Pediatric Neurology 50 (2014) 581e585 Contents lists available at ScienceDirect Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu Original Article Post-Varicella Angiopathy: A Series of 4 Patients With Focus on Virologic and Neuroimaging Findings Ulrike Dunkhase-Heinl MD a, Brian Stausbøl-Grøn PhD b, Johnny Christensen MD c, John R. Ostergaard MD DMSc d, * a Department of Pediatrics, Kolding Region Hospital, Denmark Section of Magnetic Resonance Imaging, Department of Radiology, Aarhus University Hospital, Aarhus, Denmark c Department of Radiology, Kolding Region Hospital, Denmark d Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark b abstract BACKGROUND: Post-varicella angiopathy is an important cause of childhood stroke and follows a particular pattern. Specific treatment guidelines have not been developed because of a lack of epidemiological, laboratory, and neuroimaging data. Prospective randomized controlled trials evaluating different treatment strategies have not been performed, and expert opinions on diagnostic criteria, prognosis, and treatment are diverging. METHODS: This case series describes the clinical course, laboratory, and neuroimaging findings of four children with post-varicella angiopathy, who all underwent cerebrospinal fluid assessment and received antiviral, immunosuppressive, and antiplatelet treatment. RESULTS: Cerebrospinal fluid analysis was positive for varicella-zoster virus markers in three children. At follow-up, three children had a mild hemiparesis and one child had no neurological symptoms. Neuroimaging showed complete vascular remission in three patients and improvement in one. CONCLUSIONS: Systematic search for virologic markers in cerebrospinal fluid will contribute to the understanding of the pathogenesis of idiopathic childhood stroke and can be considered as a prerequisite for the development of clear diagnostic criteria and relevant treatment strategies for post-varicella angiopathy. The role of antiviral and immunosuppressive medication needs to be clarified. Keywords: angiopathy, children, outcome, stroke, treatment, varicella zoster Pediatr Neurol 2014; 50: 581-585 Ó 2014 Elsevier Inc. All rights reserved. Introduction Arterial ischemic stroke (AIS) during childhood is relatively rare, but can cause significant morbidity.1,2 The etiologies are multifactorial and related to an arteriopathy in many cases. Post-varicella angiopathy (PVA) has been recognized since 1985 and seems to be one of the most important causes of childhood stroke, accounting for up to 30% to 40% of cases with AIS.1,3,4 Article History: Received September 24, 2013; Accepted in final form January 5, 2014 * Communications should be addressed to: Dr. Ostergaard; Centre for Rare Diseases; Department of Pediatrics; Aarhus University Hospital; DK-8200 Aarhus N, Denmark. E-mail address: rarejohn@gmail.com 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.01.019 PVA is usually categorized as a transient cerebral arteriopathy, and preceded by varicella zoster virus (VZV) infection within the past 12 months before AIS.5 PVA has been proposed as a diagnostic entity, characterized by infarction in the lateral lenticulostriate territory resulting from unilateral intracranial arterial wall disease that affects the distal internal carotid artery (ICA) and/or the proximal middle and/or anterior cerebral artery (MCA, ACA). With time, the arteriopathy stabilizes, improves, or resolves in most cases, sometimes after initial worsening during the first few months.6,7 The knowledge concerning epidemiology, presentation, and outcome of PVA is still limited and consistent treatment regimens have not been established. The objectives of the present case series study were to describe the clinical and neuroimaging findings in four children with PVA, to contribute to a better understanding 582 U. Dunkhase-Heinl et al. / Pediatric Neurology 50 (2014) 581e585 of the disease and to discuss treatment on the background of pathogenesis and outcome. Patients and Methods Four children with AIS secondary to PVA are reported. They were admitted to a primary pediatric referral center in southern Denmark between December 1, 2003 and December 31, 2012. PVA was defined as an AIS that (1) followed a verified varicella infection within 12 months; (2) had an accompanying evidence of a vascular disease affecting the supraclinoid internal carotid artery, A1 or A2 segments of the anterior cerebral artery, or M1 or M2 segments of the middle cerebral artery; and (3) did not have any other possible etiologies. Coagulation defects, metabolic and hematological diseases, and cardiac disorders were excluded by the diagnostic evaluation. Cerebrospinal fluid (CSF) samples were analyzed for cells, protein, glucose, and virologic markers. The virologic investigations included analysis of (VZV DNA) by polymerase chain reaction and analysis of intrathecal VZV immunoglobulin G (IgG) antibody synthesis by capture enzyme-linked immunosorbent essay. Magnetic resonance imaging (MRI) included axial T1- and T2weighted images, axial diffusion-weighted imaging, and coronal fluidattenuated inversion recovery. Magnetic resonance angiography (MRA) was based on time-of-flight angiography. The severity of arterial abnormality was categorized based on the classification proposed by Miravet8: grade 1: turbulence without evidence of reduced distal flow; grade 2: stenosis with reduced distal flow; grade 3a: occlusion with distal flow via collaterals; and grade 3b: occlusion without distal flow. MRI and MRA were repeated following 3 to 6 months. All children were treated with both intravenous acyclovir 30 mg/kg per day for 14 days and with oral prednisone. Three children received oral prednisone 2 mg/kg per day for 2 weeks with tapering over 2 to 4 weeks; one child received oral prednisone 1 mg/kg per day for 5 days. Three children started treatment at the onset of symptoms, and one child 3 months later, when the arteriopathy became evident on MRA. All children received salicylic acid (aspirin) 3-5 mg/kg for a minimum of 1 year. Consciousness was unimpaired in all children. One patient (patient 1) had two MRI-confirmed episodes of AIS with an interval of 4 days. The remaining three children had a single clinical episode of AIS, but one patient had neuroimaging evidence of a previous clinically silent infarction (patient 2). At clinical follow-up (range 6 months to 8 years), three children showed mild motor and cognitive deterioration, whereas one child was unimpaired (Table 1). CSF findings CSF findings are summarized in Table 2. CSF was obtained at onset of symptoms in three patients and with a delay of 3 months in one patient (patient 1). This child had a spinal tap when the arteriopathy became evident on MRA 3 months after the debut of symptoms. Neuroimaging Results Neuroimaging findings are summarized in Table 3. All children had neuroimaging evidence of infarction in the MCA territory. Infarction of putamen and globus pallidus was seen in all children. The nucleus caudatus was involved in two patients, and the surrounding subcortical white matter in three children. Two patients had neuroimaging evidence of recurrent infarctions; in one child, the infarction had been clinically silent (patient 2). MRA showed stenosis of the M1 segment of the MCA, classified as grade 1 arteriopathy in three children. One child had a stenosis of the supraclinoid ICA and the M1 segment of the MCA, classified as grade 2 arteriopathy. At follow-up after 6 months, the arteriopathy had resolved in three patients. In one child (patient 4), an improvement was seen, but the severity of the arteriopathy was still classified as grade 2. MRI and MRA of patients 2 and 4 are shown in the Figure. Clinical symptoms/signs Discussion The children were 13 to 22 months old at onset of symptoms. Interval from varicella rash to AIS ranged from 4 weeks to 6 months. Neurological symptoms evolved gradually over 24 hours and are summarized in Table 1. This series underlines the important role of PVA in childhood stroke and illustrates the typical clinical presentation in the pediatric population. PVA should be suspected in a young child with acute hemiparesis and basal TABLE 1. Clinical Findings at Onset and Follow-Up Patient Gender Age at AIS (Months) Interval From Varicella to AIS Symptoms Clinical Outcome at Follow-up Follow-up Period 1 Female 22 4 wk Nearly complete left hemiparesis Vomiting 8 yr 2 3 Male Male 15 18 6 mo 5 mo moderate left hemiparesis Moderate right hemiparesis 4 Female 13 6 wk Nearly complete right hemiparesis Vomiting Left hemiparesis Mild dystonia GMFCS I, MACS I Healthy Right hemiparesis Minor attention deficit GMFCS I, MACS I Right hemiparesis Minor attention deficit GMFCS I, MACS I Abbreviations: AIS ¼ Arterial ischemic stroke GMFCS ¼ Gross motor function classification system19 GMFCS I ¼ Child walks without limitations, running and jumping speed and balance and coordination are limited MACS ¼ Manual ability classification system20 MACS I ¼ Child handles objects easily and successfully, limitations in speed and accuracy without restrictions in daily activities 3 yr 2 yr 6 mo U. Dunkhase-Heinl et al. / Pediatric Neurology 50 (2014) 581e585 583 TABLE 2. CSF Findings in Four Patients With Post-Varicella Angiopathy Patient CSF Cells CSF Protein (g/L) CSF Glucose (mmol/L) CSF VZV DNA CSF VZV IgG Intrathecal Synthesis 1 2 3 4 Normal Normal 38 leucocytes, 1000 erythrocytes Normal 0.14 0.19 0.22 0.40 NA 4.2 3.5 3.5 Negative Positive Positive Positive Negative Positive Positive Negative Abbreviations: NA ¼ Not available CSF ¼ Cerebrospinal fluid VZV DNA ¼ Analysis of varicella zoster virus DNA by polymerase chain reaction VZV-IgG ¼ Analysis of intrathecal VZV immunoglobulin G antibody synthesis by capture enzyme-linked immunosorbent essay The spinal tap was performed during the first 3 days after the arterial ischemic stroke in patients 2-4, and with a delay of 3 months in patient 1. ganglia infarction, 1 to 12 months after anamnestic evidence of a varicella rash. The pathogenesis of PVA is not fully understood. It has been hypothesized that VZV spreads along the ophthalmic branch of the trigeminal nerve, causing a large-vessel granulomatous angiitis with multinucleated cells.8-10 This process can be related to primary infection and to reactivation of VZV. As a diagnostic entity, PVA has been described in several studies,3,4,7-12 but there is no consensus of the diagnostic criteria and on treatment strategies. Current guidelines for childhood stroke do not address the disease.12,13 Thus, the following questions arise: When should a practitioner suspect PVA and how should it be investigated and treated? The diagnosis of PVA is usually made based on neuroimaging evidence of stroke related to an intracranial arteriopathy and a contemporary anamnestic evidence of a varicella rash in a time frame of 12 months before the stroke. It has been described that the time course from rash to neurological symptoms can range from days to 20 months, although the risk of stroke has been found to be highest in the first 6 months after the varicella rash.14 On MRA, vascular changes can be missing at onset, as described in a number of studies.2,7,11 This was also true for patient 1 in this case series, contributing to a delayed diagnosis. In the adult population, characteristic ischemic lesions on MRI in the setting of positive CSF markers are considered the most consistent diagnostic criterion for VZV vasculopathy.9,10 Nagel et al.9 stated that VZV vasculopathy could be excluded when CSF was negative for VZV markers. They found positive VZV DNA in 30% and VZV IgG antibodies in 93% of the CSF samples in a mixed population of children and adults with VZV vasculopathy.9 In one of the patients, serial CSF analysis showed VZV DNA on admission and 7 days later, but VZV DNA became undetectable on days 14-50, when VZV antibodies appeared. In the pediatric population, the diagnostic yield of CSF analysis has been reported to be low. Positive CSF VZV markers have been found in about 50% of the patients.15,16 CSF assessment, however, has not been performed systematically and data on timing of the lumbar puncture are lacking. Moriuchi et al. reviewed 28 children with VZV associated stroke in 2000.15 Only four of 13 children having a CSF analysis performed showed intrathecal production of VZV IgG antibodies, and one child had a positive VZV DNA.15 In a recent review comprising 26 children with VZV-associated stroke,16 eight of 14 patients investigated for VZV DNA and four of 8 patients investigated for VZV IgG were positive. In total, eight children were investigated for both markers, of which two were positive and four were negative for both markers. In the present case series, we found VZV DNA in all three children investigated at onset of symptoms. Intrathecal synthesis of VZV-IgG antibodies was positive in two patients. The child with delayed CSF TABLE 3. Neuroimaging Findings at Onset and After 6 Months 1 2 3 4 MRI at Onset MRA at Onset MRI After 6 Months MRA After 6 Months Infarction right putamen, right n. caudatus Infarction, right putamen, right n. caudatus Infarction, left basal ganglia, left subcortical WM Infarction, left putamen, left n. caudatus, left subcortical WM Right MCA M1: grade 1 Tissue loss, gliosis, right basal ganglia Normal Right MCA M1: grade 1 Tissue loss, gliosis, right basal ganglia Normal Left MCA M1: grade 1 Atrophy left subcortical WM, atrophy, gliosis left putamen Normal Left ICA, left MCA M1: grade 2 Atrophy left internal capsula, subcortical white matter, gliosis of left putamen, n. caudatus Left ICA, left MCA M1: grade 2 Abbreviations: MCA, M1 ¼ Middle cerebral artery, the sphenoidal segment ICA ¼ Internal carotid artery n. ¼ Nucleus WM ¼ White matter 584 U. Dunkhase-Heinl et al. / Pediatric Neurology 50 (2014) 581e585 FIGURE. (A) Magnetic resonance imaging (MRI) and magnetic resonance angiogram (MRA) in patient 2. (A1) MRA at onset, showing turbulence in the right middle cerebral artery (MCA) M1 (arrow). (A2) MRA 6 months later showing normalization of the flow in the right MCA (arrow). (B1/C1) MRI (T2 and fluidattenuated inversion recovery [FLAIR]) at onset showing edema in the right nucleus caudatus, putamen, and globus pallidus, and loss of substance in the right putamen and globus pallidus, indicating the presence of a previous (silent) infarction. (B2/C2) MRI (T2 and FLAIR) 6 months later. The edema had disappeared. (B) MRI and MRA in patient 4. (A1) MRA at onset showing stenosis of the left internal carotid artery/MCA M1 (arrow). The distal flow is best seen on the contrast-enhanced MRA of aorta and neck vessels (inserted picture). (A2) MRA at 6 months follow-up, still showing stenosis but with improved flow in the left internal carotid artery/MCA M1. (B1/C1) MRI (T2 and FLAIR) at onset showing edema in the left putamen, globus pallidus, and in the surrounding subcortical area (arrow). (B2/C2) MRI (T2 and FLAIR) at follow-up 6 months later, showing loss of substance related to the left globus pallidus, gliosis to the left putamen and atrophy of the internal capsule and of the surrounding subcortical white matter. analysis until 3 months after symptoms onset had negative VZV markers in CSF. These findings underline the importance of CSF assessment in the diagnostic workup in children with PVA and indicate that proper timing of CSF analysis and investigations for both VZV-DNA and VZV-IgG antibodies might be relevant. The clinical course of PVA has been described in several studies. The risk of persistent or progressive arterial disease and recurrent AIS/transient ischemic attack seems to be low, but it is difficult to draw consistent conclusions.5,7,17,18 Lanthier7 reported that PVA tended to have a monophasic course, occasionally with a radiological progression for up U. Dunkhase-Heinl et al. / Pediatric Neurology 50 (2014) 581e585 to 6 months, succeeded by spontaneous regression. In that series, however, one third of patients experienced recurrent AIS up to 33 weeks after onset despite antithrombotic prophylaxis with aspirin or anticoagulants. Miravet8 showed improvement of PVA in half of the patients, whereas in the other half, abnormalities either remained static or progressed. They found that 25% had recurrent events 2 weeks to 17 months after the initial AIS. Braun5 described residual lesions at repeated angiography in 77% and recurrent neurological symptoms in 18% of children with a unilateral intracranial arteriopathy. Preceding VZV showed a trend towards prediction of a nonprogressive arteriopathy and a better outcome.5 The present case series shows clinical improvement in all patients, vascular recovery in three patients and improvement in one patient after 6 months. It is not clear whether the result is related to our treatment regimen, which included both antiviral and immunosuppressive treatment, or whether it might be related to a benign course of the condition. Expert opinion on treatment diverges. Some authors underline the efficacy of anticoagulant and antiplatelet therapy in idiopathic childhood stroke17; other authors consider antiviral and immunosuppressive medication as appropriate treatment modalities in VZV vasculopathy. Gilden11 has suggested that all patients with a unifocal or multifocal vasculopathy should be investigated for intrathecal VZV-DNA and VZV antibodies and treated with intravenous acyclovir, supplemented by oral prednisone. Braun5 stated that a short-term treatment with immunosuppression, possibly combined with antiviral medication if the stroke was preceded by VZV, would be the most rational choice of treatment in children with unilateral intracranial arteriopathy. Several studies underline the high risk for recurrent attacks in the early stage of the disease,4,8 and quick establishment of treatment might be crucial. It is difficult to withhold antiviral drugs when we deal with an arteriopathy related to an inflammatory process and are aware of the presence of VZV DNA/antibodies in CSF. Despite the lack of randomized controlled trials, we recommend the use of acyclovir 30-45 mg/day for a minimum of 14 days. It is more difficult to comment on the need and efficacy of immunosuppressive therapy. Several studies have described the protracted neuroradiological course of the arteriopathy,5,7,8 and because of the presence of an inflammatory process, use of prednisone seems rational, for instance in a dose of 1 mg/kg per day for 5 days, as proposed by Gilden.11 In summary, PVA might be an underdiagnosed and undertreated condition because of the lack of clear diagnostic criteria, diagnostic workup strategies, and treatment guidelines. CSF analysis for viral markers should be an essential part of the diagnostic workup in children with idiopathic stroke. Systematic CSF assessment will contribute to the understanding of the pathogenesis of childhood stroke and can be considered a prerequisite for developing clear diagnostic criteria and relevant treatment 585 strategies for PVA. Multicentre randomized controlled trials are warranted to establish the need and efficacy of antiviral and immunosuppressive treatment modalities. References 1. Bernard TJ, Goldenberg NA. Pediatric arterial stroke. Pediatr Clin North Am. 2008;55:323-338. 2. Lyle CA, Bernard TJ, Goldenberg NA. Childhood arterial ischemic stroke: a review of etiologies, antithrombotic treatments, prognostic factors and priorities for future research. Semin Thromb Hemost. 2011;37:786-793. 3. Kamholz J, Tremblay G. Chickenpox with delayed contralateral hemiparesis caused by cerebral angiitis. Ann Neurol. 1985;18: 358-360. 4. Askalan R, Laughlin S, Mayank S, et al. Chickenpox and stroke in childhood. Stroke. 2001;32:1257-1262. 5. Braun KP, Bulder MM, Chabrier S, et al. The course and outcome of unilateral intracranial arteriopathy in 79 children with ischemic stroke. Brain. 2009;132:544-557. 6. Sébire G, Fullerton H, Riou E, deVeber G. Toward the definition of cerebral arteriopathies of childhood. Curr Opin Pediatr. 2004;16: 617-622. 7. Lanthier S, Armstrong D, Domi T, deVeber G. Post-varicella arteriopathy of childhood: natural history of vascular stenosis. Neurology. 2005;64:660-663. 8. Miravet E, Danchaivijitr N, Basu H, Saunders DE, Ganesan V. Clinical and radiological features of childhood cerebral infarction following varicella zoster virus infection. Dev Med Child Neurol. 2007;49: 417-422. 9. Nagel MA, Cohrs RJ, Mahalingam R, et al. The varicella zoster virus vasculopathies: clinical, CSF, imaging, and virologic features. Neurology. 2008;70:853-860. 10. Nagel MA, Forghani B, Malingham R, et al. The value of detecting anti-VZV antibody in CSF to diagnose VZV vasculopathy. Neurology. 2007;68:1069-1073. 11. Gilden D, Randall J, Mahalingam R, Nagel M. Varicella zoster vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment. Lancet Neurol. 2009;8:731-740. 12. Roach ES, Golomg MR, Adams R, et al. Management of stroke in infants and children: a scientific statement from a special writing group of the American Heart Association Stroke Council on Cardiovascular Disease in the Young. Stroke. 2008;39:2644-2691. 13. Amlie-Lefond C, Sébire G, Fullerton HJ. Recent developments in childhood arterial ischaemic stroke. Lancet Neurol. 2008;7:425-435. 14. Thomas SL, Minassian D, Ganesan V, Langan SM, Smeeth L. Chickenpox and risk of stroke: a self-controlled case series analysis. Clin Infect Dis. 2014;58:61-68. 15. Moriuchi H, Rodriguez W. Role of varicella-zoster virus in stroke syndromes. Pediatr Infect Dis J. 2000;19:648-653. 16. Monteventi O, Chabrier S, Fluss J. Current management of postvaricella stroke in children: a literature review [in French]. Arch Pediatr. 2013;20:883-889. 17. Darteyre S, Chabrier S, Presles E, et al. Lack of progressive arteriopathy and stroke recurrence among children with cryptogenic stroke. Neurology. 2012;79:2342-2348. 18. Sträter R, Becker S, von Eckardstein A, et al. Prospective assessment of risk factors for recurrent stroke during childhood e a 5-year follow-up study. Lancet. 2002;360:1540-1545. 19. Palisano RJ, Rosenbaum P, Bartlett D, Livingston MH. Content validity of the expanded and revised Gross Motor Function Classification System. Dev Med Child Neurol. 2008;50:744-750. 20. Eliasson AC, Krumlinde-Sundholm L, Rösblad B, et al. The manual ability classification system (MACS) for children with cerebral palsy: scale development and evidence of validity and reliability. Dev Med Child Neurol. 2006;48:549-554.