Seen in 70% of cases– Migraine or tension like headache are the msot

common• Peripheral neuropathy (doubtful relationship)• Myositis: may occur especially children

Behcet disease: Investigations• Diagnosis is mainly clinical with no specific test• Blood tests

– ESR: elevated with activity– CBC: to exclude infections– HLA typing: good exclusion test– Coagulation profile: in patient presenting with venous

thrombosis• CSF:

– Abnormal in 80% of patients with parencymal disease– Raised proteins– Cells: neutrophila followed by lymphocytosis– Oligoclonal bands may be positive– Cytokine levels: under research– Normal CSF with vacular complications

Behcet disease: Investigations

MRI of the brain• Characteristic changes:

Hyperintense lesions in T2 involving the upper brain stem extending into basal ganglia and thalamus

• Positive enhancement• Subcortical white matter

changes, MS-like if extensive

• DWI: to differentiate from acute stroke

Behcet disease: Investigations• Spinal MRI

– Single lesions– Extend over two or three

lesions– Edema is common

• MRC or CT venography• SPECT:

– not clinically valuable– Abnormal metabolism

seen in patients without neurological symptoms

• EEG:– Non specific slowing– Differentiate NBD from

viral encepahlitis

Behcet disease:Treatment

• No controlled studies for any aspect of neurological involvement in Behcet disease

• Parenchymal disease– IV methyl predniolone followed by oral steroids– Other imune suppressors used if unresponsive or

recurrent– Influximab: tried successfully in aggressive disease

not responding to other treatments• Venous thrombosis

– Steroids and immune modulators needed– Anticoagulation: controversial

Behcet disease: Prognosis

• Acute parenchymal inflammation– Usually resolves but residual deficit seen in 20-30%– One third of patients have recurrent attacks, one

third single attacks, one third have progressive accumulation of neurological deficits

– Adverse prognostic factors include• Frequent relapses

• Residual neurological impairment

• Brain stem and spinal cord lesions

• More abnormal CSF

• Venous thrombosis: recover well• Vision: severe vision loss occur in less than 20%

of cases with adequate treatment

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