Intrathecal antibody production against Epstein-Barr and other neurotropic viruses in pediatric and adult onset multiple sclerosis.

Epstein-Barr virus (EBV) has been implicated in the pathogenesis of multiple sclerosis (MS). Recent reports proposed an increased EBV-targeted humoral immune response in MS, which appears to be more pronounced in pediatric patients. However, little is known about the CNS-derived antibody production against EBV in patients with MS. The objective of this study was to assess the frequency and intensity of intrathecal antibody production against EBV as compared to other neurotropic viruses in pediatric and adult onset MS. In cohorts of 43 childhood, 50 adult onset MS patients, 20 children and 12 adults with other CNS disorders, paired CSF and serum samples were studied. Frequency and intensity of intrathecal antibody production against EBV as compared to measles, rubella, varicella zoster (VZV) and herpes simplex virus (HSV) were analyzed by determination of virus-specific CSF-to-serum Antibody Indices (AI). Intrathecally synthesized EBV antibodies were detectable in 26% pediatric and 10% adult onset MS patients, compared to frequencies ranging in both groups from 10 to 60% for the other viruses. Median AIs for EBV were lower than those for all other viruses, with more than twofold higher median AI for measles, rubella and VZV. The EBV-targeted humoral immune response in the CNS is only part of the intrathecal polyspecific antibody production in MS, directed against various neurotropic viruses. Our results do not rule out the possibility that EBV is involved in the pathogenesis of MS by triggering diverse cellular immune mechanisms, but they argue against a direct pathogenic role of EBV-targeted humoral immune response within the CNS.

Early reduction of total N-acetyl-aspartate-compounds in patients with classical vanishing white matter disease. A long-term follow-up MRS study.

The neuropathology of vanishing white matter (VWM) disease is characterized by a loss of white matter (WM). Although recent histopathological studies suggest a primary glial dysfunction, the purpose of this work was to assess the extent of axonal involvement in VWM using long-term follow-up proton MR spectroscopy. White and gray matter of nine children with genetically proven VWM and late infancy/early childhood onset were investigated with short-echo time, single-voxel proton MR spectroscopy over up to 8 years starting as early as less than 2 years after the onset of symptoms (5 patients). Total N-acetyl-aspartate (-51% from normal control), creatine and phosphocreatine (-47%), and myo-inositol (-49%) were reduced in WM at early disease stages. Choline-containing compounds were less severely decreased (-31%). Follow-up investigations revealed progressive reduction of all metabolites in WM. In gray matter, no distinct changes were detected at early stages. Later total N-acetyl-aspartate decreased slightly (-22%). Assuming the metabolite alterations to primarily reflect changes in cellular composition, the observed pattern indicates early axonal involvement or loss as well as relatively enhanced turnover of myelin. These early stages are followed by a complete cellular loss in cerebral WM.

Common infectious agents in multiple sclerosis: a case-control study in children.

Environmental factors, in particular infections, have been linked with the risk of developing multiple sclerosis (MS). The association of Epstein-Barr virus infection with childhood onset of MS has been recently recognized. As other infections characteristically experienced during childhood have not yet been studied in larger cohorts of paediatric MS, we conducted a study on 152 German children with MS (age at onset <16 years) and matched controls in the hope of gaining evidence for their possible aetiological role in MS. Patterns of antibody responses were determined to a range of infections which, in prior studies principally on adult patients, had revealed possible associations with MS. In this study on children the serology of several infections showed associations with MS. In the exceptional case of Chlamydia pneumoniae there was a significantly higher prevalence of IgM antibody but, more typically, as in the case of influenza A, measles, parainfluenza 2, varicella/zoster viruses and particularly to the herpes simplex virus type 2 (HSV-2) lysate antigen, there were significantly higher concentrations of IgG antibody. Additional investigations, however, make it highly unlikely that a relevant number of children have experienced infections with HSV-2. In general this study supports and emphasizes a complex infectious and immunologic background of MS.

Pediatric multiple sclerosis: a short history of a long story.

Shortly after multiple sclerosis (MS) was described by Charcot in 1872-1873, symptoms of MS were noted in children. At the time of these observations (late 19th century), the many inherited demyelinating diseases that manifest during childhood had not yet been recognized. Once the inherited demyelinating disorders became known, MS as a childhood disease was dismissed as a possible diagnosis. Only a half century later, with increased understanding of both inherited leukodystrophies as well as MS, was it acknowledged that children can develop MS. Our present challenges in the differential diagnoses of demyelinating disorders presenting in childhood are reflected in the history of pediatric MS.

Valproic acid-induced pancreatitis: 16 new cases and a review of the literature.

BACKGROUND: Acute pancreatitis is rarely seen in children, and, in contrast to cases in adults, it is often drug induced. One possible medication is the antiepileptic drug valproic acid (VPA), which is commonly prescribed for generalized and focal epilepsy, migraine, neuropathic pain, and bipolar disorder. The common side effects associated with VPA are typically benign, but less common but more serious adverse effects may occur. These include hepatotoxicity, hyperammonemic encephalopathy, coagulation disorders, and pancreatitis. Since 1979, a few cases of pancreatitis induced by VPA have been published in the medical literature. METHODS: We mailed a questionnaire to all members of the "German Section of the International League against Epilepsy," asking about VPA-induced side effects. We also reviewed the medical literature for VPA-induced pancreatitis. RESULTS: Fifty-three publications (90 patients) published from 1979 to 2005 were found. Our survey in Germany, however, yielded 16 cases of pancreatitis from 1994 to 2003 whose original files we could study in detail. None of these patients had been published previously. CONCLUSIONS: The difference between 90 patients reported worldwide from 1979 to 2005 and the 16 new documented cases from only Germany over 10 years corroborates that the occurrence of this severe side effect is under reported.

Paediatric multiple sclerosis and acute disseminated encephalomyelitis in Germany: results of a nationwide survey.

UNLABELLED: The aim of this study was to evaluate the incidence of paediatric multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) in Germany. In a prospective nationwide survey carried out between 1997 and 1999, all registered new cases of paediatric MS and ADEM with an onset before the age of 16 years were evaluated using a standardised questionnaire. A total of 132 patients with suspected or definite MS and 28 patients with an assumed diagnosis of ADEM were reported. Among these, 82% of the MS patients were 10 years of age or older, as opposed to 18% in the ADEM-cohort. The female-to-male ratio was 1.2:1 in the MS-cohort and 0.8:1 in the ADEM-cohort. Manifestation was polysymptomatic in 67% of the MS patients compared to 86% of the ADEM patients. The most frequent primary symptoms in the MS-cohort were cerebellar (44%), sensory (39%) or visual (36%), followed by brainstem (30%), pyramidal (29%) and cerebromental (22%) complaints. CONCLUSION: The incidence of paediatric MS in Germany is more than fourfold higher than that of paediatric ADEM; in addition, it shows a strikingly different age-distribution. With an estimated minimum of 50 new cases per year, the incidence of paediatric MS in Germany is much more frequent than previously believed.

Virchow-Robin spaces on magnetic resonance images of children with adrenoleukodystrophy.

BACKGROUND: Perivascular spaces of the brain, also known as Virchow-Robin spaces (VRS), are of immunological and neuropathological relevance and can be observed in magnetic resonance images (MRI). Their histopathological significance in X-linked adrenoleukodystrophy (ALD) has been reported. Aim of this study was to elucidate the prognostic or diagnostic value of VRS on MRI of the brain in the evaluation of onset or severity of the clinical course in ALD. METHODS: Clinical data and MRI from 35 patients with the cerebral form of X-ALD, 29 with the asymptomatic form (including those with adrenal insufficiency), and 36 control patients were studied retrospectively. RESULTS: VRS could be visualised by MRI in 87% of patients with asymptomatic ALD, in 80% of control patients, and in 47% of patients with cerebral ALD. None of them were found to be dilated. The number of visible VRS correlated negatively with the degree of demyelination both in patients with the cerebral and the asymptomatic form. Furthermore, in the group of patients with cerebral ALD the number of visible VRS correlated positively with a milder course of the disease. CONCLUSION: VRS on MRI of patients with ALD seem to reflect the perivascular inflammatory component of this disease. It is possible to speculate that the appearance or a higher number of visible VRS in ALD is associated with an earlier stage of the disease, or even a more benign clinical course.

Quantitative proton MRS of cerebral metabolites in laminin alpha2 chain deficiency.

Congenital muscular dystrophy (CMD) due to merosin (laminin alpha2 chain) deficiency is an autosomal recessively inherited disorder characterized by severe muscular weakness and hypotonia from birth on. Brain involvement is the rule and characterized by variable T2 hyperintensities of white matter which appears swollen on cranial MRI. The pathophysiology of these white matter changes is not clear. In five patients with laminin alpha2 deficient CMD we performed short-echo time localized proton MRS with determination of absolute metabolite concentrations in grey and white matter. In affected white matter, a consistent pattern of metabolites was detected comprising reduced concentrations of N-acetylaspartate and N-acetylaspartylglutamate, creatine, and phosphocreatine, and to a milder degree of choline-containing compounds. In contrast, concentrations of myo-inositol were in the normal range. Spectra of cortical and subcortical grey matter were normal. The observed metabolite profile is consistent with white matter edema, that is reduced cellular density, and relative astrocytosis. This interpretation is in line with the hypothesis that laminin alpha2 deficiency results in leakage of fluids across the blood-brain barrier and a histopathological report of astrocytic proliferation in CMD.

Recurrent optic neuritis associated with Chlamydia pneumoniae infection of the central nervous system.

It has been suggested that Chlamydia pneumoniae (C. pneumoniae) is involved in the pathogenesis of diverse diseases of the central nervous system (CNS), including multiple sclerosis. We report the case of a 12-year-old male with isolated recurrent optic neuritis and an associated CNS infection with C. pneumoniae. The patient presented with three attacks of optic neuritis within 5 months. A positive polymerase chain reaction for C. pneumoniae in the cerebrospinal fluid led to the diagnosis of a CNS infection with C. pneumoniae. After treatment with the antibiotic rifampicin, he experienced no further attacks during the follow-up period of 6 years. These findings suggest the possibility of a C. pneumoniae infection as a contributing factor or even causative event for the development of optic neuritis.

Virchow-Robin spaces on magnetic resonance images: normative data, their dilatation, and a review of the literature.

INTRODUCTION: Virchow-Robin spaces (VRS) are perivascular spaces in the brain and can be visualized on magnetic resonance images (MRI). We attempt to provide a better understanding of the significance of VRS for pathological and physiological processes by reviewing the literature, presenting normative data for the first time, and proposing a definition for the dilatation of the VRS on MRI that is based on shape rather than size. METHODS: We evaluated the VRS in 125 healthy subjects (age range 1-30 years) using high-resolution 3D images, and in 36 patients (age range 2-16 years) with normal MRI, using routine clinical sequences. RESULTS: VRS were visible in all high-resolution images of the 125 healthy subjects. Two of them revealed dilated VRS, giving a prevalence of 1.6%. VRS could be visualized in 29 (80%) of the 36 paediatric clinical scans; none was dilated. It was demonstrated that the visibility of VRS on MRI is sequence-dependent. CONCLUSION: From the results of this study and the literature on the nature and pathology of VRS, we conclude that VRS on MR images of healthy individuals are normal findings, even if they are dilated. A judgement on whether dilated VRS in an individual patient is a normal variant or part of a disease process can be made by taking into account the appearance of the adjacent tissue on MRI and the clinical context.

Pediatric multiple sclerosis: detection of clinically silent lesions by multimodal evoked potentials.

Pediatric patients with multiple sclerosis (MS) frequently do not meet MRI criteria for diagnosis because of lack of evidence of dissemination in space. We assessed the diagnostic utility of multimodal evoked potentials (EP). In 46% of 85 childhood patients with MS, spatial dissemination was detected by EP before the second clinical attack. EP may constitute an important tool for earlier diagnosis of pediatric MS.

Magnetic resonance imaging and proton magnetic resonance spectroscopy of megalencephaly and dilated Virchow-Robin spaces.

Megalencephaly with dilated Virchow-Robin spaces has been suggested to represent a new clinical entity. This report describes two males and a female who have been monitored from pregnancy. The patients manifest a relatively normal psychomotor development with some minor neurologic symptoms such as mild muscle hypotonia and clumsy motor performance. Biochemical and electrophysiologic tests were normal. In the white matter of the brain, a prominent dilatation of the Virchow-Robin spaces with some adjacent signal alterations could be demonstrated by magnetic resonance imaging. Magnetic resonance spectroscopy revealed normal metabolite concentrations in the cortical and deep gray matter and normal-appearing white matter. Affected white matter was characterized by mildly reduced to normal levels of myo-inositol and a decrease of all other metabolites including total N-acetyl moieties, choline-containing compounds, and total creatine. These data indicate that the dilatation of Virchow-Robin spaces reflects an underlying brain pathology causing neuroaxonal damage. Possible differential diagnoses are discussed.

X-linked paroxysmal dyskinesia and severe global retardation caused by defective MCT8 gene.

We previously reported two unrelated boys aged 3 and 8 years with mutations in the thyroid hormone transporter gene MCT8 resulting in severe global retardation and an uncommon pattern of thyroid hormone abnormalities. We now further describe an unusual neurological phenotype associated with these mutations, namely paroxysmal kinesigenic dyskinesias (PKD), provoked by certain stimuli including changing of their clothes or diapers. It is not clear how the MCT8 defect causes PKDs. PKDs have been previously noted in patients with thyroid abnormalities. This novel X-linked condition widens the spectrum of secondary PKDs.

Identification of ten novel mutations in patients with eIF2B-related disorders.

Autosomal recessive inherited mutations in each of the five eukaryotic initiation factor 2B (eIF2B) subunits are known to cause white matter abnormalities with a wide continuum of clinical signs and severity leading to the concept of eIF2B-related disorders. The clinical spectrum extends from fatal infantile forms to adult forms with slow or absent neurological deterioration. In this study 15 well-characterised patients with the classical form of leukoencephalopathy with vanishing white matter (VWM) or with phenotypic variants like ovarioleukodystrophy were investigated for mutations in the genes EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5 encoding eIF2B. We identified one novel nonsense mutation (EIF2B4, c.625C>T, p.Arg209X), one novel frameshift mutation (EIF2B5, c.453_454del, p.Tyr152fsX12), eight novel missense muations (EIF2B1, c.547G>T, p.Val183Phe; EIF2B2, c. 586C>T, p.Pro196Ser; EIF2B4, c.806T>G, p.Leu269Arg; EIF2B5, c.203T>C, p.Leu68Ser; EIF2B5, c.220G>A, p.Ala74Thr; EIF2B5, c.805C>G, p.Arg269Gly; EIF2B5, c.929G>T, p.Cys310Phe; EIF2B5, c.1003T>C, p.Cys335Arg), and eight previously described alterations.

Treatment of early onset multiple sclerosis with subcutaneous interferon beta-1a.

The authors studied the tolerability of subcutaneous interferon beta-1a (IFNbeta-1a) in 51 patients with early-onset multiple sclerosis. The most frequent systemic adverse effects were flu-like symptoms in 65%. Laboratory abnormalities included asymptomatic leukopenia (27%) and elevated hepatic transaminases (35%). Treatment with IFNbeta-1a was safe and well tolerated in the majority of children and adolescents.

Ullrich congenital muscular dystrophy: connective tissue abnormalities in the skin support overlap with Ehlers-Danlos syndromes.

Ullrich congenital muscular dystrophy (UCMD) is caused by mutations in the three genes coding for the alpha chains of collagen VI and characterized by generalized muscle weakness, striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints, and normal intellectual development. The diagnosis is supported by abnormal immunoreactivity for collagen VI on muscle biopsies. As patients with UCMD show clinical characteristics typical of classical disorders of connective tissue such as Ehlers-Danlos syndromes (EDS), we investigated the ultrastructure of skin biopsy samples from patients with UCMD (n=5). Electron microscopy of skin biopsies revealed ultrastructural abnormalities in all cases, including alterations of collagen fibril morphology (variation in size and composite fibers) and increase in ground substance, which resemble those seen in patients with EDS. Our findings suggest that there is a true connective tissue component as part of the phenotypic spectrum of UCMD and that there is considerable clinical as well as morphological overlap between UCMD and classic connective tissue disorders.

Monocyte/macrophage differentiation in dermatomyositis and polymyositis.

Recent advances have revealed significant differences in the pathogenesis of inflammatory myopathies. To determine whether different patterns of macrophage differentiation are a useful tool to delineate the major groups of inflammatory myopathies, the muscle biopsies of 11 patients with dermatomyositis and 12 patients with polymyositis were studied using different macrophage markers. In polymyositis, the early-activation markers MRP14 and 27E10 stained the majority of macrophages, which were recognized by the pan-macrophage marker Ki-M1P and which were located primarily in the endomysium. In dermatomyositis, macrophages predominantly expressed the late-activation marker 25F9 and were found mainly in the perimysium. Thus, the location and presence of different subsets of macrophages distinguish dermatomyositis and polymyositis. The predominance of early-activated macrophages in polymyositis indicates a more acute disease process. The findings in dermatomyositis, by contrast, suggest a role of persistent monocytes/macrophages in the disease process.

Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene.

Desmin-related myopathies (DRMs) are a heterogeneous group of muscle disorders, morphologically defined by intrasarcoplasmic aggregates of desmin. Mutations in the desmin and the alpha-B crystallin genes account for approximately one third of the DRM cases. The genetic basis of the other forms remain unknown, including the early-onset, recessive form with Mallory body-like inclusions (MB-DRMs), first described in five related German patients. Recently, we identified the selenoprotein N gene (SEPN1) as responsible for SEPN-related myopathy (SEPN-RM), a unique early-onset myopathy formerly divided in two different nosological categories: rigid spine muscular dystrophy and the severe form of classical multiminicore disease. The finding of Mallory body-like inclusions in two cases of genetically documented SEPN-RM led us to suspect a relationship between MB-DRM and SEPN1. In the original MB-DRM German family, we demonstrated a linkage of the disease to the SEPN1 locus (1p36), and subsequently a homozygous SEPN1 deletion (del 92 nucleotide -19/+73) in the affected patients. A comparative reevaluation showed that MB-DRM and SEPN-RM share identical clinical features. Therefore, we propose that MB-DRM should be categorized as SEPN-RM. These findings substantiate the molecular heterogeneity of DRM, expand the morphological spectrum of SEPN-RM, and implicate a necessary reassessment of the nosological boundaries in early-onset myopathies.