Seminar

Adult primary central nervous system vasculitis

Carlo Salvarani, Robert D Brown Jr, Gene G Hunder

Primary CNS vasculitis is an uncommon disorder of unknown cause that is restricted to brain and spinal cord. The Lancet 2012; 380: 767–77
median age of onset is 50 years. The neurological manifestations are diverse, but generally consist of headache, Published Online
altered cognition, focal weakness, or stroke. Serological markers of inflammation are usually normal. Cerebrospinal May 9, 2012
http://dx.doi.org/10.1016/
fluid is abnormal in about 80–90% of patients. Diagnosis is unlikely in the presence of a normal MRI of the brain.
S0140-6736(12)60069-5
Biopsy of CNS tissue showing vasculitis is the only definitive test; however, angiography has often been used for
Unit of Rheumatology,
diagnosis even though it has only moderate sensitivity and specificity. The size of the affected vessels varies and Department of Internal
determines outcome and response to treatment. Early recognition is important because treatment with corticosteroids Medicine, Azienda Ospedaliera
with or without cytotoxic drugs can often prevent serious outcomes. The differential diagnosis includes reversible ASMN, Istituto di Ricovero e
Cura a Carattere Scientifico,
cerebral vasoconstriction syndromes and secondary cerebral vasculitis.
Reggio Emilia, Italy
(C Salvarani MD);
Introduction patients without histological verification but with a Department of Neurology
Primary CNS vasculitis is an uncommon and poorly high-probability angiogram, an abnormal MRI, and (Prof R D Brown Jr MD),
and College of Medicine
understood vasculitis restricted to brain and spinal cord. cerebrospinal fluid (CSF) analysis consistent with pri-
(Prof G G Hunder MD), Mayo
Recognition of this disorder as a distinct nosological mary CNS vasculitis. Clinic, Rochester, MN, USA
entity dates back to the mid-1950s when Cravioto Advances in neuroimaging techniques used to study Correspondence to:
and Feigin1 described several cases of non-infectious the wall of intracranial blood vessels could improve Dr Carlo Salvarani, Unit of
granulomatous angiitis associated with the nervous detection of inflammation and therefore the validity Rheumatology, Department of
Internal Medicine, Azienda
system.2 Since then, primary CNS vasculitis has been of the criteria.19 Angiographic changes that are highly
Ospedaliera ASMN, Istituto di
referred to as granulomatous angiitis of the CNS,3,4 suggestive of vasculitis are alternating areas of smooth- Ricovero e Cura a Carattere
or more specifically, non-infectious5 or idiopathic6 gran- wall narrowing and dilatation of cerebral arteries or Scientifico, 42123 Reggio Emilia,
ulomatous angiitis of the CNS, and giant-cell arteritis of arterial occlusions affecting many cerebral vessels in the Italy
salvarani.carlo@asmn.re.it
the CNS,7 isolated angiitis of the CNS,8 primary angiitis absence of proximal vessel atherosclerosis or other recog-
of the CNS,9 and benign angiopathy of the CNS.10 nised abnormalities.15 One abnormality in several arteries
Outcome in early reports was frequently fatal, and or several abnormalities in one artery is less consistent
diagnosis was often made at autopsy.1–3,5,7,11 By contrast, in with primary CNS vasculitis.
later studies outcomes were more favourable, and biopsy Because of the invasive nature of CNS biopsy, angi-
and angiography were used for diagnosis.8,9,12 Primary ography is often used to verify diagnosis in patients with
CNS vasculitis needs to be differentiated from disorders compatible clinical findings. However, the accuracy of
that closely resemble it so that appropriate treatment can angiography is uncertain because angiographic changes
be provided.10,13 typical of vasculitis can also be seen in non-vasculitic
disorders.12,20 Furthermore, in pathologically documented
Diagnostic criteria cases, cerebral angiography might be normal, suggesting
Calabrese and Mallek9 proposed criteria for diagnosis of that vascular abnormalities can occur in arteries smaller
primary CNS vasculitis on the basis of clinical experience than the resolution of angiography.4,6,21
and evidence from published work. Diagnosis is made if Cerebral and meningeal biopsy is the gold standard
all three of the following criteria are met: history or for diagnosis of primary CNS vasculitis.12,22–24 The risk is
clinical findings of an acquired neurological deficit of low when skilled surgeons do the biopsy (1% risk of
unknown origin after a thorough initial basic assessment; neurological sequelae). A positive biopsy sample verifies
cerebral angiogram with classic features of vasculitis, or the presence of vasculitis, and excludes mimickers.
a CNS biopsy sample showing vasculitis; and no evidence
of systemic vasculitis or any other disorder to which the
angiographic or pathological features could be secondary. Search strategy and selection criteria
These criteria were also adopted for childhood primary We searched the Cochrane Library, Medline, and Embase
CNS vasculitis, and although they have never been with the search terms “vasculitis”, “angiitis”, or
validated for use in children or adults, they have been “angiopathy” in combination with the terms “central
widely used in clinical practice and research.14 However, nervous system”, “cerebral”, or “intracranial”. We selected
the use of angiography as a gold standard for diagnosis articles mostly in English from the past 5 years, without
has limitations. Overall, the sensitivity of angiography excluding older articles that we thought were highly
varies between 40% and 90%,6,15–17 and cerebral angiograms relevant to this Seminar. We searched the reference lists of
have a specificity as low as 30%.16 To prevent misdiagnosis, articles identified by this search and selected those that we
Birnbaum and Hellmann18 proposed that diagnostic judged relevant. We included some reviews providing
certainty could be classed as definite for patients with insightful overviews on primary CNS vasculitis.
biopsy-proven cerebral vasculitis, and probable for

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 Seminar
The diagnostic histopathological feature is transmural
vascular inflammation of leptomeningeal or paren-
chymal vessels.
An optimum biopsy should consist of samples of dura,
leptomeninges, cortex, and white matter. Vasculitis affects
arteries in a segmental way, therefore a negative biopsy
does not exclude diagnosis. Evidence suggests that biopsy
has low sensitivity for diagnosis of primary CNS vascu-
litis. Two studies reported sensitivities of 53% and 63%,
respectively.16,23 Biopsy of a radiographically abnormal
area is preferable to random sampling of the non-
dominant frontal lobe or temporal tip. Miller and
colleagues23 showed that 78% of targeted biopsies were
diagnostic, whereas none of the untargeted biopsies
showed vasculitis. Inclusion of leptomeninges might
increase the diagnostic yield when primary CNS vasculitis
is suspected. Stereotactic guidance can be used for deeper
lesions but is usually unnecessary for frequently biopsied,
more superficial lesions.
Epidemiology
In the Mayo Clinic series,15 the incidence of primary CNS
vasculitis in Olmsted County, MI, USA, was estimated to
be 2·4 cases per 1 000 000 person-years, which is the only
Panel: Causes of secondary CNS vasculitis
Viral infections
Varicella zoster virus, HIV, hepatitis C virus, cytomegalovirus,
parvovirus B19
Bacterial infections
Treponema pallidum, Borrelia burgdorferi, Mycobacterium
tuberculosis, Mycoplasma pneumoniae , Bartonella henselae,
Rickettsia spp
Fungal infections
Aspergillosis, mucormycosis, coccidioidomycosis, candidosis
Parasitic infections
Cysticercosis
Systemic vasculitides
Wegener’s granulomatosis, Churg-Strauss syndrome, Behçet’s
disease, polyarteritis nodosa, Henoch-Schönlein purpura,
Kawasaki disease, giant-cell arteritis, Takayasu’s arteritis
Connective tissue diseases
Systemic lupus erythematosus, rheumatoid arthritis,
SjÖgren’s syndrome, dermatomyositis, mixed connective
tissue disease
Miscellaneous
Antiphospholipid antibodies syndrome, Hodgkin’s and
non-Hodgkin lymphomas, neurosarcoidosis, inflammatory
bowel disease, graft-versus-host disease, bacterial
endocarditis, acute bacterial meningitis, drug-induced CNS
vasculitis (cocaine, amphetamine, ephedrine,
phenylpropanolamine)
768
incidence information available. Primary CNS vasculitis
occurs at the same frequency in men as in women.15,25 The
median age at diagnosis is about 50 years, and 50% of
patients were between 37 and 59 years of age at diagnosis.
Long-term survival is reduced in primary CNS vasculitis.15
Increased mortality has been linked to cerebral infarctions
and large-vessel associations, whereas a lower mortality
rate has been seen in patients with MRI gadolinium
enhancement of cerebral lesions or the meninges.
Pathophysiology
The cause and pathogenesis of primary CNS vasculitis
are unknown. Infectious agents have been proposed as
triggers because of the well known association of cerebral
vasculitis with infections—in particular varicella zoster
virus (VZV).26 In fact, a wide array of infectious agents
have been linked to vasculitis of CNS (panel).
Inoculation of turkeys intravenously with Mycoplasma
gallisepticum induced cerebral vasculitis similar to primary
CNS vasculitis,27 and in two cases of primary CNS vascu-
litis diagnosed at autopsy, electronmicroscopy showed
structures resembling mycoplasma organisms within
giant cells in the wall of affected cerebral arteries.28
The nature of inflammatory infiltrate has rarely been
studied in primary CNS vasculitis. Immunohistochemical
staining of a biopsy sample showed predominant
infiltration by CD45R0+ T cells in and around small
cerebral vessels.29 These findings implicate memory
T cells in the pathogenesis of vasculitis, suggesting
that primary CNS vasculitis can result from an
antigen-specific immune response occurring in the
wall of cerebral arteries. Although the triggers of the
inflammatory process are unknown, specific activation by
pathogen-derived antigens might be crucial in initiation
of vasculitis in CNS. In terms of effector molecules,
matrix metalloproteinases (MMPs), particularly MMP-9,
seem to be pivotal in animal models of vasculitis.30 These
molecules can contribute to vessel wall damage and
might represent possible therapeutic targets.
Finally, the link between primary CNS vasculitis
and cerebral amyloid angiopathy is noteworthy.31 The
inflammatory reaction to the presence of amyloid β varies
from little or no inflammation, to perivascular infil-
trates, and to granulomatous vasculitis. The inflam-
matory response to vascular amyloid reported in a
transgenic mouse model of cerebral amyloid angiopathy
accords with a role for amyloid deposition as a trigger of
vascular inflammation.32 Eng and colleagues33 showed
that there was a substantial over-representation of the
APOE ε4/ε4 genotype in patients with inflammation
related to cerebral amyloid angiopathy, raising the
possibility that the ε4 isoform of apolipoprotein E might
play a part in the progression of inflammation to
cerebral amyloid angiopathy. Elucidation of the molecu-
lar basis of inflammation in cerebral amyloid angiopathy
might identify new targets for treatment of this subset
of patients.
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 Seminar

Histopathology symptoms. Headache, the most common symptom, can

Primary CNS vasculitis is a vasculitis histologically be generalised or localised, it often slowly worsens, can
affecting small and medium-sized leptomeningeal and spontaneously remit for periods, and varies in severity.
parenchymal arterial vessels. Three main histopatho- Cognitive impairment is also often insidious in onset,
logical patterns are seen:23,34 granulomatous, lymphocytic, and is the second most frequent manifestation. Focal
and necrotising vasculitis. Granulomatous vasculitis is
the most common (58%), showing vasculocentric mono- A
nuclear inflammation and well formed granulomas with
multinucleated cells (figure 1A). β4 amyloid deposition is
seen in almost 50% of biopsy specimens with this pattern
(figure 1B), but is rarely noted in specimens with non- 100 μm
granulomatous primary CNS vasculitis. Lymphocytic
Amyloid
vasculitis is the second most common pattern (28%).
Lymphocytic inflammation predominates, with occa-
sional presence of plasma cells and vessel destruction
(figure 1C). Lymphocytic vasculitis is typically reported in Ischaemic
neurons
children with angiography-negative primary CNS Epithelioid
vasculitis.30 Necrotising vasculitis is the least common 20 μm histocytes 20 μm

pattern (14%) and is characterised by transmural fibrinoid

necrosis similar to that seen in polyarteritis nodosa B
(figure 1D). This process is associated with intracranial
haemorrhage. Occasionally, necrotising and granulo-
matous vasculitis can coexist. Vasculitis can also affect
spinal cord.35 These histological patterns are not closely
linked to specific clinical manifestations, treatment
response, and outcomes. Histological patterns seem to
remain stable over time, suggesting that they do not
represent different phases of the disease. 50 μm 50 μm βA4

Clinical manifestations 20 μm
C
Clinical manifestations at diagnosis are non-specific, and
many symptoms are usually present (table 1).12,15,25 The
onset of disease can be acute, but it is more frequently
insidious and slowly progressive. Diagnosis is made in
75% of patients within 6 months of the onset of

Figure 1: Histopathological features of primary CNS vasculitis

(A) Granulomatous pattern of primary CNS vasculitis. Left-hand image shows
transmural inflammation of a leptomeningeal artery with prominent
mononuclear (bracket) and granulomatous (arrow) adventitial inflammation, and
focal fibrin thrombus formation (asterisk; haematoxylin and eosin [H&E] stain).
20 μm
Inset picture on right shows noticeable thickening and luminal obliteration of
several leptomeningeal vessels (H&E stain). The right-hand image shows focal
collections of epithelioid histiocytes arranged in granuloma-like aggregates.
20 μm 20 μm
Where the lumen is preserved, the vessel wall is thickened by an amorphous D
eosinophilic material (amyloid). Ischaemic neurons can be seen in the adjacent
parenchyma (H&E stain). (B) Granulomatous pattern with amyloid angiopathy in
primary CNS vasculitis. Left-hand image shows destructive vasculitis with well
formed granulomas in leptomeningeal vessels (arrows) and wall thickening with
eosinophilic material (asterisk; H&E stain). The right-hand image shows amyloid-β
deposits in all vessels (immunoperoxidase stain for βA4 amyloid).
(C) Lymphocytic pattern of primary CNS vasculitis. Left-hand and right-hand
images show substantial thickening and luminal obliteration (asterisks mark
lumen remnant) of several leptomeningeal vessels. The infiltrate is predominated
by lymphocytes, but has few histiocytes and granulocytes. Granuloma-like
features are not seen (H&E stain). (D) Necrotising pattern of primary CNS
vasculitis. Left-hand image shows a small leptomeningeal artery with transmural
acute inflammation (H&E stain). Right-hand image shows segmental transmural
fibrinoid necrosis (asterisk), which displays as red-staining material in the vessel
wall (Masson’s trichrome). Haemorrhage and acute infarction are evident in the
underlying cortical parenchyma (right-hand image, bottom).

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All patients Patients Patients

Special subsets
(n=101) diagnosed diagnosed by Several subsets of primary CNS vasculitis have been
by biopsy angiography identified that can differ in terms of prognosis and
(n=31) (n=70) optimum management. Spinal cord abnormalities are
Headache 64 (63%) 16 (52%) 48 (69%) implicated in about 5% of patients but are rarely
Altered cognition 50 (50%) 22 (71%) 28 (40%) the only manifestation.35 The thoracic cord is predomin-
Hemiparesis 44 (44%) 6 (19%) 38 (54%) antly affected. Careful medical assessment should be
Persistent neurological 40 (40%) 8 (26%) 32 (46%) undertaken to verify diagnosis of primary CNS vasculitis
deficit or stroke and to exclude other disorders associated with acute or
Aphasia 28 (28%) 11 (36%) 17 (24%) subacute transverse myelitis.
Transient ischaemic attack 28 (28%) 5 (16%) 23 (33%) Angiography-negative, biopsy-positive primary CNS
Ataxia 19 (19%) 5 (16%) 14 (20%) vasculitis is a subset in which only very small arteries or
Seizure 16 (16%) 2 (7%) 14 (20%) arterioles are affected—ie, those that are smaller than the
Visual symptom (any kind) 42 (42%) 9 (29%) 33 (47%) resolution of angiography.20 Such patients often present
Visual field defect 21 (21%) 5 (16%) 16 (23%) with cognitive dysfunction, have greatly raised concen-
Diplopia (persistent or 16 (16%) 5 (16%) 11 (16%) trations of CSF protein, have meningeal or parenchymal
transient) enhancing lesions on MRI, respond favourably to
Blurred vision or decreased 11 (11%) 0 (0%) 11 (16%) treatment, and have a good outcome.
visual acuity
Another subset of primary CNS vasculitis is charac-
Monocular visual symptoms 1 (1%) 0 (0%) 1 (1%)
terised by prominent leptomeningeal enhancement on
or amaurosis fugax
MRI.38 These patients have acute clinical onset and
Papilloedema 5 (5%) 2 (7%) 3 (4%)
frequently present with cognitive dysfunction, whereas
Intracranial haemorrhage 8 (8%) 2 (7%) 6 (9%)
magnetic resonance angiography (MRA) and cerebral
Amnestic syndrome 9 (9%) 4 (13%) 5 (7%)
angiography are often negative. CNS biopsy samples
Paraparesis or quadriparesis 7 (7%) 4 (13%) 3 (4%)
show granulomatous vascular inflammation. Most
Parkinsonism or 1 (1%) 0 (0%) 1 (1%)
extrapyramidal sign
patients respond to glucocorticoids (alone or combined
Prominent constitutional 9 (9%) 4 (13%) 5 (7%)
with immunosuppressive agents), go on to attain a
symptom normal MRI, and have an overall favourable course.
Fever 9 (9%) 4 (13%) 5 (7%) About a quarter of patients with biopsy-positive pri-
Nausea or vomiting 25 (25%) 6 (19%) 19 (27%) mary CNS vasculitis have evidence of cerebral amyloid
Vertigo or dizziness 9 (9%) 3 (10%) 6 (9%) angiopathy.31 Brain biopsy samples show a granulo-
Dysarthria 15 (15%) 2 (7%) 13 (19%) matous histopathological pattern plus vascular deposits
Unilateral numbness 13 (13%) 0 (0%) 13 (19%) of amyloid β. Patients with cerebral amyloid angiopathy
are older than those with primary CNS vasculitis without
Data are number (%). Reproduced from Salvarani and colleagues,15 by permission amyloid deposits, but typically younger than those with
of John Wiley & Sons.
cerebral amyloid angiopathy with no inflammation. They
Table 1: Clinical manifestations at presentation have a high frequency of cognitive dysfunction and
enhancing meningeal lesions on MRI, but usually have
a monophasic disease course and good response to
neurological manifestations with or without distinct immunosuppressive treatment.
cerebral infarction are present in many patients. Other Rapidly progressive primary CNS vasculitis represents
features such as ataxia, seizure, and intracerebral the most ominous subset of this vasculitis, and often has
haemorrhage are less frequent. By contrast with other a fatal outcome. Typically, many bilateral large cerebral
systemic vasculitides, constitutional symptoms such as vessel lesions are seen on angiography, along with several
fever and weight loss are uncommon. bilateral cerebral infarctions. The predominant histo-
Some reports have suggested that patients with primary pathological pattern is granulomatous or necrotising.
CNS vasculitis diagnosed on the basis of abnormal The response to conventional immunosuppressive treat-
angiography alone have a more benign course than do ment is poor.39
those diagnosed by biopsy.10,36 However, in other series, About 4% of patients with primary CNS vasculitis
the clinical characteristics and outcomes in patients present with a solitary tumour-like mass lesion.40 An
diagnosed by biopsy and angiography were similar association with cerebral amyloid angiopathy has been
(table 1).15 Furthermore, others have described a pro- reported in 29% of these patients. Excision of the lesion
gressive course in patients diagnosed by angiography has been curative in some. In others, aggressive
alone.37 The inclusion of patients who are clinically immunosuppressive therapy has resulted in a favourable
suggestive of reversible cerebral vasoconstriction syn- outcome, obviating the need for surgery.
drome diagnosed on the basis of angiography alone with Intracranial haemorrhage is a presenting feature in
a benign course might account for these differences.13 11–12% of patients.25,41 Intracerebral haemorrhage is

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 Seminar

the most common, followed by subarachnoid haem-

A
orrhage. Compared with patients without intracranial
haemorrhage, those with it are less likely to have
altered cognition, a persistent neurological deficit,
or MRI evidence of cerebral infarctions during the
disease course. Necrotising vasculitis is the predominant
histopathological pattern of biopsy specimens.

Laboratory findings, electroencephalography,

and imaging
Results of blood tests in patients with primary CNS
vasculitis are usually normal, and consist of tests for
acute-phase reactants, antinuclear antibodies, anti-
neutrophil cytoplasm antibodies, and antiphospholipid
antibodies.15,25
CSF analysis is abnormal in 80–90% of patients.15
Changes consist of a mildly increased leucocyte
count and total protein concentration. Patients with B
angiography-negative primary CNS vasculitis often have
greatly raised protein concentrations.20 CSF analysis
should be composed of appropriate stains, cultures, sero-
logical and molecular tests, and flow cytometry studies to
exclude infection or malignancy. Most patients have
mild, non-specific electroencephalographic findings.
Cerebral angiography supports diagnosis of primary
CNS vasculitis when biopsy is not undertaken or is
negative despite other indicative clinical and laboratory
evidence.15,25 Suggestive angiographic findings are alter-
nating segments of stenosis with normal or dilated
intervening segments, and arterial occlusions (figure 2).
Other abnormalities are delayed arterial emptying and
anastomotic channels.42 Microaneurysms are rarely seen. C D
Vasculitic lesions usually affect several arteries bilaterally.
In many cases, both large arteries (internal carotid and
intracranial vertebral arteries, basilar artery, and their
primary branches) and smaller arteries are affected.
A limit of angiography is its low specificity. Angio-
graphic findings compatible with vasculitis might be
encountered in several non-vasculitic disorders such as
vasospasm, CNS infection, cerebral arterial emboli, and
atherosclerosis.6,43 Two studies have compared the sensi-
tivity of angiography for detection of vasculitis with the Figure 2: Imaging of patients with primary CNS vasculitis
sensitivity of biopsy. In the Mayo Clinic series,15 43% of (A) Cerebral angiogram shows alternating stenosis and dilatation of the distal
middle cerebral artery (arrows) and the anterior cerebral artery (arrowheads).
angiograms undertaken at diagnosis in patients with
(B) Magnetic resonance angiography of the brain shows a short-segment
histologically proven primary CNS vasculitis were diag- stenosis of the anterior cerebral artery (green arrow) and stenosis of the distal
nostic for vasculitis, whereas in a retrospective review middle cerebral artery (white arrow). (C) Fluid attenuation inversion recovery
only 27% revealed vasculitis.6 Inflammatory changes of (FLAIR)-weighted MRI shows a large abnormality within the right cerebral
hemisphere consistent with ischaemia (arrowheads). (D) MRI shows diffuse,
brain arteries smaller than the resolution of angiography
asymmetric, nodular, and linear leptomeningeal enhancement, with dura only
might partly account for false-negative results.20 How- slightly affected.
ever, despite these limitations, cerebral angiography is
the radiological gold standard for identification of
primary CNS vasculitis. Diagnosis should not be based posterior circulation and distal vessels.15,44 Therefore, in
on positive angiography alone, and angiography results patients with abnormal MRI but normal MRA in the
should always be interpreted in conjunction with clinical, context of strongly suggestive clinical history, cerebral
laboratory, and MRI findings. angiography should be done. Additionally, MRA can
MRA is less invasive than is angiography (figure 2), but overestimate the severity of stenoses at points of vessel
it is less sensitive in detection of lesions associated with branching or vascular occlusions.

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 Seminar
Primary CNS vasculitis is unlikely if MRI is normal.
Several studies have reported a sensitivity of MRI close
to 100%.16,45 However, patients with primary CNS
vasculitis and normal MRI have been reported.15,43,46
Abnormal MRI findings are non-specific and are cortical
and subcortical infarction, parenchymal and lepto-
meningeal enhancement, intracranial haemorrhage,
tumour-like mass lesions, and areas of increased signal
intensity on fluid attenuation inversion recovery
(FLAIR) or T2-weighted images.15,43,45,47,48 Infarctions are
the most common lesions, and are usually multiple and
bilateral, affecting both the cortex and subcortical
regions (figure 2). Prominent leptomeningeal enhance-
ment might suggest a favourable prognosis38 (figure 2).
Both intracerebral and subarachnoid haemorrhage have
been described.25,41
Multiple, bilateral supratentorial foci of hyperintensity
on FLAIR and T2-weighted sequences associated most
frequently with white matter are often seen.15,47 However,
these abnormalities are not specific and are associated
with other disorders.49 By contrast, vessel wall thicken-
ing and intramural enhancement of large arteries
are specific to primary CNS vasculitis.50 Occasionally,
enhancement can be very noticeable and extend into the
adjacent leptomeningeal tissue (perivascular enhance-
ment).43,51,52 Fat-suppressed T1-weighted images are
especially sensitive for vessel-wall enhancement.53 The
role of other MRI sequences, such as diffusion-weighted
imaging and perfusion-weighted imaging, in the
detection of vasculitic lesions needs to be defined.54
High-resolution 3-Tesla contrast-enhanced MRI might
be able to differentiate enhancement patterns of intra-
cranial atherosclerotic plaques (eccentric), inflam-
mation (concentric), and other wall abnormalities.19
However, the sensitivity and specificity of this technique
remain to be established.
With respect to other imaging techniques, CT is less
sensitive than is MRI in assessment of lesions of cerebral
vasculitis, apart from cerebral haemorrhage. Transcranial
colour-coded sonography, sometimes used for the
PCNSV
Precipitating factor None
Onset More insidious, progressive course
Headaches Chronic and progressive
CSF findings Abnormal (leucocytosis and high total protein concentration)
MRI Abnormal in almost all patients
Angiography Possibly normal; otherwise, diffuse abnormalities are often
indistinguishable from RCVS; irregular and asymmetrical arterial abnormalities reversible within 6–12 weeks
stenoses or multiple occlusions are more suggestive of PCNSV;
abnormalities might be irreversible
Cerebral biopsy Vasculitis
Drug treatment Prednisone with or without cytotoxic agents
PCNSV=primary CNS vasculitis. RCVS=reversible cerebral vasoconstriction syndrome. CSF=cerebrospinal fluid.
Table 2: Characteristics of primary CNS vasculitis and reversible cerebral vasoconstriction syndrome
772
screening of cerebral artery stenosis or occlusion,55 might
be useful to diagnose and monitor primary CNS vasculitis.
Differential diagnosis
Primary CNS vasculitis should be differentiated from
other similar disorders to avoid therapeutic and prog-
nostic errors. The most common mimicker of primary
CNS vasculitis is reversible cerebral vasoconstriction
syndrome.
In 2007, reversible cerebral vasoconstriction syndrome
was proposed as a collective name for various disorders
that are characterised by brain vasoconstriction rather
than by vasculitis13 (ie, Call-Fleming syndrome, post-
partum angiopathy, migrainous vasospasm, drug-
induced cerebral vasculopathy, and, probably, benign
angiopathy of the CNS10,36). Reversible cerebral vaso-
constriction syndrome presents with sudden severe
headache (thunderclap), with or without seizures and
focal neurological deficits. Angiography shows constric-
tions of cerebral arteries that resolve spontaneously
within 1–3 months. This disorder affects mainly women
with a mean age of around 45 years. About 60% of
patients develop the syndrome in the post-partum period
or after exposure to vasoactive substances.56 The major
complications of reversible cerebral vasoconstriction
syndrome are localised subarachnoid haemorrhage
(22%) over the sulci and, less frequently, ischaemic or
haemorrhagic stroke. To make a diagnosis, evidence of
multifocal segmental cerebral artery vasoconstriction on
cerebral angiography or MRA has to be seen, with
complete or almost complete resolution on repeat
examination within 12 weeks of onset. Because reversible
cerebral vasoconstriction syndrome can closely mimic
primary CNS vasculitis, differentiation is crucial since
immunosuppressive therapy (beyond a short course of
prednisone) is not warranted for syndromes caused by
vasoconstriction (table 2).
Common causes of secondary CNS vasculitis are
infection, systemic vasculitis, connective tissue diseases,
and miscellaneous disorders (panel). These disorders
RCVS
Post-partum onset or onset after exposure to vasoactive substances
Acute onset followed by a monophasic course
Acute, thunderclap type
Normal to near normal
Normal in 70% of patients
Always abnormal, strings of beads appearance of cerebral arteries;
No vasculitic changes
Nimodipine
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should be carefully excluded before primary CNS
vasculitis is diagnosed. Pathogens can induce CNS
vasculitis through many mechanisms, such as direct
endothelial invasion and damage. However, in most
patients, vasculitis is thought to be mainly the result of
the immune response triggered by an invading agent.
VZV vasculitis causes stroke secondary to viral infection
of both large and small cerebral arteries.26 Rarely, unifocal
vasculitis can follow ophthalmic-distribution zoster in
elderly adults or chickenpox in children, and affects large
arteries of the anterior or posterior circulation. By
contrast, multifocal vasculitis usually affects branches of
large or small cerebral arteries, mostly in immuno-
compromised patients. Diagnosis is based on a history of
recent VZV infection followed by neurological mani-
festations, and is verified by the detection of antiVZV
IgG antibody in CSF. Tests for VZV DNA in CSF are
often negative.
Cerebral vasculitis has been reported with HIV
infection, often in association with concomitant infection
or lymphoproliferative disease of CNS. However, in a few
patients, CNS vasculitis can occur in the absence of other
detectable diseases, suggesting a direct pathogenic role
for HIV.57 Treatment is glucocorticoid therapy.
In the meningovascular form of neurosyphilis,
vasculitis is believed to result from direct spirochaetal
invasion of vascular endothelial cells. The most
common presentation is an ischaemic stroke in a young
adult.58,59 The middle cerebral artery is most often
affected, followed by basilar artery. Diagnosis of
neurosyphilis is verified with positive results from the
fluorescent treponemal antibody with absorption test
and CSF venereal disease research laboratory test
together with evidence of CSF pleocytosis and raised
concentrations of CSF protein.
Other infectious agents have been linked to vasculitis
of CNS, such as hepatitis C virus,60 parvovirus B19,61
cytomegalovirus,62 Mycoplasma pneumoniae,63 Borrelia
burgdorferi,64 Mycobacterium tuberculosis,65 Bartonella spp,66
and Rickettsia spp.67 Fungal infections (aspergillosis,
mucormycosis, coccidioidomycosis, and candidosis) and
subarachnoid cysticercosis have also been implicated in
some cases.68–70
CNS vasculitis might stem from systemic vasculitides,
such as antineutrophil cytoplasmic antibody (ANCA)-
associated vasculitis and Behçet’s disease, and less
often from polyarteritis nodosa, Henoch-Schönlein
purpura, Kawasaki disease, giant-cell arteritis, and
Takayasu’s arteritis.71–80 CNS symptoms have been
described in 7–11% of patients with Wegener’s
granulomatosis71,72 and 1–8% of patients with Churg-
Strauss syndrome.73,74 In ANCA-associated vasculitis,
CNS manifestations might be caused by vasculitis
affecting the brain, but also by granulomata, uncon-
trolled hypertension, sepsis, and coagulation disorders.
However, radiographically verified vasculitis of CNS is
rare, and occurs in fewer than 2% of patients with
www.thelancet.com Vol 380 August 25, 2012
Seminar
Wegener’s granulomatosis71 and in only 4% with Churg-
Strauss syndrome.73 These patients usually also have
evidence of active disease elsewhere.
Neurological symptoms arise in 5·3–14·3% of patients
with Behçet’s disease, and split the disease into two
groups.75 In the parenchymal group, meningoencephalitis
predominantly affecting the brainstem occurs, whereas
in non-parenchymal neurological Behçet’s disease,
thrombosis within the dural venous sinuses is seen. The
most prominent histopathological feature of neurological
Behçet’s disease is the presence of perivascular infil-
tration of T lymphocytes and monocytes.81
With respect to the role of connective tissue diseases,
primary CNS vasculitis is rare in patients with neuro-
psychiatric lupus, occurring in fewer than 7%.82–84
Secondary cerebral vasculitis in rheumatoid arthritis is a
rare complication of longstanding, nodular, erosive, and
seropositive rheumatoid arthritis.85 Clinical CNS mani-
festations are rare in Sjögren’s syndrome (about 5% of
unselected patients).86 CNS biopsy specimens show
vasculitis in a few patients, but a more typical finding is
perivascular mononuclear infiltration, which can extend
into the surrounding brain parenchyma.87 Secondary
CNS vasculitis has also been described in dermato-
myositis and mixed connective tissue disease.88,89 Angio-
graphic abnormalities suggestive of cerebral vasculitis
have occasionally been seen in patients with anti-
phospholipid antibodies and ischaemic cerebrovascular
events.90 However, thrombotic vasculopathy rather than
true vasculitis is the mechanism underlying angiographic
changes in such patients.
Primary CNS vasculitis has been associated with
lymphoma, particularly Hodgkin’s disease, and rarely
with non-Hodgkin lymphoma.91,92 Additionally, intra-
vascular lymphoma characterised by the proliferation of
clonal lymphocytes within small vessels with little to no
association with the organ parenchyma can affect the
CNS and resemble cerebral vasculitis.93 Angiographic
changes suggestive of arteritis have occasionally been
reported in neurosarcoidosis; however, histological
changes characteristic of vasculitis in the CNS are
uncommon in this disorder.94 Secondary CNS vasculitis
has also been described in patients with inflammatory
bowel disease and graft-versus-host disease.95,96
In bacterial endocarditis, valvular emboli can produce
cerebrovascular occlusions and a vasculitic pattern on
cerebral angiography. The differentiation from primary
CNS vasculitis is very important because the treatment
differs.97 A vasculitic pattern on vascular imaging has
also been reported in patients with acute bacterial
meningitis.98
Although most cases of drug-induced cerebral
vasculitis identified by cerebral angiography alone are
caused by vasospasm and should be regarded as part of
reversible cerebral vasoconstriction syndrome, histo-
logically documented cases of drug-associated CNS
vasculitis have infrequently been described.99
773
 Seminar
Treatment and course
No randomised clinical trials of medical management in
primary CNS vasculitis exist; therefore, treatment for
primary CNS vasculitis has been derived from therapeutic
strategies used in other vasculitides, from anecdotal
reports, and from cohort studies. Earliest reports
suggested a poor outlook with fatal outcome in most
patients, and transient or doubtful effectiveness of
glucocorticoids.4,12,100 Studies, including those by Cupps
and colleagues,8 reported the effectiveness of cyclo-
phosphamide in combination with corticosteroids.8,101
Since these early reports, cohort studies have described
a more favourable course of primary CNS vasculitis. In a
cohort study of 101 patients, glucocorticoids alone or in
combination with cyclophosphamide achieved a favour-
able response in most patients.15 Response rates were
similar (81%) in both treatment groups with improvement
of Rankin scale scores over time. Glucocorticoid therapy
should be started as soon as primary CNS vasculitis is
diagnosed. We recommend an initial dose of prednisone
of 1 mg/kg per day (or equivalent) as a single or divided
dose. If a patient does not respond promptly, cyclo-
phosphamide should be started.
In an approach to reduce the toxic effects of drugs, a
3–6 month course of oral cyclophosphamide (2 mg/kg
per day) might also be beneficial to induce remission in
primary CNS vasculitis because it has proved effective in
See Online for appendix other vasculitides102 (appendix). Intravenous pulses of
cyclophosphamide (0·75 g/m² per month for 6 months)
are probably safer than is daily oral therapy, although
whether the two regimens differ in terms of effectiveness
is unclear. Infection, cancer (in particular transitional
cell carcinoma of the bladder), and infertility are the
most serious toxic effects of cyclophosphamide.102
Subsequently, consideration of a low-risk immuno-
suppressant such as azathioprine (1–2 mg/kg daily),
methotrexate (20–25 mg/week), or mycophenolate
mofetil (1–2 g daily) for maintenance of remission is
advised. However, little direct evidence exists for the
effectiveness of these drugs. A treatment course of
12–18 months is adequate in most patients.15
In patients with severe or progressive primary CNS
vasculitis that is life-threatening, high-dose intravenous
methylprednisolone (1000 mg daily for 3 days) and
cyclophosphamide can be used immediately after
diagnosis, although no evidence exists that methyl-
prednisolone pulses are more effective than oral
prednisone.15 Repeated pulses of intravenous methyl-
prednisolone can also be given for disease flares. Tumour
necrosis factor α (TNFα) blockers and mycophenolate
mofetil (2 g daily) can successfully treat patients with
primary CNS vasculitis that is resistant to glucocorti-
coids and immunosuppressants.103,104 However, only two
reported patients given TNF blockade for primary CNS
vasculitis exist, given to both as adjunctive treatment.
Infliximab (5 mg/kg) seemed to rapidly and effectively
improve the neurological status and MRI abnormalities of
774
one patient with a rapidly progressive course, and long-
term etanercept (50 mg/week) stopped relapse and led to
the discontinuation of prednisone in the second patient.103
Anti-CD20 therapy with rituximab has been used
successfully in refractory Wegener’s granulomatosis with
CNS features, suggesting a possible therapeutic role for
this drug in primary CNS vasculitis.105
All patients should receive prophylactic treatment
for osteoporosis and prophylaxis against Pneumocystis
jirovecii infection (co-trimoxazole [trimethoprim 80 mg
and sulfamethoxazole 400 mg, per day]).
Evidence that all patients with primary CNS vasculitis
do not need the same therapy is emerging (appendix).
Those with several bilaterally affected large vessels, rapidly
progressive disease, and many recurrent cerebral infarc-
tions39 should be started promptly on aggressive therapy,
although those with progressive disease usually have a
poor response to therapy with a fatal outcome. By contrast,
patients with affected small vessels, characterised by
prominent leptomeningeal enhancement on MRI or by
negative cerebral angiogram and a positive brain biopsy,
typically have a rapid response to treatment with a
favourable neurological outcome.21,38 These patients can
thus be given, at least initially, glucocorticoids alone,
although immunosuppressive agents can be added should
clinical history, changes to brain or spinal cord MRI
abnormalities, or worsening of spinal fluid examination
results suggest persistent disease activity and insufficient
response to therapy. Patients with primary CNS vasculitis
with cerebral amyloid angiopathy might also respond to
glucocorticoids alone,31 but often cyclophosphamide has to
be added to obtain an adequate response. In patients with
primary CNS vasculitis presenting as a tumour-like mass
lesion, aggressive immunosuppressive therapy is associ-
ated with improved outcomes compared with gluco-
corticoids alone.40 Relapses and recurrences were recorded
in only 26% of patients in the Mayo Clinic series.15 Patients
with relapsing disease needed therapy for longer than did
those with non-relapsing disease, but otherwise had
outcomes similar to those without relapses.
Thus, although there have been no controlled thera-
peutic trials, treatment seems to be associated with a
favourable outcome in most patients. In the Mayo Clinic
series most patients with low disability at diagnosis
continued to have low disability at last follow-up, and
most of the 22 patients with severe disability at diagnosis
had less disability at follow-up.15 These data emphasise
the need for early diagnosis, since prompt treatment
frequently leads to a favourable outcome.
Serial MRI and MRA (4–6 weeks after the beginning of
treatment, then every 3–4 months during the first year of
treatment, or when a new neurological deficit arises),
and repeat careful neurological examinations, are useful
to monitor disease course. In patients with stable
imaging but worsening clinical symptoms, repeat spinal
fluid examination and repeat angiography might be
necessary. For those patients without biopsy verification
www.thelancet.com Vol 380 August 25, 2012

at the time of initial diagnosis who have worsening
symptoms despite immunosuppressive therapy, a brain
biopsy should be considered.
Treatment of reversible cerebral vasoconstriction syn-
drome needs a detailed patient history of intake of
vasoactive substances, with prompt cessation of any
potentially offending agent. In the absence of randomised
trials, empirical treatment is oral nimodipine (60 mg
every 4–8 h for 4–12 weeks), started as soon as the typical
angiographic pattern is noted. The effectiveness of a short-
term course of high-dose glucocorticoids is unclear.13,56
Future directions
Our understanding of primary CNS vasculitis and the
delineation of its range and subsets has advanced, but
we still need to clarify methods of diagnosis and opti-
mum management. Biomarker and outcome investi-
gations might identify risk factors for an aggressive
course leading to treatment tailored to disease severity.
Effectiveness and safety profiles of intravenous pulse
and oral cyclophosphamide treatment, and clarification
of which patients need cyclophosphamide at disease
onset, need to be established. Other drugs should
be studied as substitutes for cyclophosphamide in
selected subgroups.
Because primary CNS vasculitis is uncommon, an
international collaborative registry for primary CNS
vasculitis would help with the development of stan-
dardised classification and diagnostic criteria, help to
define homogeneous patient groups for randomised
clinical trials, and might aid clinicians in differentiation
of primary CNS vasculitis from its much more common
mimickers. Finally, international concerted efforts could
be instrumental in the development of repositories of
biological specimens that are essential for translational
studies. In turn, a better understanding of the molecular
mechanisms associated with the pathogenesis of
primary CNS vasculitis should provide opportunities to
improve therapy.
Contributors
All authors contributed equally.
Conflicts of interest
We declare that we have no conflicts of interest.
Acknowledgments
We thank John Huston III, Teresa J H Christianson,
Kenneth T Calamia, James F Meschia, Caterina Giannini, and
Dylan Miller for their collaboration in clinical studies on primary CNS
vasculitis, John Huston III for providing angiographic and MRI
documentation, and Caterina Giannini and Dylan Miller for providing
histopathological documentation.
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