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Autoimmunity Reviews 16 (2017) 123–131
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Autoimmunity Reviews
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Review
Central nervous system vasculitis in adults: An update
Lívia Almeida Dutra a,b, Alexandre Wagner Silva de Souza c, Gabriela Grinberg-Dias b,
Orlando Graziani Povoas Barsottini a, Simone Appenzeller d,⁎
a General Neurology Division, Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, São Paulo, Brazil
b Hospital Israelita Albert Einstein, São Paulo, Brazil
c Rheumatology Division, Universidade Federal de São Paulo, São Paulo, Brazil
d Rheumatology Division, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil
⁎ Corresponding author.
E-mail address: appenzellersimone@gmail.com (S. Ap
http://dx.doi.org/10.1016/j.autrev.2016.12.001
1568-9972/© 2016 Published by Elsevier B.V.
a b s t r a c t
a r t i c l e i n f o
Article history:
Received 4 September 2016
Accepted 8 September 2016
Available online 11 January 2017
Primary central nervous systemvasculitis (PCNSV) is a challenging diagnosis due to broad clinicalmanifestations
and variable specificity and sensitivity of laboratory and imaging diagnostic tools. Differential diagnosis includes
reversible cerebral vasoconstriction syndrome (RCVS), secondary vasculitis of the CNS and other noninflamma-
tory vasculopathies. Brain biopsy is essential for definitive diagnosis and to excludemimickers. Recent data show
that data large-vessel PCNSV present worse prognosis when compared to small-vessel PCNSV. Herein we review
diagnosis and management of PCNSV, secondary vasculitis of CNS and RCVS.
© 2016 Published by Elsevier B.V.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
2. Primary vasculitis of central nervous system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
3. Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
3.1. Reversible cerebral vasoconstriction syndrome (RCVS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
4. Secondary vasculitis of the CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
4.1. Vasculitis secondary to connective tissue diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
4.2. CNS vasculitis secondary to systemic vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
4.3. Infectious CNS vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
4.4. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
1. Introduction
Central nervous system (CNS) vasculitis is a rare disease that pre-
sents variable neurological manifestations depending on size and loca-
tion of involved vessels within the nervous system. CNS vasculitis may
be classified either by the size of the vessel involved (i.e. small, medium
penzeller).
or large vessel vasculitis) or by the neuropathological findings (i.e. gran-
ulomatous, lymphocytic and necrotizing) [1–3]. CNS vasculitis may also
be classified according to etiology as secondary, when associated with
other systemic disorders such as autoimmune or infectious diseases,
or as primary CNS vasculitis (PCNSV) when it is restricted to the CNS
[1,2,4].
Suspicion of CNS vasculitis should be raised with the new onset of
neurological symptoms associated with ischemic or hemorrhagic le-
sions in different stages in brain magnetic resonance imaging (MRI)
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124 L.A. Dutra et al. / Autoimmunity Reviews 16 (2017) 123–131
affecting different vascular territories [5]. Since a wide variety of dis-
eases may mimic CNS vasculitis and some of them do not benefit from
immunosuppression, accurate diagnosis is of paramount importance.
Table 2
Differential diagnosis of PACNS.
Systemic vasculitides: BD, PAN, polyarteritis nodosa, granulomatosis with
polyangiitis (Wegener), EGPA (Churg Strauss), urticarial hypocomplementemic
vasculitis, Cogan's syndrome
Systemic inflammatory diseases: SLE, sarcoidosis, dermatomyositis, inflammatory
bowel diseases, celiac disease, graft versus host diseases, Buerger's disease,
rheumatoid arthritis, relapsing polychondritis
Infections: viral (HSV, VZV, HIV, HBV, HCV), bacterial (tuberculosis, syphilis,
Neisseria, Lyme), fungal (aspergillosis, nocardiosis, cryptococcus,
histoplasmosis)
Vasculopathies: RCVS, PRES, radiation vasculopathy, small-vessel arterial
dissection, Moya-moya syndrome, fibromuscular dysplasia, CADASIL, HERNS,
COL4A01 mutations, Susac syndrome, Kohlmeier-Degos, Fabry disease,
mitochondriopathies
Thrombo-embolism: atrial fibrillation and cholesterol atheroembolism,
endocarditis, left atrial myxoma and other cardiac tumors
Thrombophilias: APS, hyperhomocysteinemia, thrombocytic purpura, Sneddon
2. Primary vasculitis of central nervous system
PCNSV is a rare single-organ vasculitis that affects small andmedium
vessels restricted to the CNS. All age groups may be affected, however a
peak incidence in middle-aged men is observed [2,6]. The diagnosis of
PCNSV is challenging, since it requires extensive investigation to rule
out various differential diagnoses [6].
There are nopathognomonicfindings in PCNSV and the proposed di-
agnostic criteria are based on the demonstration of vasculitic findings
either on angiography or on brain biopsy in the appropriate clinical con-
text (Table 1). Definite PCNSV requires brain biopsy confirmation [6–8].
PCNSV may involve the brain and/or the spinal cord and patients
may present variable clinical manifestations, depending on the CNS re-
gion involved [7,9]. Approximately 63% of thepatientswith PCNSVpres-
ent subacute headache, which is the most common symptom, often
followed bymemory and cognitive impairment, focal muscle weakness
or stroke [1,2,6,9]. Constitutional symptoms such as fever or weight loss
are usually absent [2].
Laboratory tests may all display normal results, including acute
phase reactants. Serum autoantibodies are typically not detected. Cere-
brospinal fluid (CSF) analysis is important to exclude infections or sub-
arachnoid hemorrhage. An extensive review of 101 cases of PCNSV
showed that mild pleocytosis and protein elevation may be found in
the active phase [1,9–11]. Culture and serologic tests to identify infec-
tious agents should be performed in CSF from all patients with suspi-
cious PCNSV. The extent of investigation to exclude infectious process
should be tailored to risk factors and exposures of individual patient [2].
MRI is a very sensitive tool for initial evaluation of PCNSV and should
be the neuroimagingmodality of choice. MRI abnormalities are found in
90% to 100% of patients with PCNSV [2,3,6]. The most common findings
in PCNSV are cortical and subcortical infarcts, with leptomeningeal en-
hancement, intracranial hemorrhage, and areas of increased signal on
FLAIR and T2-weighted sequences [2,6]. Other commonfindingsinclude
diffuse small vessel changes suggestive of ischemic demyelination and
confluent white-matter lesions, which can be mistaken for multiple
sclerosis, or cortical necrosis [6,12]. Mass lesions, meningeal enhance-
ment and intracranial hemorrhages can be seen in 5%, 8% and 9% of
cases, respectively [2]. Prominent leptomeningeal enhancement occurs
in 10 to 15% of PCNSV patients and indicates a favorable prognosis [9]. In
addition, parenchymal and subarachnoid hemorrhage have also been
described in PCNSV [2,6,9].
Conventional digital subtraction angiogram (DSA) provide informa-
tion on changes in vessel contours without providing information about
the underlying pathologic processes and mechanisms that caused the
abnormal findings [6]. Diffuse, bilateral and alternating areas of stenosis
and dilatation seen by DSA, MRI angiography (MRA) or computed to-
mography angiography (CTA) referred to as “beading”, can be found
in patients with PCNSV [2,6]. Other angiographic findings include single
regions of vessel narrowing in tributaries, collateral circulation, and re-
gionally prolonged circulation time [6]. Microaneurysms are rarely
found in PCNSV [6].
Table 1
Diagnostic criteria for PACNS.
Adapted from [2]
1. The presence of an acquired otherwise unexplained neurological or psychiatric
symptom
2. The presence of either classic angiographic or histopathological features of
angiitis within the CNS
3. No evidence of systemic vasculitis or any disorder that could cause or mimic the
angiographic or pathological features of the disease
A range of noninflammatory vasculopathies such as reversible vaso-
constriction syndrome (see above), atherosclerosis, vasospasm, radia-
tion vasculopathy, infections, atrial myxomas, neurofibromatosis, and
fibromuscular dysplasia may display angiographic findings similar to
those seen with PCNSV [6,10,8]. Primary CNS lymphomas and
lymphomatoid granulomatosis may also cause patterns of beading in a
multivessel distribution that is indistinguishable from vasculitis [11].
Thus, although angiographic findings are part of the diagnostic criteria
of PCNSV, its sensibility is only 70% while specificity is as low as 30%
[13]. A useful general approach is to remember that a negative MRI ex-
cludes intracranial vasculitis more definitively than a negative DSA
does, because abnormalities in small vessels may not be observed in
DSA and MRA [13].
Three-tesla vessel wall imaging MRI is an emerging technique that
may improve the specificity of MRA in diagnosing PCNSV, as the vessel
wall may be better visualized [2]. Atherosclerotic plaques and intracra-
nial dissection show eccentric irregularwall thickening, whereas vascu-
litis produces smooth circumferential concentric wall thickening with
diffuse gadoliniumenhancement of the inflamedwall. In atherosclerotic
lesions, gadolinium enhancement of the plaque may correlate with
plaque instability [14]. Moreover, there is evidence that the 3-Tesla-
MRA may increase the sensitivity for detecting intracranial stenosis in
approximately 30% [13].
Brain biopsy is the gold standard for the diagnosis of PCNSV and
should be performed to confirm all suspicious cases if possible. In
order to improve biopsy yield, it needs to include cortical andmeningeal
tissue [6,10]. In a review of 61 patients referred for brain biopsy for
suspected vasculitis, an alternative diagnosis such as infections or neo-
plasms, especially lymphomawas established in 39% [6,10]. Another se-
ries evaluating all brain biopsies performed in suspected CNS vasculitis
showed that noneof the 14patientswith clinical and angiographic com-
patible features were found to be having PCNSV [15]. The likelihood of
positive biopsy findings is higher if a specimen is obtained from areas
presenting abnormalities at brain MRI and the risk of neurological com-
plication from this procedure is as low as 1% [1,9,10,16]. Vessel wall MRI
might aid in directing a favorable biopsy site if areas of abnormal vessel
enhancement are chosen as opposed to a “blind” approach.
Since small vessels are not adequately seen in angiographic studies,
all suspected cases of PCNSV that present unrevealing angiographic
syndrome
Tumors: intravascular lymphoma, gliomatosis cerebri, glioblastomas
Demyelinating: MS, ADEM, PML
Abbreviations: BD, Behçet's disease; PAN, polyarteritis nodosa; EGPA, eosinophilic granu-
lomatosis with polyangiitis; SLE, systemic lupus erythematosus; HSV, herpes virus; VZV,
varicella-zoster virus; HIV, human immune deficiency virus; HBV, hepatitis B virus; HCV,
hepatitis C virus; RCVS, reversible vasoconstriction syndrome; PRES: posterior reversible
encephalopathy syndrome; CADASIL, cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy; HERNS, hereditary endotheliopathy with
retinopathy, nephropathy, and stroke; APS, antiphospholipid syndrome; MS, multiple
sclerosis; ADEM, acute demyelinating encephalomyelitis; PML, progressive multifocal
leukoencephalopathy.
Fig. 2. Brain biopsy in lymphocytic vasculitis. Arrow: observe the lymphocytic infiltrate in
arterial wall.
125L.A. Dutra et al. / Autoimmunity Reviews 16 (2017) 123–131
findings should undergo brain biopsy [1,3,6]. Table 2 depicts differential
diagnosis of PCNSV.
The pathology patterns found in PCNSV are granulomatous (58%),
lymphocytic (28%) and necrotizing vasculitis (14%) [1,9]. Granuloma-
tous vasculitis is the most common pattern found in PCNSV, showing
vasculocentric mononuclear inflammation and well-formed granulo-
maswithmultinucleated giant cells. Lymphocytic vasculitiswas typical-
ly reported in children with angiography-negative primary CNS
vasculitis, nonetheless it may also be found in adults [1,9,17]. Necrotiz-
ing vasculitis is the least common pathological pattern of PCNSV, and it
is characterized by transmuralfibrinoid necrosis [1] (Figs. 1 and 2). In al-
most 31% of PCNSV patients, amyloid-beta co-localizes with inflamma-
tory findings within the vessel wall, and this entity is recognized as
ABRA (amyloid beta related angiitis) [6,18,19]. ABRA is considered a
subtype of PCNSV and there is evidence that amyloid-beta deposition
triggers the vasculitic process [3,20].
According to the largest PCNSV report on 163 patients, involvement
of larger vessels is associated with a more aggressive course. Small-
vessel PCNSV (angiography-negative PCNSV) which frequently pre-
sents with cognitive dysfunction, relapses, hyperproteinorachia and
meningeal or parenchymal enhancing lesions have better prognosis [1,
6,21,22].
Although previous studies reported a rapid evolution and reserved
prognosis in PCNSV, new data showed that 85% of patients present a fa-
vorable response to therapy. Approximately 27% relapse and the mor-
tality rate is up to 15% [21]. In another large series of 52 patients from
the COVAC study, mortality rates were even lower (6%) than the previ-
ously reported [23]. There is body of evidence suggesting that histo-
pathological pattern also matters to prognosis, as French series
presentedmore lymphocytic PCNSVwith lowermortality rates, and pa-
tients with necrotizing PCNSV may present up to twenty-years of dis-
ease course [20].
Patients with inflammation restricted to small cortical and
leptomeningeal vessels should receive prednisone alone (initial dose
of 1 mg/kg/day). Patients with PACNS involving large vessels and in
those with a rapidly progressive course should be treated with steroids
combined with cyclophosphamide (CYC). Data on treatment of PCNSV
with azathioprine (AZA) or mycophenolate mofetil (MMF) are scarce
and there are case reports of TNF-alpha blockers and rituximab (RTX)
use in PCNSV patients intolerant or non-responders to CYC [24–29].
3. Differential diagnosis
3.1. Reversible cerebral vasoconstriction syndrome (RCVS)
RCVS is characterized by recurrent episodes of headache and brain
vasoconstriction that resolve in months [30,31]. It is most commonly
seen in middle-aged women [6], patients usually present a monophasic
disease, although 5% mayexperience recurrence [32]. Most patients
Fig. 1. Necrotizing PCNSV. A: Brain MRI FLAIR sequence showing multiple inflammatory lesion
lesions. C: Brain biopsy disclosing necrotizing vasculitis. Observe the necrotic aspect of the arte
present thunderclap headache (TCH), characterized by hyperacute se-
vere headaches, reaching a maximum intensity in 1 min, with or with-
out neurologic symptoms [33]; nonetheless approximately 15%
develop other headache types or no headache. Hence, the absence of
TCH should not lead to discard the diagnosis of RCVS [30].
Pathophysiology involves disturbances in cerebral vascular tone
triggered by sympathetic overactivity, endothelial dysfunction, and ox-
idative stress [7,33]. In half of the cases exposure to vasoactive drugs
such as antidepressants, marijuana and vasoconstrictors have been re-
ported (Table 1) [30]. Clinical conditions commonly associated with
RCVS are eclampsia, carotid surgery and neuroendocrine tumors. Pa-
tientswith RCVSmay present posterior reversible leukoencephalopathy
syndrome (PRES) in 10–38% of cases [30,34,35]. Cervical artery dissec-
tion was described in 8% and other vascular malformations may also
be found such as venous anomaly, cavernous malformations and
fibromuscular dysplasia, suggesting that there might be a predisposing
vascular condition [36,37]. Approximately 5–10%of the patients present
severe forms with brain edema; 34% present worsening of symptoms,
however estimatedmortality is of 1.4% [38–40]. Table 2 shows diagnos-
tic criteria for RCVS.
Laboratory results are normal and CSF analysis usually disclosesmild
hyperproteinorrachia and less than 10 cells/mm3. BrainMRI is frequent-
ly normal in RCVS but may reveal infarct areas in 55% of the patients at
initial MRI and during follow-up approximately 81% of the patientswith
RCVS will present brain lesions. Besides ischemic strokes, patients may
develop hemorrhages overlying the cortical surface (34%), parenchymal
hemorrhages and small non-aneurysmal subarachnoid hemorrhages
(SAH) [30,41] (Fig. 3). Digital angiographic findings of RCVS and
PCNSV are rather similar and clinical symptoms of both entities may
overlap. Therefore, RCVS is defined by the reversal of angiographic find-
ings within 12 weeks.
s in periventricular area. B: T1 weighted sequence showing multiple contrast enhancing
rial vessels (arrow).
Fig. 3. Reversible cerebral vasoconstriction syndrome. A: Diffusion weighted image (DWI) shows two small areas of restricted diffusion (arrow) in the right frontal centrum semiovale, in
keeping with internal watershed zone acute infarcts. B: FLAIR sequence depicted cortical SAH in left superior frontal sulcus (arrow). C: 3D time-of-flight (TOF) sequence. Multifocal
narrowings and post-stenotic dilatation in the distal branches of the medium cerebral arteries - beaded appearance (arrowhead) D: TOF sequence. Normal appearance of the
intracranial arteries in follow-up.
126 L.A. Dutra et al. / Autoimmunity Reviews 16 (2017) 123–131
While DSA provides superior resolution, it only images the vessel
lumen [42]. Vesselwall high resolutionMRI (HRMRI)may help differen-
tiate RCVS and PCNSV. RVCS presents with no significant arterial wall
thickening and absent or mild contrast enhancement, while on PACNS
there are short segments of concentric wall thickening with concentric
(70%) or eccentric enhancement (30%) in a unilateral distribution or bilat-
eral artery distribution localized at one or multivessel segments [42,43].
Most patients with RCVS are managed with calcium channel
blockers such as nimodipine or verapamil [41]; although these drugs
do not improve outcome, they relieve pain. Nearly 90% of RCVS patients
present good prognosis, although 53% of RCVS patients continue to
present headaches,most of themwith little impact and disability, differ-
ently from the classic thunderclap features [44]. Patients without ische-
mic stroke, SAH or intracerebral hemorrhage had a higher rate of
developing persistent headache compared to those who suffered an ini-
tial stroke [44]. RCVS patients do not benefit from immunosuppressive
therapy and it is possible that steroids' use may be associated with
poor outcomes [41].
4. Secondary vasculitis of the CNS
4.1. Vasculitis secondary to connective tissue diseases
CNS involvement in connective tissue diseases (CTDs) occurs more
frequently in systemic lupus erythematosus (SLE), Sjögren's syndrome
(SS), mixed connective tissue disease (MCTD), and dermatomyositis
[45].
CNS involvement in SLE occurs in more than 50% of patients [46].
Disruption of the blood-brain barrier is universal in neuropathology of
SLE and the pathogenesis is multifactorial, involving various inflamma-
tory cytokines, autoantibodies, and immune complexes, resulting in
vasculopathic, cytotoxic and autoantibody-mediated neuronal injury
[47,48].
The incidence of CNS vasculitis in postmortem studies of SLE pa-
tients does not exceed 7%–10% of cases involving more frequently
small rather than large vessels [1,49]. Patients more commonly present
a non-inflammatory vasculopathywith unclear clinical correlation, pre-
sumably associated with antiphospholipid (aPL), immune complexes
and complement activation, cardiac emboli and accelerated athero-
sclerosis [49,50]. Since 25% to 40% of SLE patients have secondary
antiphospholipid syndrome (APS), all SLE patients presenting
neurological symptoms should be tested for antiphospholipid
antibodies [47].
Angiographic abnormalities suggestive of cerebral vasculitis have
occasionally been seen in patients with aPL and ischemic cerebrovascu-
lar events, better justified by thrombotic vasculopathy [34,51,52]. Pa-
tients who usually receive anticoagulation and severe manifestations
may also be managed with steroids, immunoglobulin, plasmapheresis
or RTX [53,54].
Patients with systemic sclerosis and en coup de sabre localized
scleroderma (ECSLS) may present neurological involvement, especially
headache and seizures. Brain MRI may disclose cavernomas, calcifica-
tions, localized brain atrophy, and white-matter hyperintensities [55,
56]. Approximately 73% of ECSLS patients present seizures; other man-
ifestations are headache, movement disorders and neuropsychiatric
symptoms [56]. Although pathogenesis is not fully understood, brain bi-
opsy specimens disclosed chronic perivascular lymphocytic inflamma-
tion, scattered inflammatory cells within vessel walls, and microglial
activation, supporting the diagnosis of vasculitis [55–58]. Moreover, it
was reported that patients with systemic sclerosis may present cerebral
hypoperfusion due to noninflammatory vasculopathy with progressive
obliterative lesions [59].
Neurological involvement in SS occurs in 5–19% of patients with pri-
mary SS, andmay precede systemicmanifestations inmore than 5 years
[60,61]. Patients may present overlap with ANCA-associated vasculitis
and neuromyelitis optica [60,62]. Common SS neurological manifesta-
tions are optic neuritis, peripheral neuropathy, myelitis, seizures and
strokes. It seems that different pathophysiological mechanisms contrib-
ute for CNS involvement in SS and the vasculitic process is amongst
them [63].
127L.A. Dutra et al. / Autoimmunity Reviews 16 (2017) 123–131
Rheumatoid vasculitis affecting the CNS is very rare andmaypresent
with seizures, dementia, hemiparesis, cranial nerve palsy, blindness,
cerebellar ataxia, or dysphasia. Secondary cerebral vasculitis in rheuma-
toid arthritis is a rare complication of longstanding, nodular, erosive,
and seropositive rheumatoid arthritis [1,64].
CNS vasculitis may be rarely found in juvenile dermatomyositis
(JDM), [65,66]. Most children with JDM presented CNS involvement
shortly after the diagnosis together with vasculitis in other sites includ-
ing skin, retina and lungs. Interestingly, an adult with biopsy-proven
vasculitis secondary to dermatomyositis presented neurological mani-
festation two years after diagnosis [67].
4.2. CNS vasculitis secondary to systemic vasculitis
Most systemic vasculitismay involve the CNS, especially Behçet's
disease (BD), granulomatosis with polyangiitis (GPA) formerly
Wegener's granulomatosis, eosinophilic granulomatosis with polyangi-
itis (EGPA) formerly Churg–Strauss syndrome, and polyarteritis nodosa
(PAN) [45].
BD is characterized by recurrent oral and genital ulcers, ocular in-
flammation, arthritis, skin lesions, vascular and gastrointestinal involve-
ment [68,69]. Neuro-Behçet's disease (NDB) is found in 5–30% of BD
patients and is classified as parenchymal and non-parenchymal. Paren-
chymal NBD is more common and more severe than non-parenchymal
NBD [70–74]. Meningoencephalitis involving brainstem, cranial nerve
palsies, epilepsy and myelitis are parenchymal manifestations of NBD
[70]. Cerebral venous thrombosis (CVT) and aseptic meningitis are clas-
sified as non-parenchymal NBD [72]. NBDmaymimic multiple sclerosis
and other uveo-meningeal syndromes such as sarcoidosis, SLE and SS
[74] (Fig. 4).
Approximately 30–50% of patients with NBD have a relapsing course
[71] and adverse prognostic factors include brainstem or spinal cord
presentation, frequent relapses, early disease progression, residual neu-
rological impairments in remission and high CSF pleocytosis [74,70,73].
Patients with severe manifestations are managed with steroids and im-
munosuppressant agents such as AZA, CYC, methotrexate (MTX) and
MMF [74,75]. Infliximab (IFX) is an option for refractory patients with
NBD, continued benefit from IFX is observed in follow-up studies over
Fig. 4. Brain MRI in neuro-Behçet's disease. FLAIR sequence. Brainstem vasculitis invo
a 4-year period [76,77]. Adalimumab and tocilizumab have been report-
ed as an alternative to IFX [78,79]. It is believed that thrombus formation
in CVT fromNBD patients is secondary to an inflammatory vascular pro-
cess; thus,management of CVT inNBD includes steroidswith orwithout
immunosuppressive agents. There is no evidence that NBD with CVT
may benefit from therapy with anticoagulants, although it is prescribed
in many centers [74,80].
The most common neurological manifestation in GPA is peripheral
neuropathy, occurring in 60% of the patients with generalized disease.
CNS involvement may be found in 4–11% of GPA patients. Three differ-
ent pathogenic patterns of CNS involvement in GPA were identified:
vasculitis affecting the small to medium size vessels of the brain or spi-
nal cord, (generalized disease), granulomatous masses from the upper
respiratory tract invading CNS structures (localized disease) and granu-
lomatous lesions within the cerebral tissue such as the meninges (e.g.
pachymeningitis) or the brain [81]. Therefore GPA patients with CNS in-
volvement may be either classified as vasculitic or granulomatous GPA
as well [82]. Treatment of neurological manifestations of GPA involves
the combination of steroids and CYC or RTX [1].
PAN is a medium-vessel necrotizing vasculitis that also involves pe-
ripheral nerves and CNS. Rare neurologicalmanifestations of PAN are in-
tracranialmicroaneurysms formation and stroke-like episodes thatmay
present with intracerebral bleeding or SAH (Fig. 5).
EGPA has traditionally been described to evolve through a prodro-
mal phase characterized by asthma and nasal polyps or rhinosinusitis,
an eosinophilic phase marked by peripheral eosinophilia and organ in-
volvement (e.g. lungs or gastrointestinal tract), and a vasculitic phase
with clinical manifestations due to small vessel vasculitis [83]. Although
EGPA patients more frequently present involvement of peripheral ner-
vous system, about 6% to 10% of patients with EGPA have brain involve-
ment, with encephalopathy, brain infarcts, transient ischemic attacks,
parenchymal and SAH due to vasculitis [84,85].
4.3. Infectious CNS vasculitis
Brain large vessels may also be affected in the course of bacterial
meningitis by Streptococcus pneumoniae, Neisseria meningitidis, Myco-
bacterium tuberculosis, Treponema pallidum and Borrelia burgdorferi
lving midbrain (A) extending to the thalamus and bilateral internal capsule (B).
Fig. 5. BrainMRI in Polyarteritis nodosa. A, B: FLAIR sequence showing ischemic lesions in periventricular and left temporal regions. C: BrainMRI angiogram disclosingmultiple aneurisms
in vessels (arrows) supplying left temporal region (inferior middle cerebral artery and posterior cerebral artery).
128 L.A. Dutra et al. / Autoimmunity Reviews 16 (2017) 123–131
infections [1,5]. Moreover, T. pallidum and B. burgdorferi present vessel
tropism and may cause encephalopathy, cerebrovascular disease and
cranial neuritis. In bacterial endocarditis, valvular emboli may cause ce-
rebrovascular occlusions and a vasculitic pattern on cerebral angiogra-
phy [1].
Varicella-zoster virus (VZV) vasculopathy is an infectious arteritis
that causes ischemic and hemorrhagic strokes aswell as transient ische-
mic attacks. It is found in both immunocompetent and immunocompro-
mised individuals, and involves large and small intracranial vessels.
Patients usually present varicella or herpes zoster months prior to the
development of stroke, but CSF may be normal. The best virological
test for diagnosis is the detection of anti-VZV IgG antibodies in CSF rath-
er than VZV PCR because of the protracted course of the disease [86,87].
Patients may benefit from steroids and antiviral treatment. More re-
cently it was found that VZV may trigger the inflammatory cascade
that characterizes giant cell arteritis [88].
HIV-associated vasculopathy includes any abnormality of intracrani-
al or extracranial blood vessels that results directly or indirectly from
HIV infection, excluding associated opportunistic infectious vasculitis
or neoplastic involvement [89,90]. Although HIV-1 is unlikely to be
vasculotropic, the virus affects endothelial homoeostasis and function
in ways that could initiate and propagate atherogenesis [89]. Patients
with HIVmay present extracranial or intracranial aneurysmal dilatation
as well as focal stenotic areas [89,91] and this manifestation may be
treated with steroids therapy [1].
4.4. Miscellaneous
Intravascular lymphoma (IVL), a subtype of extranodal diffuse large
B-cell lymphoma, is an important differential diagnosis of PCNSV char-
acterized by intravascular proliferation with a predilection for the CNS
and skin. It usually affects the middle aged to elderly population; clini-
cally patients may present weight loss, fever, encephalopathy, seizures,
myelopathy, and focal neurological deficits attributed to vascular occlu-
sion, neuropathies, radiculopathies, and myopathies [92,93]. Brain MRI
patterns differ from primary CNS lymphoma and may include ischemic
lesions, nonspecific white matter lesions, meningeal enhancement,
mass-like lesions, and T2 hyperintense lesions in the pons [94]. Contrast
enhancement and diffusion restriction may be absent. The clinical
course of IVL is usually fatal within few weeks to several months.
Most reported caseswere post-mortem; IVL diagnosis is challenging be-
cause there is no diagnostic test other than pathological examination
[92].
Lymphomatoid granulomatosis (LYG) is a rare angiocentric and
angiodestructive B-cell lymphoproliferative disorder driven by
Epstein-Barr virus (EBV) infection and associatedwith reactive T cell in-
filtration. LYGusually affectsmiddle aged adults between the fourth and
sixth decades of life, but it may affect children and teenagers [95,96].
LYG has a slight predominance of men over women (2:1) and affects
extranodal sites. The lungs are predominantly involved with bilateral
nodular infiltrates that may lead to large necrotic and cavitating lesions.
Pulmonary manifestations of LYG range from cough, dyspnea and chest
pain to overt respiratory failure. Subsequently, LYG evolves to affect the
skin and CNS in up to 20% of cases. LYGmay also involve the kidney and
the liver, but it is rarely associated with lymph node or spleen enlarge-
ment at diagnosis [97].
The CNS involvement in LYG leads to symptoms of dementia, multi-
focal infarcts, and seizures.Different MRI findings have been described
in LYG and include multiple focal parenchymal lesions, leptomeningeal
and cranial nerve involvement. LYG mimics several conditions such as
GPA and sarcoidosis due to lung involvement, whereas in CNS it mimics
IVL [95,96].
Diagnosis of LYG can be made by biopsy findings of atypical lym-
phoid cells (CD20-positive B cells) in affected tissues surrounded by
CD3-positive small T cells, plasma cells and histiocytes. Angiocentric
and destructive intravascular infiltration by mononuclear cells is a pre-
dominant feature of LYG. Atypical B cells bear EBV and this infection can
be confirmed by in situ hybridization for EBV RNA [98,99]. Currently,
there are two histological diagnostic criteria for LYG: the 2008 WHO
(World Health Organization) criteria and Katzenstein et al. criteria [98,
99]. Histologically, LYG is divided into three grades according to the pro-
portion of large atypical positive B-cells and necrosis compared to reac-
tive T cell infiltrate. The distinction from grade I or II to grade III is
important for therapeutic decisions, since patients presenting as grade
III LYG are treated as diffuse large B cell lymphoma, while grade I and
II patients may be treated only with interferon-alpha only [97].
Susac syndrome (SuS) is amultisystemic and immune-mediated oc-
clusive endotheliopathy that predominantly affects young women aged
between 20 and 40 years old but can occur at any age. SuS is charac-
terized by a triad of encephalopathy, hearing loss and branch retinal
artery occlusions and pathogenesis is still obscure. Other clinical
manifestations included headache, dementia, vertigo and psychiat-
ric manifestations. As the three components of the triad may not al-
ways be present, the condition is underdiagnosed. Frequently SuS is
misdiagnosed as multiple sclerosis or atypical forms of encephalitis.
The final diagnosis is based on clinical presentation, lesions ob-
served at brain MRI, retinal angiography and audiometry findings.
Retinal fluorescein angiography and fundoscopy show evidence of
vasculopathy. CSF may reveal lymphocytic pleocytosis and elevated
protein levels. Brain MRI may show characteristic white matter
lesions and microinfarcts in the centrum semiovale, corpus callosum,
periventricular white matter and internal capsule.
The most typical MRI lesions of SuS are callosal lesions, within the
corpus, genu or splenium of the corpus callosum (Fig. 6). The disease
Fig. 6. Brain MRI in Susac syndrome. A: FLAIR sequence, observe multiple foci of T2 increased signal oval-shaped lesions in the periventricular region (arrow) B: T1 weighted sequence
showing the characteristic involvement of the genu of the corpus callosum (arrow).
129L.A. Dutra et al. / Autoimmunity Reviews 16 (2017) 123–131
may be self-limited, fluctuating or relapsing, sometimes with residual
neurological sequela [100–102]. SuS should be treated early and aggres-
sively and first options are steroids and IVIG; plasmapheresis and CYC
can be considered as well in refractory disease. SuS patients should re-
ceive immunosuppressive treatment with AZA to prevent relapses. In
addition, antiplatelet agents (aspirin or dipyridamole) should be con-
sidered and hearing loss can be treated with cochlear implants [100,
101,103].
Cogan syndrome (CS) is a rare form of systemic vasculitis character-
ized by the presence of ocular and audiovestibular symptoms. The etiol-
ogy of CS is unknown and there is no specific confirmatory diagnostic
testing. Typical manifestations include non-syphilitic interstitial kerati-
tis and Meniere's-like symptoms such as hearing loss, sometimes with
attacks of tinnitus and vertigo. Atypical manifestations of CS include
other types of ocular inflammation (e.g. choroiditis, episcleritis), sys-
temic inflammation and an interval between audiovestibular symptoms
and ocular symptoms higher than 2 years. CS may be associated with
other inflammatory diseases like rheumatoid arthritis and inflam-
matory bowel disease. The initial treatment includes steroids or
others immunosuppressive drugs like AZA, MTX and CYC. In non-
responsive or refractory cases IFX, MMF and RTX are therapeutic
options [104–106].
5. Conclusion
PCNSV is a challenging diagnosis due to the broad clinicalmanifesta-
tions and variable specificity and sensitivity of laboratory and imaging
diagnostic tools. Brain biopsy should be performed whenever possible.
Large vessel PCNSV should be managed with steroids and CYC whereas
small vessel PCNSVwith steroids alone due to recent data on prognosis.
Themost important differential diagnosis is RCVS, that may occur with-
out thunderclap headache. Other differential diagnoses include second-
ary CNS vasculitis such as SLE, GPA, BD and PAN. One should also
consider IVL, LYG and non-inflammatory vasculopathies.
Conflict of interest
Drs. Dutra, Grinberg, Barsottini, and Silva de Souza report no disclo-
sure. Dr. Appenzeller receives a Grant from Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq 304255/2015-7)
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	Central nervous system vasculitis in adults: An update
	1. Introduction
	2. Primary vasculitis of central nervous system
	3. Differential diagnosis
	3.1. Reversible cerebral vasoconstriction syndrome (RCVS)
	4. Secondary vasculitis of the CNS
	4.1. Vasculitis secondary to connective tissue diseases
	4.2. CNS vasculitis secondary to systemic vasculitis
	4.3. Infectious CNS vasculitis
	4.4. Miscellaneous
	5. Conclusion
	Conflict of interest
	References