Case report Post-varicella intracranial haemorrhage in a child Nasuda Danchaivijitr MD, Department of Radiology, Great Ormond Street Hospital; Elena Miravet MD, Neurosciences Unit, Institute of Child Health, University College London; Dawn E Saunders MD MRCP FRCR; Tim Cox FRCR, Department of Radiology, Great Ormond Street Hospital; Vijeya Ganesan* MB ChB MD, Neurosciences Unit, Institute of Child Health, University College London, London, UK. *Correspondence to last author at Neurology Department, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, UK. E-mail: v.ganesan@ich.ucl.ac.uk We report a case of a 7-month-old male with primary intracranial haemorrhage 2 months after infection with varicella zoster virus (VZV). His initial clinical course was complicated by seizures and right hemiparesis; when last seen at 22 months the only positive finding was of left hand preference. Although the literature has recently established the association of arterial ischaemic stroke and VZV infection, primary intracranial haemorrhage has been reported only in one case. The child reported here had anterior interhemispheric haemorrhage due to a focal arteritis of the left anterior cerebral artery. The vascular abnormality was transient and had radiological features compatible with either a focal arteritis or vasospasm as a direct result of blood surrounding the vessels. We postulate that direct invasion of VZV caused extensive inflammation of the vessel wall and aggressive tissue penetration resulting in necrotizing angiitis and intracranial haemorrhage. We suggest that VZV infection should be considered a potential risk factor for intracranial haemorrhage in children. See end of paper for list of abbreviations. Primary varicella zoster virus (VZV) infection is associated with complications in the central nervous system (CNS) in 0.1–0.75% of cases (Barnes and Whitley 1986). It has recently been recognized that VZV is a risk factor for arterial ischaemic stroke (AIS) in childhood, especially in the 12 months after clinical chickenpox (Ichiyama et al. 1990, Sebire et al. 1999). Primary intracranial haemorrhage has been previously reported as a complication of infection with VZV in an adult (Jain et al. 2003) but, although chickenpox is much more common in the paediatric age group, this complication is not widely recognized in children. We report a case of childhood intracranial haemorrhage 2 months after infection with VZV and discuss the possible underlying mechanisms. Case report A previously healthy 7-month-old male presented to the emergency department of a local district general hospital with acute onset of increasing drowsiness, culminating in apnoea and bradycardia. He was resuscitated and admitted to the intensive care unit. Neurological examination revealed no focal signs. He had been born at 41 weeks gestation after an unremarkable delivery, weighing 3.2kg. He had uncomplicated chickenpox 2 months before presentation. The initial computerized tomography (CT) of the child’s brain, performed a few hours after admission, revealed an anterior interhemispheric haematoma with subarachnoid and intraventricular haemorrhage, associated with a moderate degree of hydrocephalus (Fig. 1). The findings were confirmed the next day by magnetic resonance imaging (MRI) of his brain. Magnetic resonance angiography (MRA) of the circle of Willis revealed narrowing and irregularity of the A2 segment of the left anterior cerebral artery (ACA) with normal distal flow. The remaining intracranial arteries were normal. These findings Developmental Medicine & Child Neurology 2006, 48: 139–142 139 140 a b a b c d Developmental Medicine & Child Neurology 2006, 48: 139–142 erythrocyte sedimentation rate, and white cell count but a moderate increase in C-reactive protein. Further evaluation for both bleeding and prothrombotic tendencies (anticardiolipin antibodies, protein S and C, antithrombin, plasminogen, alpha2-antiplasmin, factor II, V, VII, VIII, IX, X, XI, XII, XIII, Von Willebrand factor and factor V Leiden, thermolabile methylene tetrahydrofolate reductase, and prothrombin 20210 Figure 1: (a,b) Axial non-contrast enhanced brain computerized tomography shows a large interhemispheric haematoma and surrounding cerebral infarction. Intraventricular and subarachnoid haemorrhage (arrow) were noted and a moderate degree of hydrocephalus was present. Figure 2: Coronal magnetic resonance imaging confirmed computerized tomography findings. Interhemispheric haematoma was isointense on (a) T1-weighted image and very low intensity (blooming effect) on (b) T2-weighted image. (c) Magnetic resonance angiography showed segmental narrowing and irregularity of A2 segment of left anterior cerebral artery (inset) with normal distal flow. (d) Selective left internal carotid angiography showed long segment narrowing of same vessel (arrow) which may reflect vasospasm from haemorrhage or an area of vasculitis. No other obvious cause of intracerebral haemorrhage was visible. 14698749, 2006, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1017/S0012162206000302, Wiley Online Library on [12/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License were confirmed by catheter cerebral angiography 1 week later. There was no evidence of an intracranial aneurysm, arteriovenous malformation, or cerebral venous sinus thrombosis (Fig. 2). Laboratory investigations showed mild anaemia, normal coagulation profile (prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen), biochemistry, Discussion Although the association between recent VZV infection and AIS in childhood is well established (Ichiyama et al. 1990, Sebire et al. 1999), the association with primary, non-traumatic, intracranial haemorrhage is not well recognized. The child reported here had no other risk factors for intracranial haemorrhage. We suggest that the anterior interhemispheric haemorrhage was due to a focal arteritis of the left ACA. The vascular imaging showed a transient abnormality with radiological features compatible with either a focal arteritis or vasospasm as a direct result of blood surrounding the vessels. In either event, the ACA must have been abnormal to result in intracerebral haemorrhage as no other cause was found. There is a well-known relation between herpes zoster opthalmicus and delayed hemiplegia (Hilt et al. 1983). The virus is thought to spread along the ophthalmic branch of the trigeminal nerve, causing a granulomatous angiitis of the internal carotid artery with multinucleated cells (Linnemann and Alvira 1980). Vascular lesions in children with AIS associated with VZV consistently affect large cerebral arteries in a distribution similar to that of trigeminal innervation at the circle of Willis (Asklalan et al. 2001). Haematogenous spread or dissemination via the sympathetic nervous system are other potential routes for viral spread to intracranial arteries (Ichiyama et al. 1990, Hausler et al. 1998). Pathological studies of VZV vasculitis have found viral particles within the media of the affected large cerebral arteries, with potential to induce functional damage to the vascular endothelium. This may result in thrombosis and proliferation of the subendothelial smooth muscle cells, fibroblasts, and collagen, leading to areas of stenosis and occlusion (Sotrel 1998). Invasion of VZV usually occurs in the immunosupressed patient, resulting in small vessel angiopathy (multifocal leukoencephalopathy), ependymitis (ventriculitis), and necrotizing angiitis (Kleinschmidt-Demasters and Gilden 2001). We postulate that in our patient there was focal arterial VZV invasion or secondary inflammation resulting in necrotizing angiitis and intracranial haemorrhage. In a previous case report of intracranial haemorrhage associated with VZV infection (Jain et al. 2003), a 61-year-old female presented with subarachnoid haemorrhage (SAH) mainly in the anterior interhemispheric fissure. She had no other risk factors for bleeding, despite extensive investigation, but had a concurrent dermatomal herpes zoster rash. Cerebral angiography showed evidence of a generalized vasculopathy. In contrast, in our patient, there was an interval of 2 months between chickenpox and intracranial haemorrhage, and there were no signs of active VZV infection in the CNS. The diagnosis of VZV angiitis is supported by the clinical history, radiological findings, and absence of other aetiology, but ultimately remains speculative. Intravenous acyclovir is advocated in adults with VZV arteritis, who usually have evidence of active VZV infection in the CNS (Gilden et al. 2005). The role of antiviral or anti-inflammatory treatment in children with postVZV AIS is not established; most have a monophasic course without such treatment (Lanthier et al. 2005). In general, there are two main mechanisms of intracranial haemorrhage related to infection or inflammation: rupture of an intracranial aneurysm or cerebral venous sinus thrombosis (Takeoka and Takahashi 2002). Intracranial aneurysms complicating infection and inflammation are usually located peripherally and affect medium- and small-sized arteries, which can then rupture and result in SAH. Venous infarction may be associated with haemorrhagic transformation because of increased venous pressure. The latter mechanism is typically found in patients with hypercoagulable states, dehydration, or head and neck infection, such as otitis media, sinusitis, and mastoiditis (deVeber and Andrew 2001). However, the child reported here had no evidence of an intracranial aneurysm or of venous sinus pathology on angiography. Conclusion Almost 90% of non-traumatic intracranial haemorrhage in children is associated with one or more risk factors including vascular malformation, coagulopathies, and haemorrhage into tumours (Livingston and Brown 1986, Al-Jarallah et al. 2000). In 10% of the cases, no cause is identified (Al-Jarallah et al. 2000). Because of its high incidence and association with arteriopathy of the CNS, we suggest that VZV infection should be considered as a potential risk factor for intracranial haemorrhage in children. DOI: 10.1017/S0012162206000302 Accepted for publication 6th June 2005. References Al-Jarallah A, Al-Rifai MT, Riela AR, Roach ES. (2000) Nontraumatic brain hemorrhage in children: etiology and presentation. J Child Neurol 15: 284–289. Asklalan R, Laughlin S, Mayank S, Chan A, MacGregor D, Andrew M, Curtis R, Meaney B, deVeber G. (2001) Chickenpox and stroke in childhood. A study of frequency and causation. Stroke 32: 1257–1262. Barnes DW, Whitley RJ. 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Anti-VZV immunoglobulin G (IgG) was detected in blood but VZV immunoglobulin M (IgM) was not present. Cerebrospinal fluid (CSF), examined 8 days after presentation, was xanthochromic but acellular. CSF protein was elevated (0.94g/L, upper limit of normal 0.3g/L) and glucose was normal. CSF anti-VZV IgM, IgG, and polymerase chain reaction for VZV DNA were negative. The haematoma was managed conservatively. Four days later, the child developed two generalized seizures within a few hours of each other (treated with lorazepam and phenobarbitone), a right hemiparesis, and right VIth and VIIth nerve palsies; he subsequently made a rapid clinical improvement. Repeat MRI and MRA at 6 months showed resolution of the interhemispheric haematoma and residual infarction of the underlying frontal lobes. A further catheter cerebral angiogram 8 months later was normal. Physical examination at 22 months of age revealed left hand preference but was otherwise normal. Sebire G, Meyer L, Chabrier S. 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