J Neurosurg Pediatrics 13:62–67, 2014
©AANS, 2014

Angiography-negative primary angiitis of the central nervous
system in childhood
Case report
Michael S. Park, M.D., Arthur E. Marlin, M.D., and Sarah J. Gaskill, M.D.
Department of Neurosurgery & Brain Repair, Division of Pediatric Neurosurgery, Morsani College of
Medicine, University of South Florida, Tampa, Florida
Childhood primary angiitis of the CNS is a recently characterized, potentially reversible disease process. A
favorable outcome requires early diagnosis and appropriate treatment. The histological findings of childhood primary angiitis of the CNS are characterized by a lymphocytic, nongranulomatous vasculitis. This disorder can lead
to neurological deficits, seizures, and strokes. Laboratory and radiographic investigation are part of the evaluation,
but are often nonspecific. Conventional angiography can fail to show any abnormality, and biopsy may ultimately be
required for diagnosis. Although there can be significant rates of morbidity and mortality if untreated, patients who
receive appropriate therapy can experience excellent outcomes, and in many cases will demonstrate near-complete or
total clinical and radiographic resolution. The case of a previously healthy 13-year-old girl with new-onset generalized tonic-clonic seizures is presented, with a review of the literature.
(http://thejns.org/doi/abs/10.3171/2013.9.PEDS13159)

Key Words
•
primary angiitis of the central nervous system •
childhood primary angiitis of the central nervous system
•
arteriopathy
vasculitis
•
vascular disorders

I

n 1959 Cravioto and Feigin15 first described a nonin-

fectious granulomatous primary angiitis of the CNS
(PACNS). They proposed that their 2 cases and 6 other
previously reported cases in the literature represented a
unique clinicopathological entity characterized by a granulomatous angiitis with necrosis, giant cells, and lymphocytic infiltration found exclusively in the vessels of the
CNS. In 1988 Calabrese and Mallek12 proposed diagnostic criteria for adult PACNS based on an extensive review
of 40 previously reported cases and 8 additional cases of
their own. These criteria included the recent onset of headaches, confusion, and unexplained multifocal neurological deficits, angiographic evidence of vasculitis, exclusion
of systemic conditions known to cause secondary vasculopathies, and biopsy to confirm vasculitis and exclude
neoplasm, infection, and noninflammatory cerebrovascular disease. Using the Calabrese criteria for PACNS, there
has been a marked increase in the recognition, diagnosis,
and successful treatment of this disease. Similarly, using
Abbreviations used in this paper: cPACNS = childhood primary
angiitis of the CNS; ESR = erythrocyte sedimentation rate; MMF =
mycophenolate mofetil; MRA = MR angiography; NAA = N-acetyl­
aspartate; vWF = von Willebrand factor.

62

•

the Calabrese criteria has led to an increased recognition
and diagnosis of childhood PACNS (cPACNS). Numerous case reports and series of patients with cPACNS have
now been published, primarily in the rheumatology literature.4,5,19,25,27,29,32
Early diagnosis followed by aggressive treatment is
critical to improve survival and neurological outcome in
cPACNS.4,8,19,22,23,37 We report a case of biopsy-proven,
angiography-negative PACNS in a 13-year-old girl. To our
knowledge there are no reports of cPACNS in the neurosurgical literature.

Case Report
History and Examination. This right-handed 13-yearold girl presented to the emergency room after a 5-minute
seizure characterized by flailing of her upper extremities,
drooling, and a loss of consciousness. Following the seizure she reported an ill-defined numbness in her entire
body. Results of her neurological evaluation including
funduscopy examination were within normal limits, except for mild scoliosis.
The patient’s medical history revealed a positive purified protein derivative test for Mycobacterium tuberculoJ Neurosurg: Pediatrics / Volume 13 / January 2014

Angiography-negative childhood primary angiitis of the CNS
sis 2 years prior to admission with treatment noncompliance. She also had a history of asthma. She had traveled
in the US and the Caribbean, with animal exposure a few
years previously.

Neuroimaging. Admission CT scanning showed a 17
× 19–mm enhancing lesion in the left frontal lobe with
surrounding edema and a 5-mm left frontal lobe convexity lesion. The MRI studies showed multifocal enhancing
lesions throughout the brain, most pronounced in the left
frontal and parietal lobes (Fig. 1). Magnetic resonance
spectroscopy revealed elevated choline peaks and decreased N-acetylaspartate (NAA) peaks. Results of MR
angiography (MRA) were negative, and the 4-vessel angiogram was also negative.

Laboratory Findings. Laboratory results were as follows: white blood cell count 5.6 × 103 cells/ml, ESR 6 mm/
hour, and C-reactive protein < 0.5 mg/dl. Analysis of CSF
showed 7 × 103 cells/ml for white blood cells (10% segmented leukocytes, 90% lymphocytes), glucose 47 mg/dl,
and protein 34 mg/dl. Based on the recommendations of
the infectious disease specialists, extensive testing of CSF
for infectious causes, including acid-fast bacillus, fungus,
Cryptococcus, and cysticercosis, was negative. Serology
for an infectious cause was significant only for evidence
of a probable past infection with cytomegalovirus and
Bartonella henselae (causative agent for cat scratch fever).
The angiotensin-converting enzyme level was 48 U/L,
ruling out sarcoidosis.
Operation. Because of the spectroscopy results the pa-

tient was brought to the operating room for definitive diagnosis. Two lesions in the left frontal lobe were excised.
Pathological investigation revealed gliosis with focal infarction. Vessels in and around the necrotic areas were
thickened, with chronic inflammatory cells surrounding
and within the vessel walls. Lymphocytes showed a mixture of CD3 T cells and CD20 B cells, which was consistent with a lymphocytic vasculitis or primary cerebral
angiitis (Figs. 2 and 3).

Postoperative Course. The patient was seen by rheumatology and oncology specialists and started on prednisone. Over the ensuing year she remained neurologically
intact but became cushingoid. Her follow-up MRI studies
have shown marked improvement in the enhancing lesions
and no new lesions.

Discussion

Childhood primary angiitis of the CNS has been described primarily in the rheumatological literature.4,5,19,27,29,
32,41
Since 2006, the Calabrese criteria have been adopted
for use in children > 1 month and < 18 years of age.5 These
criteria are as follows: a newly acquired and otherwise unexplained neurological or psychiatric deficit, angiographic
or histological evidence of angiitis limited to the CNS, and
the absence of a systemic condition that could cause or
mimic findings.12 The differential diagnosis can be broad
and includes primary, inflammatory (such as lupus), and
infectious vasculitides. Herpes zoster in particular has
been described in association with CNS vasculitis. Demyelinating diseases as well as metabolic disorders such as
J Neurosurg: Pediatrics / Volume 13 / January 2014

Fig. 1. Preoperative axial T1-weighted MRI study obtained with contrast.

MELAS (mitochondrial encephalopathy with lactic acidosis and strokelike episodes) can also present in a similar
fashion to PACNS.10,17,23 Consultation with rheumatological and infectious disease specialists, as in this case, may
be helpful during the evaluation. In children who present
with a possible diagnosis of cPACNS, the workup should
be prompt, and includes a variety of hematological tests,
examination of the CSF (primarily to rule out mimicking
conditions such as demyelinating disorders), electroencephalography, CT scanning, MRI including MRA, cerebral angiography, and brain biopsy.
Two distinct subtypes of cPACNS have been identified. Angiography-positive cPACNS affects large and medium-sized cerebral blood vessels. Angiography-negative
cPACNS affects the small vessels.14,17,23 Each has a unique
clinical presentation and radiographic appearance. The
approach to treatment and outcome also differs between
these 2 distinct entities. Although this case represents a
case of angiography-negative cPACNS, both clinical entities will be reviewed (Table 1).
Angiography-Positive cPACNS

The typical presentation consists of headache, acute
hemiparesis, hemisensory deficits, or fine motor deficits.
Electroencephalography most often reveals generalized
slow waves.12 The ESR is the most commonly elevated
inflammatory marker, but laboratory abnormalities are
insensitive, nonspecific, and incapable of ruling out or diagnosing primary or secondary CNS vasculitis.9 Analysis
of the CSF reveals pleocytosis and elevated protein in only
63

M. S. Park, A. E. Marlin, and S. J. Gaskill

Fig. 2. Photomicrograph of a histopathological section of the lesion.
Multiple regions of subacute necrosis with macrophages are present.
H & E, original magnification ×2.

30% of cases, and oligoclonal banding is usually absent.
Large- to medium-vessel cPACNS is defined by Calabrese
criteria as for adult PACNS;11 in most instances the diagnosis hinges on a combination of either positive biopsy
results or high-probability vascular imaging, and laboratory testing is largely relegated to detecting the myriad of
mimicking conditions, including infections, malignancies,
hypercoagulable and embolic states, and other inflammatory diseases.9,17
More recently von Willebrand factor (vWF) antigen,
a factor that is released by endothelial cells after vascular
injury, has been proposed as a potential biomarker to help
diagnose and monitor the effectiveness of the treatment
in cPACNS.13 In their study of 39 patients with cPACNS
(25 with angiography-negative and 14 with angiographypositive disease), Cellucci et al. found that vWF antigen
levels were increased at diagnosis in 65% of children and
decreased significantly after treatment.
Sensitivity of MRI approaches 100%;3,12,20,37 combining neuroimaging with lumbar puncture increases the
overall sensitivity, and normal findings on both would
have a high negative predictive value.9,10 The most specific
findings are provided by serial examinations in which
multiple foci of ischemia are detected in varying anatomical locations and developing over time. Such studies typically demonstrate areas of acute ischemia with unilateral
or bilateral, multifocal, proximal, and supratentorial T2
hyperintensities involving both the gray and white matter.3,5,20 Lesions can also manifest as hemorrhages.20,32
Leptomeningeal enhancement can occur in the granulomatous variant of PACNS,9,20 and vessel-wall enhancement is highly suggestive of inflammation of the vascular
wall in cPACNS.23,26 Furthermore, approximately 15% of
patients with PACNS can present with a masslike lesion,
mimicking those often seen in tumor, including vasogenic
edema and multifocal Gd enhancement.6,34
The initial report of spectroscopy findings included
marked elevations of the glutamate and glutamine peaks,
which have been associated with inflammatory disorders,
but only minimal elevation of the choline peak, which is
64

Fig. 3. Photomicrograph of a histopathological section of the lesion.
Vessels in and around the area of necrosis are thickened, with chronic
inflammatory cells around and in the vessel walls. The lymphocytes
present are a mixture of CD3 T cells and CD20 B cells. H & E, original
magnification ×40.

typically elevated in aggressive neoplastic processes secondary to increased cell turnover. There was also marked
elevation of the lipid peak, which is indicative of destructive processes with release of free lipids from cell membranes, without lactate peak elevation or evidence of gross
necrosis, and mild decrease of the NAA peak.34
A second report, however, detected elevation of choline-containing compounds, as well as in the creatine,
NAA, and lipid peaks, in contrast to findings from Panchal et al.34 The authors postulate that this may be due
to granulomas retaining moderate proliferation potential.
There was mild elevation of the glutamate and glutamine
peaks, however. It is interesting to note that in the latter
case report central necrosis was identified in the gross
specimen. These investigators also point out that the low
fractional anisotropy value on diffusion tensor imaging
lowers the probability of the radiographic lesion being
consistent with malignant glioma.6 In both cases there was
resolution of MRI findings after completion of appropriate therapy.
Conventional angiography or MRA is required for
diagnosis of large- to medium-vessel vasculitis. Beading
of one or more vessels is often described,1,3,12,16,20,32 and
there may be vessel stenosis, tortuosity, and occlusion
as well. The involved vessels usually, but do not always,
correspond to the territory of radiographically confirmed
lesions.3 Transient aneurysm formation has been reported,3,21,32 and in rare cases the clinical presentation occurs
secondary to intracranial hemorrhage.7,19,27,32,33,36,37
Given the positive findings on angiography, brain biopsy is typically not pursued. It should also be kept in
mind that there are reports of spinal cord involvement of
PACNS.16,28,33,42 Reported histological characteristics of
granulomatous CNS vasculitis include a transmural infiltrate in which lymphocytes, plasma cells, and histiocytes
predominate, with ill-defined granulomas, evidence of giant cells, and areas of vessel wall necrosis. The giant cells
may appear eccentrically in any layer of the vessel wall.
J Neurosurg: Pediatrics / Volume 13 / January 2014

Angiography-negative childhood primary angiitis of the CNS
TABLE 1: Comparison of angiography-positive and angiography-negative cPACNS*
Feature
presentation

Angio-Positive cPACNS

Angio-Negative cPACNS

HA; acute hemiparesis; hemisensory deficit; fine motor
deficit; stroke (nonprogressive)

systemic symptoms (fever, malaise, flulike symptoms); HA;
intractable Szs; ataxia; cognitive decline; behavior
changes; hemiparesis; facial droop; optic neuritis;
myelitis
significant laboratory results ESR can be elevated or normal; CSF may or may not
ESR can be elevated or normal; CSF may or may not demdemonstrate elevated protein &/or pleocytosis
onstrate elevated protein &/or pleocytosis
MRI findings
unilat or bilat multifocal lesions on T2/FLAIR imaging; lep- unilat or bilat multifocal lesions on T2/FLAIR imaging; leptomeningeal &/or vessel wall enhancement, parenchytomeningeal &/or vessel wall enhancement, parenchymal edema, or hemorrhage may be present
mal edema, or hemorrhage may be present
angiographic findings
focal areas of stenosis; “beading” or “sausage” pattern
negative (by definition)
pathology & types of lymgranulomatous & lymphocytic infiltrate w/ T & B cells
nongranulomatous lymphocytic infiltrate of T > B cells
phocytes present
treatment
progressive: monthly cyclophosphamide & high-dose cor- cyclophosphamide induction × 6 mos followed by 18 mos
ticosteroids × 6 mos followed by 18 mos maintenance
of MMF maintenance therapy w/ or w/o antiplatelet
therapy; nonprogressive: 5 days intravenous methyltherapy
prednisolone followed by 3 mos tapered oral glucocorticoids; both w/ & w/o antiplatelet therapy (now recommended)
outcomes
generally excellent, w/ only a minority w/ persistent neuro- generally excellent, w/ no detectable neurological deficit on
logical deficit on completion of therapy
completion of therapy
* Angio = angiography; HA = headache; Sz = seizure.

The process can involve both arteries and veins, with the
media and adventitia most often affected. Chronic angiitis
may demonstrate intimal fibrocellular proliferation, and
there may be thrombosis within the vessels.15,28 Weakening of the arterial walls secondary to fibrinoid necrosis
and leading to aneurysm formation has been postulated to
occur.21,32,42 Beta-amyloid deposition has been described
in a subset of granulomatous adult PACNS.30,37
The initial literature on adult PACNS reported a high
mortality rate, and many of the histological studies were
performed postmortem.12,15 Rapid progression leading to
death was also reported in the early pediatric cases.27,29,32
Treatment with corticosteroids and cyclophosphamide
was initially reported by Cupps et al.,16 and treatment regimens are now largely based on this paradigm. The early
reports of cPACNS, once the diagnosis was recognized,
included treatment with high-dose corticosteroids and immunosuppression, usually with cyclosporine.19 Treatment
for progressive angiography-positive cPACNS now commonly consists of induction therapy of monthly intravenous cyclophosphamide in addition to high-dose steroids
for 6 months, followed by maintenance treatment with either oral methotrexate or azathioprine for 18 months.5,8,27
Mycophenolate mofetil (MMF) is also sometimes used as
the oral maintenance therapy, based on a report of 3 children (2 with angiography-negative cPACNS and 1 with
angiography-positive cPACNS) who had been weaned off
the maintenance steroids, with recurrence of cPACNS; excellent results were obtained using MMF.38 A short course
of heparin followed by an antiplatelet agent is frequently
given, although anticoagulation for cerebral vessel inflammation remains controversial. Excellent results have been
reported in cases of cPACNS treated using this protoJ Neurosurg: Pediatrics / Volume 13 / January 2014

col.3,5 Treatment for nonprogressive angiography-positive
cPACNS is also controversial, although patients may benefit from a short course of high-dose steroids and an antiplatelet agent;17 one group recommends a 5-day course
of pulsed intravenous methylprednisolone followed by a
3-month course of tapered oral glucocorticoids, with a
low-dose antiplatelet agent.23
Benseler et al.5 reviewed a series of 62 conventional
or MRA-positive cases of cPACNS for the purpose of
identifying prognostic factors. Presence of neurocognitive dysfunction (as opposed to focal neurological deficit),
multifocal parenchymal lesions on T2-weighted MRI, and
distal stenosis on angiography were predictive of progressive cPACNS. Other factors associated with worse prognosis identified by Lanthier et al.27 include acute stroke
presentation secondary to involvement of large and medium-sized arteries, granulomatous pathology, and delayed
treatment.
Angiography-Negative cPACNS

The presentation of small-vessel vasculitis frequently includes systemic features (fever, malaise, and flulike
symptoms), headache, intractable seizures, ataxia, cognitive decline, or behavior changes.4,17,18,23,24 Hemiparesis or
facial droop may be presenting features, and optic neuritis
or myelitis may be present.23,24,38 The course of presentation can vary over weeks to months, although acute presentations may also occur.17 Seizures at presentation were
found to be associated with higher disease activity, and
the presence of seizures, cognitive dysfunction, or visual
symptoms is more likely to be found with small-vessel
PACNS, whereas motor deficits were more frequently
found in medium- to large-vessel PACNS.14
65

M. S. Park, A. E. Marlin, and S. J. Gaskill
As for angiography-positive cPACNS, ESR and C-reactive protein may be mildly elevated, and CSF pleocytosis or elevated protein may be present, but again these are
neither sensitive nor specific.2,4,9,23,24,27,39,40 The C3 complement and vWF antigen may also be elevated.23,24 The electroencephalography findings will often be abnormal, but
this too is neither specific nor sensitive.18,23,24
T2-weighted MRI studies reveal multifocal hyperintensities in both white and gray matter, which may be
unilateral or bilateral.17,18,23,24 Diffusion restriction is uncommon but can detect areas of acute ischemia in the deep
or subcortical white matter.31 Lesions do not typically conform to a large-vessel vascular territory, and Gd enhancement has been postulated to be sensitive for small-vessel
PACNS.18,35 By definition, angiography is negative;17 it has
been postulated that the affected vessels are smaller than
the resolution of the angiogram.27,35 Elevated intracranial
pressure may be detected.4,39
Biopsy, which is of lower diagnostic yield in adults
than in children,2,11,17 reveals necrotizing granulomatous
le­sions in adults,28,40 but lesions consisting of segmental,
nongranulomatous, intramural infiltration of B and pre­
domi­nantly T lymphocytes involving small arteries, arterioles, capillaries, or venules in children.18,24,29,41 Occasional
plasma cells, polymorphonuclear cells, and eosinophils
may be present.18 There may be gliosis, calcification, and
pal­lor of myelin staining surrounding the areas of active
inflammation.4,18,27 Biopsy sampling comes with a high
false-negative rate, as high as 25%,12 and can prove to be
nondiagnostic because of the skip-lesion nature of the disease.1,11,16 A technically adequate biopsy sample should
in­clude the leptomeninges, cortex, and white matter,9,10,12,
16,17,40
because the leptomeninges often enhance on MRI
sequences.9 In one review negative biopsy results were reported in cases in which the leptomeninges were not included on the biopsy samples, but PACNS was confirmed
on postmortem examination.12
Alrawi et al.2 have put forth a set of histopathological
criteria for angiography-negative small-vessel cPACNS: a
minimum of 2 layers of lymphocytes within or around the
walls of parenchymal or leptomeningeal and dural vessels;
structural alterations of the vessel wall such as prominence of endothelial cells, with or without necrosis; pink
neuronal cytoplasm and pyknotic neuronal nuclei with or
without pyknotic glial nuclei and astrocytic gliosis; neu­
ronophagia; parenchymal edema; and exclusion of alternate diagnoses. Definitive diagnosis requires fulfillment of
all criteria and probable diagnosis requires fulfillment of
all criteria except the first.
At the present time there is no standard treatment protocol for angiography-negative cPACNS, although there
are reports of generally excellent long-term outcomes with
6 months of cyclophosphamide induction followed by 18
months of MMF maintenance therapy.23,24 Azathioprine
has also been used for maintenance therapy, but was found
to be associated with disease flares, and is not typically
used at this time.14,24

Conclusions

Diagnosis of cPACNS is a challenge due to several
factors, including its rarity, wide differential diagnoses that
66

can manifest similarly to cPACNS, and nonspecific laboratory and radiographic findings. Small-vessel cPACNS, in
particular, can demonstrate negative results on angiography. The development of newly acquired neurological deficits with rapid progression in a previously healthy child
without evidence of infection or malignancy should lead
to the clinical suspicion of cPACNS, and in angiographynegative cases, small-vessel cPACNS, keeping in mind
that the diagnosis may ultimately be made solely on the
basis of biopsy findings. Although there can be significant
morbidity and mortality if cPACNS is untreated, patients
who receive appropriate therapy can experience excellent
outcomes, and in many cases demonstrate near-complete
or total clinical and radiographic resolution.
Disclosure
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this
paper.
Author contributions to the study and manuscript preparation
include the following. Conception and design: Marlin, Gaskill.
Acquisition of data: Marlin, Gaskill. Analysis and interpretation of
data: all authors. Drafting the article: all authors. Critically revising
the article: all authors. Reviewed submitted version of manuscript: all
authors. Approved the final version of the manuscript on behalf of all
authors: Park. Administrative/technical/material support: all authors.
Study supervision: all authors.
References
1. Ackerman RH, Richardson EP Jr: Case 35-1985—Abrupt onset
of headache followed by rapidly progressive encephalopathy in
a 30-year-old woman. N Engl J Med 313:566–574, 1985
2. Alrawi A, Trobe JD, Blaivas M, Musch DC: Brain biopsy in
primary angiitis of the central nervous system. Neurology 53:
858–860, 1999
3. Aviv RI, Benseler SM, Silverman ED, Tyrrell PN, Deveber G,
Tsang LM, et al: MR imaging and angiography of primary
CNS vasculitis of childhood. AJNR Am J Neuroradiol 27:
192–199, 2006
4. Benseler SM, deVeber G, Hawkins C, Schneider R, Tyrrell PN,
Aviv RI, et al: Angiography-negative primary central nervous
system vasculitis in children: a newly recognized inflammatory central nervous system disease. Arthritis Rheum 52:
2159–2167, 2005
5. Benseler SM, Silverman E, Aviv RI, Schneider R, Armstrong
D, Tyrrell PN, et al: Primary central nervous system vasculitis
in children. Arthritis Rheum 54:1291–1297, 2006
6. Beppu T, Inoue T, Nishimoto H, Nakamura S, Nakazato Y,
Ogasawara K, et al: Primary granulomatous angiitis of the
cen­tral nervous system: findings of magnetic resonance spectroscopy and fractional anisotropy in diffusion tensor imaging
prior to surgery. Case report. J Neurosurg 107:873–877, 2007
7. Biller J, Loftus CM, Moore SA, Schelper RL, Danks KR, Cornell SH: Isolated central nervous system angiitis first presenting as spontaneous intracranial hemorrhage. Neurosurgery
20:310–315, 1987
8. Bitter KJ, Epstein LG, Melin-Aldana H, Curran JG, Miller
ML: Cyclophosphamide treatment of primary angiitis of the
central nervous system in children: report of 2 cases. J Rheumatol 33:2078–2080, 2006
9. Calabrese LH: Diagnostic strategies in vasculitis affecting
the central nervous system. Cleve Clin J Med 69 (Suppl 2):
SII105–SII108, 2002
10. Calabrese LH, Duna GF, Lie JT: Vasculitis in the central nervous system. Arthritis Rheum 40:1189–1201, 1997

J Neurosurg: Pediatrics / Volume 13 / January 2014

Angiography-negative childhood primary angiitis of the CNS
11. Calabrese LH, Furlan AJ, Gragg LA, Ropos TJ: Primary angiitis of the central nervous system: diagnostic criteria and clinical approach. Cleve Clin J Med 59:293–306, 1992
12. Calabrese LH, Mallek JA: Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature,
and proposal for diagnostic criteria. Medicine (Baltimore) 67:
20–39, 1988
13. Cellucci T, Tyrrell PN, Pullenayegum E, Benseler SM: von
Willebrand factor antigen—a possible biomarker of disease
activity in childhood central nervous system vasculitis? Rheumatology (Oxford) 51:1838–1845, 2012
14. Cellucci T, Tyrrell PN, Sheikh S, Benseler SM: Childhood primary angiitis of the central nervous system: identifying disease trajectories and early risk factors for persistently higher
disease activity. Arthritis Rheum 64:1665–1672, 2012
15. Cravioto H, Feigin I: Noninfectious granulomatous angiitis
with a predilection for the nervous system. Neurology 9:599–
609, 1959
16. Cupps TR, Moore PM, Fauci AS: Isolated angiitis of the central nervous system. Prospective diagnostic and therapeutic
experience. Am J Med 74:97–105, 1983
17. Elbers J, Benseler SM: Central nervous system vasculitis in
children. Curr Opin Rheumatol 20:47–54, 2008
18. Elbers J, Halliday W, Hawkins C, Hutchinson C, Benseler SM:
Brain biopsy in children with primary small-vessel central nervous system vasculitis. Ann Neurol 68:602–610, 2010
19. Gallagher KT, Shaham B, Reiff A, Tournay A, Villablanca JP,
Curran J, et al: Primary angiitis of the central nervous system
in children: 5 cases. J Rheumatol 28:616–623, 2001
20. Greenan TJ, Grossman RI, Goldberg HI: Cerebral vasculitis:
MR imaging and angiographic correlation. Radiology 182:
65–72, 1992
21. Griffin J, Price DL, Davis L, McKhann GM: Granulomatous
angiitis of the central nervous system with aneurysms on multiple cerebral arteries. Trans Am Neurol Assoc 98:145–148,
1973
22. Hajj-Ali RA, Furlan A, Abou-Chebel A, Calabrese LH: Benign angiopathy of the central nervous system: cohort of 16
patients with clinical course and long-term followup. Arthritis
Rheum 47:662–669, 2002
23. Hajj-Ali RA, Singhal AB, Benseler S, Molloy E, Calabrese LH:
Primary angiitis of the CNS. Lancet Neurol 10:561–572, 2011
24. Hutchinson C, Elbers J, Halliday W, Branson H, Laughlin S,
Armstrong D, et al: Treatment of small vessel primary CNS
vasculitis in children: an open-label cohort study. Lancet Neurol 9:1078–1084, 2010
25. Katsicas MM, Russo R, Taratuto A, Pociecha J, Zelazko M:
Primary angiitis of the central nervous system presenting as a
mass lesion in a child. J Rheumatol 27:1297–1298, 2000
26. Küker W, Gaertner S, Nagele T, Dopfer C, Schoning M, Fiehler
J, et al: Vessel wall contrast enhancement: a diagnostic sign of
cerebral vasculitis. Cerebrovasc Dis 26:23–29, 2008
27. Lanthier S, Lortie A, Michaud J, Laxer R, Jay V, deVeber G:
Isolated angiitis of the CNS in children. Neurology 56:837–
842, 2001
28. Lie JT: Primary (granulomatous) angiitis of the central nervous system: a clinicopathologic analysis of 15 new cases and
a review of the literature. Hum Pathol 23:164–171, 1992
29. Matsell DG, Keene DL, Jimenez C, Humphreys P: Isolated an-

J Neurosurg: Pediatrics / Volume 13 / January 2014

giitis of the central nervous system in childhood. Can J Neurol Sci 17:151–154, 1990
30. Miller DV, Salvarani C, Hunder GG, Brown RD, Parisi JE,
Christianson TJ, et al: Biopsy findings in primary angiitis of
the central nervous system. Am J Surg Pathol 33:35–43, 2009
31. Moritani T, Hiwatashi A, Shrier DA, Wang HZ, Numaguchi
Y, Westesson PL: CNS vasculitis and vasculopathy: efficacy
and usefulness of diffusion-weighted echoplanar MR imaging.
Clin Imaging 28:261–270, 2004
32. Nishikawa M, Sakamoto H, Katsuyama J, Hakuba A, Nishimura S: Multiple appearing and vanishing aneurysms: primary
angiitis of the central nervous system. Case report. J Neurosurg 88:133–137, 1998
33. Ozawa T, Sasaki O, Sorimachi T, Tanaka R: Primary angiitis of
the central nervous system: report of two cases and review of
the literature. Neurosurgery 36:173–179, 1995
34. Panchal NJ, Niku S, Imbesi SG: Lymphocytic vasculitis mimicking aggressive multifocal cerebral neoplasm: mr imaging
and MR spectroscopic appearance. AJNR Am J Neuroradiol
26:642–645, 2005
35. Salvarani C, Brown RD Jr, Calamia KT, Christianson TJH,
Huston J III, Meschia JF, et al: Angiography-negative primary
central nervous system vasculitis: a syndrome involving small
cerebral vessels. Medicine (Baltimore) 87:264–271, 2008
36. Salvarani C, Brown RD Jr, Calamia KT, Christianson TJH,
Huston J III, Meschia JF, et al: Primary central nervous system
vasculitis presenting with intracranial hemorrhage. Arthritis
Rheum 63:3598–3606, 2011
37. Salvarani C, Brown RD Jr, Calamia KT, Christianson TJH,
Weigand SD, Miller DV, et al: Primary central nervous system
vasculitis: analysis of 101 patients. Ann Neurol 62:442–451,
2007
38. Sen ES, Leone V, Abinun M, Forsyth R, Ramesh V, Friswell
M, et al: Treatment of primary angiitis of the central nervous
system in childhood with mycophenolate mofetil. Rheumatology (Oxford) 49:806–811, 2010
39. Singh S, Soloman T, Chacko G, Joseph TP: Primary angiitis of
the central nervous system: an ante-mortem diagnosis. J Postgrad Med 46:272–274, 2000
40. Vollmer TL, Guarnaccia J, Harrington W, Pacia SV, Petroff
OAC: Idiopathic granulomatous angiitis of the central nervous
system. Diagnostic challenges. Arch Neurol 50:925–930,
1993
41. Yaari R, Anselm IA, Szer IS, Malicki DM, Nespeca MP, Gleeson JG: Childhood primary angiitis of the central nervous system: two biopsy-proven cases. J Pediatr 145:693–697, 2004
42. Yoong MF, Blumbergs PC, North JB: Primary (granulomatous)
angiitis of the central nervous system with multiple aneurysms
of spinal arteries. Case report. J Neurosurg 79:603–607, 1993
Manuscript submitted March 31, 2013.
Accepted September 10, 2013.
Please include this information when citing this paper: published
online October 25, 2013; DOI: 10.3171/2013.9.PEDS13159.
Address correspondence to: Michael S. Park, M.D., Department
of Neurosurgery & Brain Repair, Division of Pediatric Neurosurgery, 2 Tampa General Circle, 7th Floor, Tampa, FL 33606. email:
mpark1@health.usf.edu.

67