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
1. Large Vessel Arteritis: Temporal Arteritis
Granulomatous angitis Confined to internal
elastic lamina Inflammatory infiltrate
formed of mononuclear and giant cells
Activated T cells predominate
1. Large Vessel Arteritis: Temporal Arteritis
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
1. Large Vessel Arteritis: Temporal Arteritis
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
1. Large Vessel Arteritis: Temporal Arteritis
Other manifestations of head and neck ischemia
Jaw claudications Ischaemic
occulopathy Ischaemic necrosis
of lips, nasal septum and palate
Investigations: Arteriography MRA
1. Large Vessel Arteritis: Temporal Arteritis
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
2. Medium Vessel Arteritis: Classical polyarteris nodosa
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
2. Medium Vessel Arteritis: Classical polyarteris nodosa
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
3. ANCA associated vascultis: Churg Strauss syndrome
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
3. ANCA associated vascultis: Churg Strauss syndrome
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
3. ANCA associated vascultis: Wegner's granulomatosis
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
3. ANCA associated vascultis: Wegner's granulomatosis
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
Antiphospholipid syndrome
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
Antiphospholipid syndrome
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
Antiphospholipid syndrome
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
Antiphospholipid syndrome: Clinical manifestations
Systemic:
– Repeated abortions
– Endocarditis
– Deep venous thrombosis
– Arterial thrombosis in any organ
– Livedo reticularis
Antiphospholipid syndrome: Clinical manifestations
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
Rheumatoid Arthritis: Neurological Manifestations
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
Rheumatoid Arthritis: Neurological Manifestations
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 Arthritis: Neurological Manifestations
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
Sjogren Syndrome: Neurological Manifestations
• 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
Sjogren Syndrome: Neurological Manifestations
• 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
Sjogren Syndrome: Neurological Manifestations
• 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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