Download Central nervous system vasculitis

Central nervous system vasculitis
Rula A. Hajj-Alia and Leonard H. Calabreseb
a
Center for Vasculitis Care and Research and bRJ
Fasenmyer Chair of Clinical Immunology, Department
of Rheumatic and Immunologic Diseases, Cleveland
Clinic, Cleveland, Ohio, USA
Correspondence to Rula A. Hajj-Ali, Center for
Vasculitis Care and Research, Department of
Rheumatic and Immunologic Diseases, Cleveland
Clinic, 9500 Euclid Avenue, Cleveland, OH 44195,
USA
Tel: +1 216 444 9643; e-mail: [email protected]
Current Opinion in Rheumatology 2009,
21:10–18
Purpose of review
In the past decade, primary and secondary central nervous system (CNS) vasculitides
have been more commonly diagnosed and recognized than previously. With the
increasing awareness of these disorders, it is crucial for the treating physician to
differentiate between causes of CNS vasculitis and to recognize their marked clinical
and pathophysiological heterogeneity. This review focuses on the major forms of primary
CNS vasculitis, as well as secondary CNS vasculitis with emphasis on their clinical
findings, diagnoses, and treatment.
Recent findings
The proposal of reversible cerebral vasoconstriction syndromes (RCVS) as a unifying
concept for a group of disorders which are characterized by acute-onset severe
recurrent headaches, with or without additional neurologic signs and symptoms, and
prolonged but reversible vasoconstriction of the cerebral arteries, has been a major
breakthrough in this field over the past decade. Recognition of this common mimic (i.e.
RCVS) has allowed optimal management of a sizable group of patients previously
confused with pathologically documented CNS vasculitis.
Summary
Sound treatment decisions are based on accurate diagnosis. It is essential for the
clinicians involved in the evaluation of patients with CNS vasculitis to be aware of its
mimics especially RCVS. This article provides a comprehensive review of CNS
vasculitis and its differential diagnosis. Furthermore, it touches upon workup and
treatment of CNS vasculitis.
Keywords
granulomatous angiitis of the central nervous system, primary angiitis of the central
nervous system, reversible cerebral vasoconstriction syndromes
Curr Opin Rheumatol 21:10–18
! 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
1040-8711
Introduction
Vasculitis that affects the central nervous system (CNS) is
one of the most formidable diagnostic and therapeutic
challenges for physicians. The ischemic symptoms and
findings induced by CNS vasculitis may be identical to
those produced by infection, occlusive vascular disease,
or malignancy. Adding to the diagnostic challenge is the
lack of an accurate and sensitive diagnostic test. The
ability of the treating physician to tackle the diagnostic
and therapeutic challenges is 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. Fortunately, over the past
several years, multiple advances occurred in these areas.
This review will summarize the clinical presentations,
the differential diagnoses, and the diagnostic and therapeutic modalities of CNS vasculitis.
Primary central nervous system vasculitis
Broadly, CNS vasculitis can be classified as primary
angiitis of the CNS (PACNS) when it is confined to
1040-8711 ! 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
the CNS and secondary when associated with various
other disorders. Initial reports of PACNS described it
as a fatal and progressive granulomatous vasculitis and
referred to it as granulomatous angiitis of the CNS
(GACNS) [1]. Increasing interest in the disease emerged
with the reports of successful treatment with cyclophosphamide and glucocorticoids. In 1988, Calabrese and
Mallek [2] 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.
In the 1990s, it was recognized that PACNS is a heterogeneous disorder with clinical subsets that significantly
differ in terms of prognosis and therapy. PACNS comprise different subsets including GACNS, and atypical
DOI:10.1097/BOR.0b013e32831cf5e6
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Central nervous system vasculitis Hajj-Ali and Calabrese 11
cases. Recently, the term reversible cerebral vasoconstriction syndrome (RCVS) was proposed to comprise a
group of disorders characterized by acute onset of headaches, with or without neurologic deficit, and prolonged
but reversible cerebral vasoconstriction. RCVS are confined to the CNS but has marked clinical and pathophysiological heterogeneity than GACNS. Being a major
mimic of PACNS, RCVS will be discussed in the section
of primary central nervous system vasculitis. However, it
cannot be overemphasized that RCVS is not a form of
true CNS vasculitis, but rather a group of vasoconstrictive
syndromes.
Granulomatous angiitis of the central nervous system
GACNS represents about 20% of all patients with
PACNS. It appears to be male-predominant and occurs
at any age. It is 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. Because the
vasculitis may 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 are
summarized below:
(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 of chronic
meningitis, recurrent focal neurologic symptoms, unexplained diffuse neurologic dysfunction, or unexplained
spinal cord dysfunction not associated with systemic
disease or any other process.
The characteristic pathologic findings include classic
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 that elicits the inflammatory
process in GACNS remains unknown. 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
[3–8].
Reversible cerebral vasoconstriction syndromes
Benign angiopathy of the CNS (BACNS) was initially
proposed as a term to characterize 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 [9]. The term
‘angiopathy’ was used because of uncertainty regarding
the nature of the pathologic process affecting the vessel
wall and the lack of evidence of blood vessel inflammation. In 2002, Hajj-Ali et al. [10] described dramatic
resolution of angiographic abnormalities in 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. Further on, the term BACNS evolved into a new
terminology referred to as reversible cerebral vasoconstriction syndromes. The evolvement in the terminology
to RCVS occurred with the recognition that RCVS comprise a group of diverse conditions, all characterized by
reversible multifocal narrowing of the cerebral arteries
heralded by sudden, severe (thunderclap) headaches
with or without associated neurologic deficits and most
importantly by reversible angiographic findings. RCVS
include BACNS, Call–Fleming syndrome, postpartum
angiopathy, migrainous vasospasm, and drug-induced
‘arteritis’ [11!!]. Calabrese et al. [11!!] proposed critical
elements for the diagnosis of RCVS which are summarized below.
(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 <80 mg%, leukocytes <10 mm3, 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.
It is essential to differentiate between RCVS and
GACNS given the different therapeutic and prognostic
implications. The signs and symptoms of the two subsets
are sharply different (Table 1). Ducros et al. [12!!]
recently described their experience of 67 patients with
RCVS. The clinical and radiographic findings of this
series are summarized in Table 2. The disturbance in
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12 Vasculitis syndromes
Table 1 Comparison of clinical and diagnostic characteristics of reversible cerebral vasoconstriction syndromes and granulomatous
angiitis of the central nervous system
RCVS
GACNS
Patients
Headaches
CSF findings
Angiography
Female predominant
Acute
Normal to near-normal
Diffuse areas of multiple stenoses and dilatation
involving intracranial cerebral arteries, which
are reversible within 6–12 weeks
CNS biopsy
No vasculitic changes
Male predominant
Chronic, insidious
Abnormal
Frequently normal; otherwise, findings range from single
or multiple arterial cut-off areas, to luminal irregularities
in single or multiple arteries, to diffuse abnormalities that
are occasionally indistinguishable from RCVS. These
abnormalities are frequently irreversible
Granulomatous angiitis
CNS, central nervous system; CSF, cerebrospinal fluid; GACNS, granulomatous angiitis of the central nervous system; RCVS, reversible cerebral
vasoconstriction syndrome. Adapted with modification from [11!!] with permission.
the control of cerebral vascular tone seems to be the
critical element in the pathophysiology of RCVS
[10,13!!]. In support of this hypothesis is the dearth of
inflammatory changes in CNS pathology of patients with
RCVS. Our recent report [13!!] 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. In addition, 98% of the follow-up
vascular imaging in this series revealed partial or full
reversibility of the initial vascular abnormalities.
The alteration in vascular tone in RCVS may be spontaneous or evoked by various exogenous or endogenous
factors. Exogeneous factors include sympathomimetic or
serotonergic drugs [14–20], and direct or neurosurgical
trauma [21–23]. Endogenous factors include serotonergic
tumors and uncontrolled hypertension [24].
Primary angiitis of the central nervous system:
atypical cases
Most PACNS patients present atypically. This subset
does not fit the diagnostic features for either GACNS or
RCVS, yet these patients demonstrate angiographic or
histopathologic evidence of PACNS. Included in this
Table 2 Clinical and radiographic data in 67 patients with
reversible cerebral vasoconstriction syndrome
Age
Female/male
Precipitating factor
None
Postpartum
Vasoactive substance
Headaches
Recurrent thunderclap
Single thunderclap
Recurrent severe
Focal neurological deficits
Seizures
Abnormal brain MRI
cSAH
Silent infarct
RPLS
42.5 (range 19–70)
43/24
25
5
37
67
63
3
1
14
2
19
15
1
6
(37%)
(8%)
(55%)
(100%)
(94%)
(4.5%)
(1.5%)
(21%)
(3%)
(28%)
(22%)
(1%)
(9%)
cSAH, cortical subarachnoid hemorrhage; RPLS, reversible posterior
leukoencephalopathy. Adapted with permission from [12!!].
group are 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. In addition,
patients presenting with PACNS at unusual anatomic
sites such as the spinal cord or those presenting with mass
lesions are included in this category.
Secondary central nervous system vasculitis
Secondary CNS vasculitis has been described in association with multiple conditions including systemic vasculitides, connective tissue disease (CTD), sarcoidosis,
infections, and lymphoproliferative diseases. CNS involvement in these setting is frequently a presumed diagnosis, on the basis of radiographic rather than pathologic
modalities.
Infectious causes of central nervous system vasculitis
Infections affecting the CNS are great mimickers of
PACNS. The infection may be occult and a high degree
of suspicion coupled with the epidemiologic features and
the individual risk factors are important features in the
workup of patients with possible PACNS. In the workup
of patients for possible PACNS, it is imperative to search
for an infectious process through CSF or pathologic
examination, even when a vasculitic process is established by pathologic basis. 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
[25] and the disease 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 [26].
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Central nervous system vasculitis Hajj-Ali and Calabrese 13
Figure 1 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. Reprinted with permission from [29].
Cerebrovascular disease in HIV is very complex and
challenging. Although a significant number (35%) of
pathologic findings of AIDS-associated CNS disease
demonstrate encephalitis, leptomeningitis, and/or vasculitis, opportunistic infections account for the majority of
the brain disorder [27]. This demonstrates the complexity of CNS disease in AIDS and the high degree of
scrutiny needed in establishing an accurate diagnosis.
Treponema pallidum can invade any vessel in the subarachnoid space and results in thrombosis, ischemia and
infarction. In the current era, neurosyphilis is most common in patients with HIV infections [28]. 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 (Fig. 1)
[29].
Of a special interest is the increasing report of CNS
vasculitis associated with hepatitis C virus (HCV) without
underlying cryoglobulinemia [30]. The detection of
HCV genetic sequences in postmortem brain tissue
has suggested a biologic mechanism that underlies the
cognitive findings in patients with HCV infection [31].
Other organisms of interest that can affect the CNS
include Borrelia burgdorferi [32], Bartonella [33], and
Mycobacterium tuberculosis [34] causing mainly meningitis-like pictures. Interestingly, cysticercosis can involve
middle-size cerebral vessels in subarachnoid cysticercosis
even in patients without clinical evidence of cerebral
ischemia [35].
Systemic vasculitides
Most systemic vasculitides involve the CNS, but are most
commonly reported in polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), Behçet’s disease, Wegener’s
granulomatosis [36], and Churg–Strauss syndrome [37].
Ascertaining the cause of neurologic dysfunction in
systemic vasculitides is a multifaceted challenge. A
diligent workup should be sought in these patients to
exclude any opportunistic infections, metabolic dysfunction, and drug toxicity. The CNS may be involved
in around 2–8% of Wegener’s granulomatosis patients
[36]. Stroke, seizures headaches, confusion, and transient
neurologic events such as paresthesia, blackouts, or visual
loss are common manifestations [38]. Radiographically
confirmed vasculitis of the CNS in Wegener’s granulomatosis is rare, because the small vessels (50–300 mm in
diameter) are typically below the sensitivity of routine
angiography [36].
The CNS may be affected in 10–49% of patients with
Behçet’s disease resulting either from primary inflammation of CNS tissue or from vasculitis with a venous
predominance leading to ischemic stroke [39,40].
Connective tissue diseases
CNS involvement in CTDs in not uncommon, especially
in patients with systemic lupus erythematosus (SLE)
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14 Vasculitis syndromes
[41!]. Other CTDs that can involve the CNS include
Sjögren’s syndrome, rheumatoid arthritis, mixed CTDs,
and dermatomyositis. An important consideration in the
diagnostic approach to a patient with neurologic dysfunction in the setting of CTDs is 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
is a bland vasculopathy consistent with small-vessel
hyalinization, thickening and thrombus formation [42],
and microinfarcts [43]. Sjögren’s syndrome, like Behçet
disease, may mimic multiple sclerosis and present as a
relapsing-remitting or primary progressive neurologic
dysfunction [44]. Rheumatoid vasculitis affecting the
CNS is rare and may present with seizures, dementia,
hemiparesis, cranial nerve palsy, blindness, hemispheric
dysfunction, cerebellar ataxia, or dysphasia [45,46].
Miscellaneous disorders
Antiphospholipid syndrome (APS) is one of the syndromes that are highly encountered in the differential
diagnosis of CNS vasculitis [47,48!]. Thrombotic-related
events are the most common APS neurologic manifestation. Seizures, cognitive dysfunction, or psychosis may
be the target of antibody-mediated endothelial damage in
APS [49]. Antiplatelet or anticoagulant therapies are
currently indicated for APS-related ischemic strokes,
but they remain controversial for nonthrombotic neurologic manifestations.
Vasculitis of the CNS has been reported in association
with Hodgkin’s and non-Hodgkin’s lymphoma and
angioimmunolymphoproliferative lesions [50]. The anatomic lesions of the lymphoproliferative disease could be
within or outside the CNS. 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 include 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 [51]. Another is the cerebroretinal vasculopathy
syndrome, which is an autosomal-dominant retinal vasculopathy with cerebral leukodystrophy leading to
stroke and dementias with middle-age onset [52!].
Other miscellaneous conditions include amyloid angiopathy and inflammatory bowel diseases.
Diagnosis
The first task of the clinician is to accurately catalogue
areas of disease involvement by careful history and
physical examination. The evolution of the differential
diagnosis and test selection depends on the expected
prevalence of an illness in the population and the physician’s prior experience. 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. There are 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. If the history and physical
examination point to a systemic vasculitis, testing should
proceed accordingly. 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 is an essential tool in the diagnostic evaluation; CSF analysis is of great value in ruling out infectious mimics. CSF findings are abnormal in 80–90% of
pathologically documented cases of PACNS. Findings
usually reflect aseptic meningitis, with modest pleocytosis, normal glucose, elevated protein levels, and
occasionally the presence of oligoclonal bands and
elevated IgG synthesis. The importance of obtaining
appropriate stains, cultures, and serology evaluations to
exclude any infectious causes cannot be overstressed,
especially in patients presenting with chronic meningitis.
Patients with RCVS typically have a normal or near-normal
CSF analysis.
Neuroimaging studies, such as computed tomography
(CT) and magnetic resonance imaging (MRI)2, are not
specific or sufficient for diagnosis of CNS vasculitis. MRI
is a more sensitive diagnostic imaging technique than
CT, except when cerebral hemorrhage is suspected. The
sensitivity of MRI in biopsy-proven cases approaches
100% [50,53]. MRI findings include multiple and often
bilateral infarcts in cortex, deep white matter, or leptomeninges, with or without contrast enhancement [54–
56]. Normal MRI of the brain is not infrequent in RCVS.
The most common findings in RCVS include infarction,
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Central nervous system vasculitis Hajj-Ali and Calabrese 15
Figure 2 Cerebral angiography of a patient with reversible cerebral vasoconstriction syndrome at diagnosis (left) and after 1 month of
calcium-channel blocker therapy (right)
Note the multiple areas of stenosis (white arrows) and dilatation in multiple vessels (black arrows) and their resolution after treatment. Reprinted with
permission from [10].
particularly in arterial ‘watershed’ and ‘borderzone’
regions, parenchymal hemorrhages and small nonaneurysmal subarachnoid hemorrhages overlying the cortical
surface [21]. In RCVS, 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 [57].
Cerebral angiography is a critical modality in evaluating
patients with CNS vasculitis. However, a treating physician should be aware of its limited specificity and lack of
quantitative and qualitative codification. The sensitivity
of cerebral angiography decreases with the calibre of the
vessel, being most sensitive for disease of larger vessels.
Moreover, the angiographic findings should be interpreted cautiously, given its poor specificity [58]. The
findings of alternating areas of vascular constriction and
ectasia or beading are not specific for vasculitis, and these
findings should be interpreted along with clinical features
and CSF findings [58,59]. These findings can be encountered in vasospastic, infectious, embolic, atherosclerotic
diseases, and hypercoagulable states. In pathologically
proven cases, such as GACNS, the sensitivity of cerebral
angiography findings is as low as 10–20% [60]. Cerebral
angiogram is not considered the procedure of choice in
ascertaining the diagnosis of GACNS. However, 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, which is essential to secure the diagnosis of
RCVS (Fig. 2) [10].
Pathologic evaluation of the CNS is usually entertained
in patients with a chronic meningitis-like picture and
whether there is any suspicion for infectious or neoplastic
process [61]. 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 [50]. Alternatively, 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 [62]. Finally, the
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
The therapeutic guidelines of CNS vasculitis are based
largely on extrapolation from other systemic vasculitides
and from experts’ consensus opinion. There are no
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16 Vasculitis syndromes
controlled trials that direct the treatment. On the basis of
the grave historical prognosis of GACNS, and the original
reports of the successful treatment with use of cyclophosphamide, 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. This therapeutic paradigm is
extrapolated from the recent studies in Wegener’s granulomatosis [63]. 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.
microbial 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.
In RCVS, successful treatment has been reported with
calcium channel blockers, short-term glucocorticoids and
magnesium sulfate [11!!]. Spontaneous remission has
also been encountered in the literature. Nimodipine or
verapamil should be considered as first-line therapy.
Alternatively, short-term high-dose glucocorticoids have
been reported to be effective. The rationale for this
approach is based on the efficacy of high-dose glucocorticoids to reverse experimentally induced vasoconstriction [64]. Documentation of dynamic angiographic
changes within 6–12 weeks after therapy is essential in
securing the diagnosis.
There are no specific laboratory tests for CNS vasculitis.
Brain imaging is nonspecific for the diagnosis of CNS
vasculitis including cerebral angiography. CSF examination is a fundamental tool, especially to rule out infectious process. Careful clinical, radiological, and laboratory
correlation is essential for the right diagnosis.
Most cases of 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.
There is a need for controlled trials in the treatment of
CNS vasculitis. Future research should be directed to
better delineate the therapeutic modalities.
Treatment of CNS disease in systemic vasculitis is
directed by the underlying 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 [65]; however, tumor necrosis factor inhibitors such as infliximab may be successful in treatmentresistant rheumatoid vasculitis [66]. 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 [67!]. These results warrant
further analysis of rituximab as treatment of NPSLE.
The prognosis of infection-associated CNS vasculitis is
highly variable. In addition to the appropriate anti-
Conclusion
Considerable progress has been made over the past
decade in our understanding of CNS vasculitis. The
recognition of RCVS as different syndromes from
GACNS has been a major breakthrough in this field. It
is crucial to be aware of RCVS, giving its different
therapeutic and prognostic implications.
When faced by a patient with suspected CNS vasculitis, a
diligent workup should be performed to exclude any
mimics. Hypercoagulable state, systemic vasculitides,
and infections are important disorders to be ruled out.
There are no controlled therapeutic trials for the treatment of CNS vasculitis. Glucocorticoids and cyclophosphamide remain the treatment core of GACNS. Calcium
channel blockers and intravenous magnesium sulfate
appear to be effective in RCVS.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
!
of special interest
!! of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 85).
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