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Mechanisms of Pediatric Cerebral Arteriopathy: An Inflammatory Debate

  • Aleksandra Mineyko
    Affiliations
    Calgary Pediatric Stroke Program, Section of Neurology, Department of Pediatrics, Alberta Children’s Hospital Research Institute, Calgary, Alberta, Canada
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  • Adam Kirton
    Correspondence
    Communications should be addressed to: Dr. Kirton; Calgary Pediatric Stroke Program; Section of Neurology; Department of Pediatrics; Alberta Children’s Hospital Research Institute; 2888 Shaganappi Trail NW; Calgary, Alberta T3B 6A8, Canada.
    Affiliations
    Calgary Pediatric Stroke Program, Section of Neurology, Department of Pediatrics, Alberta Children’s Hospital Research Institute, Calgary, Alberta, Canada
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      Abstract

      Arteriopathy is the leading cause of childhood arterial ischemic stroke, but its mechanisms are poorly understood. This review explores the possible role of inflammatory mechanisms and evidence for inflammatory pathophysiology in specific pediatric cerebral arteriopathies. Pathologically proven small-vessel central nervous system vasculitis provides a definitive inflammatory model where available treatments are likely improving outcomes. In contrast, a common large-vessel arteriopathy presents many features suggestive of inflammation, but definitive proof remains elusive. Recent advances and future research directions, including biomarker, neuroimaging, and pathologic approaches and how they might address these important clinical questions, are discussed.

      Introduction

      Arteriopathy is the leading cause of childhood arterial ischemic stroke, but its mechanisms are poorly understood. This review explores the possible role of inflammatory mechanisms and the evidence for an inflammatory pathophysiology in specific pediatric cerebral arteriopathies. Pathologically proven small-vessel central nervous system vasculitis provides a definitive inflammatory model where available treatments are likely improving outcomes. In contrast, a common large-vessel arteriopathy presents many features suggestive of inflammation, but definitive proof remains elusive. Recent advances and future research directions, including biomarker, neuroimaging, and pathologic approaches and how they might address these important clinical questions, are discussed.

      Impact

      Childhood arterial ischemic stroke causes significant lifelong morbidity, mortality, and economic burden [
      • Long B.
      • Anderson V.
      • Jacobs R.
      • et al.
      Executive function following child stroke: The impact of lesion size.
      ,
      • Fullerton H.J.
      • Wu Y.W.
      • Zhao S.
      • Johnston S.C.
      Risk of stroke in children: Ethnic and gender disparities.
      ,
      • Perkins E.
      • Stephens J.
      • Xiang H.
      • Lo W.
      The cost of pediatric stroke acute care in the United States.
      ]. Arteriopathies are the leading mechanism of both cause and recurrence [
      • Mackay M.T.
      • Wiznitzer M.
      • Benedict S.L.
      • Lee K.J.
      • deVeber G.A.
      • Ganesan V.
      Arterial ischemic stroke risk factors: The International Pediatric Stroke Study.
      ,
      • Amlie-Lefond C.
      • Bernard T.J.
      • Sebire G.
      • et al.
      Predictors of cerebral arteriopathy in children with arterial ischemic stroke: Results of the International Pediatric Stroke Study.
      ,
      • Fullerton H.J.
      • Wu Y.W.
      • Sidney S.
      • Johnston S.C.
      Risk of recurrent childhood arterial ischemic stroke in a population-based cohort: The importance of cerebrovascular imaging.
      ], but an incomplete understanding of pathophysiology has prevented the development of targeted therapies or prevention strategies. A recent large, international study of childhood arterial ischemic stroke listed “potential” inflammatory arteriopathies as the leading etiologies of childhood stroke [
      • Mackay M.T.
      • Wiznitzer M.
      • Benedict S.L.
      • Lee K.J.
      • deVeber G.A.
      • Ganesan V.
      Arterial ischemic stroke risk factors: The International Pediatric Stroke Study.
      ]. An inflammatory pathophysiology presents direct and immediate therapeutic implications for readily available anti-inflammatory medications. However, the evidence for such treatments is minimal, and moreover, the issue is not thoroughly addressed in published pediatric stroke guidelines [
      • Roach E.S.
      • Golomb M.R.
      • 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 and the Council on Cardiovascular Disease in the Young.
      ,
      • Monagle P.
      • Chalmers E.
      • Chan A.
      • et al.
      Antithrombotic therapy in neonates and children: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition).
      ]. Such a lack of expert consensus opinion on this issue translates into confusion among those caring for children with stroke, and this problem will only be overcome by an improved understanding of disease mechanisms.

      Classification and definitions

      The adult classification of stroke etiologies according to the criteria of the Trial of Org 10172 in Acute Stroke Treatment (TOAST) divides stroke subtypes into large-artery atherosclerotic, cardioembolic, small-vessel lacunar, other determined etiologies, and undetermined etiologies [
      • Adams Jr., H.P.
      • Bendixen B.H.
      • Kappelle L.J.
      • et al.
      Classification of subtype of acute ischemic stroke: Definitions for use in a multicenter clinical trial: TOAST. Trial of Org 10172 in Acute Stroke Treatment.
      ]. Such classification has been essential in advancing adult stroke care, but several studies have demonstrated limited applicability of these criteria in young stroke patients [
      • Putaala J.
      • Metso A.J.
      • Metso T.M.
      • et al.
      Analysis of 1008 consecutive patients aged 15 to 49 with first-ever ischemic stroke: The Helsinki Young Stroke Registry.
      ]. Moreover, the mechanisms of stroke overall are vastly different in children, in whom nonatherosclerotic arteriopathy causes most arterial ischemic strokes [
      • Mackay M.T.
      • Wiznitzer M.
      • Benedict S.L.
      • Lee K.J.
      • deVeber G.A.
      • Ganesan V.
      Arterial ischemic stroke risk factors: The International Pediatric Stroke Study.
      ,
      • Amlie-Lefond C.
      • Bernard T.J.
      • Sebire G.
      • et al.
      Predictors of cerebral arteriopathy in children with arterial ischemic stroke: Results of the International Pediatric Stroke Study.
      ,
      • Fullerton H.J.
      • Wu Y.W.
      • Sidney S.
      • Johnston S.C.
      Risk of recurrent childhood arterial ischemic stroke in a population-based cohort: The importance of cerebrovascular imaging.
      ]. An improved system to classify pediatric stroke etiologies is currently in development. The Childhood Arterial Ischemic Stroke Standardized Classification and Diagnostic Evaluation is attempting to address the unique causes of stroke in children, including their predilection for arteriopathy [
      • Bernard T.J.
      • Manco-Johnson M.J.
      • Lo W.
      • et al.
      Towards a consensus-based classification of childhood arterial ischemic stroke.
      ]. This step forward is important but incomplete, because analyses were based on magnetic resonance or computed tomography angiography, and not on conventional angiography. It also highlights the confusion surrounding the consideration of inflammation as a primary mechanism (or not), which will have to be overcome to increase the accuracy of classification and clinical applicability. Both classification systems can define well established patterns of cerebral arteriopathy in both adults and children, such as dissection or moyamoya disease. However, these only account for a minority of pediatric arterial ischemic strokes.
      Ironically, the most common pattern of childhood cerebral arteriopathy is also the least understood. Although it may represent one or multiple different diseases, a distinct pattern of large-vessel arteriopathy is frequently observed in otherwise healthy school-aged children. The clinical and radiographic features of this syndrome have much in common, consistently featuring four characteristics [
      • Amlie-Lefond C.
      • Bernard T.J.
      • Sebire G.
      • et al.
      Predictors of cerebral arteriopathy in children with arterial ischemic stroke: Results of the International Pediatric Stroke Study.
      ,
      • Bernard T.J.
      • Manco-Johnson M.J.
      • Lo W.
      • et al.
      Towards a consensus-based classification of childhood arterial ischemic stroke.
      ,
      • Sebire G.
      • Fullerton H.
      • Riou E.
      • deVeber G.
      Toward the definition of cerebral arteriopathies of childhood.
      ,
      • Braun K.P.
      • Bulder M.M.
      • Chabrier S.
      • et al.
      The course and outcome of unilateral intracranial arteriopathy in 79 children with ischaemic stroke.
      ]:
      • (1)
        Unilateral arteriopathy of the large vessels of the anterior circulation, typically affecting the distal internal carotid artery and proximal segments of the middle cerebral artery and anterior cerebral artery;
      • (2)
        A unique angiographic appearance, with unilateral focal or segmental stenosis or occlusion of these vessels. Contiguous alternating areas of stenosis and dilatation with a “banding” or “striated” appearance are often described, whereas definitive features of other arteriopathies, such as dissection or moyamoya, are absent (differential diagnoses will be discussed later);
      • (3)
        A dynamic nature during the first days and weeks, with repeated imaging often demonstrating a fluctuating course of arterial changes; and
      • (4)
        A monophasic course over the long-term, with follow-up imaging after 6 months confirming no progression, and the potential for partial or complete resolution of the arteriopathy.
      A representative case example of this syndrome is presented in Fig 1. Many different terms have emerged to describe this syndrome, some of which directly imply a parainfectious or inflammatory mechanism. Unfortunately, our understanding of pathophysiology is too limited to allow such definitive distinctions. Four different diagnostic terms that share many of these features have emerged, each with differing degrees of implication regarding inflammatory mechanisms.
      Figure thumbnail gr1
      Figure 1Focal cerebral arteriopathy. A 14-year-old previously healthy girl with no history of trauma presented with acute left hemiparesis. She had demonstrated viral upper respiratory tract signs 2 weeks earlier. (A) Initial axial diffusion weighted imaging magnetic resonance imaging reveals restricted diffusion involving the right middle cerebral artery territory, consistent with an acute arterial ischemic stroke. (B) Conventional cerebral angiogram of the right internal carotid artery indicates abnormal striae in the distal internal carotid artery and middle cerebral artery (arrow). (C) Initial magnetic resonance angiography demonstrates irregularity of the right M1 and M2 segments (arrow). The patient was treated with antithrombotics and steroids. (D) Follow-up magnetic resonance angiography at 6 months demonstrates the improved caliber of these vessels (arrow).
      Transient cerebral arteriopathy is a recognized term that features all of the characteristics we have listed. The diagnosis requires that angiography (computed tomographic angiography, magnetic resonance angiography, or conventional angiography) performed within 3 months of the acute stroke demonstrates unilateral focal or segmental stenosis or occlusion involving the distal carotid artery, the A1 segment of the anterior cerebral artery, or the M1 segment of the middle cerebral artery. Although the arteriopathy may progress during the acute period, follow-up imaging after 6 months must confirm a lack of progression of the arteriopathy [
      • Sebire G.
      • Fullerton H.
      • Riou E.
      • deVeber G.
      Toward the definition of cerebral arteriopathies of childhood.
      ,
      • Braun K.P.
      • Bulder M.M.
      • Chabrier S.
      • et al.
      The course and outcome of unilateral intracranial arteriopathy in 79 children with ischaemic stroke.
      ,
      • Chabrier S.
      • Rodesch G.
      • Lasjaunias P.
      • Tardieu M.
      • Landrieu P.
      • Sebire G.
      Transient cerebral arteriopathy: A disorder recognized by serial angiograms in children with stroke.
      ].
      Recognition that a syndrome of transient nature is impossible to determine acutely, and that the primary mechanism is unknown, has led some leading investigators to favor less specific terminology. The term “focal cerebral arteriopathy” has been increasingly adopted to serve this purpose [
      • Amlie-Lefond C.
      • Bernard T.J.
      • Sebire G.
      • et al.
      Predictors of cerebral arteriopathy in children with arterial ischemic stroke: Results of the International Pediatric Stroke Study.
      ,
      • Bernard T.J.
      • Manco-Johnson M.J.
      • Lo W.
      • et al.
      Towards a consensus-based classification of childhood arterial ischemic stroke.
      ]. Consistent with its vague definition, focal cerebral arteriopathy is the most inclusive label for children with the syndrome we have described. Consequently, less specificity increases the probability of categorizing different childhood cerebral arteriopathies as focal cerebral arteriopathy, particularly those that are progressive [
      • Bernard T.J.
      • Manco-Johnson M.J.
      • Lo W.
      • et al.
      Towards a consensus-based classification of childhood arterial ischemic stroke.
      ].
      In contrast to the terminologies of transient cerebral arteriopathy and focal cerebral arteriopathy, two related classifications have attempted to imply the underlying mechanism more specifically. As will be described, the implication of either an inflammatory (e.g., childhood primary angiitis of the central nervous system) or infectious (e.g., postvaricella angiopathy) label risks the potential misassignment of true disease causation, but allows for the exploration of more specific mechanistic possibilities, with important treatment implications.
      An expanding literature is based on the possibility that an arteriopathy syndrome involves a primary inflammatory mechanism unique to the cerebral arteries. Such cerebral vasculitis is considered primary when it occurs exclusively in the central nervous system, and the term “primary angiitis of the central nervous system” carries established diagnostic criteria in adults [
      • Calabrese L.H.
      • Furlan A.J.
      • Gragg L.A.
      • Ropos T.J.
      Primary angiitis of the central nervous system: Diagnostic criteria and clinical approach.
      ]. Accordingly, the term “childhood primary angiitis of the central nervous system” has emerged to represent similar conditions in children [
      • Elbers J.
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ,
      • Benseler S.M.
      • Silverman E.
      • Aviv R.I.
      • et al.
      Primary central nervous system vasculitis in children.
      ].
      The most consistent classification of childhood primary angiitis of the central nervous system distinguishes subtypes based on vessel size, angiographic and pathologic findings, and the presence or absence of disease progression [
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ]. Large/medium-vessel vasculitis is divided into progressive and nonprogressive types [
      • Benseler S.M.
      • Silverman E.
      • Aviv R.I.
      • et al.
      Primary central nervous system vasculitis in children.
      ,
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ], and the nonprogressive types are more common and bear marked similarity to the transient cerebral arteriopathy and focal cerebral arteriopathy syndromes already described. This classification system, which will be described further, has yet to be validated.

      Large/medium-vessel childhood primary angiitis of the central nervous system

      The nonprogressive type of this large/medium-vessel vasculitis shares many of the features already described for transient cerebral arteriopathy and focal cerebral arteriopathy, and they may represent the same disease or closely related diseases within a spectrum [
      • Elbers J.
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ,
      • Benseler S.M.
      • Silverman E.
      • Aviv R.I.
      • et al.
      Primary central nervous system vasculitis in children.
      ]. Progressive large-vessel childhood primary angiitis of the central nervous system is uncommon, but associated features may include neurocognitive dysfunction, headaches, and seizures at presentation, multifocal and bilateral parenchymal lesions on magnetic resonance imaging, and multiple, bilateral, and distal vessel stenoses on angiography [
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ]. Because of the selective involvement of larger intracranial arteries, antemortem tissue diagnosis is generally not possible. The result involves a reliance on neuroimaging, specifically angiography, which continues to improve but cannot definitively implicate inflammation (as will be described). Long-term surveillance and outcome studies are required to better understand the natural history and predictors of recurrent forms of large/medium-vessel childhood primary angiitis of the central nervous system.

      Small-vessel childhood primary angiitis of the central nervous system

      The distinctly different disease of primary vasculitis of the small cerebral blood vessels is also well defined. In contrast to large/medium-vessel vasculitis, definitive evidence of vessel wall inflammation is often obtainable by brain biopsy, allowing for pathologic confirmation of the mechanism [
      • Matsell D.G.
      • Keene D.L.
      • Jimenez C.
      • Humphreys P.
      Isolated angiitis of the central nervous system in childhood.
      ,
      • Lanthier S.
      • Lortie A.
      • Michaud J.
      • Laxer R.
      • Jay V.
      • deVeber G.
      Isolated angiitis of the CNS in children.
      ] and definitive inclusion criteria within research studies [
      • Benseler S.M.
      • deVeber G.
      • Hawkins C.
      • et al.
      Angiography-negative primary central nervous system vasculitis in children: A newly recognized inflammatory central nervous system disease.
      ,
      • Elbers J.
      • Halliday W.
      • Hawkins C.
      • Hutchinson C.
      • Benseler S.M.
      Brain biopsy in children with primary small-vessel central nervous system vasculitis.
      ]. Patients may present with focal signs, but are more likely to develop subacute, nonlocalizing neurologic complaints such as headache, behavioral changes, seizures, or cognitive decline [
      • Lanthier S.
      • Lortie A.
      • Michaud J.
      • Laxer R.
      • Jay V.
      • deVeber G.
      Isolated angiitis of the CNS in children.
      ,
      • Elbers J.
      • Halliday W.
      • Hawkins C.
      • Hutchinson C.
      • Benseler S.M.
      Brain biopsy in children with primary small-vessel central nervous system vasculitis.
      ,
      • Gallagher K.T.
      • Shaham B.
      • Reiff A.
      • et al.
      Primary angiitis of the central nervous system in children: 5 cases.
      ]. Strokes, when they occur, are not limited to large-vessel territories [
      • Matsell D.G.
      • Keene D.L.
      • Jimenez C.
      • Humphreys P.
      Isolated angiitis of the central nervous system in childhood.
      ,
      • Lanthier S.
      • Lortie A.
      • Michaud J.
      • Laxer R.
      • Jay V.
      • deVeber G.
      Isolated angiitis of the CNS in children.
      ]. Results of neuroimaging are far less specific compared with the large-vessel varieties already described. The results of parenchymal magnetic resonance imaging can range from normal to diffusely abnormal, with a wide array of lesion characteristics described [
      • Lanthier S.
      • Lortie A.
      • Michaud J.
      • Laxer R.
      • Jay V.
      • deVeber G.
      Isolated angiitis of the CNS in children.
      ]. Even conventional angiography often reveals negative findings, and this disease is sometimes also referred to as angiography-negative small-vessel vasculitis [
      • Elbers J.
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ,
      • Lanthier S.
      • Lortie A.
      • Michaud J.
      • Laxer R.
      • Jay V.
      • deVeber G.
      Isolated angiitis of the CNS in children.
      ,
      • Benseler S.M.
      • deVeber G.
      • Hawkins C.
      • et al.
      Angiography-negative primary central nervous system vasculitis in children: A newly recognized inflammatory central nervous system disease.
      ,
      • Elbers J.
      • Halliday W.
      • Hawkins C.
      • Hutchinson C.
      • Benseler S.M.
      Brain biopsy in children with primary small-vessel central nervous system vasculitis.
      ]. Recent evidence from a single-center cohort study suggests that patients with angiography-negative childhood primary angiitis of the central nervous system manifest persistently higher disease activity than patients with angiography positive childhood primary angiitis of the central nervous system [
      • Cellucci T.
      • Tyrrell P.N.
      • Sheikh S.
      • Benseler S.M.
      Childhood primary angiitis of the central nervous system: Identifying disease trajectories and early risk factors for persistently higher disease activity.
      ]. Small-vessel cerebral vasculitis can be subdivided into primary (affecting only the central nervous system, e.g., small-vessel childhood primary angiitis of the central nervous system) or secondary (e.g., associated with other systemic disorders) [
      • Elbers J.
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ]. The diagnostic criteria of Calabrese et al. [
      • Calabrese L.H.
      • Furlan A.J.
      • Gragg L.A.
      • Ropos T.J.
      Primary angiitis of the central nervous system: Diagnostic criteria and clinical approach.
      ] for adults with primary angiitis of the central nervous system have also been applied to the pediatric population [
      • Benseler S.M.
      • Silverman E.
      • Aviv R.I.
      • et al.
      Primary central nervous system vasculitis in children.
      ,
      • Benseler S.
      • Schneider R.
      Central nervous system vasculitis in children.
      ]. These include: (1) an acquired neurologic deficit that remains unexplained after thorough evaluation, (2) either classic angiographic or histopathologic features of angiitis within the central nervous system, and (3) no evidence of systemic vasculitis or any other condition to which the angiographic or pathologic features could be attributed [
      • Calabrese L.H.
      • Furlan A.J.
      • Gragg L.A.
      • Ropos T.J.
      Primary angiitis of the central nervous system: Diagnostic criteria and clinical approach.
      ].

      Association with infection

      Infection represents both a differential diagnosis (e.g., the direct infection of cerebral arteries) and a potential “trigger” for inflammatory cerebral arteriopathy (e.g., parainfectious or postinfectious). The association of pediatric stroke with infection has long been suspected [
      • Harwood-Nash D.C.
      • McDonald P.
      • Argent W.
      Cerebral arterial disease in children: An angiographic study of 40 cases.
      ]. The simplest, most direct evidence is observed in patients with proven bacterial meningitis and stroke. Here, the pathophysiology is presumed to represent an inflammation of the vessels coursing through the subarachnoid space and traversing infected meninges, consistent with the common involvement of perforating and pial arteries [
      • Snyder R.D.
      • Stovring J.
      • Cushing A.H.
      • Davis L.E.
      • Hardy T.L.
      Cerebral infarction in childhood bacterial meningitis.
      ,
      • Chang C.J.
      • Chang W.N.
      • Huang L.T.
      • et al.
      Cerebral infarction in perinatal and childhood bacterial meningitis.
      ]. However, both perforating and large-artery involvement has been reported in bacterial meningitis [
      • Snyder R.D.
      • Stovring J.
      • Cushing A.H.
      • Davis L.E.
      • Hardy T.L.
      Cerebral infarction in childhood bacterial meningitis.
      ,
      • Chang C.J.
      • Chang W.N.
      • Huang L.T.
      • et al.
      Cerebral infarction in perinatal and childhood bacterial meningitis.
      ]. An additional, poorly understood condition involves a late large-vessel arteriopathy beginning during the recovery phases of bacterial meningitis that often leads to a severe outcome [
      • Chang C.J.
      • Chang W.N.
      • Huang L.T.
      • et al.
      Bacterial meningitis in infants: The epidemiology, clinical features, and prognostic factors.
      ,
      • Schut E.S.
      • Brouwer M.C.
      • de Gans J.
      • Florquin S.
      • Troost D.
      • van de Beek D.
      Delayed cerebral thrombosis after initial good recovery from pneumococcal meningitis.
      ]. The incidence of this arteriopathy may be underestimated, because it was common (37%) in a consecutive series of adults undergoing conventional angiography after meningitis [
      • Pfister H.W.
      • Borasio G.D.
      • Dirnagl U.
      • Bauer M.
      • Einhaupl K.M.
      Cerebrovascular complications of bacterial meningitis in adults.
      ]. The role of infection in vascular injury can include direct invasion by the pathogen, the promotion of vascular cell-wall infiltration by inflammatory cells, the stimulation of vascular smooth muscle cell proliferation, or the activation of prothrombotic states [
      • Amlie-Lefond C.
      • Fullerton H.J.
      Rashes, sniffles, and stroke: A role for infection in ischemic stroke of childhood.
      ,
      • Takeoka M.
      • Takahashi T.
      Infectious and inflammatory disorders of the circulatory system and stroke in childhood.
      ]. This diagnosis is relatively easy to establish, given readily available clinical findings and biomarkers for the presence of bacterial meningitis, but other infectious mechanisms may be more occult.
      Further evidence for an inflammatory association with large-vessel cerebral arteriopathy in children arises from its similarities to postvaricella angiopathy. Large case-control [
      • Sebire G.
      • Meyer L.
      • Chabrier S.
      Varicella as a risk factor for cerebral infarction in childhood: A case-control study.
      ] and cohort studies [
      • Askalan R.
      • Laughlin S.
      • Mayank S.
      • et al.
      Chickenpox and stroke in childhood: A study of frequency and causation.
      ] have indicated a link between childhood arterial ischemic stroke and Varicella zoster infection within the year preceding the stroke. A relationship between stroke and Varicella zoster has been recognized for many years [
      • Eda I.
      • Takashima S.
      • Takeshita K.
      Acute hemiplegia with lacunar infarct after varicella infection in childhood.
      ]. Many case reports have implied an association between recent Varicella zoster infection and focal arteriopathy [
      • Alehan F.K.
      • Boyvat F.
      • Baskin E.
      • Derbent M.
      • Ozbek N.
      Focal cerebral vasculitis and stroke after chickenpox.
      ,
      • Ganesan V.
      • Kirkham F.J.
      Mechanisms of ischaemic stroke after chickenpox.
      ,
      • Liu G.T.
      • Holmes G.L.
      Varicella with delayed contralateral hemiparesis detected by MRI.
      ,
      • Ichiyama T.
      • Houdou S.
      • Kisa T.
      • Ohno K.
      • Takeshita K.
      Varicella with delayed hemiplegia.
      ,
      • Shuper A.
      • Vining E.P.
      • Freeman J.M.
      Central nervous system vasculitis after chickenpox: Cause or coincidence?.
      ,
      • Kamholz J.
      • Tremblay G.
      Chickenpox with delayed contralateral hemiparesis caused by cerebral angiitis.
      ,
      • Caekebeke F.V.
      • Peters A.C.
      • Vandvik B.
      • Brouwer O.F.
      • de Bakker H.M.
      Cerebral vasculopathy associated with primary varicella infection.
      ,
      • Bodensteiner J.B.
      • Hille M.R.
      • Riggs J.E.
      Clinical features of vascular thrombosis following varicella.
      ]. Pleocytosis [
      • Kamholz J.
      • Tremblay G.
      Chickenpox with delayed contralateral hemiparesis caused by cerebral angiitis.
      ,
      • Caekebeke F.V.
      • Peters A.C.
      • Vandvik B.
      • Brouwer O.F.
      • de Bakker H.M.
      Cerebral vasculopathy associated with primary varicella infection.
      ,
      • Silverstein F.S.
      • Brunberg J.A.
      Postvaricella basal ganglia infarction in children.
      ] or Varicella zoster antigens [
      • Alehan F.K.
      • Boyvat F.
      • Baskin E.
      • Derbent M.
      • Ozbek N.
      Focal cerebral vasculitis and stroke after chickenpox.
      ,
      • Ichiyama T.
      • Houdou S.
      • Kisa T.
      • Ohno K.
      • Takeshita K.
      Varicella with delayed hemiplegia.
      ,
      • Shuper A.
      • Vining E.P.
      • Freeman J.M.
      Central nervous system vasculitis after chickenpox: Cause or coincidence?.
      ,
      • Caekebeke F.V.
      • Peters A.C.
      • Vandvik B.
      • Brouwer O.F.
      • de Bakker H.M.
      Cerebral vasculopathy associated with primary varicella infection.
      ] in the cerebrospinal fluid of patients with stroke and recent infection with Varicella zoster have been described. Herpes zoster ophthalmicus, associated with adult middle cerebral artery arteriopathy and stroke [
      • Kang J.H.
      • Ho J.D.
      • Chen Y.H.
      • Lin H.C.
      Increased risk of stroke after a Herpes zoster attack: A population-based follow-up study.
      ,
      • Nogueira R.G.
      • Sheen V.L.
      Images in clinical medicine: Herpes zoster ophthalmicus followed by contralateral hemiparesis.
      ,
      • Lin H.C.
      • Chien C.W.
      • Ho J.D.
      Herpes zoster ophthalmicus and the risk of stroke: A population-based follow-up study.
      ], has also been reported in children [
      • Hung P.Y.
      • Lee W.T.
      • Shen Y.Z.
      Acute hemiplegia associated with Herpes zoster infection in children: Report of one case.
      ,
      • Moriuchi H.
      • Rodriguez W.
      Role of Varicella-zoster virus in stroke syndromes.
      ,
      • Burbaud P.
      • Berge J.
      • Lagueny A.
      • et al.
      Delayed-onset hemidystonia secondary to Herpes zoster ophthalmicus-related intracerebral arteritis in an adolescent.
      ]. Biopsy specimens of a patient with postvaricella angiopathy revealed vasculitis with lymphocytic infiltration surrounded by macrophages [
      • Hayman M.
      • Hendson G.
      • Poskitt K.J.
      • Connolly M.B.
      Postvaricella angiopathy: Report of a case with pathologic correlation.
      ]. An autopsy in another patient revealed an immunohistochemistry positive for Varicella zoster in the affected vessel, with antigen deposition in the smooth muscle cell layer of the vessel wall [
      • Berger T.M.
      • Caduff J.H.
      • Gebbers J.O.
      Fatal Varicella-zoster virus antigen-positive giant cell arteritis of the central nervous system.
      ].
      Postvaricella angiopathy therefore represents a fourth possibility when considering unilateral large-vessel childhood arteriopathy syndrome. In terms of clinical presentation and imaging, postvaricella angiopathy is virtually indistinguishable from transient cerebral arteriopathy, except for the history of Varicella zoster infection within the (arguably arbitrary) preceding 12 months [
      • Sebire G.
      • Fullerton H.
      • Riou E.
      • deVeber G.
      Toward the definition of cerebral arteriopathies of childhood.
      ]. This natural history also parallels that of transient cerebral arteriopathy, with a monophasic course and the subsequent stabilization or improvement of arteriopathy over months [
      • Lanthier S.
      • Armstrong D.
      • Domi T.
      • deVeber G.
      Post-varicella arteriopathy of childhood: Natural history of vascular stenosis.
      ]. Consistent with selective proximal middle cerebral artery involvement, infarct patterns typically involve lenticulostriate territories [
      • Braun K.P.
      • Bulder M.M.
      • Chabrier S.
      • et al.
      The course and outcome of unilateral intracranial arteriopathy in 79 children with ischaemic stroke.
      ,
      • Chabrier S.
      • Rodesch G.
      • Lasjaunias P.
      • Tardieu M.
      • Landrieu P.
      • Sebire G.
      Transient cerebral arteriopathy: A disorder recognized by serial angiograms in children with stroke.
      ] and the proximal segments of the internal carotid artery and anterior cerebral artery, again sounding very much like transient cerebral arteriopathy, focal cerebral arteriopathy, and childhood primary angiitis of the central nervous system.
      Other infectious agents are less commonly associated with arteriopathic stroke in children. Fusiform aneurysms, focal arteriopathy, and stroke occur in children with human immunodeficiency virus [
      • Shah S.S.
      • Zimmerman R.A.
      • Rorke L.B.
      • Vezina L.G.
      Cerebrovascular complications of HIV in children.
      ,
      • Patsalides A.D.
      • Wood L.V.
      • Atac G.K.
      • Sandifer E.
      • Butman J.A.
      • Patronas N.J.
      Cerebrovascular disease in HIV-infected pediatric patients: Neuroimaging findings.
      ,
      • Narayan P.
      • Samuels O.B.
      • Barrow D.L.
      Stroke and pediatric human immunodeficiency virus infection: Case report and review of the literature.
      ], and vasculitis has been demonstrated pathologically in children with acquired immunodeficiency syndrome [
      • Joshi V.V.
      • Pawel B.
      • Connor E.
      • et al.
      Arteriopathy in children with acquired immune deficiency syndrome.
      ]. Isolated reports have associated neuroborreliosis [
      • Cox M.G.
      • Wolfs T.F.
      • Lo T.H.
      • Kappelle L.J.
      • Braun K.P.
      Neuroborreliosis causing focal cerebral arteriopathy in a child.
      ,
      • Heinrich A.
      • Khaw A.V.
      • Ahrens N.
      • Kirsch M.
      • Dressel A.
      Cerebral vasculitis as the only manifestation of Borrelia burgdorferi infection in a 17-year-old patient with basal ganglia infarction.
      ,
      • Klingebiel R.
      • Benndorf G.
      • Schmitt M.
      • von Moers A.
      • Lehmann R.
      Large cerebral vessel occlusive disease in Lyme neuroborreliosis.
      ], parvovirus B19 [
      • Guidi B.
      • Bergonzini P.
      • Crisi G.
      • Frigieri G.
      • Portolani M.
      Case of stroke in a 7-year-old male after parvovirus B19 infection.
      ,
      • Bilge I.
      • Sadikoglu B.
      • Emre S.
      • Sirin A.
      • Aydin K.
      • Tatli B.
      Central nervous system vasculitis secondary to parvovirus B19 infection in a pediatric renal transplant patient.
      ], influenza A [
      • Bell M.L.
      • Buchhalter J.R.
      Influenza A-associated stroke in a 4-year-old male.
      ], enterovirus [
      • Ribai P.
      • Liesnard C.
      • Rodesch G.
      • et al.
      Transient cerebral arteriopathy in infancy associated with enteroviral infection.
      ], and Mycoplasma pneumoniae [
      • Ovetchkine P.
      • Brugieres P.
      • Seradj A.
      • Reinert P.
      • Cohen R.
      An 8-y-old boy with acute stroke and radiological signs of cerebral vasculitis after recent Mycoplasma pneumoniae infection.
      ,
      • Parker P.
      • Puck J.
      • Fernandez F.
      Cerebral infarction associated with Mycoplasma pneumoniae.
      ,
      • Leonardi S.
      • Pavone P.
      • Rotolo N.
      • La R.M.
      Stroke in two children with Mycoplasma pneumoniae infection: A causal or casual relationship?.
      ] with focal cerebral arteriopathy and stroke in the pediatric population. Although such case reports and small series may suggest associations, we emphasize that these associations do not prove causation. These data only strengthen the need for further research into the influence of infections on the pathophysiology of arteriopathy and childhood stroke.
      Parainfectious or postinfectious mechanisms have also been implicated in childhood cerebral arteriopathy pathogenesis, whereby the activation of the immune system induced by common or specific infections increases stroke risk. Recent population-based studies demonstrated significant associations between recent infections and arterial strokes in children [
      • Amlie-Lefond C.
      • Bernard T.J.
      • Sebire G.
      • et al.
      Predictors of cerebral arteriopathy in children with arterial ischemic stroke: Results of the International Pediatric Stroke Study.
      ]. Previous case-control studies demonstrated an increased risk of stroke with preceding infection [
      • Syrjanen J.
      • Valtonen V.V.
      • Iivanainen M.
      • Kaste M.
      • Huttunen J.K.
      Preceding infection as an important risk factor for ischaemic brain infarction in young and middle aged patients.
      ,
      • Grau A.J.
      • Buggle F.
      • Heindl S.
      • et al.
      Recent infection as a risk factor for cerebrovascular ischemia.
      ,
      • Bova I.Y.
      • Bornstein N.M.
      • Korczyn A.D.
      Acute infection as a risk factor for ischemic stroke.
      ,
      • Grau A.J.
      • Buggle F.
      • Becher H.
      • et al.
      Recent bacterial and viral infection is a risk factor for cerebrovascular ischemia: Clinical and biochemical studies.
      ,
      • Paganini-Hill A.
      • Lozano E.
      • Fischberg G.
      • et al.
      Infection and risk of ischemic stroke: Differences among stroke subtypes.
      ]. The Vascular Effects of Infection in Pediatric Stroke Study, currently underway, was designed to test the hypothesis that infection predisposes children to arteriopathy, arterial ischemic stroke, and recurrence [
      • Fullerton H.J.
      • Elkind M.S.
      • Barkovich A.J.
      • et al.
      The Vascular Effects of Infection in Pediatric Stroke (VIPS) Study.
      ].

      Differential diagnosis

      Several other pediatric cerebral arteriopathies may present with similar clinical and radiographic appearance as the large vessel diseases described above. We present some examples of important disorders that need to be considered in the differential diagnosis of pediatric cerebral inflammatory arteriopathies. To distinguish between these syndromes is challenging, particularly when imaging characteristics may be similar, serologic markers are nonspecific, and presenting features are identical. Future advancements in the understanding of the pathophysiology and diagnostic strategies of inflammatory arteriopathies will aid in separating these disease entities.
      Dissection is an important cause of stroke in children, and may be more common intracranially compared with adults [
      • Mackay M.T.
      • Wiznitzer M.
      • Benedict S.L.
      • Lee K.J.
      • deVeber G.A.
      • Ganesan V.
      Arterial ischemic stroke risk factors: The International Pediatric Stroke Study.
      ,
      • Fullerton H.J.
      • Johnston S.C.
      • Smith W.S.
      Arterial dissection and stroke in children.
      ]. Recently, the importance of differentiating focal cerebral arteriopathy from intracranial dissection was made evident by the description of four patients with classic clinical focal cerebral arteriopathy presentations, but with definitive evidence (three pathologic, and one with detailed wall imaging) confirming intracranial dissection [
      • Dlamini N.
      • Freeman J.L.
      • Mackay M.T.
      • et al.
      Intracranial dissection mimicking transient cerebral arteriopathy in childhood arterial ischemic stroke.
      ]. Additional well defined or very distinct examples of childhood arteriopathies include moyamoya disease [
      • Scott R.M.
      • Smith E.R.
      Moyamoya disease and moyamoya syndrome.
      ], postradiation vasculopathy [
      • Omura M.
      • Aida N.
      • Sekido K.
      • Kakehi M.
      • Matsubara S.
      Large intracranial vessel occlusive vasculopathy after radiation therapy in children: Clinical features and usefulness of magnetic resonance imaging.
      ], and a variety of congenital arteriopathies [
      • Sebire G.
      • Fullerton H.
      • Riou E.
      • deVeber G.
      Toward the definition of cerebral arteriopathies of childhood.
      ]. Reversible cerebral vasoconstriction syndrome (also known as Call-Flemming syndrome) can occur in children [
      • Kirton A.
      • Diggle J.
      • Hu W.
      • Wirrell E.
      A pediatric case of reversible segmental cerebral vasoconstriction.
      ]. Fibromuscular dysplasias are probably different in children compared with adults, but are associated with arteriopathic stroke and historically may have been confused with focal cerebral arteriopathy [
      • Elbers J.
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ,
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ,
      • Benseler S.
      • Schneider R.
      Central nervous system vasculitis in children.
      ].
      Different disorders may mimic small-vessel vasculitis in children. Given the protean nature of both the clinical and imaging findings, broad categories must be considered, including demyelinating, toxic, metabolic, hypertensive, and other mechanisms. A difficult diagnostic distinction is rendered between small-vessel childhood primary angiitis of the central nervous system and the ever increasing number of autoimmune encephalitides. Patients may present with similar neurologic signs of headaches, personality changes, and other neurologic findings with a variety of lesions on imaging indistinguishable from small-vessel childhood primary angiitis of the central nervous system. Patients with autoimmune encephalitis will exhibit normal cerebral angiograms and different serum biomarkers or brain biopsy pathology [
      • Wells E.M.
      • Dalmau J.
      Paraneoplastic neurologic disorders in children.
      ]. A variety of systemic vasculitides and collagen vascular disease can present with a small-vessel central nervous system vasculitis [
      • Elbers J.
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ,
      • Benseler S.
      • Schneider R.
      Central nervous system vasculitis in children.
      ]. As will be discussed, with the possibility of skipped lesions, a false-negative biopsy may occur in primary central nervous system vasculitis [
      • Lie J.T.
      Primary (granulomatous) angiitis of the central nervous system: A clinicopathologic analysis of 15 new cases and a review of the literature.
      ]. This possibility is minimized via lesional, full-thickness biopsies [
      • Elbers J.
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ,
      • Vollmer T.L.
      • Guarnaccia J.
      • Harrington W.
      • Pacia S.V.
      • Petroff O.A.
      Idiopathic granulomatous angiitis of the central nervous system: Diagnostic challenges.
      ].

      Diagnosis and investigations

      Imaging

      Neuroimaging (specifically, much improved cerebral vascular imaging modalities) has increased the sensitivity of detecting and defining the unique features of these arteriopathies. Readily available angiography, including computed tomography, magnetic resonance, and conventional modalities, confirm arteriopathy in most children with arterial ischemic stroke. Common features of stenosis, narrowing, or occlusion with luminal irregularities or other suggestions of arterial wall disease, without definitive evidence of dissection, often raise the consideration of inflammation. However, we emphasize that there are no validated imaging biomarkers of inflammation in childhood stroke.
      Without the availability of brain biopsy, the diagnosis of large/medium-vessel primary angiitis of the central nervous system according to the criteria of Calabrese et al. requires conventional cerebral angiography demonstrating findings of arteritis [
      • Calabrese L.H.
      • Furlan A.J.
      • Gragg L.A.
      • Ropos T.J.
      Primary angiitis of the central nervous system: Diagnostic criteria and clinical approach.
      ]. Conventional angiography is the preferred modality for demonstrating specific vascular abnormalities such as banding or striae in large/medium-vessel vasculitis or alternating areas of stenosis and dilatation in distal arterial beds in small-vessel childhood primary angiitis of the central nervous system (Fig 1B) [
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ,
      • Benseler S.
      • Schneider R.
      Central nervous system vasculitis in children.
      ]. Sensitivity is only moderate for predominantly distal, small-vessel disease [
      • Aviv R.I.
      • Benseler S.M.
      • deVeber G.
      • et al.
      Angiography of primary central nervous system angiitis of childhood: Conventional angiography versus magnetic resonance angiography at presentation.
      ]. Conventional angiography is very safe in pediatric populations [
      • Burger I.M.
      • Murphy K.J.
      • Jordan L.C.
      • Tamargo R.J.
      • Gailloud P.
      Safety of cerebral digital subtraction angiography in children: Complication rate analysis in 241 consecutive diagnostic angiograms.
      ], and should be considered among children with arterial ischemic stroke in whom a specific mechanism has not yet been determined.
      Less invasive vascular imaging modalities are preferable, particularly for the ongoing surveillance of fluctuating diseases with a high risk of recurrence. Magnetic resonance imaging and magnetic resonance angiography were evaluated in a single-center cohort study [
      • Aviv R.I.
      • Benseler S.M.
      • Silverman E.D.
      • et al.
      MR imaging and angiography of primary CNS vasculitis of childhood.
      ]. All patients with abnormal conventional angiography demonstrated abnormalities on magnetic resonance imaging at time of diagnosis if T2-weighted, fluid attenuated inversion recovery, and diffusion weighted imaging/apparent diffusion coefficient sequences were included. However, only 71% manifested magnetic resonance angiography abnormalities [
      • Aviv R.I.
      • Benseler S.M.
      • Silverman E.D.
      • et al.
      MR imaging and angiography of primary CNS vasculitis of childhood.
      ]. When comparing magnetic resonance angiography with conventional angiography, sensitivity and specificity amounted to 70% and 98%, respectively, in one study [
      • Aviv R.I.
      • Benseler S.M.
      • deVeber G.
      • et al.
      Angiography of primary central nervous system angiitis of childhood: Conventional angiography versus magnetic resonance angiography at presentation.
      ]. However, angiography-negative cases are well-documented, and are estimated at 16% in the pediatric population [
      • Aviv R.I.
      • Benseler S.M.
      • deVeber G.
      • et al.
      Angiography of primary central nervous system angiitis of childhood: Conventional angiography versus magnetic resonance angiography at presentation.
      ].
      The characteristics of parenchymal magnetic resonance imaging lesions in small-vessel cerebral vasculitis, although not specific for inflammation, may be helpful when combined with other clinical markers. Magnetic resonance imaging abnormalities are often present even in angiogram-negative cases [
      • Benseler S.M.
      • Silverman E.
      • Aviv R.I.
      • et al.
      Primary central nervous system vasculitis in children.
      ,
      • Benseler S.M.
      • deVeber G.
      • Hawkins C.
      • et al.
      Angiography-negative primary central nervous system vasculitis in children: A newly recognized inflammatory central nervous system disease.
      ,
      • Aviv R.I.
      • Benseler S.M.
      • Silverman E.D.
      • et al.
      MR imaging and angiography of primary CNS vasculitis of childhood.
      ]. Variability is great, but hallmark abnormalities may include supratentorial, asymmetric, and anterior circulation lesions of the white matter or deep gray structures, observed most commonly as T2/fluid attenuated inversion recovery hyperintensities [
      • Benseler S.M.
      • Silverman E.
      • Aviv R.I.
      • et al.
      Primary central nervous system vasculitis in children.
      ,
      • Aviv R.I.
      • Benseler S.M.
      • Silverman E.D.
      • et al.
      MR imaging and angiography of primary CNS vasculitis of childhood.
      ]. Imaging predictors of progressive vasculitis include multifocal, bilateral, and gray matter lesions, combined with multiple, bilateral, or distal vessel stenoses [
      • Benseler S.M.
      • Silverman E.
      • Aviv R.I.
      • et al.
      Primary central nervous system vasculitis in children.
      ]. Areas of restricted diffusion, observed on diffusion weighted imaging/apparent diffusion coefficient sequences, are reported in up to 60% in some series [
      • Benseler S.M.
      • Silverman E.
      • Aviv R.I.
      • et al.
      Primary central nervous system vasculitis in children.
      ,
      • Aviv R.I.
      • Benseler S.M.
      • Silverman E.D.
      • et al.
      MR imaging and angiography of primary CNS vasculitis of childhood.
      ]. Gadolinium enhancement is occasionally observed; hemorrhagic lesions are rare [
      • Benseler S.M.
      • deVeber G.
      • Hawkins C.
      • et al.
      Angiography-negative primary central nervous system vasculitis in children: A newly recognized inflammatory central nervous system disease.
      ,
      • Aviv R.I.
      • Benseler S.M.
      • Silverman E.D.
      • et al.
      MR imaging and angiography of primary CNS vasculitis of childhood.
      ]. These parenchymal abnormalities do not definitively exclude other possible diagnoses, and the lack of specificity further emphasizes the need for research into improved diagnostic strategies.
      Recently, various vessel-wall imaging techniques were used to describe arterial pathology in adult central nervous system vasculitis [
      • Kuker W.
      • Gaertner S.
      • Nagele T.
      • et al.
      Vessel wall contrast enhancement: A diagnostic sign of cerebral vasculitis.
      ,
      • Kuker W.
      Imaging of cerebral vasculitis.
      ,
      • Kuker W.
      Cerebral vasculitis: Imaging signs revisited.
      ,
      • Aoki S.
      • Hayashi N.
      • Abe O.
      • et al.
      Radiation-induced arteritis: Thickened wall with prominent enhancement on cranial MR images: Report of five cases and comparison with 18 cases of moyamoya disease.
      ,
      • Swartz R.H.
      • Bhuta S.S.
      • Farb R.I.
      • et al.
      Intracranial arterial wall imaging using high-resolution 3-tesla contrast-enhanced MRI.
      ]. These include high-resolution anatomic and blood-sensitive sequences that attempt to delineate pathologic processes within the vessel wall. Such approaches have yet to be validated and are not yet well described in children, but demonstrate excellent potential to address the pathophysiologic questions discussed here. Case reports of focal cerebral arteriopathy have suggested reversible wall enhancement [
      • Payne E.T.
      • Wei X.C.
      • Kirton A.
      Reversible wall enhancement in pediatric cerebral arteriopathy.
      ]. We recently described normal cerebral arterial wall enhancement that may assist in defining abnormal patterns in children with stroke [
      • Mineyko A.
      • Wei X.
      • Kirton A.
      Cerebrovascular enhancement on MRI in children.
      ,

      Mineyko A, Narendran A, Fritzler ML, Wei X, Schmeling H, Kirton A. Inflammatory biomarkers of pediatric focal cerebral arteriopathy. Neurology (in press).

      ]. Further studies in this area could provide additional noninvasive imaging biomarkers of inflammation or other processes, and could help delineate the evolution of disease over time and response to treatment.

      Serology

      Consistent with the isolated and primary nature of their condition, many children with cerebral arteriopathy do not manifest systemic inflammatory markers. However, mild nonspecific elevations may be observed [
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ]. Elevations in acute-phase reactants such as erythrocyte sedimentation rate, C-reactive protein, and von Willebrand factor are reported [
      • Lanthier S.
      • Lortie A.
      • Michaud J.
      • Laxer R.
      • Jay V.
      • deVeber G.
      Isolated angiitis of the CNS in children.
      ,
      • Gallagher K.T.
      • Shaham B.
      • Reiff A.
      • et al.
      Primary angiitis of the central nervous system in children: 5 cases.
      ,
      • Yaari R.
      • Anselm I.A.
      • Szer I.S.
      • Malicki D.M.
      • Nespeca M.P.
      • Gleeson J.G.
      Childhood primary angiitis of the central nervous system: Two biopsy-proven cases.
      ], although many studies suggest that such serum inflammatory markers are often normal [
      • Matsell D.G.
      • Keene D.L.
      • Jimenez C.
      • Humphreys P.
      Isolated angiitis of the central nervous system in childhood.
      ,
      • Lanthier S.
      • Lortie A.
      • Michaud J.
      • Laxer R.
      • Jay V.
      • deVeber G.
      Isolated angiitis of the CNS in children.
      ,
      • Gallagher K.T.
      • Shaham B.
      • Reiff A.
      • et al.
      Primary angiitis of the central nervous system in children: 5 cases.
      ,
      • Nishikawa M.
      • Sakamoto H.
      • Katsuyama J.
      • Hakuba A.
      • Nishimura S.
      Multiple appearing and vanishing aneurysms: Primary angiitis of the central nervous system: Case report.
      ]. A single-center retrospective study of 62 children with childhood primary angiitis of the central nervous system reported that elevations in erythrocyte sedimentation rate (51%) and C-reactive protein (74%) were common. The same study described proportions of elevated immunoglobulin G (35%) and anticardiolipin antibodies (44%), although antineutrophil cytoplasmic antibodies were normal. Inflammatory markers were not predictive of outcome, progression of disease, or type of vasculopathy [
      • Benseler S.M.
      • Silverman E.
      • Aviv R.I.
      • et al.
      Primary central nervous system vasculitis in children.
      ]. Elevations in antinuclear antibodies have been reported but are very nonspecific, whereas more distinctive antibody testing typically produces normal results [
      • Gallagher K.T.
      • Shaham B.
      • Reiff A.
      • et al.
      Primary angiitis of the central nervous system in children: 5 cases.
      ,
      • Yaari R.
      • Anselm I.A.
      • Szer I.S.
      • Malicki D.M.
      • Nespeca M.P.
      • Gleeson J.G.
      Childhood primary angiitis of the central nervous system: Two biopsy-proven cases.
      ]. Therefore, studies to date have failed to identify serologic biomarkers of vascular inflammation or other insights into childhood arterial ischemic stroke pathophysiology. Whether such unimpressive findings denote the weak biomarker of an inflammatory process, a secondary response to acute brain injury, or some other epiphenomenon remains to be determined.

      Cerebrospinal fluid

      Could direct sampling of spinal fluid provide more sensitive detection of pathophysiologic processes in pediatric cerebral arteriopathy? The postvaricella angiopathy story may provide the best, albeit limited, evidence. Isolated case reports of children with postvaricella angiopathy have indicated mild cerebrospinal fluid pleocytosis [
      • Moriuchi H.
      • Rodriguez W.
      Role of Varicella-zoster virus in stroke syndromes.
      ]. The detection of cerebrospinal fluid anti-Varicella zoster immunoglobulin G antibodies is more sensitive than testing for Varicella zoster DNA using the polymerase chain reaction, and some have suggested that the diagnosis can be excluded when cerebrospinal fluid is negative for both [
      • Nagel M.A.
      • Forghani B.
      • Mahalingam R.
      • et al.
      The value of detecting anti-VZV IgG antibody in CSF to diagnose VZV vasculopathy.
      ]. The use of an antibody index to better determine significant elevations of Varicella zoster antibodies in cerebrospinal fluid has also been suggested, e.g., (cerebrospinal fluid/serum anti-Varicella zoster-specific immunoglobulin G)/(cerebrospinal fluid/serum total immunoglobulin G) [
      • Hausler M.G.
      • Ramaekers V.T.
      • Reul J.
      • Meilicke R.
      • Heimann G.
      Early and late onset manifestations of cerebral vasculitis related to Varicella zoster.
      ]. With the exact role of Varicella zoster in childhood arteriopathy yet to be determined, these findings and other isolated cases of infection-associated arteriopathy [
      • Cox M.G.
      • Wolfs T.F.
      • Lo T.H.
      • Kappelle L.J.
      • Braun K.P.
      Neuroborreliosis causing focal cerebral arteriopathy in a child.
      ,
      • Heinrich A.
      • Khaw A.V.
      • Ahrens N.
      • Kirsch M.
      • Dressel A.
      Cerebral vasculitis as the only manifestation of Borrelia burgdorferi infection in a 17-year-old patient with basal ganglia infarction.
      ,
      • Klingebiel R.
      • Benndorf G.
      • Schmitt M.
      • von Moers A.
      • Lehmann R.
      Large cerebral vessel occlusive disease in Lyme neuroborreliosis.
      ,
      • Ribai P.
      • Liesnard C.
      • Rodesch G.
      • et al.
      Transient cerebral arteriopathy in infancy associated with enteroviral infection.
      ] at least suggest the means by which cerebrospinal fluid infectious biomarkers may be investigated in the future [
      • Fullerton H.J.
      • Elkind M.S.
      • Barkovich A.J.
      • et al.
      The Vascular Effects of Infection in Pediatric Stroke (VIPS) Study.
      ].
      Elevated opening pressures, pleocytosis, and increased levels of cerebrospinal fluid protein have also been described in both the large-vessel and small-vessel varieties of childhood primary angiitis of the central nervous system [
      • Lanthier S.
      • Lortie A.
      • Michaud J.
      • Laxer R.
      • Jay V.
      • deVeber G.
      Isolated angiitis of the CNS in children.
      ,
      • Elbers J.
      • Halliday W.
      • Hawkins C.
      • Hutchinson C.
      • Benseler S.M.
      Brain biopsy in children with primary small-vessel central nervous system vasculitis.
      ,
      • Yaari R.
      • Anselm I.A.
      • Szer I.S.
      • Malicki D.M.
      • Nespeca M.P.
      • Gleeson J.G.
      Childhood primary angiitis of the central nervous system: Two biopsy-proven cases.
      ], although these parameters are often normal [
      • Matsell D.G.
      • Keene D.L.
      • Jimenez C.
      • Humphreys P.
      Isolated angiitis of the central nervous system in childhood.
      ,
      • Lanthier S.
      • Lortie A.
      • Michaud J.
      • Laxer R.
      • Jay V.
      • deVeber G.
      Isolated angiitis of the CNS in children.
      ,
      • Gallagher K.T.
      • Shaham B.
      • Reiff A.
      • et al.
      Primary angiitis of the central nervous system in children: 5 cases.
      ,
      • Nishikawa M.
      • Sakamoto H.
      • Katsuyama J.
      • Hakuba A.
      • Nishimura S.
      Multiple appearing and vanishing aneurysms: Primary angiitis of the central nervous system: Case report.
      ]. A single-center, retrospective study of 62 children with childhood primary angiitis of the central nervous system described abnormal cerebrospinal fluid in 39% (9/23 with biosamples). Findings included a nonspecific or lymphocyte-predominant pleocytosis in 32%, and elevated protein in 32%. Oligoclonal bands were never evident. Cerebrospinal fluid markers did not demonstrate significant associations with outcomes, the progression of disease, or subtypes of vasculopathy [
      • Benseler S.M.
      • Silverman E.
      • Aviv R.I.
      • et al.
      Primary central nervous system vasculitis in children.
      ]. Similarly, as with the results reported for serologic markers, it is impossible to discern at this stage whether any changes in these cerebrospinal fluid parameters constitute indicators of an inflammatory process, a secondary response to acute brain injury, or other epiphenomena.

      Tissue pathology

      A definitive pathologic diagnosis of inflammation is often available in small-vessel childhood primary angiitis of the central nervous system, but postmortem samples from larger-vessel arteriopathies are rare. The typical pathologic description in adult small-vessel primary angiitis of the central nervous system involves granulomatous or nongranulomatous infiltration of the walls of arterioles and venules [
      • Calabrese L.H.
      • Furlan A.J.
      • Gragg L.A.
      • Ropos T.J.
      Primary angiitis of the central nervous system: Diagnostic criteria and clinical approach.
      ,
      • Lie J.T.
      Primary (granulomatous) angiitis of the central nervous system: A clinicopathologic analysis of 15 new cases and a review of the literature.
      ,
      • Vollmer T.L.
      • Guarnaccia J.
      • Harrington W.
      • Pacia S.V.
      • Petroff O.A.
      Idiopathic granulomatous angiitis of the central nervous system: Diagnostic challenges.
      ,
      • Panda K.M.
      • Santosh V.
      • Yasha T.C.
      • Das S.
      • Shankar S.K.
      Primary angiitis of CNS: Neuropathological study of three autopsied cases with brief review of literature.
      ]. Both forms can occur in the same patient, limiting the utility of the distinction between granulomatous and nongranulomatous [
      • Lie J.T.
      Primary (granulomatous) angiitis of the central nervous system: A clinicopathologic analysis of 15 new cases and a review of the literature.
      ,
      • Panda K.M.
      • Santosh V.
      • Yasha T.C.
      • Das S.
      • Shankar S.K.
      Primary angiitis of CNS: Neuropathological study of three autopsied cases with brief review of literature.
      ]. Lesions are also often focal, with a tendency for skipped lesions likely contributing to a significant false-negative biopsy rate [
      • Lie J.T.
      Primary (granulomatous) angiitis of the central nervous system: A clinicopathologic analysis of 15 new cases and a review of the literature.
      ]. The granulomatous form consists of a predominantly lymphocytic vasculitis, although various proportions of plasma cells, histiocytes, and giant cells have been described [
      • Lie J.T.
      Primary (granulomatous) angiitis of the central nervous system: A clinicopathologic analysis of 15 new cases and a review of the literature.
      ].
      Nongranulomatous, predominantly T-cell lymphocytic vasculitis of the small vessels in both lesional and nonlesional biopsies of angiography-negative childhood primary angiitis of the central nervous system has been described in children. Occasional macrophages, polymorphonuclear cells, and eosinophils may also be present. The vessels involved may be widely distributed, including the leptomeninges, cortical gray matter, white matter, or all three layers. Inflammatory infiltrates are typically observed, both intramurally and perivascularly [
      • Lanthier S.
      • Lortie A.
      • Michaud J.
      • Laxer R.
      • Jay V.
      • deVeber G.
      Isolated angiitis of the CNS in children.
      ,
      • Benseler S.M.
      • deVeber G.
      • Hawkins C.
      • et al.
      Angiography-negative primary central nervous system vasculitis in children: A newly recognized inflammatory central nervous system disease.
      ,
      • Elbers J.
      • Halliday W.
      • Hawkins C.
      • Hutchinson C.
      • Benseler S.M.
      Brain biopsy in children with primary small-vessel central nervous system vasculitis.
      ,
      • Yaari R.
      • Anselm I.A.
      • Szer I.S.
      • Malicki D.M.
      • Nespeca M.P.
      • Gleeson J.G.
      Childhood primary angiitis of the central nervous system: Two biopsy-proven cases.
      ]. Surrounding reactive changes are also common [
      • Elbers J.
      • Halliday W.
      • Hawkins C.
      • Hutchinson C.
      • Benseler S.M.
      Brain biopsy in children with primary small-vessel central nervous system vasculitis.
      ]. Granulomatous inflammatory vasculitis is more rarely described in children [
      • Nishikawa M.
      • Sakamoto H.
      • Katsuyama J.
      • Hakuba A.
      • Nishimura S.
      Multiple appearing and vanishing aneurysms: Primary angiitis of the central nervous system: Case report.
      ]. A full-thickness leptomeningeal-cortical biopsy, ideally localized to imaging-based evidence of disease, should be considered for confirmatory diagnoses or the exclusion of small-vessel childhood primary angiitis of the central nervous system [
      • Elbers J.
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ,
      • Vollmer T.L.
      • Guarnaccia J.
      • Harrington W.
      • Pacia S.V.
      • Petroff O.A.
      Idiopathic granulomatous angiitis of the central nervous system: Diagnostic challenges.
      ]. A definitive diagnosis is important in cases where long-term immunosuppressive treatment will be initiated, and future biopsy results may be compromised.
      One autopsy involving Varicella-associated angiopathy revealed granulomatous arteritis with multinuclear giant cells and a lymphocytic infiltrate of the vascular cell wall, and destruction of the internal elastic lamina. Staining for Varicella zoster produced positive results, with the deposition of Varicella zoster antigen in the smooth muscle cell layer [
      • Berger T.M.
      • Caduff J.H.
      • Gebbers J.O.
      Fatal Varicella-zoster virus antigen-positive giant cell arteritis of the central nervous system.
      ]. The biopsy of a patient with postvaricella angiopathy revealed a lymphocytic arteriopathy of the small vessels, but no viral inclusions and a polymerase chain reaction negative for Varicella zoster. However, for obvious reasons, the affected large vessel was not included in the biopsy [
      • Hayman M.
      • Hendson G.
      • Poskitt K.J.
      • Connolly M.B.
      Postvaricella angiopathy: Report of a case with pathologic correlation.
      ].
      No animal models of pediatric cerebral arteriopathies are yet available.

      Disease-specific inflammatory markers

      As already demonstrated, the diagnosis of primary central nervous system vasculitis is often difficult, because diverse clinical presentations are coupled with insensitive and nonspecific serologic and cerebrospinal fluid biomarkers. Imaging, although steadily improving, may be normal or nonspecific, particularly in small-vessel vasculitis, whereas tissue-based diagnoses are invasive or impossible. Therefore, the search for more specific and sensitive diagnostic markers continues. The overlapping goals are twofold: (1) to provide novel insights into disease pathophysiology, especially the role of specific disease mechanisms such as inflammation; and (2) to help guide clinical care, including appropriate treatment options, prognoses, and surveillance over time.
      Several avenues have been explored, but results to date are limited. Cerebrospinal fluid neurofilament and glial fibrillary acidic protein was elevated in the cerebrospinal fluid of 32 adult patients with central nervous system vasculitis, compared with control subjects [
      • Nylen K.
      • Karlsson J.E.
      • Blomstrand C.
      • Tarkowski A.
      • Trysberg E.
      • Rosengren L.E.
      Cerebrospinal fluid neurofilament and glial fibrillary acidic protein in patients with cerebral vasculitis.
      ]. Studies evaluating biomarkers in pediatric stroke are also scarce. One study suggested elevated D-dimers and C-reactive protein in childhood arterial ischemic stroke [
      • Bernard T.J.
      • Fenton L.Z.
      • Apkon S.D.
      • et al.
      Biomarkers of hypercoagulability and inflammation in childhood-onset arterial ischemic stroke.
      ], whereas another suggested differences in more specific inflammatory proteins such as tumor necrosis factor-α, interleukin-2, interleukin-6, and interleukin-8 [
      • Yururer D.
      • Teber S.
      • Deda G.
      • Egin Y.
      • Akar N.
      The relation between cytokines, soluble endothelial protein C receptor, and factor VIII levels in Turkish pediatric stroke patients.
      ]. We recently demonstrated the potential of multiplex assay platforms (Eve Technologies, Calgary, AB, Canada) to compare dozens of inflammatory biomarkers among children with focal cerebral arteriopathy and cardioembolic stroke and control subjects [

      Mineyko A, Narendran A, Fritzler ML, Wei X, Schmeling H, Kirton A. Inflammatory biomarkers of pediatric focal cerebral arteriopathy. Neurology (in press).

      ]. Further studies will require careful differentiation between primary stroke mechanisms such as inflammation and secondary responses to brain injury and illness.
      Further indirect evidence of inflammatory pathophysiology in pediatric stroke can be gleaned from genetic studies. One case-control study reported a higher incidence of single-nucleotide polymorphisms in the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene among children with idiopathic stroke compared with control subjects [
      • Wang J.J.
      • Jiang L.Q.
      • He B.
      • Shi K.L.
      • Li J.W.
      • Zou L.P.
      The association of CTLA-4 and CD28 gene polymorphisms with idiopathic ischemic stroke in the paediatric population.
      ].

      Treatment: Implications and options

      The possible but unproven role of inflammation in children with stroke and cerebral arteriopathy raises difficult treatment issues. Pediatric stroke consensus guidelines acknowledge the possibility of considering anti-inflammatory or immunosuppressive interventions, but offer little direction [
      • Roach E.S.
      • Golomb M.R.
      • 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 and the Council on Cardiovascular Disease in the Young.
      ]. Perhaps the single largest factor involves the questionable classification of disease, as already described. Definitive or suggestive evidence of inflammation in childhood primary angiitis of central nervous system syndromes, coupled with generally favorable short-term side-effect profiles, appears to make anti-inflammatory interventions such as corticosteroids very appealing. In contrast, the lack of certainty surrounding transient cerebral arteriopathy or focal cerebral arteriopathy pathophysiology, or even then possibility of “active” infection in postvaricella angiopathy, may strongly influence some to avoid immunosuppressive or otherwise potentially toxic treatments.
      The added certainty of biopsy-proven inflammation and an often chronic and recurring course has led some with extensive experience in small-vessel childhood primary angiitis of the central nervous system to suggest immunomodulatory intervention. Possible protocols include a combination of 6 months of treatment-dose steroids coupled with monthly pulses of intravenous cyclophosphamide (500-750 mg/m2), followed by maintenance with azathioprine (2 mg/kg) plus low-dose steroids for an additional 18 months [
      • Elbers J.
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ,
      • Lanthier S.
      • Lortie A.
      • Michaud J.
      • Laxer R.
      • Jay V.
      • deVeber G.
      Isolated angiitis of the CNS in children.
      ,
      • Benseler S.M.
      • deVeber G.
      • Hawkins C.
      • et al.
      Angiography-negative primary central nervous system vasculitis in children: A newly recognized inflammatory central nervous system disease.
      ]. Case reports of other immunomodulatory therapies such as methotrexate or mycophenolate mofetil for longer-term maintenance have been reported [
      • Gallagher K.T.
      • Shaham B.
      • Reiff A.
      • et al.
      Primary angiitis of the central nervous system in children: 5 cases.
      ,
      • Benseler S.
      • Schneider R.
      Central nervous system vasculitis in children.
      ,
      • Yaari R.
      • Anselm I.A.
      • Szer I.S.
      • Malicki D.M.
      • Nespeca M.P.
      • Gleeson J.G.
      Childhood primary angiitis of the central nervous system: Two biopsy-proven cases.
      ]. Evidence for intravenous immunoglobulin in any variety of childhood strokes is lacking, perhaps partly because of the increased risk of thrombosis [
      • Katz U.
      • Shoenfeld Y.
      • Zandman-Goddard G.
      Update on intravenous immunoglobulins (IVIG) mechanisms of action and off-label use in autoimmune diseases.
      ].
      The immunosuppressive treatment of focal cerebral arteriopathy or transient cerebral arteriopathy is much less certain, with minimal data available regarding safety or efficacy, and a limited ability to distinguish progressive from transient cases. However, focal cerebral arteriopathy demonstrates measurable mortality, often extensive morbidity, and a high risk of early stroke recurrence, all of which emphasize an imperative need to define effective therapies. A treatment course of high-dose steroids for a duration of 3 months has been suggested [
      • Elbers J.
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ]. For progressive forms of large-vessel childhood primary angiitis of the central nervous system, protocols comparable to those for small-vessel childhood primary angiitis of the central nervous system methods, including high-dose steroids for 6 months followed by maintenance with oral mycophenolate mofetil or azathioprine for 18 months [
      • Elbers J.
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ,
      • Bitter K.J.
      • Epstein L.G.
      • Melin-Aldana H.
      • Curran J.G.
      • Miller M.L.
      Cyclophosphamide treatment of primary angiitis of the central nervous system in children: Report of 2 cases.
      ], have been suggested. We emphasize that the dose-dependent toxicities of these agents are generally well established through other uses in children, whereas steroids are unlikely to be harmful in adults with stroke [
      • Sandercock P.A.
      • Soane T.
      Corticosteroids for acute ischaemic stroke.
      ].
      The treatment of postvaricella angiopathy also remains controversial. Patients with postvaricella angiopathy have been treated with short-course pulses of intravenous methylprednisolone and a 2-week course of acyclovir [
      • Amlie-Lefond C.
      • Fullerton H.J.
      Rashes, sniffles, and stroke: A role for infection in ischemic stroke of childhood.
      ,
      • Alehan F.K.
      • Boyvat F.
      • Baskin E.
      • Derbent M.
      • Ozbek N.
      Focal cerebral vasculitis and stroke after chickenpox.
      ,
      • Kramer L.A.
      • Villar-Cordova C.
      • Wheless J.W.
      • Slopis J.
      • Yeakley J.
      Magnetic resonance angiography of primary varicella vasculitis: Report of two cases.
      ]. Others reported that acute antiviral treatment may not be necessary [
      • Askalan R.
      • Laughlin S.
      • Mayank S.
      • et al.
      Chickenpox and stroke in childhood: A study of frequency and causation.
      ,
      • Lanthier S.
      • Armstrong D.
      • Domi T.
      • deVeber G.
      Post-varicella arteriopathy of childhood: Natural history of vascular stenosis.
      ]. Acyclovir suppresses active viral replication and may exert no effect on the autoimmune reaction to dormant virus [
      • Hausler M.G.
      • Ramaekers V.T.
      • Reul J.
      • Meilicke R.
      • Heimann G.
      Early and late onset manifestations of cerebral vasculitis related to Varicella zoster.
      ]. A review of antiviral and immunosuppressive treatments in varicella-associated stroke indicated no benefit, because most patients recovered almost completely regardless of therapy [
      • Moriuchi H.
      • Rodriguez W.
      Role of Varicella-zoster virus in stroke syndromes.
      ].
      Regardless of the presence of inflammation, the basic principles of childhood stroke care are established, including antithrombotic therapy in most patients and supportive neuroprotective care [
      • Elbers J.
      • Benseler S.M.
      Central nervous system vasculitis in children.
      ,
      • Benseler S.M.
      • deVeber G.
      • Hawkins C.
      • et al.
      Angiography-negative primary central nervous system vasculitis in children: A newly recognized inflammatory central nervous system disease.
      ,
      • Benseler S.
      • Schneider R.
      Central nervous system vasculitis in children.
      ]. An improved understanding of more specific disease mechanisms should advance therapeutic options and their testing through clinical trials.

      Conclusions

      Arteriopathy causes most strokes in children, and most of these strokes involve focal arteriopathies of an unknown mechanism. Inflammation and vasculitis constitute popular considerations that, although unproven in most cases, carry important implications for current treatment approaches and future research directions.

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