Central nervous system vasculitis

Baghbanian SMNeurologist

Introduction

• one of the most formidable diagnostic and therapeutic challenges for physicians.

• may be identical to those produced by infection, occlusive vascular disease, or malignancy.

• lack of an accurate and sensitive diagnostic tests.• based on familiarity with the various clinical

syndromes associated with CNS vasculitis, the understanding of the nature of the disease, and the knowledge of its mimics.

classification

• Primary angiitis of the CNS (PACNS) when it is confined to the CNS.

• secondary when associated with various other disorders.

• Reversible cerebral vasoconstriction syndromes

Primary central nervous system vasculitis

• Initial reports of PACNS described it as a fatal and progressive granulomatous vasculitis and referred to it as granulomatous angiitis of the CNS (GACNS) .

• Increasing interest in the disease emerged with the reports of successful treatment with cyclophosphamide and glucocorticoids.

proposed the criteria for the diagnosis of PACNS.

• The presence of an acquired and otherwise unexplained neurologic deficit and with– (a) the presence of either classic angiographic or

histopathologic features of angiitis within the CNS, and

– (b) no evidence of systemic vasculitis or any condition that could elicit the angiographic or pathologic features

different subsets

• GACNS,• and atypical cases• Recently, the term reversible cerebral

vasoconstriction syndrome (RCVS

Granulomatous angiitis of the central nervous system

• about 20% of all patients with PACNS.• male-predominant and occurs at any age.• characterized by a long prodromal period, with

few patients presenting acutely.• Signs and symptoms of systemic vasculitis such

as peripheral neuropathy, fever, weight loss, or rash are usually lacking.

• affect any area of the CNS, its presentation may vary widely, and no set of clinical signs is specific for the diagnosis.

Signs and symptoms of GACNS

• (1) Chronic headaches.• (2) Encephalopathy.• (3) Strokes/transient ischemic attack (more

common recurrent).• (4) Seizures.• (5) Behavioral and cognitive changes.• (6) Focal motor/sensory abnormalities.• (7) Ataxia.• (8) Myelopathy

GACNS may be suspected in the setting

• Chronic meningitis, • recurrent focal neurologic symptoms,• unexplained diffuse neurologic dysfunction,• or unexplained spinal cord dysfunction not

associated with systemic disease

characteristic pathologic findings

• granulomatous angiitis affecting – the small and medium leptomeningeal and

cortical arteries with Langhans or foreign body giant cells, necrotizing vasculitis, or a lymphocytic vasculitis.

– The inflamed vessels become narrowed, occluded, and thrombosed,

– causing tissue ischemia and necrosis of the territories of the involved vessels

The primary event

• It is possible that altered host defense mechanisms tilt the balance of the immune system and allow a viral illness to escape the immune system, which sets off the vasculitic process.

Reversible cerebral vasoconstriction syndromes

• Benign angiopathy of the CNS (BACNS)• a distinct subset of patients with isolated

neurologic events, characterized by• female predominance,• acute presentation,• reversible angiographic abnormalities,• normal results on spinal fluid examination, • and monophasic course

The term ‘angiopathy’

• because of uncertainty regarding the nature of the pathologic process affecting the vessel wall and the lack of evidence of blood vessel inflammation.

• Dramatic resolution of angiographic abnormalitiesin series of 16 patients within 4–12 weeks without intensive immunosuppressive therapy.

• With these data, it became apparent that the underlying pathophysiologic disorder in BACNS patients was reversible vasoconstriction rather than vasculitis.

criticalelements for the diagnosis of RCVS

• (1) Transfemoral angiography or indirect computed tomography angiography (CTA) or magnetic resonance angiography (MRA) documenting multifocal segmental cerebral artery vasoconstriction.

• (2) No evidence for aneurysmal subarachnoid hemorrhage.• (3) Normal or near-normal cerebrospinal fluid analysis (protein

level<80mg%, leukocytes <10mm3, normal glucose level).• (4) Severe, acute headaches, with or without additional neurologic

signs or symptoms.• (5) Reversibility of angiographic abnormalities within 12 weeks after

onset.• If death occurs before the follow-up studies are completed, autopsy

rules out such conditions as vasculitis, intracranial atherosclerosis, and aneurysmal subarachnoid hemorrhage, which can also manifest with headache and stroke

Comparison of clinical and diagnostic characteristics of reversible cerebral vasoconstriction syndromes and granulomatous

angiitis of the central nervous system

RCVS

• include – BACNS,– Call–Fleming syndrome, – Postpartum angiopathy, – migrainous vasospasm,– and drug-induced ‘arteritis’

Clinical and radiographic data in 67 patients withreversible cerebral vasoconstriction syndrome

CNS pathology of patients withRCVS

• of the largest series of RCVS to date included 120 patients, 21 of whom underwent brain biopsies.

• None of these biopsies revealed any vasculitic changes.

Primary angiitis of the central nervous system:atypical cases

• Most PACNS patients present atypically.• does not fit the diagnostic features for either GACNS

or RCVS.• patients with abnormal cerebrospinal fluid (CSF)

findings that preclude a diagnosis of RCVS• or those with GACNS-like presentation but without

granulomatous features on CNS biopsies• PACNS at unusual anatomic sites such as the spinal

cord • those presenting with mass lesions

Secondary central nervous system vasculitis

• in association with multiple conditions including– systemic vasculitides,– connective tissue disease (CTD),– sarcoidosis,– infections, – lymphoproliferative diseases.

Infectious causes of central nervous system vasculitis

• great mimickers of PACNS.• The possibility of infections – with human immunodeficiency virus (HIV),– Varicella zoster (VZV),– or syphilis

• should be actively identified

VZV-associated cerebral angiitis

• affects older age groups.• tends to be more localized than PACNS as well as less

severe.• The known antecedent infection with herpes zoster

suggests the underlying cause.• Cerebral angiographic findings of segmental, unilateral

involvement of the vessels in the distribution of the middle cerebral artery and, occasionally, the internal carotid artery are characteristic findings in VZV angiitis.

• The diagnosis is confirmed by the presence of higher antibodies levels of VZV in the CSF than in the serum or by a positive VZV PCR in the CSF

Cerebrovascular disease in HIV

• very complex and challenging.• a significant number (35%) of pathologic findings of

AIDS-associated CNS disease demonstrate encephalitis, leptomeningitis, and/or vasculitis, opportunistic infections.

• neurosyphilis is most common in patients with HIV infections.– Meningitis and meningovascular disease are the usual

manifestation.– This will manifest as an ischemic stroke in a young person

and can be easily mistaken as PACNS.

Cerebral angiogram of a patient with meningovascular syphilis

• (a) Magnetic resonance angiography showing basilar artery narrowing with irregularity (long arrow) and abrupt cut off of the right vertebral artery (short arrow).

• (b) Angiogram showing narrowed left internal carotid artery.

vasculitis associated with hepatitis C virus (HCV) withoutunderlying cryoglobulinemia

• HCV genetic sequences in postmortem brain tissue has suggested a biologic mechanism that underlies the cognitive findings in patients with HCV infection.

Other organisms of interest that can affect the CNS

• include • Borrelia burgdorferi • Bartonella • Mycobacterium tuberculosis• cysticercosis can involve middle-size cerebral

vessels in subarachnoid cysticercosis even in patients without clinical evidence of cerebral ischemia.

Systemic vasculitides

• Most commonly reported in – polyarteritis nodosa (PAN),– microscopic polyangiitis (MPA),– Behc¸et’s disease,– Wegener’s granulomatosis – Churg–Strauss syndrome

Wegener’s granulomatosis

• CNS may be involved in around 2–8%.• Stroke, seizures headaches, confusion, and

transient neurologic events such as paresthesia, blackouts, or visual loss are common manifestations.

• Radiographically confirmed vasculitis of the CNS in Wegener’s granulomatosis is rare, because the small vessels (50–300mm in diameter) are typically below the sensitivity of routine angiography

Behc¸et’s disease

• The CNS may be affected in 10–49% of patients.

• either from primary inflammation of CNS tissue or from vasculitis with a venous predominance leading to ischemic stroke.

Connective tissue diseases

• CNS involvement in CTDs in not uncommon.• Especially in patients with systemic lupus

erythematosus (SLE)• Sjo¨gren’s syndrome,• rheumatoid arthritis,• mixed CTDs,• dermatomyositis.

An important consideration in thediagnostic approach to a patient with neurologic dysfunction

in the setting of CTDs

• whether the particular clinical syndrome is due to CTD-mediated organ dysfunction,

• a secondary phenomenon related to infection.• medication side-effects.• or metabolic abnormalities (e.g. uremia),• or is due to an unrelated condition.

Systemic vasculitides

• The most common disorder affecting the CNS in SLE.• Sjo¨gren’s syndrome, like Behc¸et disease, may mimic

multiple sclerosis and present as a relapsing-remitting or primary progressive neurologic dysfunction.

• Rheumatoid vasculitis affecting the CNS is rare and may present with

• seizures, • dementia, • hemiparesis, • cranial nerve palsy, • blindness,• hemispheric dysfunction, • cerebellar ataxia, • or dysphasia.

Antiphospholipid syndrome

• highly encountered in the differential diagnosis of CNS vasculitis.

• Thrombotic-related events are the most common APS neurologic manifestation.

• Seizures, cognitive dysfunction, or psychosis may be the target of antibody-mediated endothelial damage.

• Antiplatelet or anticoagulant therapies are currently indicated

• remain controversial for nonthrombotic neurologic manifestations

Hodgkin’s and non-Hodgkin’s lymphoma andangioimmunolymphoproliferative lesions

• Mass lesions, lymphocytic disease, and spinal cord involvement raise the suspicion of lymphoproliferative disease.

• Appropriate immunohistochemistry staining as well as B-cells and T-cells markers should be performed even with the pathologic finding of angiitis because the presence of vasculitic changes does not exclude an underlying lymphoproliferative condition.

Other miscellaneous disorders

• Mitochondrial encephalomyopathy, lactic acidosis, and stroke syndrome (MELAS), which is a mitochondrial genetic disorder caused by a point mutation at nucleotide 3243 (A3243G) leading to

– stroke-like episodes before age 40, – seizures, – dementia, – and ragged-red fibers in muscle.

• cerebroretinal vasculopathy syndrome, which is an autosomal-dominant retinal vasculopathy with cerebral leukodystrophy leading to stroke and dementias with middle-age onset.

Diagnosis

• The first task of the clinician is careful history and physical examination.

• The presence of • systemic features, • symptoms outside the CNS, • and clues from past medical history

• deviate the hierarchy of the differential diagnosis to either systemic vasculitides, infectious or vaso-oclusive diseases.

laboratory tests• no laboratory tests that are diagnostic for CNS vasculitis.• Acute-phase reactants, such as sedimentation rate and C-reactive

protein, are usually normal in patients with PACNS.• If serum markers of inflammation are elevated, secondary forms of CNS

vasculitis should be evaluated.• Testing for a variety of infectious organisms, such as mycobacteria,

fungi, syphilis, and HIV, is warranted in patients presenting with chronic meningitis.

• Other serologic tests are indicated if there is a history of exposure, such as tick bites in Lyme disease.

• Evaluation for hypercoagulable states, emboli,• and investigation of drug exposure, including over-the-counter

medications, are essential in patients who present with acute focal or multifocal disease

CSF analysis

• an essential tool.• great value in ruling out infectious mimics.• abnormal in 80–90% of pathologically documented cases

of PACNS.– aseptic meningitis, – with modest pleocytosis,– normal glucose, – elevated protein levels, – occasionally the presence of oligoclonal bands – and elevated IgG synthesis

• Patients withRCVS typically have a normal or near-normal CSF analysis.

Neuroimaging studies

• CT and MRI, are not specific or sufficient for diagnosis of CNS vasculitis.

• MRI findings include multiple and often bilateral infarcts – in cortex,– deep white matter, or leptomeninges,

• with or without contrast enhancement.• Normal MRI of the brain is not infrequent in

RCVS.

Neuroimaging studies

• The most common findings in RCVS include infarction particularly – in arterial ‘watershed’ and ‘borderzone’ regions, – parenchymal hemorrhages – and small nonaneurysmal subarachnoid hemorrhages

overlying the cortical surface.• brain infarction results from severe hypoperfusion

distal to severe vasoconstriction, and hemorrhage presumably results from reperfusion injury.

• Posterior reversible leukoencephalopathy has also been reported in RCVS

Cerebral angiography

• is a critical modality.• should be aware of its limited specificity and

lack of quantitative and qualitative codification.• most sensitive for disease of larger vessels.• The sensitivity decreases with the calibre of the

vessel.• should be interpreted cautiously, given its poor

specificity.

Cerebral angiography

• In GACNS, the sensitivity of cerebral angiography findings is as low as 10–20%.

• is not considered the procedure of choice in ascertaining the diagnosis of GACNS.

• Involvement of multiple vessels in multiple vascular beds (high probability angiogram) raises the possibility of RCVS. These angiographic findings are characteristic of RCVS.

• More important is the, documentation of reversibility of the angiographic abnormalities, along the course of the disease

Pathologic evaluation

• The procedure of choice is open-wedge biopsy of the tip of the nondominant temporal lobe with sampling of the overlying leptomeninges and underlying cortex.

• directing the biopsy to an area of leptomeningeal enhancement, when present, may increase the sensitivity.

• Brain biopsy is limited by its low sensitivity. • False negative biopsies can be as high as 25% of autopsy-

documented cases.• presence of vasculitis in the biopsy specimen should not

preclude performing special stains and cultures for occult infections that may produce secondary vascular inflammation

Treatment in GACNS

• patients are treated with a combination regimen of cyclophosphamide and glucocorticoids.

• Upon securing remission for 3–6 months, cyclophosphamide is switched to an alternative immunosuppressant agent such as azathioprine,methotrexate, or mycophenolate mofetil.

Treatment in GACNS

• Serial MRI examinations at 3–4-month intervals to search for silent progression during tapering of therapy and evaluation and documentation of clearance of CSF abnormalities are important measures in following these patients.

• Adjunctive therapies, such as prophylaxis for pneumocystis carinii infection and adequate prophylaxis for osteoporosis, should be implemented to avoid treatment-related toxicities.

Treatment In RCVS

• successful treatment has been reported with calcium channel blockers, short-term glucocorticoids and magnesium sulfate.

• Nimodipine or verapamil should be considered as first-line therapy.

• short-term high-dose glucocorticoids have been reported to be effective.

• Documentation of dynamic angiographic changes within 6–12 weeks after therapy is essential in securing the diagnosis.

Treatment In PACNS

• in the atypical category can be initially treated with glucocorticoids alone, with tailoring of treatment according to severity and/or progression of the disease. For those patients with a RCVS-like presentation, the addition of a calcium channel blocker is warranted. The addition of cyclophosphamide may be needed in patients with a severe presentation.

Treatment in systemic vasculitis• In general, high-dose glucocorticoids are essential in all

patients in addition to other immunomodulating agents.• Cyclophosphamide is favored in extraarticular disease

manifestations in RA. • however, tumor necrosis factor inhibitors such as infliximab

may be successful in treatment resistant rheumatoid vasculitis .

• Rituximab use in neuropsychiatric systemic lupus erythematosis (NPSLE) therapy is promising.

• Rapid improvement of CNS-related manifestations, particularly acute confusional state was described in a recent report .

• These results warrant further analysis of rituximab as treatment of NPSLE.

infection-associated CNS vasculitis

• Antimicrobial drugs, • adjunctive immunosuppressive therapy may

be required in patients who do not respond to antimicrobial therapy, though there are no supportive data for this recommendation.