Childhood central nervous system vasculitis

Handbook of Clinical Neurology, Vol. 112 (3rd series) Pediatric Neurology Part II O. Dulac, M. Lassonde, and H.B. Sarnat, Editors © 2013 Elsevier B.V. All rights reserved

Chapter 108

Childhood central nervous system vasculitis SUSANNE BENSELER1* AND DANIELA POHL2 Division of Rheumatology, Department of Pediatrics, University of Toronto and Child Health Evaluative Sciences, Research Institute, Hospital for Sick Children, Toronto, Canada

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Department of Neurology, Faculty of Medicine, University of Ottawa, Children’s Hospital of Eastern Ontario, Ottawa, Canada

INTRODUCTION Childhood central nervous system (CNS) vasculitis encompasses a group of newly recognized inflammatory brain diseases (Benseler et al., 2006a). Childhood primary angiitis of the CNS (cPACNS) is an inflammatory disease solely targeting the blood vessels within the CNS, including brain and spinal cord, in the absence of an underlying systemic disease. Childhood CNS vasculitis can also occur in the context of a systemic illness. So-called secondary CNS vasculitis is found in rheumatological and systemic inflammatory diseases, infections, and malignancies. The clinical presentation of CNS vasculitis encompasses newly acquired neurological deficits that can be devastating, including stroke, seizures, movement disorder, optic neuritis, or progressive cognitive decline. Headaches or psychiatric manifestations including hallucinations, autistic features, or other behavior changes and mood disturbances may be present (Yaari et al., 2004; Benseler et al., 2005). Awareness and early recognition of CNS vasculitis are crucial in view of its treatable nature; yet it is challenging, given the paucity of diagnostic tools and the oftentimes invasive diagnostic approaches. Early disease recognition with rapid initiation of immunosuppressive treatment can lead to significant improvement or even complete resolution of neurological deficits.

PRIMARY CNS VASCULITIS History and terminology In 1922, Harbitz published the first description of angiitis of the CNS (Harbitz, 1922). In 1959, Cravioto and Feigin

first identified a distinct clinical entity in a series of adult patients, which we now recognize as primary angiitis of the CNS (PACNS). In 1988, Leonard Calabrese first reported a single-center experience of eight adult patients and summarized the published literature (Calabrese and Mallek, 1988). He streamlined the terminology for what was known as isolated CNS angiitis, idiopathic granulomatous angiitis of the CNS, CNS vasculopathy, and CNS vasculitis. In 1992 Calabrese first defined adult primary angiitis of the CNS and coined the term PACNS. The Calabrese criteria for the diagnosis of PACNS mandate a newly acquired neurological deficit and angiographic or histological features of CNS vasculitis in the absence of a significant underlying condition or identifiable, known cause of CNS vasculopathy or vasculitis (Calabrese et al., 1992). The criteria have not been prospectively validated elsewhere. Nevertheless they are widely used in both adult and childhood PACNS (cPACNS).

Epidemiology The incidence of CNS vasculitis is unknown. Epidemiological studies are difficult due to the inconsistent terminology and diagnostic challenges. Patients may be primarily diagnosed based on their presenting symptom such as stroke or intractable seizures rather than the underlying etiology of primary CNS vasculitis. In children, CNS vasculitis was previously considered a very rare disease. In the past, cases were predominantly identified on autopsies (Matsell et al., 1990; Nishikawa et al., 1998; Benseler and Schneider, 2004). Since 2001, several pediatric case series have been reported resulting

*Correspondence to: Susanne Benseler, Associate Scientist, Child Health Evaluative Sciences, Research Institute, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G1X8, Canada. Tel: þ1-416-813-7711, Fax: þ1-416-813-4989, E-mail: [email protected]

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in increasing awareness of this disease (Gallagher et al., 2001; Lanthier, 2002; Yaari et al., 2004; Benseler et al., 2005). Rising recognition may prove an incidence much higher than initially presumed. Recently, Amlie-Lefond suggested that cerebral arteriopathies might account for up to 80% of childhood stroke in otherwise healthy children (Amlie-Lefond et al., 2008).

Pathology Primary CNS vasculitis is an inflammatory brain and spinal cord disease, in which the immune attack solely targets the cerebral vessel wall (Salvarani et al., 2008). Brain biopsies demonstrate a lymphocytic infiltrate in the vessel wall and a vasocentric infiltrate surrounding the cerebral vessel, distinctly different from the patchy, parenchymal infiltrates of demyelinating diseases (Benseler et al., 2006a; Venkateswaran et al., 2008; Myung et al., 2009). Endothelial cells commonly show accompanying reactive changes. Tubulo-reticular inclusion can be detected on electron microscopy of affected endothelial cells (Elbers et al., 2010). In contrast to adults, granulomatous CNS vessel inflammation is very rare in children (Benseler and Schneider, 2004). The inflammatory attack can target vessels of different sizes. Based on the vessel size involved, childhood CNS vasculitis is commonly divided into large–medium size vessel vasculitis, also known as angiography positive cPACNS, and small vessel cPACNS, a disease that affects small muscular arteries, arterioles, capillaries, and venules with a vessel diameter too small to be depicted by magnetic resonance angiography (MRA) or conventional angiography (CA). The diagnosis of large–medium cPACNS is commonly based on angiography, whereas small vessel cPACNS is diagnosed via elective brain biopsy (Benseler et al., 2005). Brain biopsies of children with large–medium cPACNS are not recommended since they are frequently inconclusive, merely demonstrating ischemic brain tissue. Patients commonly have either of the two vessel sizes involved. In children with secondary CNS vasculitis rare cases of overlaps have been reported (Berger et al., 2000; Holl-Wieden et al., 2006).

Large–medium vessel cPACNS The inflammatory attack is most commonly directed toward the proximal large cerebral vessel wall causing vessel wall inflammation, edema, wall thickening, and activation of the endothelium. The angiographic correlate of this attack is vessel stenosis. In inflamed segments the lumen narrows; the vessel appears irregular on angiography, which is often described as “beading” or “string of beads.” Inflammation of proximal large– medium blood vessels can cause critically decreased

blood supply of the vessel territory, and subsequent arterial ischemic strokes. Children with large–medium vessel cPACNS typically present with transient ischemic attacks, followed by acute strokes. The hemiparesis, gait abnormalities, hemisensory deficits, or fine motor deficits frequently wax and wane over the first days. The middle cerebral artery is most commonly affected, followed by the anterior cerebral artery and the distal internal carotid artery. Movement abnormalities such as ataxia are seen in children with posterior cerebral vessel inflammation. Headaches and, especially in younger patients, temper tantrums are frequently reported at diagnosis of cPACNS. Diffuse neurological deficits such as neurocognitive dysfunction are less commonly seen; however, they have been found to correlate with progressive cerebrovascular disease (Benseler et al., 2006a). Children presenting with a newly acquired neurological deficit require a rapid workup for inflammatory brain diseases, including inflammatory markers, autoantibodies, a prothrombotic workup, and cerebrospinal fluid (CSF) analyses (see Table 108.1). Inflammatory markers are unreliable in large–medium vessel cPACNS (Benseler et al., 2006a). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), C3 complement levels, and complete blood count abnormalities are oftentimes subtle and lack both sensitivity and specificity. More than 50% of children with large–medium vessel cPACNS have normal or near normal inflammatory markers (Benseler et al., 2006a). Antiphospholid antibodies and lupus anticoagulant can be transiently raised; however, their pathogenetic role remains controversial (Levy et al., 2003; Lanthier et al., 2004). Novel markers such as von Willebrand factor antigen require further evaluation in cPACNS (Bleil et al., 1991; Hoffman and Ahmed, 1998). Only one-third of children with large–medium vessel cPACNS have CSF pleocytosis or elevated CSF protein. Lumbar puncture opening pressure elevation may be a sensitive marker of CNS vasculitis and warrants further studies. CSF oligoclonal IgG is commonly absent (Benseler et al., 2006a). Neurotropic virus assessment with serology and CSF PCR, including varicella-zoster virus, is mandatory to identify infectious causes of vasculitis (Table 108.2). Normal inflammatory markers and CSF results do not rule out the diagnosis of cPACNS. Neuroimaging is mandatory for diagnosing cPACNS. Computed tomography (CT) scans lack sensitivity for inflammatory lesions, and only larger ischemic lesions are visualized (Aviv et al., 2006). MRI, MRA, and CA are the diagnostic modalities of choice for cPACNS. Children with large–medium vessel cPACNS typically have focal areas of acute ischemia or inflammation in vascular territories. These lesions are best viewed on

CHILDHOOD CENTRAL NERVOUS SYSTEM VASCULITIS Table 108.1 Laboratory workup for suspected childhood inflammatory brain diseases Markers of inflammation/disease activity Erythrocyte sedimentation rate C-reactive protein Complete blood count Immunoglobulin G Complement C3 Von Willebrand factor antigen Autoantibodies Antinuclear antibodies Extractable nuclear antigens (ENA) if ANA positive Double-stranded DNA antibodies Rheumatoid factor Antineutrophil cytoplasmic antibodies (cANCA, pANCA) Anticardiolipin antibodies Prothrombotic workup Protein C Protein S Activated Protein C Anti-thrombin III Fibrinogen Plasminogen Homocysteine Factor V Leiden gene mutation MTHFR gene mutation Prothrombin gene mutation Lupus anticoagulant Cerebrospinal fluid analysis Opening pressure Cell count Protein Glucose Cytology Oligoclonal IgG Lactate Amino acids Infectious workup Bacterial cultures, Gram stain Tuberculosis (Tb) tests (Tb cultures, PCR, possibly additional tests) Viral cultures Varicella-zoster IgG ratio (CSF to serum) and PCR Other specific serologies and PCRs (consider regional differences, see Table 108.2) CNS antibodies (in serum and CSF) Suspected neuromyelitis optica: ● Aquaporin-4 antibodies Suspected NMDA-R encephalitis: ● NMDA receptor NR1/NR2 heteromer antibodies Suspected immune-mediated limbic encephalitis: ● Voltage-gated potassium channels (VGKC) antibodies ● Glutamic acid decarboxylase (GAD) antibodies GABA(B1) or GABA(B2) receptor antibodies

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T2/FLAIR (fluid-attenuated recovery) sequences. T2 hyperintensities are more frequently unilateral and multifocal, involving both white and gray matter (Aviv et al., 2006). Wall thickening and intramural contrast uptake are characteristic findings in patients with active cerebral vasculitis affecting large arteries (Kuker et al., 2008). Diffusion-weighted imaging (DWI) can help in differentiating acute from old areas of ischemia. Conventional angiography and MRA visualize characteristic features of large–medium cPACNS-like proximal vessel stenosis, vessel tortuosity, beading, and less commonly occlusions (Aviv et al., 2007). The most commonly affected vascular territories are the lenticulostriate branches/perforator arteries of the anterior circulation due to upstream stenoses of the proximal middle cerebral artery. Involvement of the anterior circulation occurs more frequently than of the posterior circulation (Aviv et al., 2007). MRA is an excellent screening tool for proximal vessel stenosis and is equally sensitive for detecting large–medium vessel disease in cPANCS when compared to conventional angiography (Aviv et al., 2007). However, conventional angiography is superior to MRA with regard to providing a dynamic view of the vasculature including areas of low flow, collaterals, possible artery-to-artery embolism sources and distal narrowing, thereby identifying brain areas at risk for (re-)stroke. Furthermore, conventional angiography identifies characteristic features of noninflammatory vasculopathies such as dissections. CT angiography can also be used to detect flow patterns and characterize vessel wall changes; however, it has the disadvantage of substantial radiation exposure attached to each study. The treatment of large–medium vessel cPACNS remains controversial. In a large single-center study, baseline predictors for progressive large–medium vessel cPACNS (associated with significantly increased risk for further vessel narrowing and development of new stenoses at  3 months of disease) were established (Benseler et al., 2006b). In this study, children presenting with neurocognitive dysfunction, bilateral MRI lesions, or distal arterial stenoses were at significantly higher risk for disease progression (Benseler et al., 2006b). Patients with these risk factors should therefore be considered as progressive cPACNS and be treated with immunosuppressive medication in addition to anticoagulation (Barron et al., 1993). Adequately treated, these children appear to have a very low risk for recurrence of stroke or other symptoms. In a recent retrospective study, 45% of children with large–medium vessel vasculitis made a full neurological recovery, and all of these had been treated with immunosuppressants (Benseler et al., 2006a). The proposed cPACNS induction–maintenance protocol for progressive large–medium vessel vasculitis includes: (1) induction: seven monthly pulses of intravenous

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Table 108.2 Secondary childhood CNS vasculitides, CNS vasculitis mimics, and inflammatory brain diseases in children Inflammatory conditions Collagen vascular diseases Systemic lupus erythematosus Behc¸et syndrome Sj€ ogren syndrome Juvenile dermatomyositis Scleroderma/morphea Sarcoidosis Systemic vasculitides Henoch–Schonlein purpura Kawasaki disease Polyarteritis nodosa ANCA-associated vasculitides Wegener’s granulomatosis Microscopic polyarteritis Churg–Strauss syndrome Infectious/postinfectious Bacterial Streptococcus pneumoniae Salmonella species Mycoplasma pneumoniae Mycobacterium tuberculosis Treponema pallidum Borrelia burgdorferi Viral Varicella-zoster virus Cytomegalovirus Epstein–Barr virus Human immunodeficiency virus Hepatitis C virus Parvovirus B19 Enterovirus West Nile virus JC virus Fungal Actinomycosis

Candida albicans Aspergillus Cryptococcus Systemic inflammatory diseases Autoinflammatory syndromes (periodic fever syndromes) Inflammatory bowel disease Celiac disease Other Malignancy/graft-versus-host disease Radiation vasculopathy Drug-induced vasculopathy Immunodeficiencies Hemophagocytic lymphohistocytosis Inflammatory brain diseases Demyelinating diseases Acute demyelinating encephalomyelitis (ADEM) Multiple sclerosis Optic neuritis T cell-associated inflammatory brain diseases Rasmussen’s encephalitis Antibody-associated inflammatory brain diseases NMDA-R encephalitis Neuromyelitis optica Limbic encephalitis Mimics Fibromuscular dysplasia Dissection Vasospasmus/migraine Reversible vasconstrictive syndromes (RVS) Channelopathies Moyamoya disease (primary/secondary) Hemoglobin disorders Thrombi/emboli

cyclophosphamide (500–750 mg/m2) in addition to highdose daily oral corticosteroids, followed by (2) maintenance: an 18-month protocol with oral mycophenolate mofetil (MMF) while tapering the corticosteroids and discontinuing at 13 months. Patients also receive anticoagulation and/or antiplatelet therapy depending on their individual characteristics. Prospective trials are required to evaluate this protocol. Children with nonprogressive cPACNS have extensive commonalities with patients diagnosed with transient cerebral angiopathy (Braun et al., 2009) and postvaricella angiopathy (Lanthier et al., 2005). A new unifying terminology is currently being developed. The inflammatory nature of those disorders can be confirmed by serial images (see Fig. 108.1) and by vessel wall

imaging techniques (Fig. 108.2) (Kuker et al., 2008). The treatment of nonprogressive cPACNS varies from center to center. Commonly children are treated with anticoagulation (Braun et al., 2009). In patients with high-degree proximal vessel stenosis or evidence of thrombus, heparin is started. In the absence of a thrombus or a high-risk profile for thrombus formation, an antiplatelet agent may be preferred. There appears to be a role for a short course of immunosuppression in nonprogressive cPACNS. In a recent retrospective series, patients received a 3-month course of high-dose steroids, in addition to anticoagulation, which decreased the recurrence risk of ischemic events (Soon et al., 2008). Larger prospective studies need to be conducted. Of note: a small percentage of children with non-progressive cPACNS do

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Fig. 108.1. Nonprogressive primary CNS vasculitis (NP-cPACNS) in a 4-year-old previously healthy child presenting with headache and stroke: magnetic resonance (MR) angiography (A), conventional angiography (B), T2 sequences (C), and DWI (D) of magnetic resonance imaging (MRI) study at time of diagnosis of NP-cPACNS.

Fig. 108.2. Gadolinium contrast enhancement of the inflamed vascular wall in nonprogressive childhood primary CNS vasculitis (NP-cPACNS): magnetic resonance imaging (MRI) coronal T1 sequences demonstrate narrow caliber of left distal internal carotid artery and proximal anterior and medial cerebral artery (A). Post-gadolinium MRI sequences reveal contrast enhancement of the thickened vascular wall in the affected segments (B).

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in fact progress beyond 3 months and have to be re-classified as having progressive cPACNS. Monitoring of patients with large–medium vessel cPACNS includes standardized clinical evaluation, inflammatory markers, and neuroimaging at 3–6-month intervals. The Pediatric Stroke Outcome Measure (PSOM) is a validated clinical assessment tool (deVeber et al., 2000). It captures focal and diffuse neurological deficits and their functional impact in children with stroke and cPACNS (Benseler et al., 2006a). Neurocognitive testing should be performed at baseline and yearly thereafter. The natural history of “transient cerebral arteriopathy (TCA)” or “post-varicella angiopathy (PVA)” has been reported (Lanthier et al., 2005; Braun et al., 2009). Similar to nonprogressive cPACNS these diseases are considered monophasic and, by definition, nonprogressive. However, they are not transient with regard to their impact: only 31% of patients had a complete neurological recovery in a recent large single-center study (Benseler et al., 2006a). Askalan reported re-stroke rates of 45%, and only 32% of children were described to make a full neurological recovery (Askalan et al., 2001). Fullerton reported a 5-year cumulative stroke recurrence rate of 66% in children with vascular stenosis (Fullerton et al., 2007). Children with nonprogressive cPACNS similar to PVA/TCA patients appear to have devastating early recurrence rates of stroke and severe neurological long-term disability. Further studies are necessary to evaluate the impact of treatment and to identify prognostic indicators for recovery. Children with large–medium vessel cPACNS have a low risk of disease recurrence or flares, once treated appropriately according to disease category (Cantez and Benseler, 2008). The chance for complete recovery, however, depends on the extent of the initial injury, the recurrence of strokes (Fullerton et al., 2007), and likely a number of other variables that need to be determined. Treatment suppresses inflammation, thereby decreasing recurrence risk and disease progression, but does not reverse ischemic neurological deficits. Due to the often extensive area of ischemic damage from large–medium vessel disease, there is a lesser chance of complete recovery when compared to small vessel cPACNS.

Small vessel cPACNS Inflammation solely affecting the small vessels of the CNS is a novel disease entity in children. Brain vessel inflammation causes devastating neurological and psychiatric deficits. In 2001, Lanthier reported two pediatric cases of primary or isolated CNS angiitis and reviewed the published literature (Lanthier et al., 2001). He was the first to suggest two distinct subgroups of children with cPACNS, one of which had a normal cerebral angiography including one of the two new cases.

Subsequently, the Toronto cohort was reported to include a series of four girls who had negative conventional and MR angiographies with brain biopsies confirming the diagnosis of CNS vasculitis affecting exclusively small arteries (Benseler et al., 2005). Following these initial publications, disease recognition has increased, as demonstrated by a number of published case reports and case series (Elbers and Benseler, 2008; Myung et al., 2009). Children with small vessel cPACNS may have some overlapping clinical features with large–medium vessel cPACNS, such as focal neurological deficits including hemiparesis or ataxia often developing over time. However, small vessel cPACNS patients usually present with distinct features, like diffuse neurological deficits and neuropsychiatric manifestations such as cognitive decline, decrease in school performance, or behavior changes. Headaches and concentration difficulties are commonly reported. Higher executive functioning is frequently impaired. Seizures can evolve; some children are diagnosed only when admitted in status epilepticus, often therapy-refractory. Optic neuritis or spinal cord inflammatory symptoms such as partial or transverse myelitis can be present at diagnosis, at times leading to a misdiagnosis of inflammatory demyelinating disease. Usually those patients would not respond to disease-modifying treatments like interferons or glatiramer acetate or have atypical associated findings such as severe headaches or meningeal enhancement on MRI. Small vessel cPACNS patients can present with systemic features including fever, malaise, and flu-like symptoms. Meningitis or encephalitis are common initial misdiagnoses in children with small vessel cPACNS. Overall, children often demonstrate a subacute progression of symptoms over weeks to months. Acute presentations, although less common, occur in the form of intractable seizures or meningitis/encephalitis-like presentations and require a rapid diagnostic workup including biopsies in order to enable timely initiation of treatment with the goal of preventing further brain damage. In contrast to large–medium vessel cPACNS, the majority of children with small vessel disease have elevated inflammatory markers. CRP, ESR, and leukocytes are commonly moderately elevated. Anemia and raised platelet counts can be found. C3 complement and the vWF antigen level may be increased. Most importantly, the majority of children with small vessel cPACNS have CSF abnormalities. Lumbar puncture may reveal mild pleocytosis with predominantly lymphocytes or elevated CSF protein levels. Raised intracranial pressure, as documented by opening pressure measurement, may be a sensitive marker of CNS inflammation and is commonly found in children with small vessel cPACNS (Benseler et al., 2006a). CSF analysis and inflammatory markers

CHILDHOOD CENTRAL NERVOUS SYSTEM VASCULITIS are sensitive, but have limited specificity. They appear to change according to disease activity; therefore serial testing may be valuable. Small vessel cPACNS patients commonly present with inflammatory parenchymal brain lesions. MRI is the imaging modality of choice to detect inflammatory brain lesions (Fig. 108.3). CT lacks sensitivity and should be avoided. MRI was initially thought to have a sensitivity of 100% in detecting cPACNS; however, recent experience suggests that a normal MRI does not rule out small vessel inflammation in children presenting in status epilepticus (unpublished personal experience). Repeat MRI studies may be valuable. MRI lesions in small vessel cPACNS are highly variable in appearance and not limited to a vascular territory. Lesions are dynamic, waxing and waning over time. Inflammatory lesions can affect any CNS structure or spinal cord segment; they can affect gray or white matter, or both. Lesions can be located in the anterior or posterior circulation distribution; they can affect the optic nerve and they can be symmetrical or patchy. Lesions can occur in locations that are thought to be characteristic for a particular disease such as the temporal lobe, the basal ganglia, or the cerebellum, and can therefore lead to a misdiagnosis such as a metabolic disease, infectious condition, malignancy, or a demyelinating process (Callen et al., 2009). Lesions are typically best viewed on T2/FLAIR sequences, may enhance gadolinium in about a third of cases, and are commonly not diffusion

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restricted, except for lesions that have a significant ischemic component (Moritani et al., 2004). Meningeal enhancement can be found and is important to notice, since it may help differentiating from demyelinating white matter diseases (Aviv et al., 2006). MRA and conventional angiography are normal in small vessel vasculitis (by definition). Brain biopsy is required to confirm the diagnosis of small vessel cPACNS. In adult patients with PACNS, a low diagnostic yield of 36% for brain biopsies has been reported (Alrawi et al., 1999). A recent retrospective single-center study of 66 children aged 2 months to 16 years at the time of brain biopsy (1996–2003) revealed a diagnostic yield of 69%. The majority of those children presented with seizures and encephalopathy; the most frequently diagnosed disease was CNS vasculitis. A total of 72% of patients with diagnostic biopsies improved with appropriate treatment (Venkateswaran et al., 2008). Lesional biopsies are ideally taken of the leptomeninges, cortex, and white matter. Nonlesional biopsies, e.g., from the right frontal region, should be considered in cases of inaccessible lesions or lack of visible lesions. Biopsies should be performed prior to or within 7 days of initiation of immunosuppression to maintain the quality of the biopsy and optimize the chance of diagnosis. The histology of brain biopsies in children with cPACNS is commonly distinctly different from that in adults with PACNS. Lie reported that brain biopsies of adult PACNS commonly reveal necrotizing

Fig. 108.3. Small vessel primary CNS vasculitis (SV-cPACNS) in an 8-year-old previously healthy girl presenting with decreased level of consciousness and seizures: magnetic resonance imaging (MRI) study (A) and corresponding brain biopsy (B) at time of diagnosis of SV-cPACNS. MRI T2 FLAIR sequences demonstrate mutifocal bilateral inflammatory lesions affecting gray and white matter. Light microscopy of hematoxylin and eosin-stained brain biopsy specimen showing an inflammatory cell infiltrate within a cerebral blood vessel wall.

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granulomatous lesions (Lie, 1992). In contrast, the vast majority of cPACNS brain biopsies show lymphocytic, nongranulomatous lesions (Lanthier et al., 2001; Yaari et al., 2004; Benseler et al., 2005; Venkateswaran et al., 2008; Myung et al., 2009). Elbers recently demonstrated segmental, nongranulomatous, intramural infiltration of predominantly T- and B-lymphocytes involving small arteries, arterioles, capillaries, or venules (Elbers et al., 2009). Surrounding reactive changes may include perivascular gliosis, calcification, and pallor of myelin staining. The presence of viral inclusions, microglial nodules, or significant loss of myelin should alert the physician to an alternative diagnosis. Brain biopsy in children is often met with resistance; however, the treatable nature of small vessel cPACNS, if ascertained, or the probability of identifying an alternative diagnosis, should be considered when assessing the risks and benefits of the procedure. Small vessel cPACNS is an inflammatory and therefore potentially reversible brain disease. Initial case reports of small vessel cPACNS describe poor outcomes with high mortality; however, recent cohort studies suggest that cPACNS is treatable with appropriate management (Elbers and Benseler, 2008; Hutchinson et al., 2010). Possibly the most important predictor of outcome in cPACNS is time to diagnosis. The longer the disease remains unrecognized and untreated, the more acquired brain injury has to be expected. An institutional protocol has recently been established. The small vessel cPACNS Induction–Maintenance Protocol includes (1) induction: 7 monthly pulses of intravenous cyclophosphamide (500–750 mg/m2) for 7 months, plus high-dose corticosteroid, followed by (2) maintenance: 18 months of MMF. There is no consensus on the use of antiplatelet agents in this group (Hutchinson et al., 2010). Children with small vessel cPACNS can experience disease flares. Any change in neurological or psychiatric status should be evaluated. Commonly children relapse with symptoms similar to their initial clinical presentation such as recurrence or increased frequency of seizures, behavior changes, or headaches. However, new onset of optic neuritis has been repeatedly observed (unpublished data). Testing of inflammatory markers and neuroimaging is mandated when flares occur. Breakthrough disease is commonly successfully treated with increased immunosuppression. Addition of alternative immunomodulation such as intravenous immunoglobulins (IVIG) for optic neuritis or experimental treatment for refractory cases such as anti-TNF alpha agents has been used successfully in individual cases (unpublished personal experience). The long-term outcome of children with small vessel disease is not yet known. A small single-center experience suggests that early recognition and treatment is associated with complete or near-complete resolution of the disease in the majority of children (Benseler et al., 2005).

The PSOM can be used as a standardized tool to monitor the clinical progress of these patients (deVeber et al., 2000). Long-term prognosis depends on the duration and severity of symptoms, and associated extent of brain involvement. Children presenting with status epilepticus appear to have the slowest recovery. Longitudinal studies are necessary to characterize better the functional and neurocognitive outcome of these patients.

SECONDARY CNS VASCULITIS Infections CNS vasculitis can develop in the context of systemic infectious or inflammatory illnesses, systemic vasculitides, or other rheumatological diseases and malignancies. A variety of infections and malignancies are known to be associated with secondary CNS vasculitis (Elbers and Benseler, 2008). In children, viral infections such as Epstein–Barr virus (Baskin and Hedlund, 2007), parvovirus B19 (Bakhshi et al., 2002; Bilge et al., 2005), and human immunodeficiency virus (HIV) (Melica et al., 2009) infections were found to cause cerebral vasculitis. Varicella-zoster virus (VZV) is the most common viral cause of CNS vasculitis. Reactivation of latent VZV from the trigeminal ganglion can cause focal, proximal cerebral vessel stenosis, and vascular stroke in children (Askalan et al., 2001). The resulting PVA is indistinguishable from TCA and nonprogressive cPACNS, and may in fact represent the same disease entity (Sebire, 2006). The diagnosis of VZVassociated vasculitis is difficult. Gilden suggested determining the VZV IgG CSF-to-serum ratio in addition to VZV PCR in the CSF to confirm the diagnosis (Gilden et al., 2000; Kleinschmidt-DeMasters and Gilden, 2001). Increased CSF-to-serum ratio of VZV IgG confirms intrathecal immunoglobulin synthesis possibly reflecting virus reactivation (Nagel et al., 2008). Gilden suggested adding antiviral therapy to corticosteroids for the treatment of VZV-associated CNS vasculitis (Gilden et al., 2000). Bacterial infections including Mycoplasma pneumoniae (Narita, 2009) and Mycobacterium tuberculosis (Starke, 1999) can be associated with CNS vasculitis. Mycoplasma-associated CNS vasculitis predominantly affects the small cerebral vessels (Narita, 2009). Typical MRI lesions associated with mycoplasma are symmetrically located in the posterior basal ganglia. Large vessel vasculitis associated with mycoplasma has recently been reported in a child with antiphospholipid antibodies (Tanir et al., 2006). Mycobacterium tuberculosis meningitis on the basis of the brain can cause an inflammation of the cerebral vessel wall of the circle of Willis (Takeoka and Takahashi, 2002; Andronikou et al., 2006). Vessel wall inflammation and subsequent stenosis may lead to devastating arterial ischemic strokes in the anterior circulation (Kalita et al., 2009).

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Rheumatic and inflammatory diseases Childhood rheumatic disease can present with CNS vasculitis (Appenzeller et al., 2008; Duzova and Bakkaloglu, 2008). Systemic lupus erythematosus (Benseler and Silverman, 2007), systemic vasculitis (Morfin-Maciel et al., 2002; Nadeau, 2002), Behc¸et’s disease (Al-Araji and Kidd, 2009), and juvenile dermatomyositis (Regan et al., 2001) patients can develop small or large vessel CNS vasculitis. Associated antiphospholipid antibodies such as lupus anticoagulants, anticardiolipin antibodies, and anti-beta2-microglobulin may increase the risk for neurological or psychiatric manifestations (Avcin et al., 2008). Children with other systemic inflammatory diseases such as inflammatory bowel diseases (Nomoto et al., 2006) and autoinflammatory diseases/ periodic fever syndromes such as familial mediterranean fever (Akman-Demir et al., 2006) and other inherited immune dysregulation syndromes such as hemophagocytic lymphohistiocytosis (HLH) (Moshous et al., 2007) can present with CNS vasculitis. The initial workup has to search carefully for a potential underlying illness, in view of the impact on the choice of treatment (Warnatz et al., 2003).

Systemic vasculitis and vasculopathy In children and adults, systemic vasculitis can affect the cerebral vessels (Gedalia and Cuchacovich, 2009; O’Neil, 2009). Henoch–Schonlein purpura (HSP) is the most common childhood vasculitis characterized by IgA deposits along the walls of small arterial vessels. Most commonly children with HSP present with palpable purpura, joint symptoms, abdominal pain, and proteinuria. Overall, neurological manifestations including CNS vasculitis are rare events in HSP (Belman et al., 1985). Most commonly, hypertension-related seizures in children with nephritis are observed. Antineutrophil cytoplasmatic antibody (ANCA) associated vasculitis including granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis (Churg–Strauss syndrome) are rare vasculitides in children (Cabral et al., 2009). CNS manifestations including intracranial granulomas and hypertension-related seizures may occur in up to 10% of all adult patients with ANCA vasculitis; however, cerebral vasculitis is rare (Kraemer and Berlit, 2009). In childhood ANCA vasculitis, associated CNS vasculitis has been described in a case series (Wright et al., 2007). Kawasaki disease is the most common medium-sized vessel vasculitis in children. The diagnosis of typical Kawasaki disease is based on a minimum of 5 days of fever in addition to at least four of five clinical criteria

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of: nonpurulent conjunctivitis, red cracked lips, rash, cervical lymphadenopathy (>1.5 cm), and puffy hands and/or feet. Treatment with intravenous immunoglobulin and acetylsalicylic acid successfully treats the inflammatory syndrome in the majority of children. However, one in four children experience transient coronary artery dilatation and one in 20 children develop coronary artery aneurysms. While aseptic meningitis is frequently observed in Kawasaki patients, cerebral vasculitis is a very rare manifestation (O’Neil, 2009). Hemolytic uremic syndrome (HUS) and thromboticthrombocytopenic purpura (TTP) are the most common thrombotic microangiopathies in children, affecting the kidneys and the brain. In both diseases, a small vessel vasculopathy develops which is characterized by intravascular hyaline thrombi resulting in thrombocytopenia, microangiopathic hemolysis, and organ dysfunction. In children with TTP, mutations in the gene encoding for ADAMTS13, a von Willebrand factor (vWF) cleaving protease, lead to unusually large multimeric forms of vWF. These multimeres facilitate adherence of platelets and development of microthrombi. In contrast, the microangiopathy in typical HUS has a different etiology: HUS is triggered by gastrointestinal infections with verotoxin-producing bacteria. Verotoxin induces endothelial injury, apoptosis, and inflammation. In some children with atypical HUS mutated complement proteins are the basis for the microangiopathy. In the CNS these occlusive, thrombotic microangiopathies commonly present with multifocal cortical and subcortical hemorrhagic infarctions (Ellchuk et al., 2011).

MIMICS OF CNS VASCULITIS Large vessel cPACNS Cerebral large vessel abnormalities resulting in stroke can be seen in fibromuscular dysplasia (FMD), a noninflammatory structural abnormality of arterial blood vessels (Park et al., 2008). Distinguishing noninflammatory FMD from inflammatory CNS vasculitis may be difficult. However, FMD affects the renal arteries in 85% of cases, leading to hypertension. Isolated FMD of the CNS in children has rarely been reported (Ozdil et al., 2009). Children with FMD more commonly present with aneurysms due to the structural vessel wall abnormality of FMD (Park et al., 2008). Most importantly, MRI cerebral vessel wall imaging of FMD is distinctly different from vasculitis: vasculitic lesions reveal a thickened, contrast enhancing wall with a narrowed lumen. In contrast, FMD-associated wall irregularities do not enhance contrast in MRI (Leventer et al., 1998; Kuker et al., 2008; Swartz et al., 2009). Moyamoya disease is a multifactorial, cerebrovascular condition that predisposes affected children

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Fig. 108.4. Unilateral moyamoya disease in a previously healthy 6-year-old girl presenting with right-sided headaches, vomiting, and dizziness. Conventional angiography (A, right internal carotid injection) and magnetic resonance angiography (B) at time of diagnosis of moyamoya disease demonstrate advanced involvement of the right carotid system and the right posterior cerebral artery with extensive collateralization. The corresponding MRI revealed right cerebral “ivy sign” suggestive of altered hemodynamics in the right cerebral hemisphere, further supporting the diagnosis of moyamoya disease (images not shown).

to stroke in association with progressive stenosis of the intracranial internal carotid arteries and their proximal branches (Scott and Smith, 2009). Its characteristic angiographic appearance differentiates it from large vessel cPACNS (Fig. 108.4). In contrast, intracranial dissections, although rare, can be indistinguishable mimics of inflammatory vasculopathies, since characteristic angiographic features of a double lumen, intimal flap, or pseudoaneurysm may be missing in intracranial disease (Adams and Trevenen, 1996; Suter and El-Hakam, 2009). Other important mimics of large vessel cPACNS include thrombembolic vasculopathy in children with congenital heart disease or prothrombotic conditions, sickle cell disease arteriopathy (Steen et al., 2003), metabolic diseases including mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome (Klein et al., 2007), drug-associated vasculopathy (Martin et al., 1995), and radiation vasculopathy (Ishikawa et al., 2006; Perry and Schmidt, 2006) (see Table 108.2). Channelopathies have recently been reported not only to cause familial hemiplegic migraine, ataxia (Jen and Baloh, 2009), and familial epilepsies (Stafstrom, 2009), but also to mimic large vessel cPACNS (Vernino, 2007).

Small vessel cPACNS Both inflammatory and noninflammatory diseases can mimic small vessel cPACNS. Inflammatory diseases of the white matter are the most important differential

diagnoses of small vessel vasculitis, including acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), and neuromyelitis optica (NMO) (Pohl, 2008). Inflammatory demyelination may cause multifocal neurological symptoms including optic nerve and spinal cord involvement. Inflammatory markers and CSF analysis are often mildly abnormal. CSF oligoclonal IgG can be found in both small vessel cPACNS and inflammatory white matter diseases. The MRI appearance of inflammatory demyelination might be indistinguishable from that of small vessel cPACNS. However, MRI features such as predominant gray matter inflammation and meningeal enhancement may support a diagnosis of small vessel cPACNS. Brain biopsy is the only test to confirm either diagnosis definitively. Rasmussen’s encephalitis is a rare inflammatory brain disease primarily seen in children (Rogers et al., 1994; Bauer et al., 2007). Refractory seizures in combination with characteristic cerebral MRI findings may support the diagnosis of Rasmussen’s disease. The definite diagnosis requires a brain biopsy demonstrating perivascular lymphocytic infiltrates, microglial nodules, and neuronal loss, with or without evidence of neuronophagia (Deb et al., 2005). Mitochondrial disorders are important mimics of small vessel cPACNS. Children with MELAS commonly present with headaches and recurrent focal neurological deficits. Neuroimaging shows regions of T2hyperintensity spanning multiple vascular territories with diffusion restriction. These lesions represent tissue

CHILDHOOD CENTRAL NERVOUS SYSTEM VASCULITIS injury due to failure of oxidative metabolism, rather than ischemia from reduced cerebral perfusion. Metabolic “strokes” may be differentiated from acute ischemic strokes by an increased apparent diffusion coefficient (ADC) during the acute stage of the lesion. Lactate peaks on MR spectroscopy are nonspecific, and are also observed in acute infarction. If mitochondrial disease is suspected, direct mutation analysis or muscle biopsy should be considered. Rolandic mitochondrial encephalomyelopathy (RoME) is a newly recognized mitochondrial disease caused by MT-ND3 mutations. Acquired neurological deficits and MRI lesions can mimic cPACNS (Werner et al., 2009). The recently reported POLG1 gene encodes for the catalytic subunit of DNA polymerase gamma, an enzyme crucial for mitochondrial DNA repair and replication. In children POLG1 mutations have been reported to cause a spectrum of neurological diseases including Alpers syndrome (Wiltshire et al., 2008), ataxia neuropathy spectrum disorders, childhood neurodegenerative myocerebrohepatopathy spectrum disorders (MCHS) and myoclonus epilepsy myopathy sensory ataxia (MEMSA) (Wong et al., 2008). Similar to small vessel cPACNS, intractable seizures can be found in children with POLG1 mutations (Wolf et al., 2009). CNS manifestations in the absence of liver and muscle disease are increasingly recognized. To complicate matters further, patients with confirmed POLG1 mutations can present with an associated inflammatory brain disease targeting the small cerebral vessels, warranting immunosuppressive therapy (Elbers and Benseler, 2008). Novel inflammatory brain diseases including autoantibody mediated NMDA-receptor encephalitis share features of small vessel cPACNS such as elevated CSF inflammatory markers and MRI characteristics. The diagnosis has to be suspected in children presenting with seizures, dystonia, speech deficits, cognitive decline, autonomic instability, or psychosis. Antibody testing is important to confirm the diagnosis (Florance et al., 2009). In autoantibody-mediated limbic encephalitis antibodies against voltage-gated postassium channels (VGKC) and/or glutamic acid decarboxylase (GAD) can be found. Patients may present with a subacute onset of confusion, memory, or behavior abnormalities and/or seizures. CSF abnormalities of elevated protein and pleocytosis may be present (Graus et al., 2008; Novillo-Lopez et al., 2008; Haberlandt et al., 2011).

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