Central nervous system vasculitis
• 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.
• Primary angiitis of the CNS (PACNS) when it is
confined to the CNS.
• secondary when associated with various other
• Reversible cerebral vasoconstriction
Primary central nervous system
• 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
• 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,
– (b) no evidence of systemic vasculitis or any
condition that could elicit the angiographic or
• and atypical cases
• Recently, the term reversible cerebral
vasoconstriction syndrome (RCVS
Granulomatous angiitis of the central
• 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.
GACNS may be suspected in the
• 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
– The inflamed vessels become narrowed, occluded,
– 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
Reversible cerebral vasoconstriction
• 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
• Dramatic resolution of angiographic
abnormalitiesin series of 16 patients within 4–
12 weeks without intensive immunosuppressive
• With these data, it became apparent that the
underlying pathophysiologic disorder in BACNS
patients was reversible vasoconstriction rather
elements 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
• 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
– Call–Fleming syndrome,
– Postpartum angiopathy,
– migrainous vasospasm,
– and drug-induced ‘arteritis’
Clinical and radiographic data in 67 patients with
reversible cerebral vasoconstriction syndrome
CNS pathology of patients with
• of the largest series of RCVS to date included
120 patients, 21 of whom underwent brain
• None of these biopsies revealed any vasculitic
Primary angiitis of the central nervous system:
• 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
• those presenting with mass lesions
Secondary central nervous system
• in association with multiple conditions
– systemic vasculitides,
– connective tissue disease (CTD),
– lymphoproliferative diseases.
Infectious causes of central nervous
• 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
• 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,
• neurosyphilis is most common in patients with
– Meningitis and meningovascular disease are the usual
– This will manifest as an ischemic stroke in a young
person and can be easily mistaken as PACNS.
Cerebral angiogram of a patient with
• (a) Magnetic resonance
basilar artery narrowing
with irregularity (long
arrow) and abrupt cut off
of the right vertebral
artery (short arrow).
• (b) Angiogram showing
narrowed left internal
vasculitis associated with hepatitis C virus (HCV) without
• 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
• Borrelia burgdorferi
• Mycobacterium tuberculosis
• cysticercosis can involve middle-size cerebral
vessels in subarachnoid cysticercosis even in
patients without clinical evidence of cerebral
• 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
• 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
• The CNS may be affected in 10–49% of
• 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
• Sjo¨gren’s syndrome,
• rheumatoid arthritis,
• mixed CTDs,
An important consideration in the
diagnostic 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.
• 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
• cranial nerve palsy,
• hemispheric dysfunction,
• cerebellar ataxia,
• or dysphasia.
• highly encountered in the differential diagnosis of
• Thrombotic-related events are the most common
APS neurologic manifestation.
• Seizures, cognitive dysfunction, or psychosis may
be the target of antibody-mediated endothelial
• Antiplatelet or anticoagulant therapies are
• remain controversial for nonthrombotic
Hodgkin’s and non-Hodgkin’s lymphoma and
• Mass lesions, lymphocytic disease, and spinal
cord involvement raise the suspicion of
• 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)
– stroke-like episodes before age 40,
– 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.
• 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.
• 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
• an essential tool.
• great value in ruling out infectious mimics.
• abnormal in 80–90% of pathologically documented cases
– 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.
• CT and MRI, are not specific or sufficient for
diagnosis of CNS vasculitis.
• MRI findings include multiple and often
– in cortex,
– deep white matter, or leptomeninges,
• with or without contrast enhancement.
• Normal MRI of the brain is not infrequent in
• The most common findings in RCVS include
– 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
• is a critical modality.
• should be aware of its limited specificity and
lack of quantitative and qualitative
• most sensitive for disease of larger vessels.
• The sensitivity decreases with the calibre of
• should be interpreted cautiously, given its
• 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
• 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
• Brain biopsy is limited by its low sensitivity.
• False negative biopsies can be as high as 25% of
• presence of vasculitis in the biopsy specimen should
not preclude performing special stains and cultures for
occult infections that may produce secondary vascular
Treatment in GACNS
• patients are treated with a combination
regimen of cyclophosphamide and
• Upon securing remission for 3–6 months,
cyclophosphamide is switched to an
alternative immunosuppressant agent such as
azathioprine,methotrexate, or mycophenolate
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
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
• 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
• 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.