Journal of Neuroimmunology 341 (2020) 577190

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Journal of Neuroimmunology
journal homepage: www.elsevier.com/locate/jneuroim

Short Communication

An ischemic stroke as the presenting manifestation of rapidly progressive
primary angiitis of central nervous system in a 17-year-old boy

T

⁎

Zinovia-Maria Kefalopouloua, , Stamatis-Nick Liossisb, Theodora Sagonaa, Dimitra Veltsistaa,
Petros Zampakisc, Pantelis Kraniotisc, Aikaterini Solomouc, John Ellula, Elisabeth Chronia
a

Department of Neurology, Patras University Hospital, Patras, Greece
Department of Rheumatology, Patras University Hospital, Patras, Greece
c
Department of Radiology, Patras University Hospital, Patras, Greece
b

A R T I C LE I N FO

A B S T R A C T

Keywords:
cPACNS
Primary angiitis of the central cervous system
CNS vasculitis

Background: Childhood primary angiitis of the central nervous system (cPACNS) is an increasingly recognized
inflammatory brain disease in children.
Case presentation: We present a case of a 17-year-old boy with recurrent ischemic events over a short time
period. Diagnosis of angiography positive cPACNS was made based on neuroimaging findings while secondary
causes or mimics of CNS vasculitis were meticulously excluded. The patient exhibited rapid deterioration of his
condition with poor initial response to immunosuppressive treatment.
Conclusions: Recognition of cPACNS remains a challenge because of rarity of disease, unexplained etiopathogenesis, protean clinical presentation, as well as lack of specific laboratory and neuroimaging markers.

1. Introduction
Primary angiitis of the central nervous system (PACNS) is a rare and
debilitating disorder characterized by inflammation and destruction of
CNS vessels, without evidence of systemic vasculitis (Calabrese and
Mallek, 1988). PACNS typically arises in the fourth or fifth decade of
life, with an estimated incidence of 2.4 cases per 1,000,000 personyears (Salvarani et al., 2007). Τhe occurrence of PACNS in patients
under the age of 18, namely childhood PACNS (cPACNS), has been
increasingly recognized. The exact incidence remains unknown, in view
of the paucity of data on cPACNS in the literature. The clinical spectrum
is highly variable and nonspecific, including headaches, cognitive
dysfunction, seizures, and focal neurologic deficits. Diagnosis of
cPACNS relies on confirmatory MRI and angiographic findings, while
excluding an underlying systemic condition (Benseler et al., 2006).
Hence, early recognition and timely management that may warrant a
complete neurological recovery, present as significant challenges for

the treating physicians. We present here the diagnostic and treatment
related challenges in a case of a young boy who was diagnosed with
cPACNS in our institution.
2. Case report
Α 17-year-old boy, with no past medical or neurological family
history, presented with mixed aphasia, right-sided hemiparesis (4+/5
strength) and right central facial palsy of acute onset, 4–5 h before
admission. Plantars were flexor. Involuntary choreiform movements,
with stereotypies of right upper limb and face, were also present. Eye
movement, lower cranial nerve and sensory examinations were normal.
There were no signs of cerebellar dysfunction or meningismus. He had a
mild 3-day prodrome phase with diarrhoea and fever (< 38 °C). There
was no history of headaches, altered consciousness, or head/neck
trauma. Either a cerebrovascular event or CNS infection was suspected.
Routine laboratory workup was unremarkable apart from a

Abbreviations: PACNS, primary angiitis of the central nervous system; CNS, central nervous system; cPACNS, childhood primary angiitis of the central nervous
system; MRI, magnetic resonance imaging; NIHSS, National Institute of Health Stroke Scale; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; CT,
computed tomography; CSF, cerebrospinal fluid; CTA, computed tomography angiography; MCA, middle cerebral artery; DWI, diffusion weighted images; Fig.,
figure; IVIG, intravenous immunoglobulin; ANA, antinuclear antibodies; anti-dsDNA, anti-double-stranded DNA antibodies; ANCAs, anti-neutrophil cytoplasmic
antibodies; ENA, extractable nuclear antigen antibodies; anti-TPO, anti-thyroid peroxidase; HIV, human immunodeficiency virus; CMV, cytomegalovirus; HSV,
herpes simplex virus; VZV, varicella zoster virus; MRA, magnetic resonance angiography; IC, internal carotid; RSVS, reversible cerebral vasoconstriction syndrome;
ACA, anterior cerebral artery; PCA, posterior cerebral artery
⁎
Corresponding author at: Department of Neurology, Patras University Hospital, Patras 26504, Greece.
E-mail address: zmkefalopoulou@yahoo.com (Z.-M. Kefalopoulou).
https://doi.org/10.1016/j.jneuroim.2020.577190
Received 26 November 2019; Received in revised form 5 February 2020; Accepted 11 February 2020
0165-5728/ © 2020 Elsevier B.V. All rights reserved.

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Fig. 1. Axial MRI DWI sequences demonstrating: (A) Acute ischemic punctate lesions (arrows) in the vascular distribution of left lenticulostriate arteries, branches
of middle cerebral artery (MCA), at 24 h from symptom onset. (B) Larger areas of diffusion restriction in the left caudate, lentiform nuclei and of adjacent cortex, at
3 days follow-up. (C) Extended pathological signal in cortical and subcortical areas in the distribution of MCA, at 5 days follow-up. (D) Further radiological
deterioration including additional ischemic areas in the distribution of left anterior cerebral artery (ACA) (arrow), and (E) left posterior cerebral artery (PCA)
(arrow), at 10 days follow-up.
Angiographic findings: (F) Axial thick slab maximum intensity projection (reconstructed image) at the level of circle of Willis, showing relatively smaller diameter
of the left M1 segment of MCA (arrows), compared to the contralateral side, at baseline. (G) Coronal plain MRA demonstrating marked stenosis of left internal carotid
artery (ICA), in both extra- and intracranial segments and complete occlusion of left MCA, at 5 days follow up. (H) MRA showing more pronounced stenosis of left
ICA, near complete occlusion of left ACA, stenosis of left PCA and left spinal arteries and evident involvement of right hemispheric vasculature, including right ICA,
MCA, ACA, at 10 days follow-up. (I) MRA showing improved flow through ICA, MCA, ACA bilaterally, at 1-month follow-up.
(MRI: magnetic resonance imaging; DWI: diffusion weighted images; MCA: middle cerebral artery; ACA: anterior cerebral artery; PCA: posterior cerebral artery;
MRA: magnetic resonance angiography; ICA: internal carotid artery)

cryptococcus, toxoplasmosis, fungi and parasites) failed to identify any
infectious causative factors. Hence, corticosteroids were added on the
5th day from onset, 1 g of IV methylprednisolone for 5 days, followed
by IV prednisone. Antibiotics were gradually withdrawn. CSF autoimmune encephalitis panel was also unremarkable.
Throughout the first 2 weeks of symptom initiation the patient exhibited continuous clinical deterioration with worsening of right-sided
weakness (2+/5) and aphasia, brainstem sings and lethargy (NIHSS
score: 15), despite ongoing treatment with steroids. Accordingly, repeat
MRIs revealed a “spreading” of ischemic lesions in different vascular
territories (Fig. 1B–E). Concomitant MRAs, using time of flight (TOF)
technique, showed narrowing in the left internal carotid (IC), and flow
absence of the left MCA and its branches (Fig. 1G). Repeat tests revealed progression of stenotic and occlusive lesions (Fig. 1H). The rightsided hemichorea has gradually waned within the first week from onset.
Full body CT/CTA revealed no systemic abnormalities in keeping with
absence of clinical or other laboratory manifestations from other systems. Nerve conduction studies were also normal. PACNS was thus
considered the cardinal diagnosis. Given the poor response to steroids,
the patient was initiated on immunosuppressive therapy with pulse
cyclophosphamide (1gr IV). Three weeks after presentation the patient
began to clinically stabilize. Follow-up MRA at 1 month demonstrated
partial attenuation of vascular stenoses (Fig. 1I), in the absence of new
parenchymal ischemic lesions. Besides prednisone taper, the patient
received 6 cycles of cyclophosphamide (monthly infusions), and
maintenance therapy with azathioprine thereafter. Meanwhile, he underwent intensive physiotherapy and speech therapy at the rehabilitation department. There was residual right spastic hemiparesis and

neutrophilia shift and a mildly elevated C-reactive protein (CRP), with
normal erythrocyte sedimentation rate (ESR). Brain CT and carotid CT
angiography (CTA) were normal, while brain CTA showed a mild stenosis of the left middle cerebral artery (MCA). Lumbar puncture revealed normal CSF cell count and cytology, glucose, and protein levels.
Cardiological assessment, including transthoracic echocardiography,
showed no abnormalities. An ischemic cerebral stroke was primarily
suspected [National Institute of Health Stroke Scale (NIHSS) score: 7],
while CNS infection could not be excluded. The patient was admitted in
the Neurology Department, initially covered with both antithrombotic
and anti-viral/antibiotic therapy.
A brain MRI within 24 h of symptom onset demonstrated subtle T2/
Flair hyperintensities involving the left caudate, putamen and insular
cortex, with restriction in diffusion weighted images (DWI), compatible
with acute ischemic infarcts (Fig. 1A). Electroencephalography was
unrevealing. Thorough endocrinology and thrombophilia panels (protein C, protein S, antithrombin III, common thrombophilia mutations,
anticardiolipin antibodies, anti-beta2-glycoprotein, and lupus anticoagulant assays), as well as a peripheral blood smear evaluation were
normal. Further cardiological investigations with transoesophageal
echocardiography and 24-hour cardiac telemetry showed no irregularities. Diagnostic considerations at this stage included inflammatory/
autoimmune aetiologies and the patient was initiated on intravenous
immunoglobulin (IVIG), pending infectious workup. Testing for serum
autoantibodies such ANA, anti-dsDNA, ANCAs, ENA and anti-TPO was
negative, with normal C3 and C4. Extensive laboratory investigations in
blood and CSF (hepatitis, HIV, brucella, syphilis, borellia, tuberculosis,
CMV, HSV, VZV, West Nile, respiratory and enteroviruses panels,
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pleocytosis on CSF (Cellucci and Benseler, 2010). Further exhaustive
investigations failed to identify a secondary cause of vasculitis in our
patient, including numerous infections and autoimmune systemic conditions. There were no thunderclap headaches, no history of exposure
to vasoactive substances, or any other precipitants to support the presence of reversible cerebral vasoconstriction syndrome (RCVS). Other
non-inflammatory vasculopathies were not substantiated, and thus the
diagnosis of idiopathic CNS vasculitis was made. Performing a risky
procedure such as brain biopsy, in a patient already in critical condition, to further establish the diagnosis was considered unnecessary.
According to suggested algorithms in paediatric age groups, diagnosis
strongly depends on neuroimaging features, while brain biopsy is reserved for the angiography negative, small-vessel subtype of the disorder (Twilt and Benseler, 2012).
Our patient has shown an unusual course of relentless progression
over the first 15 days, despite initiation of immunosuppressive treatment. Although there is no unanimous pattern of progression and
treatment responsiveness of PACNS, it is mostly considered as a subacutely evolving disorder rather than a fulminant condition. Reports of
adult PACNS have recognized a small subset of patients (8–11%) with a
catastrophic form of the disease, while those with rapid progression
within 10 days are even less (Salvarani et al., 2011; Spence et al.,
2019). In children, angiography positive PACNS has been traditionally
divided into non-progressive and progressive subtypes, depending on
the involvement of new vascular territories 3 months after initial angiography (Benseler et al., 2006). However, cases of rapid progression
within this timeframe, have been rarely documented (Gallagher et al.,
2001). Our patient's initial presentation, with acute onset of focal deficit due to lenticulostriate infarction, normal CSF and no headaches or
other diffuse neurological signs, would best portray a case of non-progressive cPACNS. This phenotype typically involves unilateral stenosis
of the distal ICA or proximal MCA, and tends to be a monophasic, selflimited condition (Cellucci et al., 2012; Elbers et al., 2016). Nevertheless, his clinical picture has deteriorated in a day by day basis, following successive ischemic events, as portrayed by serial MRI and angiographic images (Fig. 1).
Induction therapy with IV corticosteroids, withheld for a few days to
exclude crucial infectious and malignant causes, failed to impede disease progression. Therefore, IV cyclophosphamide has been added
following the protocol for progressive cPACNS (Cellucci and Benseler,
2010). Disease control was achieved one month after symptoms onset,
however, the patient has suffered irreversible parenchymal damage and
remained with significant neurological deficits due to initial strokes.

severe speech difficulty mainly due to the large left MCA infarct
(NIHSS: 9, Modified Ranking scale: 3). Repeat imaging at 3, and
8 months revealed the pre-existing ischemic lesions, while there was no
evidence of new vasculopathic changes.
3. Discussion
Childhood PACNS has become an important consideration in the
workup of vascular strokes in children (Cantez and Benseler, 2008).
Adopting the Calabrese and Mallek criteria proposed for adults, the
diagnosis of cPACNS requires clinical evidence of a newly acquired
neurological or psychiatric deficit, angiographic or histopathological
features of CNS vasculitis, in the absence of an underlying systemic
condition (Calabrese and Mallek, 1988; Benseler et al., 2006). Two
distinct entities are currently recognized in the spectrum of cPACNS:
angiography-positive cPACNS, affecting large- and medium-sized cerebral vessels (Benseler et al., 2006), and angiography-negative cPACNS,
involving small-sized cerebral vessels (Benseler et al., 2005). The exact
mechanisms that drive the inflammatory response causing endothelial
injury remain unknown. Treatment of cPACNS consists of combinations
of antithrombotic therapy, corticosteroids and other immunosuppressant agents depending on the underlying subtype. Given
the rarity of the disorder, these protocols are mainly based on observational data rather than double-blind studies (Cellucci and
Benseler, 2010).
Our patient presented with clinical and imaging (MRI/CTA) findings
compatible with an acute cerebral infarct, involving a single vascular
territory (Fig. 1A,F). The concomitant involuntary movements were
consistent with basal ganglia as the primary area of ischemic insult.
Movement disorders represent an uncommon but well documented
complication of stroke, while hemichorea is systematically reported as
the most frequent manifestation in the acute phase. In accordance with
the literature, these movements have spontaneously waned within the
first week from onset, a phenomenon possibly explained by brain
plasticity. (Mehanna and Jankovic, 2013).
According to initial angiography via CTA, a left MCA pathology was
revealed, while other intracranial arterial segments appeared normal
(Fig. 1F). As soon as cardioembolic and hypercoagulable causes were
ruled out, a vasculitic process affecting large/medium size vessels was
highly suspected. Varicella-associated angiopathy, a common cause of
stroke in children, which typically affects the M1 segment of MCA with
subsequent basal ganglia infarcts, was highly considered. Other infectious or post-infectious states, systemic rheumatic conditions,
moyamoya syndrome, as well as malignancies (especially lymphoma),
were also contemplated. While CTA at presentation has revealed a benign pattern of stenosis (ie smooth, concentric and single), follow-up
MRA showed an aggressive-appearing or “classic” configuration, with
stenotic and occlusive pathology in multiple vascular beds (Aviv et al.,
2007). Whether baseline angiography has underestimated a more
widespread vascular involvement in our patient remains unknown.
Conventional catheter angiography perhaps represents a superior
technique and has long been considered the cornerstone in detecting
luminal abnormalities, such as segmental narrowing (‘beading’) or
multi-locular occlusions, ‘typical’ of CNS vasculitis. However, it is
usually unavailable on urgent grounds and carries risks of permanent
complications. Hence, in the diagnostic process of CNS vasculitis, particularly in childhood, CTA/MRA remain the preferable approaches.
(Aviv et al., 2007; Twilt and Benseler, 2012). Emerging non-invasive
techniques such as high-resolution contrast-enhanced MRI hold significant promise in distinguishing the various causes of cerebral arteriopathies. However, the evidence to determine their precise value in
early diagnosis of childhood CNS vasculitis is anticipated (Küker et al.,
2008).
In our case, CSF analysis was also unrevealing, in keeping with
findings from cPACNS series, where less than 50% of children with the
angiography positive subtype are found with raised protein or

4. Conclusion
We present here a rare case of childhood PACNS with rapid progression resulting in recurrent strokes, within a short-time period. Our
case highlights the complexities in management of this condition in the
actual clinical setting, where early features are unspecific, and confirmation of diagnosis requires rigorous exclusion of many diverse
disorders. Increased clinical suspicion, and structured rapid diagnostic
protocols are therefore crucial, since favourable prognosis relies on
instant initiation of aggressive immunosuppressive treatments.

Sources of funding
The authors did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors with regards to this
study.

Declaration of Competing Interest
None.
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