CNS vasculitis in children

Multiple Sclerosis and Related Disorders (2013) 2, 162–171

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journal homepage: www.elsevier.com/locate/msard

REVIEW

CNS vasculitis in children Marinka Twilt, Susanne M. Benseler Division of Rheumatology, Department of Pediatrics, The Hospital for Sick Children, Child Health Evaluative Science, Research Institute, University of Toronto, Toronto, ON, Canada Received 9 April 2012; received in revised form 27 October 2012; accepted 19 November 2012

KEYWORDS

Abstract

cPACNS; Childhood primary angiitis of the central nervous system; CNS vasculitis; Childhood; Vasculitis; Inflammatory brain disease

Inflammatory brain diseases in childhood are underrecognized and lead to life-threatening neurological deficits. Early recognition and diagnosis of inflammatory brain diseases is critical, as the reversibility of the neurological deficits is closely related to early initiation of treatment and prevention of secondary brain tissue damage. Primary childhood CNS vasculitis is the most common cause of inflammatory brain disease in childhood. Clinical features, laboratory tests and imaging can be non-conclusive and overlap with other inflammatory brain diseases, such as demyelinating diseases. This review focuses on recent publications on epidemiology, pathogenesis, and treatment in childhood CNS vasculitis and relevant publications from the rapidly expanding differential diagnosis for the subtypes of CNS vasculitis, particularly the demyelinating brain diseases. & 2012 Elsevier B.V. All rights reserved.

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Angiography-positive nonprogressive cPACNS (NP-cPACNS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Angiography-positive progressive cPACNS (P-cPACNS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Differential diagnosis of large vessel cPACNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Angiography-negative, small vessel cPACNS (SV-cPACNS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Differential small vessel cPACNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Summary and conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Keypoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Correspondence to: Division of Rheumatology, The Hospital for

Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8. Tel.: +1 416 813 7707; fax: +1 416 813 4989. E-mail address: [email protected] (S.M. Benseler). 2211-0348/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2012.11.002

162 164 164 165 166 167 168 169 169 169

Introduction

Brain inflammation is an increasingly recognized underlying pathomechanism leading to severe, newly acquired neurological and/or psychiatric deficits in previously healthy children.

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Inflammatory brain diseases represent a spectrum of illnesses that can occur in the context of an underlying focal or systemic condition (secondary inflammatory brain diseases) such as an infection, a systemic rheumatic disease or a distinct exposure or it can manifest as a primary, idiopathic illness (see Fig. 1) (Cellucci and Benseler, 2010; Dalmau et al., 2008; Elbers and Benseler, 2008; Dale et al., 2009). Activated immune cells, such as T- and B-cells, and macrophages can cause an inflammatory response with production of cytokines and antibodies which can target different brain structures such as specific segments of blood vessels, neurons, or CNS proteins such as myelin, cell surface receptors, channels or enzymes. Inflammatory pathways can then be activated and cause characteristic clinical, radiographic and histological findings. Childhood CNS vasculitis is an increasingly recognized inflammatory brain diseases, in which the inflammatory target is the cerebral vasculature. The hallmark of CNS vasculitis is the inflammatory infiltrate in the cerebral vessel wall. Intramural and perivascular inflammation leads to focal brain parenchyma irritation and possibly loss of function, vessel wall thickening and edema with subsequently decreased luminal diameters and reduced blood flow and potential ischemic changes in the vascular territory. The clinical phenotype is highly variable and depends on a multitude of factors including size of the affected blood vessel, extend of vascular disease, number of vascular territories involved, location of vessel inflammation within the CNS, predominant inflammatory pathway, host response to inflammation and severity and duration of inflammation. In adults, vascular stroke is most commonly due to arteriosclerosis. In contrast, non-atherosclerotic causes and most importantly vascular inflammation make up the majority of childhood strokes (Fullerton et al., 2007). Overall, vessel wall disorders are thought to be the primary mechanism in more than 50% of the pediatric patients (Nowak-Gottl et al., 2003; Ganesan et al., 2003). Childhood cerebral vasculopathies include vasculitis, mechanical injury leading to arterial dissection, fibromuscular dysplasia, Moyamoya disease and other rare metabolic or genetic

Fig. 1

Puzzle of childhood Inflammatory Brain Diseases.

arteriopathies (Testai and Gorelick, 2010; Testai and Gorelick, 2010). Given our inability to biopsy large cerebral blood vessel, there remains a controversy, to what degree the distinct childhood vasculopathies are in fact inflammatory in nature. The best examples for this controversy are post-varicella angiopathy (PVA) and transient cerebral angiopathy (TCA). Both conditions are widely overlapping in clinical presentation and neuroimaging findings and closely related to non-progressive primary CNS vasculitis (see below). Recent studies clearly demonstrate evidence of inflammation of the vessel wall for the proximal large cerebral vessels triggered by reactivation of latent varizella zoster virus (VZV) and other viruses. This causes smooth muscle cell infection and recruitment of inflammatory cells into the vessel wall, the hallmark of vasculitis (Braun et al., 2009; Berger et al., 2000). In Moyamoya disease, a condition that was previously considered purely non-inflammatory, recent studies suggest a Transforming Growth Factor (TGF)b mediated inflammatory pathway being present in the vessel wall causing slowly progressive intima layer thickening and vessel occlusion (Liu et al., 2011). Small vessel vasculitis is less controversial, since the diagnosis is made on brain biopsy. In adult with small vessel CNS vasculitis, the primary inflammatory pathway detected on brain biopsies is granulomatous (Salvarani et al., 2007). In addition, necrotizing inflammation is found in a 1 out of five adults, while lymphocytic vasculitis in a quarter (Salvarani et al., 2007). In contrast in children, the predominant histological phenotype is lymphocytic vasculitis primarily mediated by activated T cells (Elbers et al., 2010). Childhood Primary Angiitis of the CNS (cPACNS) is an increasingly recognized vasculitic inflammatory brain diseases causing severe neurological and psychiatric deficits in previously healthy children (Benseler et al., 2006; Calabrese and Mallek, 1988; Salvarani et al., 2007). PACNS was first described in adults in 1959 (Cravioto and Feigin, 1959). Initially most cases were derived from autopsy reports, describing granulomatous inflammation of the cerebral arteries (Lie, 1992). In 1988, the term PACNS was coined by Calabrese et al (Calabrese and Mallek, 1988). He reported eight new cases, reviewed the literature and proposed criteria for adult PACNS mandating: 1) a newly acquired neurological deficit, 2) angiography and/or histological evidence of CNS vasculitis, and 3) the absence of a systemic condition that could explain these findings (Calabrese and Mallek, 1988). The Calabrese criteria were adopted and modified for childhood PACNS (cPACNS), requiring a newly acquired neurological deficit and/or psychiatric symptom in a patient r18 years of age (Benseler et al., 2006). cPACNS is currently classified based on the affected cerebral vessel size involved and disease course (Benseler et al., 2006; Benseler et al., 2005). Three subtypes are recognized: (1) non-progressive large-medium vessel cPACNS (angiography positive); (2) progressive large-medium vessel cPACNS (angiography positive); and (3) small vessel cPACNS (angiography negative, brain biopsy positive) (Benseler et al., 2006; Benseler et al., 2005). All three subtypes have a distinct clinical presentation, disease course and treatment outcome (Benseler et al., 2006; Benseler et al., 2005; Hutchinson et al., 2010).

CNS vasculitis in children

1.1. Angiography-positive nonprogressive cPACNS (NP-cPACNS) Children with NP-cPACNS commonly present with sudden onset focal neurological deficits and are subsequently diagnosed with arterial ischemic stroke (Benseler et al., 2006). This disease subtype affects more commonly boys than girls corresponding to the gender predilection in stroke overall (Golomb et al., 2009). Focal deficits can include hemiparesis, hemifacial weakness, hemisensory loss and fine motor skill loss (Benseler et al., 2006). Diffuse focal deficits such as decreased cognition or behavior change are uncommon. Overall headaches are present in 40% of the children with NP-cPACNS (Benseler et al., 2006). Inflammatory markers including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are frequently normal. The endothelial cell marker von Willebrand Factor (vWF) antigen may have diagnostic properties, however it remains to be studied systematically in this population. Testing for prothrombotic abnormalities is mandatory. Cerebrospinal fluid (CSF) analysis in NP-cPACNS reveals an elevated protein or leukocytosis in less than 50% of the patients (Benseler et al., 2006; Soon et al., 2008). The role of the opening pressure remains uncertain. Magnetic resonance imaging (MRI) and angiography studies are necessary to establish the diagnosis. MRI should include T1, T2, Fluid attenuated inversion recovery (FLAIR), diffusion weighted imaging (DWI) and apparent diffusion coefficient (ADC) sequences for parenchymal lesions (Neel and Pagnoux, 2009). MRI studies commonly reveal unilateral ischemic lesions large vessel territories, most commonly the basal ganglia are affected (Aviv et al., 2006). MR angiography (MRA) plus Gadolinium contrast studies of the affected vascular wall segment should be requested (Kuker et al., 2008). In NP-cPACNS these reveal wall thickening and contrast enhancement due to wall inflammation, the exact sensitivity and specificity of these findings remain controversial at this moment. On repeat imaging vessel wall enhancement can persist until 6 weeks after diagnosis. Conventional angiography continues to be superior in younger children, to visualize the posterior circulation and for distal vessel segments. In NP-cPACNS angiography commonly demonstrates unilateral stenoses and dilatations of the proximal segments of the anterior and/or middle cerebral arteries (ACA, MCA) and/or distal Internal Carotid Artery (ICA) (Benseler et al., 2006). Beading and irregularity of stenoses can be seen. During the active phase of disease, local progression of the stenoses can often be visualized. Progression and/or involvement of new vascular territories beyond three months mandates reclassification of the patient as progressive cPACNS and treatment modification. Children with NP-cPACNS are routinely commenced on antithrombotic therapy, regimens vary between centers. During the acute setting unfractionated heparin/low molecular heparin are initiated and continued for 3–6 months treatment, this is usually followed by long term aspirin as secondary stroke prevention (Andrews, 2004). Adjunctive therapy with corticosteroids (maximum 2 mg/kg, tapering to stop in 3 months) for three months remains controversial. Guidelines for NP-cPACNS treatment are currently not available and recommendations are based on small case-series with limitations to its applicability in daily practice (Soon et al., 2008). Non-progression is confirmed on the repeat imaging at

164 3 months establishing no evidence of involvement of new vascular beds and resolution of contrast enhancement in the vascular wall in steroid treated patients. Recurrent ischemic events are seen in 30–60% of children (Soon et al., 2008). The long-term outcome remains to be systematically studied, it appears to be closely related to the location and extent of the ischemic lesion, stroke recurrence and possibly the use of corticosteroids. Early rehabilitation, as practiced in adult stroke care models, has not been systematically performed or studied in this population, however it appears to have striking benefits. Vessel wall inflammation is not yet well-established in cPACNS (Elbers et al., 2010). The use of imaging techniques designed to demonstrate vessel wall enhancement has also been suggested for post-Varicella angiopathy (PVA) (Berger et al., 2000) and for Transient Cerebral Angiopathy (TCA) (Braun et al., 2009), but the exact specificity and sensitivity of patterns observed in these entities remains to be studied. PVA and TCA, both were thought to be notorious mimics for NP-cPACNS. Autopsy studies reveal direct viral invasion and associated inflammation of the vascular wall in children (Berger et al., 2000). More recently, for TCA, cerebral vessel wall inflammation has been supported by gadolinium enhancement of the arterial wall in intracranial vessels using MRI (Swartz et al., 2009). PVA, TCA and large vessel cPACNS might all be representatives in a broad spectrum of large vessel disease. More studies to reveal the exact pathophysiology and inflammatory cascades in the different entities need to be performed.

1.2. Angiography-positive progressive cPACNS (PcPACNS) In contrast to NP-cPACNS, progressive cPACNS is a chronic inflammatory disease characterized by focal and diffuse deficits at presentation (Benseler et al., 2006; Gallagher et al., 2001), frequently raised inflammatory markers and multifocal, proximal and distal vessel inflammatory stenoses on angiography (Benseler et al., 2006; Aviv et al., 2007; Eleftheriou et al., 2010). Some children are initially classified as NP-cPACNS, however develop new stenoses on angiography beyond 3 months of disease. Interestingly, both angiography positive CNS vasculitis subtypes, NP-cPACNS and P-cPACNS, predominately affect boys. Children with PcPACNS are most frequently only diagnosed, when they develop focal deficits including hemisensory loss or fine motor skill deficits (Benseler et al., 2006). Difficulty in concentration, cognitive dysfunction, and mood and personality changes are often present in these patients, however remain unrecognized as these diffuse deficits develop insidious (Benseler et al., 2006). Correspondingly, the time from onset of any symptoms to diagnosis is frequently longer in P-cPACNS compared to NP-cPACNS patients. Headaches are the leading clinical symptom and present in 95% of P-cPACNS patients (Benseler et al., 2006). Systemic underlying conditions have to be carefully looked for and excluded, since the clinical and imaging pattern of P-cPACNS is frequently found in angiography-positive, secondary CNS vasculitis of childhood. Children with P-cPACNS may have mild-moderately raised inflammatory markers (including an increase in their white

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blood count, c-reactive protein (CRP), erythrocyte sedimentation rate (ESR)); however these inflammatory markers and CSF analysis are not discriminative (Benseler et al., 2006). A normal CSF cell count or normal ESR does not exclude an angiography-positive CNS vasculitis. Necessary MRI sequences are identical to those performed in suspected NP-cPACNS. In P-cPACNS parenchymal lesions on MRI can be ischemic and/or inflammatory and are commonly present in more than one vascular territory. One in four children has bilateral MRI lesions, which are more frequently asymmetric in appearance (Aviv et al., 2006). The angiography characteristically demonstrates vasculitis of proximal and distal segments of the cerebral arteries, typically involving multiple vascular beds (Aviv et al., 2006). Different levels of intensity of Gadolinium contrast enhancement can be found in affected vessel wall segments. At this moment it remains unclear if the intensity is a direct correlation of active inflammatory wall process or not, futher studies will hopefully help to reveal this. The anterior circulation is more commonly affected; isolated posterior circulation vasculitis is less common, however has to be considered. Conventional angiography provides additional information about the length and degree of stenosis potentially impacting on antithrombotic treatment choices (Aviv et al., 2007). It may identify additional distal vessel disease and visualizes collateral blood flow into the affected brain tissue identifying additional brain at risk. Children with P-cPACNS require a combination of immunosuppressive treatment in addition to antithrombotic therapy. At time of diagnosis, daily intravenous methylprednisolone pulses (30 mg/kg/day) are given at many centers for the duration of 3–7 days. Subsequently corticosteroid therapy is switched to daily oral prednisone (2 mg/kg/day, max 60–80 mg) with significant variation between centers. Barron et al. (1993) first documented the efficacy of cyclophosphamide in cPACNS. Gallagher et al., 2001 reported the treatment with cyclophosphamide in five children with P-cPACNS. Intravenous monthly cyclophosphamide pulses are commonly given for six months, followed by oral maintenance immunosuppression (azathioprine or mycophenlate mofetil) while tapering the child off corticosteroids. The length of oral maintenance treatment remains controversial and no long-term studies have been reported. The exact efficacy and corresponding long-term effects of immunosuppressive treatment in P-cPACNS remains controversial as all data are based on small caseseries and evidence is lacking. The long-term outcome of children with P-cPACNS has not been systematically studied. Residual focal neurological deficits are often seen in this subtype (Benseler et al., 2006).

1.3.

Differential diagnosis of large vessel cPACNS

Stroke is the leading symptom of large vessel cPACNS. The differential diagnosis includes other inflammatory vasculopathies, non-inflammatory vessel diseases, and vasospastic disorders leading to stroke (see Table 1). Other inflammatory conditions include Moyamoya disease, PVA and TCA (Braun et al., 2009; Berger et al., 2000; Ibrahimi et al., 2010). Recently the Childhood Arterial Ischemic Stroke (AIS) Standardized Classification and Diagnostic Evaluation

(CASCADE) criteria were developed, as first step to a consensus-based classification for childhood AIS (Bernard et al., 2012). Non-inflammatory diseases mimicking large vessel cPACNS include arterial dissection, thromboembolic disease, hemoglobinopathies (sickle cell disease), fibromuscular dysplasia, vasculopathies associated with an underlying disorder such as Alagille, Down syndrome, neurofibromatosis 1, and even rarer genetic and metabolic arteriopathies (Testai and Gorelick, 2010; Testai and Gorelick, 2010; Begelman and Olin, 2000). Secondary large vessel CNS vasculitis has been described in patients with systemic inflammatory diseases including systemic vasculitis and after exposures such as radiation therapy (Aoki et al., 2002). Vasospastic mimics are channelopathies and drugs, such as cocaine, amphetamines that can cause a secondary vasculitis, but are also capable of mimicking CNS vasculitis without an inflammatory component but a vasoconstrictive component (Singhal et al., 2011). Clinical symptoms, demographic information and an elaborative past history can help to differentiate or exclude certain causes. In large vessel cPACNS, laboratory blood or cerebrospinal fluid (CSF) tests for inflammation are usually normal or minimally abnormal and are certainly not specific or sensitive for cPACNS. Traditional MRIs are also unable to

Table 1

Differential diagnosis of large vessel cPACNS.

Inflammatory -Primary CNS vasculitis—large vessel -Varicella zoster virus vasculopathy (Post Varicella Angiopathy (PVA)) -Transient Cerebral Angiopathy (TCA) -Moyamoya disease Non-inflammatory vasculopathies -Arterial dissection -Thromboembolic disease -Fibromuscular dysplasia -Hemoglobinopathies -Sickle cell disease -Antiphospholipid syndrome -Post-radiation vasculopathy -Connective tissue disorders -Neurofibromatosis, Marfan syndrome, Ehler–Danlos syndrome, Alagille syndrome -Genetic diseases with vasculopathy -Down’s syndrome, Posterior fossa malformations-hemangiomas-arterial anomaliescardiac defect-eye abnormalities-sternal cleft and supraumbilical raph syndrome (PHACES), cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), Fabry disease, homocystinuria Vasospastic vasculopathies -Channelopathies (familiar hemiphlegic migraine and calcium channelopathy) -Drugs -amphetamines, cocaine -Reversible vasoconstrictive syndromes

CNS vasculitis in children differentiate between vasculopathy or vasculitis, however the discovery of gadolinium enhancement of the vessel wall has lead to a new test for vessel wall involvement (Kuker et al., 2008). It is, however not studied in a large cohort of patients with inflammatory brain diseases to look at sensitivity and specificity in the different entities. It is important to keep the differential diagnosis broad, including all the different causes for inflammatory brain diseases and its noninflammatory mimics.

2. Angiography-negative, small vessel cPACNS (SV-cPACNS) Small vessel cPACNS is increasingly recognized around the world. The constantly expanding clinical phenotype includes seizures (80%), movement disorders (15%), and diffuse neurological (50%) and psychiatric deficits (40%). Children with SV-PACNS are often admitted to the intensive care unit presenting with severe encephalopathy, extensive focal deficits and/or seizure status and require a rapid, invasive evaluation including an elective brain biopsy (Benseler et al., 2005). In contrast to angiography positive disease, SV-cPACNS has a female predominance (Benseler et al., 2005; Hutchinson et al., 2010). The mode of onset varies significantly from child to child. Some patients develop significant cognitive deficits over weeks and months, complaining of constant headaches or are diagnosed with focal seizures (Hutchinson et al., 2010). Inflammation associated cognitive decline is particularly difficult to recognize in children with an underlying learning disability or autism. In contrast, some children have a rapidly progressive disease onset and present with a meningitis-like illness. Systemic features including fever and fatigue can be present in more than 50% of children with cPACNS (Hutchinson et al., 2010). Seizures are by far the most common clinical symptom at diagnosis of SV-cPACNS to date. All seizure types are seen. Status epilepticus or refractory status epilepticus in previously healthy children mandates an evaluation for an underlying inflammatory brain disease, in particular for SV-cPACNS. In 1990, Matsell et al., 1990 was the first to report a case of a child with refractory status epilepticus, in whom the diagnosis of cPACNS was made, unfortunately only on autopsy. Inflammatory markers are frequently abnormal in children with SV-cPACNS, however the degree of abnormality varies between patients. Hutchinson et al., 2010 documented that three out of four children with SV-cPACNS had at least one abnormal inflammatory marker in the blood at diagnosis. More importantly 490% had an abnormal CSF analysis including increased CSF protein and/or cell count. Mild to moderate CSF lymphocytosis is most commonly seen. Oligoclonal banding may be detected. MRI abnormalities are present in the vast majority of SVcPACNS patients at diagnosis (Aviv et al., 2006). Serial studies may be required. MRI lesions are best viewed on T2/FLAIR sequences. Ischemic lesions are less common than in large vessel disease, but are present in SV-cPACNS. Lesional Gadolinium contrast enhancement is present in less than 50% of children with active disease at diagnosis. Meningeal contrast enhancement is equally infrequently seen; however it is one of the few specific MRI finding of

166 SV-cPACNS after infectious meningitis is excluded (Aviv et al., 2006). It is not present in other IBrainD including demyelinating diseases. Inflammatory lesions are most commonly found in the subcortical white matter and cortical gray matter (Hutchinson et al., 2010), however any MRI pattern can be seen in SV-cPACNS due to the ubiquitous presence of small blood vessels in the brain and spinal cord. Although SV-cPACNS appears to have a focal nature on MRI (with focal detectable lesions), generalized small vessel vasculitis was present on autopsy (Lie, 1992). Children presenting in status epilepticus may even have repeatedly normal MRI studies and brain biopsy evidence of SV-cPACNS. By definition, all children with SV-cPACNS have normal MRA and conventional angiography studies. Other neuroimaging techniques have so far not provided additional specificity in SV-cPACNS. The next step in the diagnostic evaluation is an elective brain biopsy, which should be completed within 10 days from starting immunosuppressive therapy. The brain biopsy should preferably target lesions identified on MRI. However, these may either not be accessible or in functionally important areas. In these children, non-lesional biopsies should be performed targeting the non-dominant frontal lobe. The diagnostic yield of elective brain biopsies performed for suspected inflammatory brain disease and other treatable conditions other than tumors in children was found to be 69% (1996–2003) (Lie, 1992; Venkateswaran et al., 2008). The yield is therefore significantly higher than adults. The review of brain biopsies in children with SV-cPACNS reveals intramural, inflammatory infiltrates consisting predominantly of lymphocytes (Benseler et al., 2005; Hutchinson et al., 2010; Elbers et al., 2010; Lanthier et al., 2001; Yaari et al., 2004). Childhood CNS vasculitis is a lymphocytic vasculitis and is therefore histologically not characterized by vessel wall destruction, fibrinoid necroses or evidence of necrosis or granulomas as seen in other types of vasculitis or adult CNS vasculitis. Granulomatous infiltrates, which are frequently described in adult PACNS, have so far not been reported in children with cPACNS (Salvarani et al., 2007; Benseler et al., 2005; Hutchinson et al., 2010; Lanthier et al., 2001). Children with SV-cPACNS require combination immunosuppressive therapy in addition to the necessary treatment of seizure, abnormal movements or psychiatric symptoms. Treatment should be initiated rapidly in order to control the devastating brain inflammation and prevent disease-related damage. Hutchinson et al., 2010 reported an open-label treatment study of 19 children with SV-cPACNS receiving a six month induction protocol consistent of monthly intravenously cyclophosphamide pulses (500–750 mg/m2, plus MESNA and hyperhydration) and corticosteroids (initial methylprednisolone pulses 30 mg/kg/day, max 1000 mg for 3–5 days followed by oral prednisone 2 mg/kg, max 60 mg/ day with defined monthly taper). After six months children were switched to maintenance treatment with initially azathioprine but more recently mycophenolate mofetil (MMF). The treatment was found to be effective and safe, but only 14 patients had completed the induction treatment at time of evaluation. A substantial number of patients did develop a flare (mainly when azathioprine was the first treatment choice in the maintenance phase). After 24 months 70% of the children had no evidence of any

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functional neurological deficit as measured by the pediatric stroke outcome measure (PSOM) (Hutchinson et al., 2010). This is the only open-label treatment study in SV-cPACNS available, up to date and although the treatment regimen seems to be effective, the limitations of this study should be kept in mind. Larger studies are necessary to establish more evidence for the ultimate treatment regimen in SV-cPACNS. Case series from other centers supported the efficacy of cyclophosphamide and MMF (Bitter et al., 2006; Sen et al., 2010). Most series document good recovery of neurological deficits. At many centers, children continue anti-convulsive medication beyond 24 months.

2.1.

Differential small vessel cPACNS

The differential diagnosis of SV-cPACNS is distinctly different from the other cPACNS subtypes. Seizures are the keypresenting symptom of small vessel disease. However clinical features such as seizures, optic neuritis or spinal cord disease are not specific features of a distinct inflammatory brain diseases in children. In small vessel vasculitis, inflammatory markers in blood and/or CSF are commonly abnormal (Hutchinson et al., 2010). However, these markers lack specificity. Differentiating SV-cPACNS from other inflammatory brain diseases also remains challenging on neuroimaging. The differential diagnostic spectrum of primary small vessel CNS vasculitis encompasses secondary small vessel vasculitis, non-vasculitic inflammatory brain diseases and mimics such as CNS infections (Ford-Jones et al., 1998), metabolic or neoplastic brain diseases. Infections are the most urgent differential diagnostic dilemma. Bacteria infecting the vessel wall as seen with streptococcus or mycobacterium tuberculosis meningitis represent a true infectious, secondary CNS vasculitis. Infections such as TB can mimic vasculitis by causing parenchymal lesions on MRI. In addition, infections can lead to post-infectious inflammatory vasculitis such as post-Varicella angiopathy. A comprehensive infectious work-up is mandated in all children with suspected inflammatory brain diseases. Secondary CNS vasculitis can develop in children with an underlying systemic rheumatic disease, such as systemic lupus erythematosus, ANCA-associated vasculitides, polyarteritis nodosa and Takayasu arteritis (Pomper et al., 1999; Nishino et al., 1993; Rossi and Di Comite, 2009; von Scheven et al., 1998; Seror et al., 2006). Inflammatory conditions such as inflammatory bowel disease (IBD), Kawasaki disease and Hemophagocytic LymphoHistiocytosis (HLH) can be associated with CNS vasculitis (Nadeau, 2002; Moshous et al., 2007). The spectrum of non-vasculitic inflammatory brain diseases includes demyelinating diseases (Dale et al., 2009), neurosarcoid (Rose et al., 2009; North et al., 1970), neuronal antibody-mediated or T-cell mediated inflammatory brain diseases (Rasmussen and McCann, 1968; Rasmussen et al., 1958; Vining et al., 1993) (see Table 2). Demyelinating diseases include the clinical entities of Acute Disseminated Encephalomyelitis (ADEM), Multiple Sclerosis (MS) and Transverse Myelitis (TM). Clinical, laboratory and neuroimaging features overlap in primary SV-CNS vasculitis and demyelinating diseases, although the underlying pathology differs distinctly.

Demyelinating CNS diseases are thought to be due to immunodysregulation triggered by an infectious or other environmental agent in a genetically susceptible host (Dale et al., 2009). ADEM is a monophasic, immune mediated, demyelinating disease. Patient present with multifocal neurological deficits accompanied by encephalopathy (Alper et al., 2009; Krupp et al., 2007). In approximately 8% ADEM is the first manifestation of MS (Dale and Pillai, 2007). Characteristic MRI lesions are diffuse and bilateral (Callen et al., 2009; Callen et al., 2009). The total lesion number does not help differentiating ADEM from MS, but the absence of a diffuse bilateral lesion pattern, the presence of black holes, and the presence of two or more periventricular lesions may predict MS (Callen et al., 2009). Symptoms are determined by location of lesions and severity of damage in the affected areas. Besides encephalopathy and neurological deficits, fever and seizures can be seen in

Table 2

Differential diagnosis of small vessel cPACNS.

Inflammatory -Primary small vessel CNS vasculitis -Secondary CNS vasculitis -Systemic rheumatic diseases (systemic lupus erythematosus, celiac disease, scleroderma, juvenile dermatomyositis, ANCA vascilitides, sarcoidosis) -systemic inflammatory diseases (inflammatory bowel disease (IBD), Kawasaki disease, Hemophagocytic lymphohistiocytosis (HLH)) -Demyelinating diseases -multiple sclerosis, ADEM, transverse myelitis -Neuronal antibody-associated inflammatory brain diseases -NMDA-receptor-associated encephalitis, antibody-mediated limbic encephalitis, neuromyelitis optica (NMO) -Hashimoto encephalitis, postmycoplasma encephalitis, celiac disease associated encephalitis, pediatric autoinflammatory neuropsychiatric disorder associated with streptococcal infections (PANDAS) -T-cell mediated inflammatory brain diseases -Rasmussen encephalitis -Granulomatous mediated IBrainD -Neurosarcoidosis, ANCA-associated vasculitis, adult primary CNS vasculitis Infectious/post-infectious -viral (VZV, HIV, EBV, CMV), bacterial (mycobacterium tuberculosis, mycoplasma pneumonia, streptococcus pneumoniae), fungal (aspergillus spp., candida albicans, actinomyces spp.) infections Metabolic diseases -Polymerase gamma deficiency (PolG) -Mitochondrial diseases (mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS), rolandic mitochondrial encephalomyopathy (ROME)) Neoplastic -Angiocentric lymphoma

CNS vasculitis in children children with ADEM (Neuteboom et al., 2008). There is no specific diagnostic test. In CSF of ADEM patients oligoclonal bands (OCB) are rarely present (0–10%) in contrast to MS (490%) (Alper et al., 2009; Dale and Pillai, 2007; Pohl et al., 2004). Patients may have elevated CSF cell counts and protein levels. MS most is a polyphasic, immune-mediated demyelinating disease of the CNS. It is seen mostly in adult patients, however 3–10% will have an onset before the age of 18 years (Banwell et al., 2011). Early childhood onset MS does not show the female predominance seen in adult MS, rather an equal distribution of boys and girls (Banwell et al., 2011; Banwell et al., 2007). Family history is positive for MS in 6– 8% of children with childhood onset MS and 20% in adult onset MS. As in ADEM, acute symptoms are determined by location of lesions and severity of damage. In many cases, chronic deficits accumulate over time. Most frequent presenting symptoms are; motor dysfunction (30%), sensory dysfunction (15–30%), brainstem function (25%), optic neuritis (10–22%), and ataxia (5–15%) (Banwell et al., 2007). There is no specific laboratory test for MS. MRI findings, supportive laboratory studies, and the clinical course are used to make the diagnosis. On MRI, well-defined lesions and the presence of lesions perpendicular to corpus callosum were found to be highly specific for MS (Callen et al., 2009; Callen et al., 2009). TM is an acute, severe monophasic illness clinically presenting as acute spinal cord dysfunction. It can occur in the context of infectious or rheumatic diseases, can represent a manifestation of primary CNS vasculitis or the sentinel event of a chronic autoimmune disorder, such as MS or NMO (Thomas et al., 2011). TM has multiple inflammatory etiologies including antibody mediated cytotoxicity, small vessel vasculits, occlusive vasculopathy and demyelination (REF). Consensus criteria for TM diagnosis include sensory, motor, or bladder and bowel dysfunction attributable to the spinal cord, with progression to nadir in less than 21 days from onset (Thomas et al., 2011). Diagnosis is based on clinical examination, CSF studies (typically showing pleiocytosis), and MRI that may reveal focal or extensive inflammatory lesions. In the recent years, novel antibody-mediated inflammatory brain diseases have been reported in children and adults (Graus et al., 2010). These conditions were first identified in patients with malignancies and thought to be solely paraneoplastic in nature. In children the neoplasms encountered most frequently are neuroblastoma, Hodgkin’s lymphoma, mullerian carcinomas, seminoma and thymoma. More recently antibody-mediated IBrainD are increasingly recognized in the absence of malignancies. These diseases are caused by antibodies directly targeting the CNS or antibodies associated to a systemic disease crossing the blood-brain barrier. They can be classified in: (1) antibodies against the neuronal, glial nuclear and cytoplasmic antigens and (2) antibodies against neuronal cell surface antigens (ion channels, receptors and synapses) (Graus et al., 2010; Irani et al., 2010). Over the last few years antibodies targeting extracellular epitopes of synaptic receptors and components of transsynaptic protein complexes have also been identified in several forms of autoimmune encephalitis or epilepsy (Dalmau et al., 2008; Graus et al., 2010; Bien and Scheffer, 2011; Luca et al., 2011).

168 Anti-NMDAR encephalitis is a newly recognized inflammatory brain diseases. Children present with psychosis, seizures, movement disorders, decreased level of consciousness, and/or life threatening autonomic instability (Dalmau et al., 2008; Luca et al., 2011; Florance et al., 2009). Dalmau et al. (2008) reported 100 anti-NMDAR patients showing a female predominance. In this series all patients presented with psychiatric symptoms or memory problems. Rapid clinical deterioration may occur (Luca et al., 2011). The diagnosis is confirmed by a positive antiNMDAR antibody test of CSF and/or serum. CSF testing seems to be more sensitive than serum. Immunosuppressive treatment including immunoglobulines, prednisone and rituximab were reported (Luca et al., 2011; Florance et al., 2009). Encephalitis associated with antibodies against a-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), and g-amino-butyric acid-B receptor (GABAB-R) were reported (Graus et al., 2010). Specific antibodies can be found in other diseases: anti TPO antibodies associated with Hashimoto encephalitis, Streptococcus antibodies in pediatric autoinflammatory neuropsychiatric disease associated with streptococcus (PANDAS) (de Oliveira, 2007), and TTG-antibodies in encephalitis associated with celiac disease (Cross and Golumbek, 2003). Neuromyelitis optica (NMO) is an increasingly recognized antibody-mediated inflammatory brain diseases associated with NMO-IgG autoantibodies and aquaporin-4 autoimmunity (Banwell et al., 2008). The clinical phenotype of NMO spectrum disease includes the characteristically sequential or concomitant optic neuritis and transverse myelitis and encephalopathy, seizures, intractable vomiting and brainstem mediated hiccups (Lotze et al., 2008; Alper and Wang, 2009). The NMO antibody is directed against aquaporin 4 (NMO-IgG). In adults, the reported outcome of NMO is poor with marked visual loss or paralysis in 60% (Banwell et al., 2008; Wingerchuk et al., 1999; Wingerchuk et al., 2007). The typical pattern of NMO MRI lesions includes optic nerves, periventricular and periaquaductal regions. Longitudinally extensive spinal cord lesions are also common. Clinical and MRI imaging features markedly overlap with other inflammatory brain diseases such as SV-cPACNS and demyelinating diseases.

3.

Summary and conclusion

Childhood primary CNS vasculitis is an increasingly recognized inflammatory brain disease. Distinct clinical subtypes of cPACNS have been identified. Specific clinical, laboratory and imaging features can expedite the diagnostic evaluation. In some children, invasive tests, such as an elective brain biopsy, are mandatory. Early tailored treatment regimens target vascular inflammation, leading to increased survival and decreased longterm morbidity. However, overlapping clinical, laboratory and imaging features represent a challenge in the care of children with inflammatory brain diseases. Active, ongoing, multicenter and interdisciplinary research will further increase our understanding of childhood CNS vasculitis, lead to biomarker discovery and will improve the long-term outcome.

169

4.

M. Twilt, S.M. Benseler

Keypoints

 Childhood CNS vasculitis is an increasingly recognized     

cause of devastating neurological deficits in previously healthy children. Inflammatory markers have moderate sensitivity and limited specificity in cPACNS. Inflammatory brain lesions are commonly detected on MRI. Gadolinium enhanced vessel wall imaging attributes to differentiate between inflammatory and noninflammatory large vessel processes. Brain biopsies are currently mandatory, when suspecting angiography-negative small vessel cPACNS. Treatment regimens are available for P-cPACNS and SVcPACNS. Adjunctive corticosteroid therapy remains controversial in NP-cPACNS. Childhood inflammatory brain diseases share clinical, laboratory and imaging features. The diagnostic evaluation requires detailed knowledge and thorough investigation of the distinct disease entities in the spectrum of inflammatory brain diseases.

Conflict of interest statement Both authors declare to have no conflict of interest.

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