ORIGINAL ARTICLE

Childhood Primary Angiitis of the Central Nervous System
Muhammad Akbar Malik1, Muhammad Zia-ur-Rehman1, Malik Muhammad Nadeem2,
Farooq Rasool Chaudhry3, Abid Ali Qureshi3, Muhammad Nawaz3 and Hamza Malik4

ABSTRACT
Objective: To analyze the clinical course and magnetic resonance angiographic (MRA) abnormalities in children with
primary angiitis of the central nervous system (cPACNS).
Study Design: Cohort study.
Place and Duration of Study: Neurosciences and Neuroradiology Department of the Children's Hospital, Lahore, from
January 2009 to December 2010.
Methodology: The cohort comprised consecutive patients diagnosed as having cPACNS based on clinical findings and
identification of arterial stenosis on magnetic resonance angiography (MRA) in the absence of an underlying condition that
could cause these findings. The treatment protocol for ischaemic infarcts consisted of induction therapy with intravenous
steroids pulses and intravenous immunoglobulin followed by maintenance therapy with azathioprine and low dose aspirin.
When indicated, they were treated with anticoagulants at least for 4 weeks along with induction therapy. Patients were
followed at a single centre and systemically assessed for clinical presentation, classification of disease as progressive or
non-progressive, adverse effects of anticoagulants, aspirin, azathioprine and their hospital course.
Results: Sixty-eight children with medium-large vessel cPACNS (62% boys, 38% girls) with mean age of 8.5 ± 3.5 years
were enrolled in this study. Motor deficit (70%); headache (64%) and fever (20%) were the commonest symptoms;
whereas hemiparesis (60%); seizures 55% (focal 35%, generalized 20%) and decreased conscious level (30%), were the
commonest neurological findings. Neuroradiological findings were ischaemic strokes in 50 (73.5%), haemorrhagic strokes
in 10 (14.7%) and ischaemic haemorrhagic lesions in 8 cases (11.8%). Angiographically 51 (51/68, 75%) of the cohort had
non-progressive (obliterative) and 17 (17/68, 25%) had evidence of progressive arteriopathy at the time of admission. No
secondary haemorrhagic lesions were documented among infarcts strokes, which were treated with heparin and oral
anticoagulants. Outcome was survival in 56 cases (81.5%) and death in 12 cases (18.5%). All survivors were discharged
on long-term oral aspirin; 15 of them were also commenced on azathioprine. Neurological findings among the 56 survivors
were; normal 20%, minor disabilities in 25%, moderate disabilities in 20% and severe disabilities in 35%.
Conclusion: The spectrum of cPACNS includes both progressive and non-progressive forms with significant morbidity
and mortality. This treatment protocol of immunosuppressive therapy may improve long-term neurological outcome in
children with medium-large vessel childhood primary angiitis of the CNS.
Key words:

Primary angiitis. Intracerebral haemorrhage. Aneurysms. Subarachnoid haemorrhage. Central nervous system.

INTRODUCTION
Childhood primary angiitis of the central nervous system
(cPACNS) is a form of idiopathic vasculitis restricted to
the brain and spinal cord with an often slow progressive
course.1 The true incidence of cPACNS remains
unknown, but as recognition of the condition increases,
so does the number of cases that are diagnosed and
treated appropriately. Children with the disorder present
with a range of neurological symptoms including
intractable seizures, hemiparesis, cranial nerve deficits,
severe cognitive deficits, and decreased consciousness.2
Medium-large vessel disease affects arteries that are
large enough to be differentiated by magnetic resonance
1

4

Department of Paediatrics Neurology/Paediatrics Neurosurgery2/
Paediatrics Radiology3, The Children's Hospital, Lahore.
Department of Paediatrics, Combined Military Hospital, Lahore.
Correspondence: Dr. Muhammad Akbar Malik, 218-D,
Model Town, Lahore.
E-mail: docmalikpk2000@yahoo.co.in
Received December 10, 2010; accepted July 02, 2012.

570

angiogram (MRA) or conventional angiography. In
patients with small vessel childhood primary angiitis of
CNS, angiography findings are typically negative and
thus diagnosis must be confirmed by brain biopsy.
Identification and appropriate diagnosis of children with
the disorder is crucial because with standardized
treatment good neurological outcome is a realistic goal
and early immunosuppressive therapy has improved the
prognosis.3 Therapeutic modalities including antiplatelet agents, corticosteroids, azathioprine, cyclophosphamide and other immunomodulatory agents have
been used with variable success. While primary angiitis
of the central nervous system (cPACNS) remains a rare
entity, the poor specificity of the available diagnostic
tests and its multiple mimics create a major diagnostic
challenge.4 In children with transient ischaemic strokes
(TIAs), prompt evaluation with neuroimaging is
important to rule out cPACNS and to initiate preventative
antithrombotic treatment without delay. Magnetic
resonance angiogram (MRA) is the imaging modality of
choice for the investigation of paediatric cPACNS due to
its greater sensitivity and specificity in the diagnosis of

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Childhood primary angiitis of the central nervous system

stroke and conditions which may cause stroke-like
symptoms, i.e. “stroke mimics”. In an ideal world,
immediate access to an MRI unit, able to provide a
timely and accurate paediatric service, should be the
gold standard.5 The children with cPACNS have shown
neurological recovery after immunosuppressive treatment suggesting that the neurological deficits caused
by brain inflammation are reversible. Azathioprine has
been used successfully in a few case reports. For
cPACNS, the data for immunomodulatory therapies
are limited, and further research is required. The
improved understanding of cPACNS facilitates a tailored
diagnostic approach that results in earlier diagnosis
and initiation of therapy for this potentially reversible
condition.6
There is no treatment protocol or standardized documentation of neurological outcome of children with cPACNS.7
The aim of this study was to describe the clinical
spectrum of a cohort of children with medium-large
vessel childhood primary angiitis of CNS, report the
efficacy and safety of a particular treatment regimen.

METHODOLOGY
This study was a retrospective analysis of a prospectively enrolled consecutive cohort of children that were
evaluated for medium-large vessel cPACNS at the
Children's Hospital, Lahore, a tertiary care centre, from
January 2009 to December 2010. Patients with
childhood primary angiitis of the CNS who were ≤ 16
years old at diagnosis were included. The inclusion
criteria were clinical diagnosis of primary CNS vasculitis
of childhood and MRA confirmation of suspected
cPACNS. The patients presented with history of acute
neurological deficits including 94 children of either
gender, with acute hemiparesis, sudden loss of
consciousness, seizures, altered sensorium and speech
disturbances with infarction or haemorrhage on
neuroimaging of the brain. These children were admitted
in the Department of Neurosciences. Cases were
identified by a detailed history and thorough neurological
examination. Children presenting with perinatal strokes,
transient ischaemic attacks, traumatic brain injuries and
neurological deficits resulting directly from an infective
agent were excluded. Children with known conditions
causing thromboembolic predisposition were also
excluded.
Arteriopathies causing stroke in children were categorized as: non-progressive (non-obliterative) and progressive (obliterative) arteriopathies, based on the findings of
CA and/or MRA. Arteriopathies causing ischaemic
strokes were treated with anticoagulation according to
the protocol approved by the paediatric neurologists of
the department in consensus (Table I).
Induction therapy was used for resuscitation and
stabilization of the patients with I/V heparin, I/V pulse
methylprednisolone or I/V immunoglobulin. Maintenance

Table I: Treatment protocol for childhood arterial ischaemic strokes at
the Children's Hospital, Lahore, Pakistan.
Induction therapy: 5-10 days
•

Methyl prednisone 25 mg/kg intravenous over 4 hours daily for 3 days
and/or intravenous immunoglobulin 400 mg/kg/day over 6 hours for 5
days.

•

Oral prednisone 2 mg/kg daily (maximum 60 mg daily) for 30 days,

•

Supplementary calcium and vitamin D also given during prednisone
treatment.

•

Heparin (for ischaemic strokes, infarction size ≤ 50% of cerebral hemisphere
size); loading dose 75 units/kg intravenously followed by 20 units/kg/hour
for children over one year of age (or 28 units/kg/hour below one year of
age) for 3-5 days, followed by oral anticoagulants for 30 days.

•

Anticonvulsants and antipsychotics as needed.

•

Antibiotics and antiviral and antacids along with other supportive cares

weaning over 30 days.

as needed.
Maintenance therapy: 24 months
•

Aspirin 3 mg/kg daily for all ischaemic strokes.

•

Aspirin 3 mg/kg and azathioprine 1 mg/kg daily for progressive arteriopathies.

•

Anticonvulsants, antipsychotics, nutrients and other supportive cares as
needed.

therapy constituted of low dose aspirin and azathioprine.
Haemorrhagic infarcts were treated conservatively but
raised intracranial hypertension was treated vigorously
to maintain critical cerebral perfusion pressure (more
than 40 mmHg in younger children and more than 60
mmHg in older children). All patients with ischaemic
infarcts were commenced on long-term aspirin 3
mg/kg/day, started on day 5-30th (depending upon
patients' condition), for two years. In addition, patients
with obliterative angiopathic stroke were put on oral
azathioprine, started on day 5-30th (depending upon
patients' condition), for 2 years. The eligible patients
were recorded and analyzed for information concerning
patient demographics, age, presentation, family history,
underlying disease or risk factors, clinical state at
presentation, investigations, diagnosis, treatment and
follow-up. Initially patients were followed monthly for 3
months, then three monthly afterwards. Based on CT,
MRI and/or MRA findings, stroke were classified as
ischaemic, ischaemic-haemorrhagic and haemorrhagicinfarcts. Information on inpatient treatment included
drugs administered, hospital course, medical therapy
and decompressive surgery for raised intracranial
pressure. Short-term outcome was measured in terms of
mortality and clinical state at discharge as compared to
that at presentation determined by neurological
examination for the presence of motor, visual and
speech difficulties.
Data were analyzed using Statistical Package for
Social Sciences (SPSS) version 12.0 (Chicago, IL).
Frequencies and percentages were calculated for
qualitative data including gender, final outcome
(discharge, residual neurological deficit, death) and
complications of anticoagulation therapy. Mean + SD
and median were calculated for quantitative variables
including age.

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Muhammad Akbar Malik, Muhammad Zia-ur-Rehman, Malik Muhammad Nadeem, Farooq Rasool Chaudhry, Abid Ali Qureshi, Muhammad Nawaz and Hamza Malik

RESULTS
Sixty-eight patients (72.3%) met the study inclusion
criteria of idiopathic large-medium size arterial disease,
whereas, 26 (27.7%) had strokes due to conditions other
than primary pathology of cerebral arteries. The mean
age at diagnosis was 8.5 ± 3.5 years (median age 7.4
years, range 1·5 - 16 years) and the median time between
disease onset and diagnosis was 12 days (range 1-18).
On the average 46000 children visited the department of
the neurosciences each year during the study period,
making an annual frequency of childhood primary
ischaemic stroke of 0.57% (34/6000, 0.57%) among
the admissions in the neurology wards (n = 4800, 80%)
and neurosurgery wards (n = 1200, 20%) and 0.07%
(34/46000, 0.07%) among the children seeking neurological (n = 35000, 76%) and neurosurgical (n = 11000, 24%)
consultations.
There were 50 ischaemic strokes (50/68, 73.5%), 10
haemorrhagic strokes (10/68, 14.7%); 8 patients had
ischaemic-haemorrhagic lesions (8/68, 11.8%). Forty
two boys (42/68, 61.7%) and 26 girls (26/68, 38.3%) with
male to female ratio of 1.6 were diagnosed with
childhood primary arterial ischaemic stroke (cPAIS) of
medium-large vessel variety. Based on the findings of
carotid angiography (CA) or magnetic resonance
angiography (MRA), 51 patients (75%) had nonprogressive and 17 patients (25%) had progressive
arteriopathies. Majority of the patients (62%) were more
than 5 years of age. Headache was a common symptom
(64%) either before the onset or on presentation of
stroke. Detailed neurological examination revealed
hemiplegia in 60%, seizure in 55% (focal in 30%,
generalized in 25%) and decreased conscious level in
30%.
Fifty-six patients completed induction and received
maintenance therapy; 41 with aspirin and 15 with
combined aspirin and azathioprine. Twelve patients
(17.6%) died (5 in haemorrhage only, 5 in haemorrhagic
infarcts and 2 in ischaemic group who had progressive
arteriopathy) on their first admission in the hospital. Of
the 12 patients who died, 7 were males, 8 had severe
bilateral involvement of major cerebral arteries and /or
massive parenchymal bleed causing clinically significant
raised intracranial pressure and deep coma (Glasgow
Coma Scale ≤ 8). No secondary haemorrhage was
observed among all the ischaemic-infarcts patients who
were treated initially with IV heparin and later on
switched over to oral anticoagulants.

DISCUSSION
This 2 years study revealed 68 cases of ischaemic and
ischaemic haemorrhagic strokes with medium vessel
cPACNS. However, as this study was limited to only
one paediatric neurology department in Punjab, the
frequency of stroke cannot be extrapolated to the whole
572

population. Studies based on hospital discharge
databases have found higher incidences.8,9 In Asia,
studies based on hospital admission database have
estimated comparatively higher incidences, ranging from
27.1 to 29.7 per 100,000 children per year.10 Similarly, in
the tertiary care paediatric neurosciences department, it
was documented that 0.57% of the admitted children
had cPACNS with an annual frequency of 570/100,000
among children admitted in neurology and/or neurosurgery wards, and frequency of 74/100,000 in children
visiting hospital for neurological and neurosurgical
consultations.
Several studies have found that paediatric ischaemic
stroke is more common in boys than in girls.11 The
explanation for the apparent male predominance is
unknown. In agreement, male dominance (62.5%) was
documented, however, a reason could not be attributed
for that. In contrast to this equal gender distribution
which has also been documented from India among
children with cPACNS.12
In this case series, median age at initial presentation
was 8.5 years; in agreement, Soman et al. have
documented median age of 8.8 years, (range 1.5 - 17
years) in 212 patients.11 DeVeber et al. have documented male dominance of 54% and median age of 5
years.12 Similarly, the median age at presentation of 4.8
years has been reported by Barnes et al.13 This wide
variation in anthropometric data indicates the care level
of paediatric neurology department receiving referrals.
In this study, fever and headache has been reported in
45% and 30% of the patients, respectively, either before
or at the onset of AIS. In this case series, 26.5% children
had decreased conscious level (GCS < 14) at the time of
admission. Adam et al. have documented in their 41
children with AIS; altered mental status 17%, fever 7%
and headache in 7%.14 In contrast to this, seizures were
documented in 55% (35% focal and 20% generalized) in
these patients, whereas, Jiun-Chang et al. from Taiwan
have reported seizures in 41.5% of their cAIS patients.15
Compared to adults, seizures, fever, lethargy and
headache are frequent in children with cPACNS. In the
Canadian paediatric ischaemic stroke registry (CPISR),
69% children with AIS presented with focal neurological
deficits and 37% with seizures. In this case series, the
focal deficits included motor deficits 78%, speech
abnormalities 16%, visual deficits 10% and other deficits
32%.7 Data from Asian countries has also revealed
similar figures.7,9,16,17 Although the majority of childhood
PACNS presented with single episode of focal
neurological deficit, preceding TIAs are present in about
one-third.18 A preceding history suggestive of TIAs was
found in 20.6% patients. Najaraja et al. in a study of 43
stroke patients between age 1 - 16 years noted that 10
patients (23%) had preceding history of febrile episode
and suggested viral infections may have a triggering

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Childhood primary angiitis of the central nervous system

factor for a vascular lesion leading to a thrombosis
phenomenon and resulting in vascular occlusion.19 In
the present series, febrile illness was reported in 30%
and 20%, preceding and at presentation, respectively.
Headache was reported among 34% and seizures in
20% of those patients; either before the onset of stroke
or on presentation. Similarly, Braun et al. have
documented headache and seizures in 45% and 16%
respectively.20
Neuroradiology of the head documented abnormal
imaging in 100% of the patients. In contrast, Makhija
et al. documented infarction in 91% of their childhood
ischaemic stroke patients.21
All the patients with haemorrhagic and haemorrhagicinfarct lesions were treated conservatively (no anticoagulants), but raised intracranial pressure was
vigorously treated to maintain the critical cerebral
perfusion pressure. Four patients required craniotomy
to remove large blood clots to lower intracranial
hypertension. Majority (80%) of the patients with infarct
strokes were administered heparin, and later these were
switched over to oral anticoagulants, where clotting
profile monitoring was possible. Ten patients (20%) in
ischaemic infarcts group had either very large infarcts
(greater than 50% of single hemisphere) or presented
later than one week, so they were not treated with
heparin and oral anticoagulants but aspirin was
commenced.
Azathioprine and mycophenolate mofetil are recommended as maintenance therapy once remission is
achieved.22 At discharge, all patients with infarct strokes
were put on oral acetylsalicylic acid (aspirin) 3 mg once
a day and patients with progressive arteriopathy were
also put on azathioprine 1 mg/kg/day, commenced on
15-30th day. These two agent would be continued for 2
years. The protocol is to treat cPACNS as; nonprogressive form for 2 years and progressive form for 5
years but azathioprine would be stopped after 2 years.
No secondary haemorrhage due to heparin or oral
anticoagulants was observed in these patients. No
adverse effects have been observed in children on long
term aspirin and azathioprine (follow-up 1 - 18 months).
In agreement, in a case series by Barnes et al. 26
patients (26%) received anticoagulation without any
adverse side-effects.13 The benefits of anti-platelet
(aspirin) therapy are well established in the acute
management of AIS in adult patients. However, aspirin,
either alone or in combination with some other antiplatelet agents, appears to be a well-justified choice for
the prevention of recurrent ischaemic stroke.21 Longterm neurologic deficits occur in 50 - 85% of infants and
children after arterial ischaemic stroke (AIS).8
Lanthier et al. reported the outcome as asymptomatic in
36%; symptomatic epilepsy or persistent neurologic
deficit in 45%; and death in 20%.18 More than a half of

these children with AIS will have neurological
sequelae.18 Eighty percent survivors in the studied
group had neurological deficit at the time of discharge;
hemiparesis being the most common (55.5%), followed
by seizures, visual disturbances, speech difficulties and
swallowing difficulties. This high percentage of
neurological deficits indicated critical and advance
stages of patients being treated at the tertiary care
paediatric neurology department. In agreement,
DeVeber et al.12 have documented that long-term
neurological deficits occur in 50 - 85% of infants and
children after arterial ischaemic stroke (AIS).
The present case series demonstrates that childhood
AIS is associated with an estimated disease related
mortality of 18.4%. In contrast, Barnes et al.13 have
recorded a mortality of 8.4% in such patients. Almost
78% of survivors have significant neurological deficits.
Infarcts in both hemispheres have been associated with
poor outcome, but haemorrhagic infarction, the number
of infarcts, and the size of the artery involved were not
predictive factors.23
Strength of this study was the large number of
consecutive cases. Compared with individual cases or
smaller previous series, this cohort provided a more
complete spectrum of clinical findings. As in any
retrospective study, incompleteness of data was a
concern. In particular, inflammatory markers were not
systematically assessed, and their predictive value for
differentiating progressive and non-progressive forms of
the disease remained unclear from this study. The use of
MRA as compared with conventional angiography at
presentation presents additional issues in the study,
since 80% patients in this study were investigated with
MRA only and brain biopsy was not done in any of these
patients.

CONCLUSION
The findings from this study underline the significant
mortality and morbidity of childhood strokes, and the
importance of having a high index of suspicion, so as to
ensure early diagnosis and prompt commencement of
specific therapies. MR imaging findings were abnormal
in all cases at diagnosis and this remained the most
sensitive technique for the detection of cPACNS of
large-medium vessel disease. This treatment protocol
may improve long-term neurological outcome in these
children.

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