Recent Understanding on Diagnosis and Management of Central Nervous System Vasculitis in Children

Abstract

Central nervous system vasculitides in children may develop as a primary condition or secondary to an underlying systemic disease. Many vasculitides affect both adults and children, while some others occur almost exclusively in childhood. Patients usually present with systemic symptoms with single or multiorgan dysfunction. The involvement of central nervous system in childhood is not frequent and it occurs more often as a feature of subtypes like childhood polyarteritis nodosa, Kawasaki disease, Henoch Schönlein purpura, and Bechet disease. Primary angiitis of the central nervous system of childhood is a reversible cause of severe neurological impairment, including acute ischemic stroke, intractable seizures, and cognitive decline. The first line therapy of CNS vasculitides is mainly based on corticosteroids and immunosuppressor drugs. Other strategies include plasmapheresis, immunoglobulins, and biologic drugs. This paper discusses on current understanding of most frequent primary and secondary central nervous system vasculitides in children including a tailored-diagnostic approach and new evidence regarding treatment.

Full text

Hindawi Publishing Corporation
Clinical and Developmental Immunology
Volume 2012, Article ID 698327, 9pages
doi:10.1155/2012/698327
Review Article
Recent Understanding on Diagnosis and Management of
Central Nervous System Vasculitis in Children
Ludovico Iannetti,1Roberta Zito,1Simone Bruschi,1Laura Papetti,2Fiorenza Ulgiati,2
Francesco Nicita,2Francesca Del Balzo,2and Alberto Spalice2
1Department of Ophthalmology, Ocular Immunovirology Service, Sapienza University of Rome,
Viale del Policlinico 155, 00161 Rome, Italy
2Department of Pediatrics, Child Neurology Division, Sapienza University of Rome, 00185 Rome, Italy
Correspondence should be addressed to Ludovico Iannetti, l.iannetti@policlinicoumberto1.it
Received 30 March 2012; Revised 28 May 2012; Accepted 13 August 2012
Academic Editor: Rolando Cimaz
Copyright © 2012 Ludovico Iannetti et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Central nervous system vasculitides in children may develop as a primary condition or secondary to an underlying systemic disease.
Many vasculitides affect both adults and children, while some others occur almost exclusively in childhood. Patients usually present
with systemic symptoms with single or multiorgan dysfunction. The involvement of central nervous system in childhood is not
frequent and it occurs more often as a feature of subtypes like childhood polyarteritis nodosa, Kawasaki disease, Henoch Sch¨
onlein
purpura, and Bechet disease. Primary angiitis of the central nervous system of childhood is a reversible cause of severe neurological
impairment, including acute ischemic stroke, intractable seizures, and cognitive decline. The first line therapy of CNS vasculitides
is mainly based on corticosteroids and immunosuppressor drugs. Other strategies include plasmapheresis, immunoglobulins, and
biologic drugs. This paper discusses on current understanding of most frequent primary and secondary central nervous system
vasculitides in children including a tailored-diagnostic approach and new evidence regarding treatment.
1. Introduction
Vasculitides constitute a heterogeneous group of diseases
characterized by inflammation of the blood vessel wall. Cen-
tral nervous system (CNS) vasculitides in children may
develop as a primary condition or secondary to an under-
lying systemic disease including infections, collagen vascular
diseases, systemic vasculitides, and malignancies (Tabl e 1 )
[1].
Although many vasculitides affect both adults and chil-
dren, some, such as Kawasaki disease, occur almost exclu-
sively in childhood. Other vasculitides (e.g., temporal arteri-
tis) rarely if ever occur in childhood, and others, like pol-
yarteritis and polyangiitis GPG (also known as Wegener’s
granulomatosis) have different etiological, clinical, and prog-
nostic characteristics in children [2]. For these reasons the
EULAR (European League against Rheumatism) recently
proposed the new consensus criteria for the classification of
childhood vasculitides (Tabl e 2)[2].
When CNS is involved in the course of vasculitides
children may present with intractable seizures, cranial nerve
deficits, paresis, and/or cognitive deficits. The diagnosis of
CNS vasculitides is particularly difficult because the avail-
able investigative modalities have limited sensitivities and
specificities. The most helpful diagnostic tests include cere-
brospinal fluid analysis, MRI (MR angiography/venography
(MRA/MRV) of the brain, and angiography. In particular
conventional angiography remains the gold standard for
identifying lesions in cerebral vasculitis due to missed lesions
with MRA, particularly in younger patients. Conventional
angiography is more sensitive than even high-quality MRA
at detecting involvement of the posterior circulation and
distal cerebral vessels. To date MRA is a reasonable initial
modality in the investigation of suspected CNS vasculitis but
in cases of abnormal parenchymal MRI and normal MRA,
CA should be considered [3]. However, brain biopsy may
be required to diagnose small vessel vasculitides. The dif-
ferential diagnosis includes a wide range of conditions, such

2Clinical and Developmental Immunology
Figure 1: MRI Axial T2-Flair image. A six-years girl with HSP
complicated by PRESS. Bilateral hyperintense lesions of subcortical
white matter in the occipital region.
as degenerative vasopathies, embolic diseases, or coagulation
disorders (Tabl e 3)[1].
Different treatments have been proposed including corti-
costeroids, immunosuppressive agents, such as methotrexate
and cyclophosphamide, and intravenous gammaglobulines
to induce or maintain remission and to prevent long-term
vascular complications (Figure 1). In addition to a specific
therapy that can vary depending on the nature of vasculitis,
patients with cerebral involvement also need an acute
symptomatic therapy which varies depending on the specific
clinical manifestation (stroke, headache, epilepsy, etc.). This
acute symptomatic treatment must be undertaken immedi-
ately, well before the precise etiologic diagnosis. Supportive
therapy for all types of CNS vasculitis may include anticon-
vulsants for children with seizures, and antipsychotic agents
for those with hallucinations or severe behavior difficulties.
Children who are treated with high-dose corticosteroids may
require ranitidine or a proton pump inhibitor to treat asso-
ciated gastritis and calcium and vitamin D supplementation
to preserve their bone health.
In this paper, we provide an update description of dif-
ferent immunointerventions in vasculitides, comparing and
discussing current literature about practical management of
childhood CNS vasculitides.
2. Childhood Polyarteritis Nodosa
Childhood polyarteritis nodosa (PAN) is a necrotizing
vasculitis, affecting medium size blood vessels. PAN includes
two different subtypes, the classical systemic form presenting
with a wide range of clinical manifestations including derma-
tologic, musculoskeletal, nervous, renal, and gastrointestinal
systems and the more frequent cutaneous form (CPAN)
that involves only the skin. Since the aim of this paper is
to describe the treatment options in vasculitis with brain
involvement, in this section will refer only to the systemic
form.
The diagnosis of PAN requires the evidence of necro-
tizing vasculitis or angiographic abnormalities of medium-
/small-sized arteries (mandatory criterion) plus one of five
criteria: (1) skin involvement; (2) myalgia/muscle tender-
ness; (3) hypertension; (4) peripheral neuropathy; (5) renal
involvement [2].
Tab le 1: Causes of secondary central nervous system vasculitis in
children [1].
Infections
Viral: varicella, HIV, hepatitis C
Bacterial: Lyme disease, tuberculosis
Fungal
Parasitic
Systemic vasculitis
Kawasaki disease
Henoch-Sch¨
onlein purpura
Polyarteritis nodosa
Wegener granulomatosis
Microscopic polyarteritis nodosa
Ta k ay a s u a r t e r i ti s
Systemic connective tissue
diseases
Systemic lupus erythematosus
Dermatomyositis
Sjogren syndrome
Inflammatory bowel
diseases
Sarcoidosis
Vascular injury Dissection
Radiation
Drugs Amphetamines
Contraceptives
Neoplasms
Graft versus host diseases
Neurological involvement has been reported in about
50% of patients, presenting with peripheral nervous sys-
tem involvement (mainly paresthesias and polyneuropa-
thies) more frequently than CNS involvement (including
encephalitis, convulsions, hemiparesis, subarachnoid hem-
orrhage, and isolated cranial nerve palsies) [4]. Myalgias are
also very frequent neurological features. A combined biopsy
of muscle usually and nerve demonstrates the necrotizing
granulomatous inflammation [5]. Ischemic stroke, hemor-
rhages, and a progressive encephalopathy with or without
seizures may occur [4]. Because of the rarity of systemic PAN
in children, treatment options are mainly based on adult
literature giving a central role to oral corticosteroid as first
line treatment [4] and indicating second line therapies based
on azathioprine, intravenous solu-Medrol, and cyclophos-
phamide. In children presenting with mild disease steroid
alone may be recommended [6].
Hashimoto et al. reported a success rate 41.7% in the
treatment of PAN with plasmapheresis [7]. In the series
reported by Guillevin et al. plasma exchange have no added
benefit to steroid ±cyclophosphamide [8].
Ozen, in her study, suggests a treatment schedule for
severe disease based on prednisone 2 mg/kg/die to be tapered
after clinical suppression. According to this author cyclo-
phosphamide should be also given, orally, in a dose of
2 mg/kg/day for the first three months, after which aza-
thioprine should be substituted and continued after a
year [9], while Dillon and colleagues, in their educational
review, also consider pulsed intravenous infusions for up to

Clinical and Developmental Immunology 3
Tab le 2: New classification of childhood vasculitis [2].
Predominantly large vessel vasculitis Takayasu arteritis
Predominantly medium-sized vessel vasculitis
Childhood polyarteritis nodosa
Cutaneous polyarteritis
Kawasaki disease
Predominantly small vessels vasculitis
(A) Granulomatous:
Wegener’s granulomatosis
Churg-Strauss syndrome
(B) Nongranulomatous:
Microscopic polyangiitis
Henoch-Sch¨
onlein purpura
Isolated cutaneous leucocytoclastic vasculitis
Hypocomplementic urticarial vasculitis
Other vasculitis
Behcet disease
Vasculitis secondary to infection (including hepatitis B associated polyarteritis
nodosa), malignancies, and drugs, including hypersensitivity vasculitis
Vasculitis associated with connective tissue diseases
Isolated vasculitis of the central nervous system
Cogan syndrome
Unclassified
6 months or for shorter periods if remission is achieved [6].
Maintenance therapy with daily or alternate-day low-dose
prednisone and oral azathioprine is usually continued up to
18 months. Other maintenance agents include methotrexate
and cyclosporin A. For those patients whose conditions
are refractory to multiple immunosuppressive agents and
corticosteroid dependent, oral mycophenolate mofetil, and
infliximab may enable tapering and eventual discontinuation
of the corticosteroids [4].
Concerning refractory cases, potential efficacy of intra-
venous Ig were reported in recent studies [10], while some
other studies report successful outcomes using biologic
agents as infliximab or rituximab [11]. Gianviti et al.,
discussed the possible benefit from the addition of plasma
exchange to immunosuppressive medication in life-threat-
ening situations, nevertheless still further trial are needed
to resolve the question of this procedure’s value in treating
childhood vascular diseases [12].
3. Kawasaki Disease
Kawasaki disease (KD) is an acute febrile systemic vasculi-
tis occurring in medium-sized vessels, especially coronary
arteries. It affects mainly infants and children under 5 years
of age and it is associated with the presence of coronary
artery lesions (CALs) such as coronary artery dilatations
and ectasias. CALs occur in almost 25% of untreated
patients [13–16] and may develop into aneurismal forma-
tion, thrombotic occlusion and fistula formation or progress
to ischemic heart disease and premature atherosclerosis
[17]. The clinical presentation is characterized by prolonged
fever, polymorphous skin rash, nonpurulent conjunctival
injection, extremity changes, oral mucosal changes, and
cervical lymphadenopathy. The CNS involvement occurs in
about 0.4% of children in the form of aseptic meningitis,
meningoencephalitis, hypoperfused brain, ischemia, cerebral
and cerebellar infarction, and subdural effusion [18,19].
In the case of aseptic meningitis we must distinguish two
different forms, first one being secondary to the disease
and second one following IVIG administration [20]. Clinical
manifestations of CNS involvement include seizures and
disturbance of consciousness [21]. Prognosis of neurological
complications is generally good, although sequelae such
as myoclonic seizures, hemiparesis, and moyamoya disease
have been reported in a small percentage of patients [18].
Although MRI scans revealed no abnormalities at the acute
stage of the disease, the CNS manifestations associated
with KD might be due to focal impairment of blood flow
caused by cerebral vasculitis. In six of 21 children with
acute Kawasaki disease, single-photon emission computed
tomography (SPECT) imaging demonstrated localized cere-
bral hypoperfusion without neurologic findings [22].
Standard therapy is intravenous immunoglobulin plus
aspirin which showed a good outcome in most of the
patients, suggesting that proinflammatory cytokines are
responsible for the progression of the disease, and that re-
moval of these cytokines from the circulation will be a major
strategy of treatment [14,23]. Randomized controlled trials
have shown that a single infusion of 2 g/kg of IVIG given
5–10 days after the onset of fever, eliminated fever in 85–
90% of children within 36 h and significantly reduced the risk
of CALs [24]. Five possible mechanisms include Fc receptor
blockade, neutralization of the causative agents, or a toxin
produced by an infectious agent, an immunomodulating
effect, induction of suppressor activity, and modulation of
the production of cytokines and cytokine antagonists [25].
Aspirin remains one of the mainstays of therapy because
of its antiinflammatory and anti-thrombotic actions [26].
During the acute phase of illness, aspirin is administered

4Clinical and Developmental Immunology
Tab le 3: Differential diagnosis of CNS vasculitides in children.
Infectous disease
Viral/bacterial encephalitis
Viral/bacterial menigitidis
Viral/bacterial sepsi
Metabolic disease
Mitochondrial disease
Amino acid disorders
Organic acidemias
Urea cycle disorders
Fatty acid oxidation disorders
Fabry disease
Homocystinuria
Leukodystrophies
Demyelinating diseases Multiple sclerosis
Acute-disseminated encephalomyelitis
Thromboembolic diseases
Antiphospholipid syndrome
Hypercoagulability states
Cholesterol embolisms
Cardiac myxoma
Nonbacterial thrombotic endocarditis
Malignancies
Multifocal glioma
CNS lymphoma
Angiocentric lymphoma
Intravascular lymphoma (malignant angioendotheliomatosis)
Autoimmune disease
Celiac disease
Hashimoto’s encephalitis
Sarcoidosis
Systemic lupus erythematosus
Neuronal antibody associated (NMDA-receptor associated encephalitis)
Vasc ul ar
Arterial dissection
Fibromuscular dysplasia
Moyamoya disease
Vasospastic disorders
Nutritional Vitamin B12 deficiency
at anti-inflammatory doses with IVIG. Still controversial
is the duration of high dose aspirin administration, which
varies between different centers. High-dose aspirin and
IVIG appear to possess an additive anti-inflammatory
effect [13]. Discontinuation of high-dose aspirin is usually
recommended when patient is afebrile, switching to low-
dose aspirin (3–5 mg/kg/die) until there is no evidence of
coronary artery lesions and inflammatory markers have
returned to normal levels (usually 6–8 weeks after disease
onset). Nevertheless, recent studies suggest that children
exposure to high dose aspirin therapy in the acute phase of
KD is unnecessary, claiming that available data do not show
appreciable benefit to IVIG therapy and clinical resolution
[13].
Other therapeutic options (in addition to retreatment
with immunoglubulins 1-2 g/kg) have been proposed for
refractory KD: pulsed corticosteroid treatment (intravenous
methylprednisolone 30 mg/kg per day for 3 days), infliximab,
abciximab, plasmapheresis, plasma exchange, and immuno-
suppressants such as Cyclophosphamide and Cyclosporin A
[13,27–31]. The TNF alpha blockers (such as infliximab)
and platelet glycoprotein Ibis/Imia receptor inhibitors (such
as abciximab), seem to benefit KD patients, especially those
patients/cases refractory to IVIG and those patients who
developed aneurysms. Concerning infliximab administra-
tion, it is currently increasing for KD patients with recrude-
scent fever or persistently elevated inflammatory markers
to prevent coronary aneurysm and stricture formation
and a dose of 4.8 mg/kg, diluted in 250 mL of normal
saline, may be suggested [29,32–35]. Instead, abciximab
administration is commonly used to prevent thrombosis and
to decrease aneurysm size in patients with large coronary
artery aneurysms [36]. A recent open label trial have
been performed by Choweiter et al. to determine safety
of Etanercept as adjunctive therapy for the treatment of
coronary artery lesions in KD and data obtained support
the performance of larger efficacy trials for etanercept use
in pediatric patients [37]. However, treatment with TNF-α
antagonists in the patients with KD does raise some safety
concerns. These include a potential for myocarditis, and
development of coronary artery abnormalities, ischemia and
the risk of TB and cancer (mainly lymphomas in patients

Clinical and Developmental Immunology 5
receiving etanercept) although the existence of a cause and
effect relationship between anti-TNF use and lymphomas
remains controversial [37].
Recent studies have shown that statin therapy seems
to significantly improve chronic vascular inflammation and
endothelial dysfunction in children with KD, but still further
study is needed to determine the safety and efficacy of statins
in children [38].
4. Henoch Sch¨
onlein Purpura
Henoch Sch¨
onlein purpura (HSP) is a systemic IgA-mediat-
ed vasculitis affecting predominantly small blood vessels. It is
the most common form of small vessel vasculitis in children
[39]. The pathogenesis of HSP remains unknown; however,
HSP is generally believed to be an immune complex-
mediated disease characterized by the presence of polymeric
IgA1 (pIgA1)-containing immune complexes predominantly
in the dermal, gastrointestinal and glomerular capillaries
[40].
HSP is a multiorgan system disease and its major man-
ifestations include cutaneous purpura, arthalgia, enteritis,
and nephritis [41]. Clinical criteria for HSP according to
EULAR include (1) purpura (mandatory criterion) or
petechiae, with lower limb predominance, (not related to
thrombocytopenia); (2) abdominal pain (may intussuscep-
tion and gastrointestinal bleeding); (3) histological changes
showing leucocytoclastic vasculitis with predominant IgA
deposit or proliferative glomerulonephritis with predom-
inant IgA deposit; (4) arthritis or arthralgias; (5) renal
involvement with hematuria and/or proteinuria. A patient
meets the classification of HSP, if at least 2 of 4 criteria are
present [42].
Pulmonary, cardiac, or genitourinary complications
occur rarely, as well as neurological manifestations. The CNS
involvement has been reported in 1–8% of children. Possible
neurological presentations include headache, altered level
of consciousness, seizures, focal neurological deficits, visual
abnormalities and verbal disability, peripheral neuropathy,
and facial palsy [43,44]. Imaging studies (MRI or CT scan)
might reveal lesions suggestive of small vessel vasculitis as
ischemic vascular lesions almost always involving two or
more vessels, intracerebral haemorrhages, diffuse (mainly
posterior) brain edema, or thrombosis of the superior sagittal
sinus [45,46]. Posterior reversible encephalopathy syndrome
(PRES) has been described in children with HSP [3]. The
pathogenesis of the PRES in HSP is not exactly clear,
although two possible mechanisms have been considered.
The first regards hemodynamic change ascribable to severe
hypertension and renal insufficiency that may complicate
HSP [47]. Since the vertebrobasilar and posterior cerebral
arteries are sparsely innervated by sympathetic nerves, severe
hypertension can easily impair autoregulation of the blood
pressure in their perfusion areas, sometimes causing RPLS
characterized by vascular edema due to damage to the blood-
brain barrier [48]. Encephalopathy can develop in HSP even
without severe hypertension and renal insufficiency [49],
and in these cases CNS vasculitis is suspected as the likely
pathogenetic mechanism, although this hypothesis remains
unproven by histopathology of the brain [47].
Pharmacologic options include prednisone, immuno-
suppressive drugs, warfarin, and dipyridamole. Not all
HSP patients need early steroid and/or immunosuppressors
treatment, and treatment should be targeted at patients who
have a high risk of renal involvement or severe extrarenal
symptoms [50]. The extrarenal manifestations of HSP are
managed by appropriate symptomatic measures.
Severe skin lesions may require oral corticosteroids,
which may also improve abdominal pain and protein-losing
enteropathy. Severe gastrointestinal complications may occa-
sionally require surgical intervention [50].
The start of therapy in children at risk of renal complica-
tions may also reduce the risk of cerebral complications when
you consider that renal hypertension is one of the most well-
known risk factors for CNS involvement in children with
HSP.
Prednisone is generally used at dose of 1 mg/kg/day for
2 weeks, with weaning over the subsequent 2 weeks. Unlike
previous data [51] a randomized-double-blind-placebo-
controlled trial showed that early prednisone treatment
did not prevent the development of renal symptoms, but
prednisone was definitely effective in altering the course of
renal disease in patients with signs of mild renal symptoms at
inclusion or within the first month after the diagnosis [52].
Recently Garzoni et al. suggested that CNS dysfunction
in HSP results from a vascular obstruction, from an intrac-
erebral haemorrhage or from severe hypertension. In this
light the author suggests that like in adults with stroke, the
initial management of patients with suspected cerebral HSP
includes control of arterial hypertension, seizures, and repair
of disordered hemostasis. In patients with intracerebral
haemorrhage, the indications for surgery are controversial
and vary with the site and the size of the bleed. Like in severe
HS glomerulonephritis, combined therapy with corticoids
and cyclophosphamide is appropriate in a patient with rel-
evant ischemic cerebral lesions and HSP, instead it is consid-
ered not necessary in those patients with peripheral or cranial
neuropathy, which spontaneously tends to recovery [45]. In
cases which are complicated by Guillain Barr´
e Syndrome the
treatment with intravenous immunoglobulin (1 g/kg/die)
or plasma exchange are suggested [4]. Furthermore, recent
studies propose leukocytapheresis for treatment of patients
with HSP refractory to both steroid and immunoglobulin
therapy, aiming to the removal of proinflammatory cytokines
produced by activated inflammatory cells [53].
5. Behcet Disease
Behcet disease (BD) is a multisystemic chronic relapsing
vasculitis characterized by recurrent mucoutaneous lesions,
ocular and vascular involvement. Clinical criteria for diagno-
sis of BD include oral ulcers at least three times in 12 months
and any two of the following: recurring genital sores/ulcers,
eye inflammation with loss of vision, characteristic skin
lesions, or positive pathergy (skin prick test) [54].

6Clinical and Developmental Immunology
The involvement of CNS occurs in 11% to 50% of
pediatric patients, with parenchymal and nonparenchy-
mal manifestations [55]. Neuro-Behcet’s disease (NBD) is
defined as evidence of Behcet’s disease plus neurologic
involvement, not explained by other conditions or exposures.
The most common manifestations of NBD are cranial
nerve palsy, dysarthria, unilateral, or bilateral pyramidal
tract signs, ataxia, consciousness disturbance. Less com-
mon CNS manifestations include hemiparesis, cognitive-
behavioral changes, emotional changes, extrapyramidal
signs, and seizures [56]. Parenchymal lesions on cranial mag-
netic resonance imaging may involve brainstem, hemispheric
white matter, cerebellum, spinal cord, and/or leptomeninges
while nonparenchymal lesions may include dural sinus
thrombosis, pseudotumor cerebri, arterial occlusion, and
aneurisms [55]. The treatment of NBD is still controversial:
the corticosteroids (starting with intravenous steroids such as
methylprednisolone 500 mg–1 g/day for 1 to 3 days and then
switching to oral prednisone 0.8 mg/kg/day [55,57]) and
disease modifying antirheumatic drugs such as azathioprine
(1-2 mg/kg orally every day [55]) and methotrexate are
conventionally used as first line agents [58], while cyclophos-
phamide treatment is usually reserved to high-risk patients
[57].
In particular, concerning neurological involvement, sug-
gested therapeutic approach, according to EULAR’s rec-
ommendations [59], include corticosteroids for dural sinus
thrombosis (brief courses of corticosteroids if presenting
with increased intracranial pressure and headaches), and
for parenchymal involvement. In this case high doses of
pulsed corticosteroids, usually 3–7 pulses of intravenous
methylprednisolone 1 mg/day, may be given during attacks,
followed by maintenance oral corticosteroids tapered over 2-
3 months. Immunosuppressive drugs may also be given to
prevent recurrences and progression. Studies on methotrex-
ate suggest beneficial effects while chlorambucil is rarely
used due to high risk of serious adverse effects (such as
myelotoxicity and increased risk of malignancies) prefer-
ring azathioprine instead (2.5 mg/kg/day or in more severe
cases monthly pulses of cyclophosphamide). Concerning
resistant cases, agents to be tried may include IFNαand
TNFαantagonists [59–64]. In fact, recent studies have
suggested that the use of biologic drugs, such as anti-TNF
antibodies (infliximab) could cause downstream effects on
cerebrospinal fluid interleukin-6 [55,65]. Up to the present
this promising therapeutic approach, was only reported to
be effective in adult patients with severe ocular and various
extraocular manifestations, including central nervous system
involvement, but not yet in pediatric patients. Adalimumab,
which has a mechanism of action similar to that of inflix-
imab, has been also suggested as an alternative therapy with a
favorable side-effect profile for paediatric patients with acute
NBD [55]. The promising results with Etanercept therapy
in juvenile-onset BD patients, characterized by refractory
multiorgan involvement, were also presented by Cantarin
and colleagues [66]. Recent studies have stressed the central
proinflammatory role of IL-6 in “in situ” evolution of NBD
[67], suggesting IL-6 inhibition as a new therapeutic strategy
for this disease.
6. Childhood Primary CNS Vasculitis
Primary angiitis of the central nervous system in children (c-
PACNS), represent a group of idiopathic vasculitis, involving
either medium/large vessels or small vessels and causing
neurological deficits and deterioration [1,68].
There are two types of c-PACNS: medium-large vessel
and small vessel vasculitis. Medium-large vessel disease
affects arteries that are large enough to be differentiated by
conventional angiography. In patients with small vessel
childhood primary angiitis of the CNS (SVcPACNS), angiog-
raphy findings are typically negative and thus diagnosis must
be confirmed by brain biopsy [68].
Recently it has been underlined that when SVcPACNS
is suspected in a child (uncertain cases where children
present with acquired neurological deficits, or abnormal
inflammatory markers or CSF analysis, with or without
an abnormal MRI) a brain biopsy should be performed.
Lesional biopsies are preferred; however, nonlesional biop-
sies may succeed in yielding the diagnosis [69]. Vas-
culitides of the large-to-medium vessels (or angiography-
positive cPACNS) are associated with headache, hemiparesis,
hemisensory deficits and fine motor deficits [70]. Intractable
seizures, cognitive decline, behavioural changes, and sys-
temic features, such as fever and malaise, tend to be
associated more frequently with small-vessel inflammation
[6].
The diagnosis of PACNS may be considered with
symptoms of a multifocal or diffuse CNS disorder with
remitting or progressive course, cerebrospinal fluid (CSF),
and MRI findings supporting the diagnosis of vasculitis,
and finally either an angiography with a vasculitic pattern
or a leptomeningeal and parenchymatous biopsy proving
vasculitis [71].
Calabrese et al., proposed the following preliminary clin-
ical criteria for PACNS in adults: (1) an acquired neurologic
deficit that remains unexplained after a thorough initial basic
evaluation, (2) either classic angiographic or histopathologic
features of angiitis within the CNS, and (3) no evidence
of systemic vasculitis or any other condition to which the
angiographic or pathologic features could be secondary.
Most reported pediatric cases fit these criteria [71].
There is a paucity of data regarding the efficacy of
immunosuppressive treatment of PACNS both in adults and
children.
Some may argue that benign angiopathy of the CNS or
transient cerebral arteriopathy needs no immunosuppressive
treatment [71] or a relatively short course of corticosteroids
(<6 months) [72]. It has recently been proposed the
term reversible cerebral vasoconstriction syndrome (RCVS)
instead benign angiopathy, referring to a group of disorders
characterized by acute onset of headaches, with or without
neurologic deficits, and prolonged but reversible cerebral
vasoconstriction. Although RCVS can mimic PACNS it is
a noninflammatory vasospastic disease primarily interesting
adults, with different therapeutic and prognostic implica-
tions [73]. In RCVS, successful treatment has been reported
with calcium channel blockers, short-term glucocorticoids,
and magnesium sulphate [74].

Clinical and Developmental Immunology 7
Particular attention should be given to exclusion of
systemic infection resembling cPACNS, such as spirochetal,
rickettsial, and viral diseases as well as bacterial endocarditis,
before giving cyclophosphamide.
Treatment recommendations in PACNS usually indicate
two subsequent phases, first one including a combination
of steroids and pulse cyclophosphamide (induction phase,
during the first 6 months) and second one with either
methotrexate (MTX), azathioprine (AZA), or mycopheno-
late mofetil (MMF) (maintenance phase, during the fol-
lowing 1 or 2 years) [68,75]. The use of antiplatelet or
anticoagulant medications in the treatment for cPACNS has
been controversial [1].
Sen et al., reported three children (two large-medium
vessels cPACNS and one SVcPACNS) treated with steroids
and cyclophosphamide in the induction phase and MTX
or MMF or AZA. All the patients presented here initially
received and responded to IV methylprednisolone followed
by oral prednisolone that was gradually tapered. All patients
relapsed while on either MTX or AZA and steroids, hence
MMF was introduced. The authors concluded that MMF is
considered as the maintenance immunosuppressive agent in
the management of refractory cPACNS [75].
Recently a similar treatment protocol has been evaluated
in SVcPACNS and it consisted of induction therapy with
steroids (2 mg/kg daily weaned every 4 weeks to 50, 40, 30,
25, and 20 mg daily and then by 2.5 mg every 4 weeks until
completed) and pulses of intravenous cyclophosphamide
(Seven pulses of 500–750 mg/m2intravenous cyclophos-
phamide every 4 weeks with cotrimoxazole prophylaxis)
followed by maintenance therapy (during 18 months) with
either azathioprine (2-3 mg/kg) or mycophenolate mofetil
(800–1200 mg/m2per day) [76].
Hutchinson et al. suggested that the mycophenolate
mofetil maintenance therapy seems to cause less adverse
events compared with azathioprine therapy [76]. Further-
more all patients should need calcium and vitamin D as
well as bone protection agents and pneumocystis infection
prophylaxis [77]. Supportive therapy for all types of CNS
vasculitis may include anticonvulsants for children with
seizures, and antipsychotic agents for those with halluci-
nations or severe behaviour difficulties. Children who are
treated with high-dose corticosteroids may require ranitidine
or a proton pump inhibitor to treat associated gastritis and
calcium and vitamin D supplementation to preserve their
bone health [1].
7. Conclusions
The involvement of the CNS must always be considered in
children with systemic vasculitis and neurological symptoms
such as headache, alterated consciousness, seizures, and focal
neurological deficits. The diagnosis of cerebral vasculitis
is often a challenge for the physician as these may be
confused with other disorders such as infectous disease and
coagulation disorders. The first line therapy of CNS vasculitis
is mainly based on corticosteroids and immunosoppressive
drugs. Plasmapheresis and IVIg may have beneficial effects
in the treatment of critical cases. Recently the possible role
of biologic drugs in the treatment of vasculitis has been
evaluated in adults. However there is a paucity of trials
testing the efficacy and safety of these therapeutic strategies
in children.
Conflict of Intrests
The authors decleared that there are no conflict of intrests.
References
[1] S. Benseler and R. Schneider, “Central nervous system vasculi-
tis in children,” Current Opinion in Rheumatology, vol. 16, no.
1, pp. 43–50, 2004.
[2] S. Ozen, N. Ruperto, M. J. Dillon et al., “EULAR/PReS en-
dorsed consensus criteria for the classification of childhood
vasculitides,” Annals of the Rheumatic Diseases, vol. 65, no. 7,
pp. 936–941, 2006.
[3] D. Eleftheriou, T. Cox, D. Saunders, N. J. Klein, P. A. Brogan,
and V. Ganesan, “Investigation of childhood central nervous
system vasculitis: magnetic resonance angiography versus
catheter cerebral angiography,” Developmental Medicine and
Child Neurology, vol. 52, no. 9, pp. 863–867, 2010.
[4] D.M.Wahezi,W.A.Gomes,andN.T.Ilowite,“Cranialnerve
involvement with juvenile polyarteritis nodosa: clinical mani-
festations and treatment,” Pediatrics, vol. 126, no. 3, pp. e719–
e722, 2010.
[5] M. Khellaf, M. Hamidou, C. Pagnoux et al., “Vasculitis re-
stricted to the lower limbs: a clinical and histopathological
study,” Annals of the Rheumatic Diseases,vol.66,no.4,pp.
554–556, 2007.
[6] M. J. Dillon, D. Eleftheriou, and P. A. Brogan, “Medium-size-
vessel vasculitis,” Pediatric Nephrology, vol. 25, no. 9, pp. 1641–
1652, 2010.
[7] H. Hashimoto, T. Yano, T. Kawanishi, H. Tsuda, and T.
Nagasawa, “Outcome of collagen vascular diseases by treat-
ment with plasmapheresis,” Therapeutic Apheresis, vol. 2, no.
4, pp. 268–272, 1998.
[8] L. Guillevin, R. Cevallos, B. Durand-Gasselin, F. Lhote, B.
Jarrousse, and P. Callard, “Treatment of glomerulonephritis in
microscopic polyangiitis and Churg-Strauss syndrome: indi-
cations of plasma exchanges meta-analysis of 2 randomized
studies on 140 patients, 32 with glomerulonephritis,” Annales
de Medecine Interne, vol. 148, no. 3, pp. 198–204, 1997.
[9] S. Ozen, “The spectrum of vasculitis in children,” Best Practice
Research in Clinical Rheumatology, vol. 16, no. 3, pp. 411–425,
2002.
[10] A. Gedalia, H. Correa, M. Kaiser, and R. Sorensen, “Steroid
sparing effect of intravenous gamma globulin in a child with
necrotizing vasculitis,” American Journal of the Medical Sci-
ences, vol. 309, no. 4, pp. 226–228, 1995.
[11] D. Eleftheriou, M. Melo, S. D. Marks et al., “Biologic therapy in
primary systemic vasculitis of the young,” Rheumatology, vol.
48, no. 8, pp. 978–986, 2009.
[12]A.Gianviti,R.S.Trompeter,T.M.Barratt,M.F.Lythgoe,
and M. J. Dillon, “Retrospective study of plasma exchange in
patients with idiopathic rapidly progressive glomerulonephri-
tis and vasculitis,” Archives of Disease in Childhood, vol. 75, no.
3, pp. 186–190, 1996.
[13] H.-C. Kuo, K. D. Yang, W.-C. Chang, L.-P. Ger, and K.-
S. Hsieh, “Kawasaki disease: an update on diagnosis and

8Clinical and Developmental Immunology
treatment,” Pediatrics and Neonatology, vol. 53, no. 1, pp. 4–
11, 2012.
[14] C. Galeotti, J. Bayry, I. Kone-Paut, and S. V. Kaveri, “Kawasaki
disease: aetiopathogenesis and therapeutic utility of intra-
venous immunoglobulin,” Autoimmunity Reviews, vol. 9, no.
6, pp. 441–448, 2010.
[15] R. Uehara and E. D. Belay, “Epidemiology of Kawasaki disease
in Asia, Europe, and the United States,” Journal of Epidemiol-
ogy, vol. 22, no. 2, pp. 79–85, 2012.
[16] J. W. Newburger, M. Takahashi, M. A. Gerber et al., “Diag-
nosis, treatment, and long-term management of Kawasaki
disease: a statement for health professionals from the com-
mittee on rheumatic fever, endocarditis, and Kawasaki disease,
council on cardiovascular disease in the young, American
Heart Association,” Pediatrics, vol. 114, no. 6, pp. 1708–1733,
2004.
[17] H. Kato, T. Sugimura, T. Akagi et al., “Long-term consequen-
ces of Kawasaki disease: a 10- to 21-year follow-up study of
594 patients,” Circulation, vol. 94, no. 6, pp. 1379–1385, 1996.
[18] B. Tabarki, A. Mahdhaoui, H. Selmi, M. Yacoub, and A. S.
Essoussi, “Kawasaki disease with predominant central nervous
system involvement,” Pediatric Neurology,vol.25,no.3,pp.
239–241, 2001.
[19] N. R. Alves, C. M. R. Magalh˜
aes, R. D. F. Almeida et al., “Pros-
pective study of kawasaki disease complications: review of 115
cases,” Revista da Associacao Medica Brasileira,vol.57,no.3,
pp. 295–300, 2011.
[20] B. Garc´
ıa Norniella, M. Mor´
an Poladura, M. Fern´
andez D´
ıaz,
E. Fern´
andez Fern´
andez, and C. Su´
arez Casta˜
n´
on, “Aseptic
meningitis secondary to intravenous immunoglobulin treat-
ment in Kawasaki disease,” Anales de Pediatria, vol. 75, no. 1,
pp. 79–80, 2011.
[21] K. Takagi, T. Umezawa, T. Saji, K. Morooka, and N. Matsuo,
“Meningoencephalitis in Kawasaki disease,” Brain and Devel-
opment, vol. 22, no. 5, pp. 429–435, 1990.
[22] T. Ichiyama, M. Nishikawa, T. Hayashi, M. Koga, N. Tashiro,
and S. Furukawa, “Cerebral hypoperfusion during acute
Kawasaki disease,” Stroke, vol. 29, no. 7, pp. 1320–1321, 1998.
[23] M.Mori,T.Imagawa,R.Haraetal.,“Efficacy and limitation
of infliximab treatment for children with Kawasaki disease
intractable to intravenous immunoglobulin therapy: report of
an open-label case series,” Journal of Rheumatology, vol. 39, no.
4, pp. 864–867, 2012.
[24] J. W. Newburger, M. Takahashi, A. S. Beiser et al., “A single
intravenous infusion of gamma globulin as compared with
four infusions in the treatment of acute Kawasaki syndrome,”
New England Journal of Medicine, vol. 324, no. 23, pp. 1633–
1639, 1991.
[25] K.-P. Weng, S.-F. Ou, C.-C. Lin, and K.-S. Hsieh, “Recent
advances in the treatment of Kawasaki disease,” Journal of the
Chinese Medical Association, vol. 74, no. 11, pp. 481–484, 2011.
[26] J. H. Baumer, S. J. Love, A. Gupta, L. C. Haines, I. Maconochie,
and J. S. Dua, “Salicylate for the treatment of Kawasaki disease
in children,” Cochrane Database of Systematic Reviews, vol. 18,
no. 4, article CD004175, 2006.
[27] S. S. Gidding and S. T. Shulman, “Diagnosis and management
of children with Kawasaki disease,” Heart Disease and Stroke,
vol. 3, no. 4, pp. 210–215, 1994.
[28] T. Imaizumi, Y. Kawasaki, H. Matsuura et al., “Efficacy of
steroid pulse, plasmapheresis, and mizoribine in a patient with
focal segmental glomerulosclerosis,” Pediatric Nephrology, vol.
22, no. 8, pp. 1215–1218, 2007.
[29] L. L. Blaisdell, J. A. Hayman, and A. M. Moran, “Infliximab
treatment for pediatric refractory Kawasaki disease,” Pediatric
Cardiology, vol. 32, no. 7, pp. 1023–1027, 2011.
[30] A. H. Rowley and S. T. Shulman, “Recent advances in the
understanding and management of kawasaki disease,” Current
Infectious Disease Reports, vol. 12, no. 2, pp. 96–102, 2010.
[31] H. Suzuki, M. Terai, H. Hamada et al., “Cyclosporin a treat-
ment for kawasaki disease refractory to initial and additional
intravenous immunoglobulin,” The Pediatric Infectious Disease
Journal, vol. 30, no. 10, pp. 871–876, 2011.
[32] M. J. O’Connor and F. T. Saulsbury, “Incomplete and atypical
Kawasaki disease in a young infant: severe, recalcitrant disease
responsive to infliximab,” Clinical Pediatrics, vol. 46, no. 4, pp.
345–348, 2007.
[33] T. Oishi, M. Fujieda, T. Shiraishi et al., “Infliximab treat-
ment for refractory kawasaki disease with coronary artery
aneurysm—A 1-month-old girl,” Circulation Journal, vol. 72,
no. 5, pp. 850–852, 2008.
[34] J. E. Weiss, B. A. Eberhard, D. Chowdhury, and B. S. Gottlieb,
“Infliximab as a novel therapy for refractory Kawasaki disease,”
Journal of Rheumatology, vol. 31, no. 4, pp. 808–810, 2004.
[35] F. Zulian, G. Zanon, G. Martini, G. Mescoli, and O. Milanesi,
“Efficacy of infliximab in long-lasting refractory Kawasaki
disease,” Clinical and Experimental Rheumatology, vol. 24, no.
4, p. 453, 2006.
[36] K. Suda, Y. Kudo, Y. Sugawara, M. Ishii, and T. Matsuishi,
“Prevention of thrombosis of coronary aneurysms in patients
with a history of Kawasaki disease,” Japanese Journal of Clinical
Medicine, vol. 66, no. 2, pp. 355–359, 2008.
[37] N. F. Choueiter, A. K. Olson, D. D. Shen, and M. A. Portman,
“Prospective open-label trial of etanercept as adjunctive
therapy for kawasaki disease,” Journal of Pediatrics, vol. 157,
no. 6, pp. 960–966, 2010.
[38] S. M. Huang, K. P. Weng, J. S. Chang, W. Y. Lee, S. H.
Huang, and K. S. Hsieh, “Effects of statin therapy in children
complicated with coronary arterial abnormality late after
Kawasaki disease—a pilot study,” Circulation Journal, vol. 72,
no. 10, pp. 1583–1587, 2008.
[39] J. M. M. Gardner-Medwin, P. Dolezalova, C. Cummins, and
T. R. Southwood, “Incidence of Henoch-Sch¨
onlein purpura,
Kawasaki disease, and rare vasculitides in children of different
ethnic origins,” The Lancet, vol. 360, no. 9341, pp. 1197–1202,
2002.
[40] C.Vogler,S.C.Eliason,andE.G.Wood,“Glomerularmem-
branopathy in children with IgA nephropathy and Henoch
Schonlein purpura,” Pediatric and Developmental Pathology,
vol. 2, no. 3, pp. 227–235, 1999.
[41] E. Pillebout, D. Nochy, and E. Thervet, “Henoch-Sh¨
onlein
purpura,” Nephrologie et Therapeutique, vol. 5, no. 7, pp. 663–
675, 2009.
[42] S. Ozen, A. Pistorio, S. M. Iusan et al., “EULAR/PRINTO/
PRES criteria for Henoch-Sch¨
onlein purpura, childhood
polyarteritis nodosa, childhood Wegener granulomatosis and
childhood Takayasu arteritis: Ankara 2008. Part II: final classi-
fication criteria,” Annals of the Rheumatic Diseases, vol. 69, no.
5, pp. 798–806, 2010.
[43] C. L. Chen, Y. H. Chiou, C. Y. Wu, P. H. Lai, and H. M. Chung,
“Cerebral vasculitis in Henoch-Schonlein purpura: a case
report with sequential magnetic resonance imaging changes
and treated with plasmapheresis alone,” Pediatric Nephrology,
vol. 15, no. 3-4, pp. 276–278, 2000.
[44]A.L.Belman,C.R.Leicher,S.L.Moshe,andA.P.Mezey,
“Neurologic manifestations of Schoenlein-Henoch purpura:

Clinical and Developmental Immunology 9
report of three cases and review of the literature,” Pediatrics,
vol. 75, no. 4, pp. 687–692, 1985.
[45] L. Garzoni, F. Vanoni, M. Rizzi et al., “Nervous system dys-
function in Henoch-Sch¨
onlein syndrome: systematic review of
the literature,” Rheumatology, vol. 48, no. 12, pp. 1524–1529,
2009.
[46] H. L. Zhang and J. Wu, “Posterior reversible encephalopathy
syndrome associated with Henoch-Sch¨
onlein Purpura,” Pedi-
atric Emergency Care, vol. 26, no. 12, p. 966, 2010.
[47] D. Sasayama, Y. Shimojima, T. Gono, K. Kaneko, M. Matsuda,
andS.I.Ikeda,“Henoch-Sch
¨
onlein purpura nephritis compli-
cated by reversible posterior leukoencephalopathy syndrome,”
Clinical Rheumatology, vol. 26, no. 10, pp. 1761–1763, 2007.
[48] J. Hinchey, C. Chaves, B. Appignani et al., “A reversible poste-
rior leukoencephalopathy syndrome,” New England Journal of
Medicine, vol. 334, no. 8, pp. 494–500, 1996.
[49] M. Dasarathi, D. Birchall, C. De San Lazaro, L. K. Fawcett,
and J. A. Eyre, “Henoch-Sch¨
onlein purpura with posterior
reversible encephalopathy syndrome,” Pediatric Neurology, vol.
46, no. 1, pp. 42–43, 2012.
[50] Y. Kawasaki, “The pathogenesis and treatment of pediatric
Henoch-Sch¨
onlein purpura nephritis,” Clinical and Experi-
mental Nephrology, vol. 15, no. 5, pp. 648–657, 2011.
[51] F. Mollica, S. Li Volti, R. Garozzo, and G. Russo, “Effectiveness
of early prednisone treatment in preventing the development
of nephropathy in anaphylactoid purpura,” European Journal
of Pediatrics, vol. 151, no. 2, pp. 140–144, 1992.
[52] J. Ronkainen, O. Koskimies, M. Ala-Houhala et al., “Early
prednisone therapy in Henoch-Sch¨
onlein purpura: a ran-
domized, double-blind, placebo-controlled trial,” Journal of
Pediatrics, vol. 149, no. 2, pp. 241–247, 2006.
[53] E. Oki, K. Tsugawa, K. Suzuki, E. Ito, and H. Tanaka, “Leuko-
cytapheresis for the treatment of refractory Henoch-Sch¨
onlein
purpura resistant to both prednisolone and intravenous
immunoglobulin therapy,” Rheumatology International, vol.
28, no. 8, pp. 823–824, 2008.
[54] D.Mendes,M.Correia,M.Barbedoetal.,“Behc¸et’s disease—
a contemporary review,” Journal of Autoimmunity, vol. 32, no.
3-4, pp. 178–188, 2009.
[55] A. B. Robinson, W. B. Gallentine, and C. E. Rabinovich,
“Pediatric neuro-Behc¸et’s disease responsive to adalimumab,”
Pediatric Neurology, vol. 43, no. 4, pp. 291–293, 2010.
[56] M. Atkinson, E. Moore, D. Altinok, and G. Acsadi, “Cerebral
infarct in pediatric Neuro-Behc¸et’s disease,” Journal of Child
Neurology, vol. 23, no. 11, pp. 1331–1335, 2008.
[57] S. Mitra and R. L. Koul, “Paediatric neuro-Behcet’s disease
presenting with optic nerve head swelling,” British Journal of
Ophthalmology, vol. 83, no. 9, p. 1096, 1999.
[58] A. B. Haghighi and A. Safari, “Proposing an algorithm for
treatment of different manifestations of neuro-Behcet’s dis-
ease,” Clinical Rheumatology, vol. 29, no. 6, pp. 683–686, 2010.
[59] G. Hatemi, A. Silman, D. Bang et al., “EULAR recommen-
dations for the management of Behc¸ et disease,” Annals of the
Rheumatic Diseases, vol. 67, no. 12, pp. 1656–1662, 2008.
[60] J. C. Nichols, A. Ince, L. Akduman, and E. S. Mann, “Inter-
feron-alpha 2a treatment of neuro-Behcet disease,” Journal of
Neuro-Ophthalmology, vol. 21, no. 2, pp. 109–111, 2001.
[61] K. Fujikowa, K. Aratake, A. Kawakami et al., “Successful treat-
ment of refractory neuro-Behc¸et’s disease with infliximab:
a case report to show its efficacy by magnetic resonance
imaging, transcranial magnetic stimulation and cytokine
profile,” Annals of the Rheumatic Diseases,vol.66,no.1,pp.
136–137, 2007.
[62] J.E.Alty,T.M.Monaghan,andJ.M.Bamford,“Apatientwith
neuro-Behc¸et’s disease is successfully treated with etanercept:
further evidence for the value of TNFαblockade,” Clinical
Neurology and Neurosurgery, vol. 109, no. 3, pp. 279–281,
2007.
[63] C. Ribi, R. Sztajzel, J. Delavelle, and C. Chizzolini, “Efficacy of
TNF αblockade in cyclophosphamide resistant neuro-Behc¸et
disease,” Journal of Neurology, Neurosurgery and Psychiatry,
vol. 76, no. 12, pp. 1733–1735, 2005.
[64] H. Sarwar, H. McGrath Jr., and L. R. Espinoza, “Successful
treatment of long-standing neuro-Behc¸et’s disease with inflix-
imab,” Journal of Rheumatology, vol. 32, no. 1, pp. 181–183,
2005.
[65] H. Kikuchi, K. Aramaki, and S. Hirohata, “Effect of infliximab
in progressive Neuro-Behc¸ et’s syndrome,” Journal of the
Neurological Sciences, vol. 272, no. 1-2, pp. 99–105, 2008.
[66] L. Cantarini, I. Tinazzi, P. Caramaschi, F. Bellisai, A. Brogna,
and M. Galeazzi, “Safety and efficacy of etanercept in children
with juvenile-onset Behcet’s disease,” International Journal of
Immunopathology and Pharmacology, vol. 22, no. 2, pp. 551–
555, 2009.
[67] A. Borhani Haghighi and A. Safari, “Tocilizumab may be a
potential addition to our weapons against neuro-Behc¸et’s
disease,” Medical Hypotheses, vol. 71, no. 1, pp. 156–157, 2008.
[68] P. Berlit, “Diagnosis and treatment of cerebral vasculitis,”
Therapeutic Advances in Neurological Disorders, vol. 3, no. 1,
pp. 29–42, 2010.
[69] J. Elbers, W. Halliday, C. Hawkins, C. Hutchinson, and S. M.
Benseler, “Brain biopsy in children with primary small-vessel
central nervous system vasculitis,” Annals of Neurology, vol. 68,
no. 5, pp. 602–610, 2010.
[70] S. Ozen, J. Anton, N. Arisoy et al., “Juvenile polyarteritis:
results of a multicenter survey of 110 children,” Journal of
Pediatrics, vol. 145, no. 4, pp. 517–522, 2004.
[71] L. H. Calabrese, A. J. Furlan, L. A. Gragg, and T. J. Ropos,
“Primary angiitis of the central nervous system: diagnostic
criteria and clinical approach,” Cleveland Clinic Journal of
Medicine, vol. 59, no. 3, pp. 293–306, 1992.
[72] R. A. Hajj-Ali, A. Furlan, A. Abou-Chebel, and L. H. Calabrese,
“Benign angiopathy of the central nervous system: cohort
of 16 patients with clinical course and long-term followup,”
Arthritis Care and Research, vol. 47, no. 6, pp. 662–669, 2002.
[73] R. A. Hajj-Ali and L. H. Calabrese, “Central nervous system
vasculitis,” Current Opinion in Rheumatology, vol. 21, no. 1,
pp. 10–18, 2009.
[74] L. H. Calabrese, D. W. Dodick, T. J. Schwedt, and A. B. Singhal,
“Narrative review: reversible cerebral vasoconstriction syn-
dromes,” Annals of Internal Medicine, vol. 146, no. 1, pp. 34–
44, 2007.
[75] E. S. Sen, V. Leone, M. Abinun et al., “Treatment of primary
angiitis of the central nervous system in childhood with myco-
phenolate mofetil,” Rheumatology, vol. 49, no. 4, pp. 806–811,
2010.
[76] C. Hutchinson, J. Elbers, W. Halliday et al., “Treatment of
small vessel primary CNS vasculitis in children: an open-label
cohort study,” The Lancet Neurology, vol. 9, no. 11, pp. 1078–
1084, 2010.
[77] M.A.Alba,G.Esp
´
ıgol-Frigol´
e, S. Prieto-Gonz´
alez et al., “Cen-
tral nervous system vasculitis: still more questions than
answers,” Current Neuropharmacology, vol. 9, no. 3, pp. 437–
448, 2011.