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Brain biopsy in children with primary small-vessel central nervous system vasculitis.

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ORIGINAL ARTICLE
Brain Biopsy in Children with Primary
Small-Vessel Central Nervous System
Vasculitis
Jorina Elbers, MD,1 William Halliday, MD,2 Cynthia Hawkins, MD, PhD,2
Clare Hutchinson, MD,3 and Susanne M. Benseler, MD3
Objective: Primary angiitis of the central nervous system in childhood (cPACNS) is an immune-mediated
inflammatory process directed toward blood vessels in the central nervous system. It has been associated with
variable clinical and radiological presentations, and devastating consequences without treatment. Brain biopsy is
required for definitive diagnosis. The objective of this study was to characterize the clinical and histopathological
features of brain biopsies in small-vessel cPACNS (SVcPACNS).
Methods: A single-center prospective cohort study of children diagnosed with cPACNS from 1998 to 2008 was
performed. All patients with negative cerebral angiography and brain biopsy were included. Patient data were
reviewed for clinical, laboratory, and radiological characteristics at presentation. Standardized brain biopsy review
protocols were established, with independent analysis by 2 neuropathologists. Histopathology was correlated with
collected clinical data.
Results: A total of 13 SVcPACNS patients were included. Ages ranged from 5 to 17 years. Presenting features
included seizures (85%), headache (62%), and cognitive decline (54%). Brain biopsy confirmed SVcPACNS in 11
patients with intramural lymphocytic infiltrate. Two had nonspecific perivascular inflammation only. All 6 nonlesional
biopsies yielded a diagnosis of SVcPACNS. Lack of specific histological features correlated with prolonged time to
biopsy, prior steroid treatment, and inadequate specimen sampling.
Interpretation: In children presenting with new onset severe headaches, seizures, or cognitive decline, SVcPACNS
and brain biopsy should be considered. Lesional biopsies are preferred; however, nonlesional biopsies may succeed
in yielding the diagnosis. Steroid treatment prior to biopsy and inadequate biopsy sampling may obscure the
diagnosis in true cases of SVcPACNS.
ANN NEUROL 2010;68:602–610
P
rimary central nervous system angiitis in children
(cPACNS) is an acquired inflammatory brain disease
directed against blood vessels in the central nervous system. The immune-mediated inflammatory reaction can
involve mainly large to medium-sized blood vessels
feeding well-defined vascular territories, or small vessels
affecting more diffuse areas of the brain. Angiographynegative, small-vessel cPACNS (SVcPACNS) has
recently been identified as a unique clinical entity that
can manifest acutely as seizures and reduced level of
consciousness, subacutely as focal neurological deficits,
or chronically in the form of headaches and cognitive
decline.1,2 Once identified, treatment can be curative
with long-term immunosuppression. Currently, there are
no sufficiently sensitive or specific inflammatory
markers, or magnetic resonance imaging (MRI) features,
that can differentiate SVcPACNS from other conditions,
such as demyelination or malignancy. Due to the variable clinical presentations and the low yield of noninvasive diagnostic testing, definitive diagnosis of cPACNS
requires brain biopsy. To date, only case reports and
small case series have described the biopsy findings in
these patients.2–5 The objective of this study is to
describe the histopathological findings on brain biopsy
from a cohort of patients diagnosed with SVcPACNS
to better understand the disease process, and to aid
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22075
Received Mar 3, 2010, and in revised form Apr 22, 2010. Accepted for publication Apr 30, 2010.
Address correspondence to Dr Benseler, Division of Rheumatology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, 555
University Ave., Toronto, Ontario, M5G 1X8, Canada. E-mail: susanne.benseler@sickkids.ca
From the 1Division of Neurology, 2Department of Pediatric Laboratory Medicine, and 3Division of Rheumatology, Department of Pediatrics, Hospital for Sick
Children, University of Toronto, Toronto, Ontario, Canada.
C 2010 American Neurological Association
602 V
Elbers et al: Brain Biopsies in SVcPACNS
both the clinician and the pathologist in identification
of this disease.
Patients and Methods
Study Design
Patients were identified from a single-center prospective cohort
of children <18 years of age, diagnosed with cPACNS between
January 1998 and June 2008. The diagnosis of cPACNS was
based on Calabrese criteria: (1) an acquired neurological deficit,
(2) angiographic or histological evidence of cPACNS, and 3)
no evidence of systemic vasculitides or any other condition to
which the findings could be secondary.6 Patients were included
if they had negative conventional angiography and a brain biopsy specimen available for review. Institutional research ethics
board approval was obtained (No. 1000012125).
Patients
CLINICAL PRESENTATION. Patient data were collected
prospectively by standardized assessments for history and physical examination. Demographic information included sex and
age at diagnosis. Clinical data consisted of presenting neurological features (headache, seizures, optic neuritis, cognitive decline,
hemiplegia, aphasia, urinary retention), systemic symptoms
(fever, malaise, lethargy, vomiting), duration of symptoms until
presentation, electroencephalogram at presentation, initial suspected diagnosis, and treatment with immunosuppression.
LABORATORY FEATURES. Presenting laboratory investigations included (1) extensive infectious disease workup to ruleout Streptococcal pneumoniae, Mycoplasma pneumoniae, Bartonella henselae, Epstein-Barr virus, cytomegalovirus, varicella zoster virus, human herpesvirus-6, human herpesvirus-7, influenza
A and B viruses, parainfluenza viruses, adenoviruses, enteroviruses, measles virus, parvovirus, West Nile virus, and syphilis;
(2) serum inflammatory markers such as erythrocyte sedimentation rate, C-reactive protein, and von Willebrand factor; (3) autoantibodies (serum immunoglobulins, C3 and C4 complement
levels, rheumatoid factor, anti–double-stranded DNA, anti-Rho,
anti-La, anti-Sm, antiribonucleoprotein, antineutrophil cytoplasmic antibodies, antinuclear antibody [ANA], lupus anticoagulant, and anticardiolipin antibody); (4) coagulation studies (partial thromboplastin time, international normalized ratio, protein
C, protein S, fibrinogen, and antithrombin III mutation); and
(5) cerebrospinal fluid (CSF) analysis. CSF analysis included
cell count, protein, glucose, oligoclonal banding, and opening
pressure when available.
NEUROIMAGING. Neuroimaging was completed using
both computed tomography (CT) and MRI techniques. MRI
sequences included T1, T2, fluid attenuated inversion recovery
(FLAIR), diffusion-weighted imaging (DWI), apparent-diffusion coefficient, and gadolinium enhancement when available.
MRI lesion localization was used to determine site of brain biopsy sampling. Serial MRI brain scans were completed as was
November, 2010
clinically indicated. MRI of the spine was performed in patients
with suspected spinal cord lesions.
Magnetic resonance angiography and conventional angiography were completed in all patients to exclude large-vessel
cPACNS. Conventional angiography was performed by direct
injection of contrast material into the anterior and posterior circulation, with images acquired and analyzed using digital subtraction software.
Brain Biopsy Analysis
SPECIMEN SAMPLING. Sites for lesional biopsies were
identified by MRI completed within 72 hours of the biopsy,
and targeted using frameless stereotactic image guidance. Nonlesional biopsies were sampled from the nondominant frontal
lobe. Burr hole brain biopsy samples were acquired by pediatric
neurosurgeons using en bloc incision with removal of tissue. In
addition to biopsy analysis, data were collected to evaluate the
time of clinical symptom onset to brain biopsy, and steroid
treatment prior to biopsy. Complications associated with brain
biopsy were also collected.
SPECIMEN PREPARATION. All biopsies were fixed in formalin and embedded in paraffin, and prepared slides were
stained with hematoxylin and eosin. Specimens were reviewed
for viral inclusions and other evidence of infection, including
bacterial culture, fungal culture, silver stain, and acid-fast bacillus smear and culture. Special staining included Gomori trichrome, reticulin, and Luxol fast blue. Immunohistochemistry
staining utilized standard immunohistochemical procedures.
Antibody panels included anti-CD20 (B-cell marker), anti-CD4
(helper T-cell marker), anti-CD8 (cytotoxic T-cell marker), and
anti-CD68 (marker of macrophages and microglia). Electron
microscopy (EM) was completed according to the discretion of
the neuropathologist.
REVIEW. Brain biopsy samples were independently reviewed
by 2 pediatric neuropathologists (W.H. and Cy.H.) according
to a standardized protocol. On review, specimens were quantified as adequate or inadequate. Adequate specimen sampling
required all 3 superficial layers of brain tissue be obtained—leptomeninges, gray matter cortex, and subcortical white matter—
whereas the designation of inadequate suggested a suboptimal
specimen from which to ascertain a diagnosis. Each specimen
was further characterized according to: lesional versus nonlesional, according to site of specimen collection when compared
to lesions identified on MRI; location of infiltrate (intramural
or perivascular), location of vessel involvement (leptomeninges,
gray matter, white matter); immunohistochemistry for inflammatory cell type (lymphocyte, polymorphonuclear, eosinophil,
and macrophage); and associated findings (demyelination, infarction, and gliosis). When available, EM was reviewed to
examine endothelial cell structure and the presence of
inclusions.
The definition of small-vessel vasculitis proposed by
Alrawi et al7 was used to define patients with SVcPACNS. Definite SVcPACNS required fulfillment of all of the following
603
ANNALS
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criteria: (1) minimum of 2 layers of lymphocytes within or
around the walls of parenchymal or leptomeningeal and dural
vessels; (2) structural alterations of the vessel wall such as prominence of endothelial cells, with or without necrosis; (3) neuronophagia; (4) parenchymal edema; and (5) exclusion of alternate diagnoses. Probable SVcPACNS required fulfillment of
criteria (2) through (5).
Statistical Analysis
The diagnosis of SVcPACNS was revisited in all patients
according to clinical presentation, biopsy findings, and response
to treatment. Agreement on diagnosis between pathologists was
noted. Lesional and nonlesional biopsy results were compared,
as were tissue samples obtained prior to and following steroid
treatment.
monly elevated inflammatory marker. Serological markers
were present in 4 patients: 1 positive anticardiolipin antibody that was negative on repeat testing, 1 positive lupus
anticoagulant, and 2 weakly positive ANA titers. Coagulation studies were within normal limits.
CSF was analyzed in all patients; 100% showed
abnormalities including increased opening pressure, pleocytosis, and increased protein. Five (71%) of 7 patients
tested had increased opening pressure. Pleocytosis was
present in 10 (77%), and elevated protein in 7 (54%)
patients. Oligoclonal banding was present in 2 (18%) of
11 patients tested. Further details about laboratory features can be obtained from Table 2.
NEUROIMAGING. Twelve patients had CT imaging of
Results
Patients
CLINICAL PRESENTATION. A total of 19 patients
with angiography-negative SVcPACNS were identified
from a total of 115 cPACNS patients. Of these, 6
patients had brain biopsies obtained at other centers that
were not available for review. Thirteen had brain biopsies
available for review and were included in our study.
Patients’ ages ranged from 5 years to 17 years, with a
mean of 10.6 years; 3 were male and 10 female. The
most common clinical presentations were seizures (85%),
headache (62%), and cognitive decline (54%). Three
patients presented with optic neuritis, and 2 had symptoms of spinal cord involvement.
Seizures were present in 11 patients: 3 with refractory clinical and electrographic generalized status epilepticus, 5 with generalized tonic-clonic seizures, and 3 with
focal seizures. Electroencephalography was completed in
12 patients, 11 of whom were abnormal. Abnormalities
included diffuse background slowing (50%), frontal
intermittent rhythmic delta activity (25%), focal slowing
(17%), focal epileptiform discharges (17%), frequent
electrographic seizures (17%), and periodic lateralizing
epileptiform discharges (8%).
Initial suspected diagnoses included infectious encephalitis (38%), demyelination (31%), cPACNS (23%),
and mitochondrial disease (8%). Twelve patients were
successfully treated with combinations of steroids and
additional immunosuppressant agent. Of these patients,
10 received SVcPACNS treatment protocol.8 One patient
who remained untreated died. Further details regarding
clinical presentation can be found in Table 1.
LABORATORY FEATURES. Elevated inflammatory
markers were seen in 12 of 13 (92%) patients, with
erythrocyte sedimentation rate (ESR) as the most com-
604
the head at the time of presentation, and of these, 3 (25%)
had abnormalities apparent. MRI was completed in all 13
patients, and showed abnormalities in 12 (Fig 1). Eleven
patients showed abnormalities attributable to cPACNS, and
1 patient showed mild swelling and increased T2 signal in
bilateral hippocampi, thought to be related to intractable
seizures. There were no cases with hemorrhage. Two (15%)
patients did not show any evidence of vasculitis on MRI
on 2 or more occasions. Abnormal MRIs with contrast
showed gadolinium enhancement in 9 (90%) of 10
patients, 7 with lesional enhancement and 2 with leptomeningeal enhancement. DWI was completed in all scans;
none showed diffusion restriction. Further details regarding
neuroimaging are summarized in Table 2.
MRI of the spine was completed in 2 cases with
urinary retention, and both showed abnormal T2 signal
in the cervical regions of the spinal cord. Both of these
patients also presented with acute optic neuritis, and
were given an initial diagnosis of demyelination. Inadequate response to steroid therapy prompted further
diagnostic workup, including brain biopsy, which led to
their current diagnosis.
Brain Biopsy Analysis
SPECIMEN
SAMPLING. Lesional
biopsies were
obtained when the lesion site on MRI was accessible and
did not correspond to an eloquent region of the brain.
Nonlesional biopsies were sampled from the nondominant frontal lobe. A total of 7 lesional and 6 nonlesional
biopsies were reviewed. One patient had postoperative
complications involving infection of the wound requiring
surgical debridement.
Brain biopsy samples were collected through
extended burr holes in all 13 patients. En bloc incisional
biopsies containing leptomeninges, cortical gray matter,
and subcortical white matter were obtained in 9 patients,
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Elbers et al: Brain Biopsies in SVcPACNS
TABLE 1: Clinical Presentation with Corresponding Biopsy Features of Patients Diagnosed with Small-Vessel
cPACNS
Patient
Age,
yr/Sex
Presenting
Neurological Features
Presenting
Systemic
Features
Duration of
Symptoms prior
to Presentation
Initial
Diagnosis
1
15/M
Headache, generalized
seizures, cognitive decline
None
2 years
Tuberculous
meningitis
2
11/M
Refractory status epilepticus
None
1 day
Encephalitis
3
17/F
B/L optic neuritis,
generalized seizures,
cognitive decline
None
2 months
cPACNS
4
6/F
Headache, B/L optic
neuritis, generalized
seizures, urinary retention,
cognitive decline
Vomiting,
lethargy, fever
1 month
Demyelination
5
5/F
Headache, acute vision loss,
refractory status epilepticus
None
1 day
Mitochondrial
disease
6
10/F
Hemiplegia
None
2 weeks
cPACNS
7
5/F
Focal seizures, progressive
hemiplegia, cognitive
decline
None
3 months
Demyelination
8
15/F
Headache, U/L optic
neuritis, generalized
seizures, urinary retention,
cognitive decline
Vomiting
lethargy,
malaise
1 week
Demyelination
9
9/F
Headache, focal seizures
None
2 months
cPACNS
10
17/F
Refractory status epilepticus
None
1 day
Encephalitis
11
7/F
Headache, cognitive decline
Lethargy, malaise,
fever
5 days
Meningoencephalitis
12
7/M
Headache, generalized
seizures
None
1 day
Tumefactive
demyelination
13
10/F
Headache, hemiplegia,
focal seizures, aphasia,
cognitive decline
Vomiting, lethargy,
fever
1 week
EBV encephalitis
cPACNS ¼ primary central nervous system angiitis in children; M ¼ male; F ¼ female; B/L ¼ bilateral, U/L ¼ unilateral; EBV
¼ Epstein-Barr virus.
whereas 4 patients had specimens obtained piecemeal.
Electrocautery was used on the cortical surface prior to
specimen sampling in 3 patients, and caused disruption
of leptomeninges and associated blood vessels in 2
patients. Inadequate specimens were observed in 4
patients. All 4 specimens were collected piecemeal, and 2
of these specimens were cauterized prior to retrieval.
REVIEW.
Inflammatory infiltrate was located in intramural blood vessels of arterioles, capillaries, or venules in 11
patients (Fig 2). One of these patients showed isolated
involvement of the venules. Affected blood vessels were
November, 2010
found in all 3 tissue layers, leptomeninges, cortex, and subcortical white matter, in 7 of 9 adequate specimens.
Inflammatory cells were predominantly a mixture of lymphocytes and macrophages, with occasional plasma cells,
polymorphonuclear cells, and eosinophils. Granulomatous
inflammation and multinucleated giant cells were not
found in any specimen. Two patients showed nonspecific
perivascular inflammation with lymphocytes. Details
regarding biopsy features can be found in Table 3.
Additional biopsy features included reactive astrocytes, parenchymal edema, and gliosis in all 13 patients,
perivascular demyelination in 4 (31%) patients (Fig 3), 2
patients with intravascular fibrin deposition, and 1
605
ANNALS
of Neurology
TABLE 2: Laboratory and Neuroimaging Characteristics of Patients with Small-Vessel cPACNS
Small-Vessel cPACNS Cohort, N513
Laboratory and Neuroimaging Results
% of Patients
Median (range)
ESR [>10mm/h]
92
90 (15–117)
CRP [>8.0mg/l]
62
62 (16.9–99.8)
vWF [>1.7IU/ml]
56 (5 of 9)
2.17 (1.97–3.64)
Positive ANA
15
Positive antiphospholipid antibody [single]
15
Inflammatory markers
Cerebrospinal fluid analysis
Pleocytosis [>10 106 white blood cells]
77
44 (13–91)
Elevated protein [>0.4g/dl]
54
0.59 (0.45–1.58)
Elevated opening pressure [>20cm H2O]
71 (5 of 7)
26 (25–30)
Positive oligoclonal banding
18 (2 of 11)
Abnormal MRI—location of T2 hyperintensities [n ¼ 11]
Bilateral involvement
91%
Cortical gray matter
72%
Subcortical white matter
82%
Deep white matter
82%
Deep gray matter
45%
Cerebellum
27%
Brainstem
18%
Spinal cord
18%
MRI—location of gadolinium enhancement
Lesional
70% (7 of 10)
Leptomeninges
20% (2 of 10)
cPACNS ¼ primary central nervous system angiitis in children; ESR ¼ erythrocyte sedimentation rate; CRP ¼ cyclic adenosine
monophosphate receptor protein; vWF ¼ von Willebrand factor; ANA ¼ antinuclear antibody; MRI ¼ magnetic resonance
imaging.
patient each with microglial nodules and infarction with
necrosis. Reticulin staining, completed in 8 cases,
revealed vessel wall reactivity in a lacelike pattern in all
cases. Parenchymal microcalcification was found in 1
patient, with a duration of symptoms of 10 months prior
to biopsy. Creutzfeld cells were noted in 1 patient. There
were no myelin figures, and no evidence of infection in
any patient, including viral inclusions or special stains for
micro-organisms. Gomori trichrome staining did not
reveal any abnormalities. EM was completed in 8
patients. All cases showed swollen, reactive endothelial
cells, and the neuropil immediately adjacent to the microvasculature was edematous. In 3 patients, tubuloreticular inclusions (TRIs) were found (Fig 4).
606
There was excellent correlation between the 2 neuropathologists who examined the brain biopsies. A diagnosis
of definite small-vessel vasculitis was unanimously declared
in 11 cases, whereas 2 were deemed to have probable
SVcPACNS with nonspecific inflammatory changes,
according to the absence of intramural infiltrate. Of the
patients diagnosed with SVcPACNS, 7 were lesional and 6
were nonlesional biopsies. The 2 cases with nonspecific
inflammatory changes were lesional biopsies; however, both
had a prolonged time to biopsy (11 and 17 months,
respectively), prolonged treatment with methylprednisolone
prior to biopsy, and inadequate specimen sampling.
Two patients with definite SVcPACNS on biopsy
had repeatedly normal MRIs. Both presented in
Volume 68, No. 5
Elbers et al: Brain Biopsies in SVcPACNS
FIGURE 1: Magnetic resonance image of 7-year-old with
small-vessel primary central nervous system angiitis
presenting with 7-day history of headache and progressive
encephalopathy. Axial fluid attenuated inversion recovery
sequence demonstrates bilateral multifocal hyperintense
lesions involving the cortex, subcortical white matter, deep
white matter, and body of corpus callosum.
refractory status epilepticus, with a time to biopsy of 12
and 14 days, respectively. There was no prior treatment
with steroids in either case. Despite the nonlesional site
of the biopsies, both demonstrated intramural inflammatory infiltrate of the small vessels. EM was notable,
revealing TRIs in both patients.
Discussion
This study systematically analyzed brain biopsy characteristics of specimens collected by elective brain biopsy
from a single-center cohort of children with small-vessel
central nervous system vasculitis. A review of the literature disclosed no previous analyses similar to ours.
Patients with SVcPACNS have variable clinical presentations. Our study supports previous literature suggesting
that new onset of severe headache, seizures, and/or focal
neurological deficits are common presenting features.2,5
This contrasts patients with cPACNS involving large vessels, who more typically present with symptoms of acute
stroke or transient ischemic attack.3,9,10 We describe the
process of diagnosis for a challenging group of patients
who presented with refractory status epilepticus, acute
meningoencephalitis, or chronic symptoms of presumed
demyelination not responding to therapy. Our study
demonstrates that inflammatory markers, specifically
ESR, are sensitive; however, CSF abnormalities have the
highest positive predictive value. Although this may indiNovember, 2010
cate a selection bias of patients selected for brain biopsy,
findings of a high ESR, elevated opening pressure, and
moderate pleocytosis may help guide the physician toward brain biopsy. Patients with atypical features of a
suspected diagnosis, or who do not respond to therapy as
expected, should be further investigated for SVcPACNS.
The radiological features with which patients presented suggest acute inflammation of cortex and leptomeninges, with inflammation or infarction of white matter
tracts. Abnormal MRIs demonstrated T2 signal abnormalities primarily in the cortex, and subcortical and deep
white matter; however, any region of the central nervous
system can be affected. Gadolinium enhancement was
especially sensitive, demonstrating either lesional or leptomeningeal enhancement in 90% of patients. These
data are supported by Salvarani et al, who reported 8
adults with biopsy-proven small-vessel PACNS with leptomeningeal enhancement.11 In our study, MRI was 85%
sensitive in detecting cases of SVcPACNS, with 2
patients having repeatedly normal MRIs. Both of these
patients presented with refractory status epilepticus, elevated inflammatory markers, CSF pleocytosis, and elevated opening pressure. Nonlesional biopsies were performed, and both specimens showed intramural
inflammatory infiltrate, with reactive endothelial cells
and TRIs on electron microscopy. TRIs are cytoplasmic
inclusion bodies that can be found in response to elevated levels of serum interferon. They have been previously reported in other conditions, including human immunodeficiency virus infection,12 herpes simplex virus
encephalitis,13 and systemic lupus erythematosus,14 but
have not been reported in cPACNS. These 2 patients
FIGURE 2: Brain biopsy of 15-year-old girl with small-vessel
primary central nervous system angiitis. Light microscopy of
hematoxylin and eosin-stained brain biopsy specimen shows
inflammatory cell infiltrate within the vessel wall of a
cerebral blood vessel.
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ANNALS
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TABLE 3: Brain Biopsy Characteristics for Patients
with SVcPACNS
Brain Biopsy Characteristics
SVcPACNS
Cohort, N 5 13
Location of biopsy
Lesional
54%
Nonlesional
46%
Adequacy of specimen
Adequate
69%
Inadequate
31%
Location of vessel involvement
Leptomeninges
85%
Cortical gray matter
100%
White matter
69%
All 3 layers
78% (7 of 9)
Location of inflammatory infiltrate
Intramural
85%
Perivascular
92%
Both intramural and perivascular77%
Inflammatory cell types
Lymphocyte
100%
Macrophage
85%
Polymorphonuclear
23%
Eosinophil
23%
Associated findings
Gliosis
100%
Perivascular demyelination
31%
Infarction
15%
Microcalcification
15%
Reactive reticulin staining
100% (8 of 8)
Our biopsy specimens demonstrated an angiocentric
lymphocytic inflammatory infiltrate involving leptomeninges, cortex, and subcortical white matter, with swollen, reactive endothelial cells on EM. There was no granulomatous inflammation noted. These findings are consistent
with previous reports of SVcPACNS.2–4 Studies describing
biopsy findings in adults with small-vessel PACNS demonstrate granulomatous inflammation with multinucleated
giant cells.16–18 The intramural distribution of inflammatory cells is felt to be specific to vasculitis, and is differentiated from the perivascular inflammation seen in other
T-cell–mediated inflammatory brain diseases. Diseases such
as Rasmussen encephalitis can be further characterized by
microglial nodules and neuronal dropout,19 whereas multiple sclerosis demonstrates myelin-laden macrophages, perivenous or confluent demyelination, and predominant axonal and oligodendrocyte injury.20 The absence of viral
inclusions or generalized inflammatory cell infiltration further differentiates SVcPACNS from infectious cerebritis.21
Two children from our cohort were considered to have
probable SVcPACNS as per Alrawi et al’s criteria,7 with biopsies showing nonspecific inflammatory changes, perivascular
lymphocytic inflammation, and gliosis. Following brain biopsy, immunosuppressant treatment was pursued in both
cases with good success. These patients were initially misdiagnosed with demyelination and tuberculosis for 11 and 17
months, respectively, and received prolonged treatment with
methylprednisolone prior to biopsy. Riemer et al22 reported
an adult case of PACNS, treated with cyclophosphamide and
prednisone, that showed no signs of vascular inflammation
on postmortem brain pathology. This confirms that
Electron microscopy, n ¼ 8
Reactive endothelial cells
100%
Tubular reticular inclusions
38%
Final biopsy diagnosis
SVcPACNS
85%
Nonspecific inflammatory
changes
15%
SVcPACNS ¼ small-vessel primary central nervous system
angiitis in children.
demonstrate that although MRI was previously thought
to be highly sensitive,15 a normal MRI does not rule out
SVcPACNS.
608
FIGURE 3: Focal inflammation and demyelination around a
cerebral blood vessel in a child with small-vessel primary
central nervous system angiitis. Light microscopy of
hematoxylin and eosin/Luxol fast blue-stained sample of
brain biopsy specimen shows perivascular demyelination in
a 9-year-old girl with generalized seizures, diagnosed with
primary central nervous system angiitis.
Volume 68, No. 5
Elbers et al: Brain Biopsies in SVcPACNS
FIGURE 4: Electron microscopy of brain biopsy specimen from
child with small-vessel primary central nervous system angiitis.
Electron micrograph reveals tubuloreticular inclusions within an
endothelial cell of cerebral blood vessel in a patient with smallvessel primary central nervous system angiitis. (A) Original
magnification, 310,000; (B) original magnification, 340,000).
immunosuppressant agents are successful at treating the disease; however, after prolonged treatment, they may resolve
inflammatory changes, preventing diagnosis on brain biopsy.
In some circumstances, it is necessary to treat quickly; however, commitment to high-dose immune-suppression with
cyclophosphamide mandates a definitive diagnosis. If the
suspicion for SVcPACNS is high, brain biopsy should be
performed prior to or within 2 weeks of steroid therapy to
ensure that a diagnosis can be made.
Although lesional biopsies increase the diagnostic
yield, our results suggest that nonlesional biopsies can be
successful in establishing SVcPACNS. In fact, all 6 nonlesional biopsies in our cohort yielded a diagnosis of
SVcPACNS, whereas the 2 patients with nonspecific
inflammatory changes had lesional biopsies. Venkateswaran
et al examined the diagnostic yield of brain biopsy in chilNovember, 2010
dren presenting with neurological deterioration over a 15year period. They found an overall diagnostic yield of
48.5%, with the most frequent diagnosis being vasculitis in
18.2%. Complications directly related to biopsy occurred
in 10.6% of patients, including transient seizures, torticollis, and cellulitis. They concluded that brain biopsies
should be considered as an investigative option, especially
when querying such diagnoses as vasculitis, where treatment options exist.23 One patient in our cohort had complications associated with brain biopsy that involved wound
infection requiring surgical debridement. This patient had
been treated with 17 months of immunosuppression prior
to the biopsy, possibly contributing to the complication. In
the remaining patients, brain biopsy was well tolerated,
with no other complications, indicating that this is a safe
procedure in this patient population.
On review of the brain biopsies and clinical correlations
for this study, we propose that uncertain cases where children
present with acquired neurological deficits, or abnormal
inflammatory markers or CSF analysis, with or without an
abnormal MRI, should undergo a brain biopsy. The biopsy
specimen should be collected prior to prolonged treatment
with steroids. Although lesional biopsies are preferred, nonlesional biopsies from the nondominant frontal lobe may be
successful in yielding a diagnosis. Specimens should be collected by en bloc incisional biopsy prior to electrocautery, and
ideally measure 1cm3, containing leptomeninges, cortical
gray matter, and subcortical white matter. Histological features consistent with SVcPACNS include lymphocytic intramural inflammatory infiltrate, surrounding gliosis, and reactive endothelial cells. Chronic features may include
perivascular demyelination, calcification, and necrosis. The
absence of intramural infiltrate may dissuade the physician
from the diagnosis of SVcPACNS; however, treatment of
such patients with long-term immunosuppression has
resulted in resolution of symptoms. We propose that intramural inflammatory infiltrate is specific, but not sensitive. In
patients without an alternative diagnosis, perivascular infiltrate, in addition to other biopsy findings described above,
may be sufficient to warrant treatment for SVcPACNS.
Potential Conflicts of Interest
Nothing to report.
References
1.
Elbers J, Benseler SM. Central nervous system vasculitis in children. Curr Opin Rheumatol 2008;20:47–54.
2.
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