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Progressive myoclonic epilepsy (PME) is a heterogeneous group of epilepsies characterized by myoclonus, seizures and progressive neurological symptoms. The index patient was a 6-year old boy showing early-onset therapy resistant PME and severe developmental delay. Genome-wide linkage analysis identified several candidate regions. The potassium channel tetramerization domain containing 7 gene (KCTD7) in the 7q11.21 linkage region emerged as a suitable candidate. Sequence analysis revealed a novel homozygous missense mutation (p.R94W) in a highly conserved segment of exon 2. This is the second family with PME caused by KCTD7 mutations, hence KCTD7 mutations might be a recurrent cause of PME., (© 2012 The Authors Annals of Human Genetics © 2012 Blackwell Publishing Ltd/University College London.) more...

Objective: To study the humoral immune response directed at myelin oligodendrocyte glycoprotein (MOG)in pediatric patients with isolated and recurrent optic neuritis(ON)., Design: Observational prospective case series., Setting: Six pediatric hospitals in Germany and Austria., Patients: Thirty-seven patients 18 years or younger with single or recurrent episodes of ON were recruited from 6 different hospitals., Main Outcome Measures: Clinical features, magnetic resonance imaging findings, intrathecal IgG synthesis,and outcome were recorded. A live cell–based immunofluorescence assay was used to measure serum IgG antibodies to MOG and aquaporin 4., Results: A single episode of ON was observed in 10 patients,and 15 experienced 2 to 12 episodes. The acute episode of ON was part of a clinically isolated syndrome in 12 patients, of whom 8 were subsequently classified as having multiple sclerosis. High-titer serum MOG-IgG antibodies (1:160) were detected in 17 patients (46%).In addition, high titers of MOG-IgG antibodies were more frequently observed in 12 of the 15 patients with recurrent episodes of ON (80%; median titer, 1:640)compared with 2 of the 10 patients with monophasic ON(20%; median titer, 0) and 3 of the 12 patients with ON as part of a clinically isolated syndrome (25%; median titer, 0)., Conclusion: High-titer MOG-IgG antibodies are predominantly detected in pediatric patients with recurrent ON, indicating that anti-MOG-specific antibodies may exert a direct role in the pathogenesis of ON in this subgroup. more...

This review is a summary of the most important clinical findings and implications of tick-borne encephalitis (TBE) in children. It is based on a Pubmed search with the terms "tick-borne encephalitis", "children", "infection", "meningitis", "meningoencephalitis", and "outcome". TBE in children shares several features with their adult counterpart but has overall a better prognosis. Nevertheless, TBE is associated with substantial morbidity and mortality in a small group of children and seems to cause cognitive dysfunctions, which needs to be studied in further detail. more...

Deletions of the short arm of chromosome 19 are rarely found by conventional cytogenetic techniques. This region has a high gene density and this is likely the reason why deletions in this region are associated with a severe phenotype. Since the implementation of modern high-resolution SNP- and CGH-array techniques more cases have been reported. Here, we present an almost 5-year-old boy with intellectual disability, minor dysmorphisms, febrile seizures, and a de novo deletion of 834.2 kb on 19p13.2 encompassing 32 genes. The deletion was found by the Illumina Infinium HD Human1M-Duo v1 BeadChip SNP-array and confirmed by the NimbleGen Human CGH 2.1M Whole Genome Tiling v2.0D oligonucleotide array. PCR amplification of the junction fragment and subsequent sequencing defined the breakpoints and indicated that formation was mediated by non-allelic homologous recombination (NAHR). The phenotype of our patient shows that microrearrangements even at gene-dense chromosomes may result in mild clinical consequences., (Copyright © 2012 Wiley Periodicals, Inc.) more...

Citrullinemia is a urea cycle disorder caused by deficiency of argininosuccinate synthetase. Late onset forms can remain undiscovered until a decompensation that can resemble encephalitis. Herein, we report a 14-year old patient with suspected encephalitis with fluctuating episodes of confusion. EEG mainly showed bilateral slowing with some spikes plus spike waves; and was interpreted as suspicious for encephalitis. Brain MRI was normal. Leukocytes in CSF were slightly elevated. Treatment for a CNS infectious disease was begun. Symptoms did not resolve and there were several episodes of confusion, so a repeat lumbar puncture was performed according to a standardized protocol including an amino acid profile. An elevation of citrulline in CSF was found, which ultimately led to the diagnosis of a late onset citrullinemia. The establishment of this diagnosis will protect the patient from the sequelae of unrecognized and thus untreated episodes of hyperammonemia. Thus, following a standardized lumbar puncture protocol can be essential to detect patients with otherwise unrecognized underlying metabolic disorders that are not suspected because of clinical symptoms. In addition, it is important to stress that an ammonia concentration should be determined in any patient with neurological signs like confusion., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.) more...

NBIA/HSS is a neurodegenerative disorder associated with iron accumulation in specific brain regions. To date, the diagnosis is obtained by typical MRI changes followed by genetic mutation analysis. This procedure is laborious and limited to a few specially equipped medical centres. Since transcranial sonography (TCS) is widely used for the early diagnosis of PD in adults displaying parenchymal metal deposits, it is likely to be a reliable diagnostic tool for the early diagnosis of NBIA. In 7 patients with proven NBIA and 13 age-matched controls without record of neurological disease TCS was performed by an experienced ultrasound examiner. Data were analysed by two blinded investigators regarding hyperechogenicity and size of the substantia nigra (SN). SN size and hyperechogenicity was significantly increased in patients with NBIA compared to controls (students t-test: p < 0.001). TCS appears to be a non-invasive and inexpensive screening technique in patients with suspected NBIA. Performed by an experienced physician, it could enable an earlier diagnosis and pre-selection of patients for the MRI scan and genetic testing, which are still the diagnostic gold standard., (Copyright © 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.) more...

Background: Serum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved., Results: We analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels., Conclusions: We could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HR-NMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4-directed humoral immune response. more...

We describe a case of a woman with epilepsy treated with primidone/phenobarbital (so-called "old" antiepileptic drug) and levetiracetam (so-called "new" antiepileptic drug) who was discouraged from breastfeeding, resulting in clinically significant withdrawal seizures in her newborn. As a consequence, even when two or more antiepileptic drugs are needed for the treatment of women with epilepsy, breastfeeding should be recommended, mothers should be informed about the possibility of drug effects on the neonate, and infants of mothers treated with primidone/phenobarbital should be closely monitored for possible signs of sedation., (Copyright © 2011 Elsevier Inc. All rights reserved.) more...

Recent studies demonstrated the presence of autoantibodies to native myelin oligodendrocyte glycoprotein (MOG) in juvenile patients with acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS). However, so far no longitudinal studies on anti-MOG antibodies have been performed. Therefore, we determined serum and CSF antibodies against native human MOG in 266 pediatric and adult subjects with ADEM, clinically isolated syndrome (CIS), MS, other neurological diseases (OND) and healthy controls (HC) and longitudinal samples of 25 patients with ADEM, CIS, MS and OND using an immunofluorescence assay. We detected serum high-titer MOG IgG in 15/34 (44%) patients with ADEM, but only rarely in CIS (3/38, 8%), MS (2/89, 2%), OND (1/58, 2%) and HC (0/47). Longitudinal analysis of serum anti-MOG IgG showed different temporal dynamics of serum antibody responses in ADEM, CIS and MS and indicated an association of a favorable clinical outcome in ADEM with a decrease in antibody titers over time., (Copyright © 2010 Elsevier Inc. All rights reserved.) more...

About 3-5% of all patients with multiple sclerosis experience the onset of their disease under the age of 16. A significant proportion of paediatric multiple sclerosis patients develop significant cognitive disturbances and persistent physical disability. The high relapse rate and the morbidity in the paediatric multiple sclerosis population has triggered the use of disease-modifying therapies that have been shown to reduce relapse rate, disease progression and cognitive decline in adult patients with multiple sclerosis. Hard evidence for the right treatment and its appropriate timing is scarce in paediatric multiple sclerosis. Nevertheless, expertise in this field has grown thanks to recent open-label trials and experience generated in specialized centres. In spring 2009, a first meeting was held in Rotterdam with clinicians from 11 European countries (one from Canada) that are all active in the management of paediatric multiple sclerosis. One of the aims was to generate a common view on the management of paediatric multiple sclerosis patients. The result of this meeting is presented here to help standardize treatment and to support clinicians with less experience in this field. more...

The objective of the study is to analyze plasma amino acid concentrations in propionic acidemia (PA) for the purpose of elucidating possible correlations between propionyl-CoA carboxylase deficiency and distinct amino acid behavior. Plasma concentrations of 19 amino acids were measured in 240 random samples from 11 patients (6 families) with enzymatically and/or genetically proven propionic acidemia (sampling period, January 2001-December 2007). They were compared with reference values from the literature and correlated with age using the Pearson correlation coefficient test. Decreased plasma concentrations were observed for glutamine, histidine, threonine, valine, isoleucine, leucine, phenylalanine and arginine. Levels of glycine, alanine and aspartate were elevated, while values of serine, asparagine, ornithine and glutamate were normal. For lysine, proline and methionine a clear association was not possible. Significant correlations with age were observed for 13 amino acids (positive correlation: asparagine, glutamine, proline, alanine, histidine, threonine, methionine, arginine; negative correlation: leucine, phenylalanine, ornithine, glutamate and aspartate). This study gives new insight over long-term changes in plasma amino acid concentrations and may provide options for future therapies (e.g., substitution of anaplerotic substances) in PA patients. more...

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. more...

The influence of levetiracetam (LEV) and valproic acid (VPA) monotherapy on sex-steroid hormone profile was investigated in thirty prepubertal children. VPA-treated children showed greatest androstendione concentrations when compared to LEV treated children (p=0.016) and to controls (p=0.011). All other reproductive endocrine hormones were similar among groups. In conclusion, LEV does not seem to induce changes in reproductive endocrine functions as well as clinically relevant endocrine side effects in prepubertal children. more...

Introduction: The cardio-neuro-endocrine axis seems to be involved in the cascade of postictal events in children. The aim of this study was to assess the relationship between childhood epilepsy and cerebrospinal fluid (CSF) or serum concentrations of the N-terminal pro B-type natriuretic peptide (NT-proBNP) interictally., Methods: A total of seventy-four children agreed to participate in the study. Twenty-two children with epilepsy and mild developmental delay (mean+/-SD [median] age 5.8+/-4.9 [4.3] years), 15 children with newly diagnosed multiple sclerosis (MS) (15.1+/-1.4 [15.3] years) and 37 children with cryptogenic mild developmental delay (8.0+/-4.6 [7.4] years), serving as controls, were eligible., Results: In children with epilepsy, interictal CSF NT-proBNP concentrations were greater when compared to the MS group and to controls (mean+/-SD [median] 193.0+/-78.1 [176.0]ng/L vs. 147.8+/-60.2 [138.0]ng/L vs. 140.4+/-36.5 [134.0]ng/L; p=0.014 and p=0.009). In contrast, serum NT-proBNP concentrations and the CSF/serum NT-proBNP ratio did not differ between groups., Discussion: Greater CSF NT-proBNP concentrations in children with epilepsy may reflect an unspecific activation of the cardio-neuro-endocrine system involving endocrinological stress-response mechanisms interictally. The relationship between epilepsy and the cardio-neuro-endocrine axis may further the understanding of seizure susceptibility in children as well as influences of epilepsy on central modulation of autonomic cardiovascular control. more...

Multiple sclerosis (MS) typically manifests in early to mid adulthood, but there is increasing recognition of pediatric-onset MS, aided by improvements in imaging techniques. The immunological mechanisms of disease are largely unexplored in pediatric-onset MS, in part because studies have historically focused on adult-onset disease. We investigated autoantibodies to myelin surface Ags in a large cohort of pediatric MS cases by flow cytometric labeling of transfectants that expressed different myelin proteins. Although Abs to native myelin oligodendrocyte glycoprotein (MOG) were uncommon among adult-onset patients, a subset of pediatric patients had serum Abs that brightly labeled the MOG transfectant. Abs to two other myelin surface Ags were largely absent. Affinity purification of MOG Abs as well as competition of binding with soluble MOG documented their binding specificity. Such affinity purified Abs labeled myelin and glial cells in human CNS white matter as well as myelinated axons in gray matter. The prevalence of such autoantibodies was highest among patients with a very early onset of MS: 38.7% of patients less than 10 years of age at disease onset had MOG Abs, compared with 14.7% of patients in the 10- to 18-year age group. B cell autoimmunity to this myelin surface Ag is therefore most common in patients with a very early onset of MS. more...

Idiopathic hypothalamic dysfunction is a rare disorder presenting at age 3-7 years. Severe hypothalamic and brainstem dysfunction leads to death in 25% of patients. The disease is presumed to be autoimmune, or in some cases paraneoplastic. No successful treatment has been reported. Patient V. developed hyperphagia, hypersomnia, and extreme aggression at age 7 years, accompanied by episodes of hyperthermia, hypothermia, sinus bradycardia, hypernatremia, hyponatremia, persistent hyperprolactinemia, hypothyroidism, and growth-hormone deficiency. At age 9 years, a diagnosis of idiopathic hypothalamic dysfunction was rendered, and immunoglobulin therapy was commenced. Nine courses of immunoglobulins, at a dose of 2 g/kg every 4 weeks, were administered. Reproducible improvements in behavior and no further episodes of hyponatremia or hypernatremia and sinus bradycardia were evident. The endocrinologic abnormalities and poor thermoregulation remained. Administration of immunoglobulins during late stages of idiopathic hypothalamic dysfunction led to improvement in some but not all signs. Assuming an autoimmune basis for this disorder, treatment during early stages of disease should be more effective. To facilitate such early treatment, increased awareness of this disorder is necessary, to allow for early diagnosis. more...

Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system affecting young adults. Although adults and children share important features of the disease, they also differ in some clinical, radiological and laboratory aspects. This review focuses on the neuroimmunological findings in the cerebrospinal fluid of children with MS pointing out that there is already at earliest time of clinical manifestation a neuroimmunological pattern, which differs only in intensity of the humoral immune response but not in frequency and does not support a neuroimmunological difference between early onset from adult onset MS. The humoral immune response with intrathecal IgG and IgM class response and the polyspecific production of antibodies against a wide range of antigens (MRZ antibody response) further helps to differentiate childhood MS from ADEM as the main differential diagnostic challenge. more...

The effects of a long-term ketogenic diet in children with Glut1 deficiency syndrome on metabolism are unknown. Our results indicate a characteristic effect of a long-term ketogenic diet on glucose and lipid homeostasis in Glut1 deficiency syndrome. Although serum lipids and apolipoproteins reflect a proatherogenic lipoprotein profile, adipocytokine constellation is not indicative of enhanced cardiovascular risk. more...

Distinct mechanisms such as humeral immunity in dermatomyositis (DM) and T-cell-mediated cytotoxicity in polymyositis (PM) contribute to the pathology of inflammatory myopathies. In addition, different subsets of macrophages are present in both diseases. Herein, the characteristics of 25F9-positive macrophages in skeletal muscle inflammation are outlined. Muscle biopsies of subjects with DM and PM were studied by immunohistochemical multi-labelling using the late-activation marker 25F9, together with markers characterizing macrophage function including IFN-gamma, iNOS, and TGF-beta. In PM, a robust expression of IFN-gamma, iNOS, and TGF-beta was observed in inflammatory cells. Double- and serial-labelling revealed that a subset of 25F9-positive macrophages in the vicinity of injured muscle fibres expressed iNOS and TGF-beta, but not IFN-gamma. In DM, IFN-gamma, iNOS and TGF-beta were also expressed in inflammatory cells in the endomysium. Double- and serial-labelling studies in DM indicated that 25F9-positive macrophages expressed TGF-beta and to a lesser degree iNOS, but not IFN-gamma. In conclusion, our data suggest that late-activated macrophages contribute to the pathology of inflammatory myopathies. more...

Chronic antiepileptic therapy with valproic acid (VPA) is associated with increased body weight and insulin resistance in adults and children. Attempts to determine the underlying pathophysiologic mechanisms have failed. Adipocytokines have recently been defined as a link between glucose and fat metabolism. We herein demonstrate that VPA-associated overweight is accompanied by lower adiponectin and higher leptin concentrations in children. The absence of any relationship with visfatin concentration does not suggest a role of this novel insulin-mimetic hormone in VPA-associated metabolic alterations. Therefore, adiponectin and leptin but not visfatin may be considered as potential regulators of glucose and fat metabolism during VPA-therapy. more...

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. more...

Opsoclonus-myoclonus syndrome (OMS) is a rare and debilitating disorder of unknown etiology affecting children and adults. Outcome is unfavourable; approximately 80% of children with OMS suffer from mild to severe neurological handicaps, mainly cognitive impairment. A standard therapy does not exist. Due to the possible immune-mediated mechanisms, treatment with steroids, ACTH, plasmapheresis and immunoglobulins can be successful. However, some children become steroid dependent and symptoms may reoccur after treatment has been finished. We present two girls with OMS, who had a prolonged clinical course lasting 4 and 9 years with many relapses. Both children developed symptoms around the age of two years. Diagnostic work-up to exclude neuroblastoma was negative. Several treatment modalities including oral steroids, dexamethasone pulses, immunoglobulin and cyclosporine were used without lasting success. In addition, cognitive impairment developed in both children. In order to prevent further clinical and mental deterioration, 6 pulses of cyclophosphamide in combination with dexamethasone pulses every 4 weeks were administered. Both children showed significant improvement of OMS symptoms. One girl is still symptom free 18 months after treatment, mild ataxia developed in the other after 12 months. Both children are mentally handicapped and in special need schools. We conclude that combination of cyclophosphamide pulses and dexamethasone pulse therapy is a therapeutic option even after a long clinical course to improve symptoms of OMS. more...

Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified. more...

Nd:YAG, argon and diode lasers have been used in neurosurgical procedures including neuroendoscopy. However, many neurosurgeons are reluctant to use these lasers because of their inappropriate wavelength and uncontrollable tissue interaction, which has the potential to cause serious complications. Recently, a 2.0-microm near infrared laser with adequate wavelength and minimal tissue penetration became available. This laser was developed for endoscopic neurosurgical procedures. It is the aim of the study to report the initial experiences with this laser in neuroendoscopic procedures. We have performed 43 laser-assisted neuroendoscopic procedures [multicompartmental congenital, posthaemorrhagic or postinfectious hydrocephalus (n = 17), tumour biopsies (n = 6), rescue of fixed and allocated ventricular catheters (n = 2), endoscopic third ventriculostomy (ETV, n = 17) and aqueductoplasty (n = 1)] in 41 patients aged between 3 months and 80 years. The laser beam was delivered through a 365-microm bare silica fibre introduced through the working channel of a rigid endoscope. It was used for the opening of cysts, perforating the third ventricular floor, and for coagulation prior to and after biopsy. The therapeutic goals [creating unhindered cerebrospinal fluid (CSF) flow between cysts, ventricles and cisterns, sufficient tissue samples for histopathological diagnosis and catheter rescue] were achieved in 40 patients by the first and in 2 patients by a second neuroendoscopic operation. In one child, a CSF shunt was later required despite patency of the created stoma proven by magnetic resonance imaging (MRI). In another patient ETV was abandoned due to a tiny third ventricle. There was neither mortality nor transient or permanent morbidity. The authors conclude that the use of the 2.0-microm near infrared laser enables safe and effective procedures in neuroendoscopy. more...

Opsoclonus-myoclonus syndrome (OMS) in children is a rare disorder including a severe eye movement disturbance, myoclonia, ataxia and often developmental retardation. Both OMS forms, idiopathic or neuroblastoma-associated (paraneoplastic), have been suspected to be autoimmune. Recently, autoantibodies have been found in OMS sera. We here show that autoantibodies in OMS, both intracellular and surface binding, belong mainly to the IgG3 subclass, although the total serum IgG3 level is normal. These results support the autoimmune hypothesis and point to a protein autoantigen as antigenic target. more...

Meningiomas are rare intracranial tumors in pediatric patients. In contrast to meningiomas in adults, childhood ones have a poorer prognosis because of their high growth potential and tendency to recur. Meningiomas are often associated with neurofibromatosis type 2 (NF2) which is an autosomal-dominant disorder. In contrast to adults who primarily present with symptoms due to vestibular tumors, the initial symptoms in children with NF2 are subtle skin tumors, posterior capsular cataracts, or neurological signs secondary to cranial nerve(s) schwannoma excluding vestibular nerve, and/or brainstem or spinal cord compression. Here we report on the clinical, radiological, and histological findings in an 8-year-old boy who was diagnosed with an isolated infratentorial meningioma and a novel splice site mutation in the NF2 gene. The same mutation was detected in the boy's mother who suffered from hearing loss and tinnitus due to a bilateral vestibular schwannoma. Our patient demonstrates the need for molecular testing for NF2 gene mutations even in isolated childhood meningiomas although they do not fulfill the clinical criteria of NF2. more...

The role of autoantibodies in the pathogenesis of multiple sclerosis (MS) and other demyelinating diseases is controversial, in part because widely used western blotting and ELISA methods either do not permit the detection of conformation-sensitive antibodies or do not distinguish them from conformation-independent antibodies. We developed a sensitive assay based on self-assembling radiolabeled tetramers that allows discrimination of antibodies against folded or denatured myelin oligodendrocyte glycoprotein (MOG) by selective unfolding of the antigen domain. The tetramer radioimmunoassay (RIA) was more sensitive for MOG autoantibody detection than other methodologies, including monomer-based RIA, ELISA or fluorescent-activated cell sorting (FACS). Autoantibodies from individuals with acute disseminated encephalomyelitis (ADEM) selectively bound the folded MOG tetramer, whereas sera from mice with experimental autoimmune encephalomyelitis induced with MOG peptide immunoprecipitated only the unfolded tetramer. MOG-specific autoantibodies were identified in a subset of ADEM but only rarely in adult-onset MS cases, indicating that MOG is a more prominent target antigen in ADEM than MS. more...

We studied seroprevalence and concentrations of Epstein-Barr virus (EBV) antibodies in 147 pediatric patients with multiple sclerosis (MS) and paired controls. The children with MS showed a near-complete seropositivity for EBV antibody against virus capsid antigen (98.6% vs 72.1% in controls, p = 0.001) but did not display serologic evidence for a recent EBV infection. EBV antibody concentrations of pediatric patients with MS were significantly higher vs controls. more...

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. more...

Background: Baló's concentric sclerosis (BCS) is a demyelinating disorder believed to be a rare variant of multiple sclerosis (MS). Human herpesvirus 6 (HHV-6) is a highly neurotropic virus causing severe central nervous system (CNS) infections predominantly following reactivation of latent HHV-6 in immunocompromised individuals. Primary infection with HHV-6 usually occurs in early childhood manifesting as exanthema subitum. The clinical spectrum of primary infection in adolescents or adults has not yet been evaluated., Case Report: A previously healthy 13 year old girl developed acute hemianopsia and anomia 5 days after an episode of fever and malaise of unknown origin. Cerebral MRI revealed three white matter lesions, one with ring-like contrast enhancement. Lumbar puncture showed mononuclear pleocytosis of 30 cells/microl, oligoclonal IgG, and a normal protein level. Follow up cerebral MRI scans revealed lamellar concentric hemispheric lesions characteristic of BCS. The first neurological symptoms of the patient coincided with primary HHV-6 CNS infection, diagnosed by a positive PCR test of the CSF together with seroconversion. Response to antiviral and corticosteroid treatment was only temporary, but immunoglobulin treatment has so far been followed by clinical stability for 30 months., Conclusions: To our knowledge, this is the first report both of an association between HHV-6 and BCS and of immunoglobulin treatment of BCS. A late primary infection with HHV-6 might be associated with BCS. Further studies in patients with this rare disease are needed to confirm this association and to evaluate the efficacy of antiviral and immunoglobulin treatment. more...

The AIDS dementia complex (ADC, also referred to as HIV-associated cognitive impairment) is a common disorder among HIV-infected patients associated with both inflammatory and neurodegenerative processes. This review describes recent advances in the clinical and basic neurosciences of HIV infection and discusses the multivariable nature of what has become a chronic disorder in the context of highly active antiretroviral therapies (HAART). Since its initial description twenty years ago, advances in cell and molecular biology along with those in neuroimaging have furthered our understanding of the underlying pathogenic mechanisms. The clinical and neuropsychological profile of ADC is generally consistent with a "frontal-subcortical" pattern of injury. Neuropathogenesis is largely driven by indirect mechanisms mediated by infected, or more commonly, immune activated macrophages, which secrete viral and host-derived factors. Magnetic resonance spectroscopy (MRS) provides a robust in vivo method to measure the inflammatory and neurotoxic events triggered by these factors and their associated signals. Although the use of combined or highly active antiretroviral therapies (HAART) has significantly improved survival rates, cerebral injury and cognitive impairment remain common events. Factors such as aging and chronic infection will likely impact the course of this disease, its pathogenesis, and treatment. The combined observations presented in this review suggest a number of critical areas for future inquiry. more...

Axonal injury and glial activation are an early neuropathologic event in adults with multiple sclerosis. To investigate whether markers of axonal injury and glial activation are already elevated in the cerebrospinal fluid of children with multiple sclerosis, we studied the cerebrospinal fluid of 25 children with multiple sclerosis and 67 controls for the presence of tau, phospho-tau, and S-100B proteins using specific enzyme-linked immunoabsorbent assays. In general, tau, phospho-tau, and S-100B protein levels did not differ significantly between groups. However, in a subgroup of nine children with multiple sclerosis, all of whom had prominent clinical symptoms at the time of lumbar puncture and radiologic disease activity, tau protein levels were significantly elevated when compared with other controls. These data indicate that axonal injury is not restricted to adult multiple sclerosis but can already occur in children with multiple sclerosis. more...

Background: Human immunodeficiency virus (HIV) leucoencephalopathy (HIVL) is an uncommon and rapidly progressive form of AIDS dementia complex (ADC) that has remained poorly understood. Tumour necrosis factor alpha (TNFalpha), which has been implicated in the pathogenesis of ADC, is predominantly localised in macrophages in the HIV infected brain, although in vitro studies indicate that neurones can express this cytokine., Objective: To examine the clinical/neuroradiological features of HIVL and the expression of TNFalpha in HIVL., Methods: Six patients who presented with rapidly progressive dementia within four to 12 weeks of the primary manifestation of their HIV infection were evaluated. Clinical history, treatment regimens, and imaging studies were reviewed, and brain samples from three of the patients were studied by means of immunohistochemistry., Results: Imaging studies showed diffuse bilateral deep white matter changes in all six patients. Clinical and imaging abnormalities improved in five of the six patients within weeks after initiation of antiretroviral treatment. Brain biopsies of two showed pronounced microglia/macrophage activation, but only scant viral protein (gp41) expression. Staining for TNFalpha was found in microglia/macrophages, and surprisingly, in neurones also. Postmortem analysis of a third patient also showed TNFalpha expression in neurones of the frontal cortex and basal ganglia., Conclusion: This study provides the first demonstration of staining for TNFalpha in the neurones of the HIV infected brain, and suggests that the process underlying this rapidly progressive form of ADC may reflect indirect mechanisms mediated by host factors, particularly TNFalpha. more...

Both host and viral factors play an important role in the pathogenesis of human immunodeficiency virus (HIV)-associated bran injury. In this study, the authors examined the interactions between tumor necrosis factor (TNF)-alpha, CXCR4, the alpha chemokine receptor, and three HIV isolates, including the T-tropic viruses, HIV-1(MN) and HIV-1(IIIB), and the dual tropic virus, HIV-1(89.6). The authors show by flow cytometry that treatment of differentiated SK-N-MC cells with TNF-alpha induces a significant increase in the cell surface expression of CXCR4 in a time- and dose-dependent manner. The effect is partly regulated at the level of transcription. To assess the biological significance of this finding, we show that TNF-alpha potentiates the ability of the above mentioned HIV isolates to induce neuronal apoptosis and that the effect is significantly reduced by pretreating cells with monoclonal antibodies to either CXCR4 and TNF-alpha. Together these results suggest that TNF-alpha may render neuronal cells vulnerable to the apoptotic effects of HIV by increasing the cell surface expression of CXCR4 and thus identify another mechanism by which TNF-alpha contributes to the pathogenesis of HIV-associated brain injury. more...

Familial, early onset, generalized torsion dystonia is the most common and severe primary dystonia. The majority of cases are caused by a 3-bp deletion (GAG) in the coding region of the DYT1 (TOR1A) gene. The cellular and regional distribution of torsinA protein and its message has been described previously in several regions of normal adult human and rodent brain. This study examines the expression of torsinA in the developing human brain of fetuses, infants and children up to 7 years of age in four selected brain regions. Expression of torsinA protein was detectable beginning at 4 to 8 weeks of age postnatally in the cerebellum (Purkinje cells), substantia nigra (dopaminergic neurons), hippocampus and basal ganglia. Prominent torsinA immunoreactivity was not seen before 6 weeks of age postnatally, a period associated with synaptic remodeling, process elimination and the beginning of myelination. Our results indicate that torsinA protein expression is temporally and spatially regulated and is present in all brain regions studied by the age of 2 months on into adulthood. more...

Autosomal recessive forms of infantile dystonia due to mutations in the tyrosine hydroxylase (TH) gene have been described recently. The main clinical manifestations are Segawa's disease, or infantile hypokinetic rigid Parkinsonism. Here, we report on a patient with hyperrigidity, psychomotor developmental delay, and dystonic posturing of the hands, symptoms that appeared after a viral infection at the age of 14 months. Low homovanillic acid/5-hydroxyindolacetic acid (HVA/5HIAA) ratio in cerebrospinal fluid suggested a TH deficiency. Molecular analysis revealed a novel (H246Y) and a known (D498G) compound heterozygote mutation in the TH gene. The patient showed a remarkable response to treatment with levodopa. The new mutation and the association of viral infections with the onset and worsening of symptoms are discussed., ((c) 2005 Movement Disorder Society.) more...

The authors studied CSF characteristics in 136 patients with multiple sclerosis (MS) with a disease onset before age 16. In the initial diagnostic lumbar puncture, CSF-pleocytosis was observed in 66%, blood-CSF barrier dysfunction in 13%, and oligoclonal IgG in 92% of the early-onset MS (EOMS) patients. CSF oligoclonal IgG supports the early diagnosis of MS in childhood with a sensitivity similar to adult-onset MS. more...

The authors investigated the frequency and quantity of intrathecal antibody synthesis against Chlamydia pneumoniae and the presence of C pneumoniae antigen in 25 children with MS. C pneumoniae genome was present in two children. In seven children an intrathecal synthesis of C pneumoniae antibodies was detected, representing only a small part of the total intrathecal immunoglobulin G, suggesting that this intrathecal synthesis is part of a polyspecific, oligoclonal immune response. more...

Recent in vitro studies suggest that the alpha chemokine stromal-derived factor-1alpha (SDF-1alpha) and its receptor CXCR-4 may contribute to neuronal apoptosis in HIV infection of the brain. The cellular and regional expression of this chemokine and its relationship to the AIDS dementia complex (ADC), however, have remained undetermined. Using immunohistochemistry and semiquantitative RT-PCR, we examined the expression of SDF-1alpha in the frontal cortex (FC), the adjacent deep white matter (DWM). and the basal ganglia (BG) of 17 patients with ADC and 5 normal controls, and the FC and temporal cortex of 6 patients with Alzheimer disease (AD). Additionally, SDF-1alpha expression was studied in 3 different neuronal cultures: differentiated SK-N-MC cells, primary human fetal neuronal, and mouse hippocampal cultures. SDF-1alpha staining was predominantly localized to astrocytes in all 3 groups in the gray matter of the FC and the BG, often in the vicinity of cortical and basal ganglia neurons, but was generally absent in the DWM. Further, the number of positive neurons was significantly greater in the BG of AIDS subjects with advanced brain disease compared to subjects with lesser disease (p = 0.029). All cultures showed prominent SDF-1alpha staining of neurons within the cytoplasm and in neurites, whereas preferential expression in GABA-ergic neurons was found in hippocampal cultures. This is the first study to show that SDF-1alpha is constitutively expressed in astrocytes of the deep and cortical gray matter as well as in neurons of the human brain. Its increased expression in basal ganglia neurons of patients with advanced HIV CNS disease suggests it may also contribute to pathogenesis. more...

Familial, early onset, generalized torsion dystonia is the most common and severe primary dystonia. Most cases are caused by a 3-bp deletion (GAG) in the coding region of the TOR1A (DYT1) gene, which is widely expressed in human brain and encodes the protein torsinA. This study compares neuropathology and torsinA expression in the normal human brain with that in dystonia cases with and without the GAG deletion. TorsinA-like protein was expressed in neuronal cytoplasm throughout the human brain, including cerebellum, substantia nigra, hippocampus, and neostriatum, with higher levels in specific neurons. This immunostaining pattern was not discernibly different in dystonia and normal brains in midbrain and neostriatal regions. However, nigral dopaminergic neurons appeared to be larger in both GAG-deletion and non-GAG-deletion dystonia brains compared to normal, and may be more closely spaced in GAG-deletion brains. Beyond these apparent changes in neuronal size and spacing in dystonia brains, there was no indication of neuron loss, inflammation, DNA strand breaks, or altered distribution of torsin-like immunoreactivity, supporting a functional rather than degenerative etiology of early onset torsion dystonia. more...

The role of NFkappaB activation and its relationship to inflammatory mediators and apoptosis in the HIV-infected brain have remained uncertain. The cellular and regional distribution of NFkappaB, TNF-alpha, and apoptosis was examined in the frontal cortex (FC), deep white matter (DWM) and the basal ganglia (BG) of 17 patients with ADC. Nuclear staining for NFkappaB was localized predominantly to perivascular microglia/macrophages in the BG and DWM and correlated with ADC severity. Correlations were further found with HLA-DR, iNOS, TNF-alpha, and gp41 expression in these regions. The number of TUNEL-positive cells, particularly in the BG, correlated with ADC stage. Logistic regression analysis further showed a significant relationship between the likelihood of TUNEL staining in the BG and worsening cognitive impairment. more...

The regional expression of immune-mediated and neurotoxic events in the human immunodeficiency virus (HIV)-infected brain in relationship to the acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) and brain pathology remains uncertain. The extent of gp41, inducible nitric oxide synthase (iNOS), and HLA-DR expression was examined in the frontal lobe and basal ganglia of 25 patients at varying stages of ADC. The expression of gp41 and iNOS was present predominantly in perivascular cells and most often in the basal ganglia. Staining for gp41 correlated significantly with iNOS in the basal ganglia, whereas the severity of staining for gp41 and iNOS in the basal ganglia and white matter was significantly greater in subjects with moderate to severe dementia compared with those with milder impairment. The degree of macrophage staining in the white matter and basal ganglia also correlated significantly with ADC severity and was more abundant than gp41 or iNOS staining, particularly in the white matter. Logistic regression analysis revealed that staining for iNOS and gp41 increased linearly with ADC severity and was significantly more abundant in the basal ganglia compared with the white matter. Double-immunolabeling studies colocalized iNOS predominantly to macrophage/microglia and to gp41-positive cells. The expression of iNOS and gp41 in the basal ganglia combined with immune activation contributes to the development and progression of the clinical syndrome. more...

Tamm-Horsfall protein (THP), a glycoprotein with a molecular weight of 95 kilodaltons, is produced and secreted in the ascending loop of Henle. To evaluate the measurement of THP in the assessment of fetal renal development and function, we stained fetal kidney sections for THP and measured THP concentrations in 129 amniotic fluid samples from healthy pregnancies, together with other parameters such as transferrin, albumin, alpha 1- and beta 2-microglobulin. After the 16th week of gestation THP could be detected immunohistochemically in the distal tubular cells, but was not consistently detected by sandwich enzyme immunoassay until after the 20th week of gestation (detection limit 50 ng/ml). Between the 15th and 19th week of gestation THP was only detected occasionally, but after the 20th week of gestation the concentration increased significantly reaching levels of 0.4-4 mg/l at term. The THP concentration was lower in samples taken directly before birth than in the corresponding first urine after birth, indicating that THP is produced from the fetal kidney only and does not pass the placental barrier. This pattern was different from other proteins studied. Transferrin and albumin were significantly lower in the first urine voided, microglobulins remained unchanged, and the creatinine concentration increased. This indicates that maternal to fetal exchange or transport is likely for most of the other proteins. Measurement of THP concentrations, in addition to other proteins in the amniotic fluid, can improve fetal renal assessment, but because the range of THP concentrations is wide accurate predictions are still not possible. more...