Frequency of an intrathecal IgM synthesis and MRZ reaction in children with MS.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the CNS. An intrathecal IgM synthesis is associated with a more rapid progression of MS and the intrathecal immune response to measles -, rubella -and varicella zoster virus (MRZR) which, if present, increases the likelihood of a diagnosis of MS in adults. OBJECTIVE: To evaluate the frequency of an intrathecal IgM synthesis and MRZR in children with MS. MethodsChildren with MS and a data set including clinical and treatment history, MRI at onset, in addition to a CSF analysis, and determination of antibody index (AI) of measles, rubella, and zoster antibodies, were eligible. The presence of an intrathecal IgM synthesis and/or a positive MRZ reaction were compared to biomarkers of a more progressive disease course. RESULTS: In 75 children with MS, OCBs were present in 93.3 %). 49,2 % experienced their first relapse within 6 months. 50.7 % had a total lesion load of more than 10 lesions in the first brain MRI. Spinal lesions were identified in 64 %. 23.5 % had a positive MRZR and 40.3 % an intrathecal IgM synthesis. No significant associations were detected between the presence of an intrathecal IgM synthesis and MRZR and parameters including the relapse rate in the first two years. CONCLUSION: An intrathecal IgM synthesis and a positive MRZR are found in a subset of MS children but are not associated with markers associated with a poor prognosis.

Qualitative and quantitative muscle ultrasound in patients with Duchenne muscular dystrophy: Where do sonographic changes begin?

OBJECTIVE: The number of studies investigating and understanding the disease mechanisms of Duchenne muscular dystrophy (DMD) in human clinical trials have increased substantially over the last decade. Suitable clinical instruments for the measurement of disease progress and drug efficiency are mandatory, but currently not available, especially in the youngest patients. The aim of this study was to detect a reproducible pattern of muscle involvement in early stages potentially preceding evidence of motor regression. MATERIAL AND METHODS: A cohort of 25 DMD patients aged 1-6 years at the first presentation were examined at multiple timepoints and compared with age-matched healthy controls. Muscle ultrasound was quantified using computer-analyzed gray scale levels (GSL) and blinded visual rating, using a modified Heckmatt scale. RESULTS: Changes in muscle echogenicity in DMD patients occurred very early, clearly preceding motor regression and in some cases, even before the motor plateau phase was reached. Visual rating and GSL identified the earliest changes in the proximal adductor magnus muscle. CONCLUSION: Muscle ultrasound can be used as an additional method to assess the disease progression and for decision-making in paucisymptomatic DMD patients. Sonographic changes in the ad-ductor magnus muscle seem to be the first detectable changes with a recognisable pattern.

The Multiple Sclerosis Inventory of Cognition for Adolescents (MUSICADO): A brief screening instrument to assess cognitive dysfunction, fatigue and loss of health-related quality of life in pediatric-onset multiple sclerosis.

OBJECTIVE: Screening for cognitive impairment (CI), fatigue and also Health-related quality of life (HRQoL) in patients with pediatric-onset multiple sclerosis (POMS) is of utmost importance in clinical practice. The aim of this study was to establish a new and validated pediatric screening tool "MUSICADO" that is easy to use and time economical. METHODS: 106 patients with POMS aged 12-18 years and 210 healthy controls (HCs) stratified for age and education underwent neuropsychological testing including a screening test "Multiple Sclerosis Inventory of Cognition" for adults and 8 standardized cognitive tests and established scales to assess fatigue and HRQoL. RESULTS: The phonemic verbal fluency task (RWT "s-words"), the Trail Making Test A (TMT-A), and the Digit Span Forward discriminated significantly between patients and HCs (p = 0.000, respectively) and showed the highest proportion of test failure in patients (24.5%, 17.9%; 15.1%, respectively). Therefore, they were put together to form the cognitive part of the "MUSICADO". After applying a scoring algorithm with balanced weighting of the subtests and age and education correction and a cut-off score for impairment, 35.8% of patients were categorized to be cognitively impaired (specificity: 88.6%). Fatigue was detected in 37.1% of the patients (specificity: 94.0%) and loss of HRQoL in 41.8% (specificity 95.7%) with the screening version, respectively. CONCLUSION: The MUSICADO is a newly designed brief and easy to use screening test to help to early identify CI, fatigue, and loss of HRQoL in patients with POMS as cut scores are provided for all three items. Further studies will have to show its usability in independent samples of patients with POMS.

[Spinal muscular atrophy : Time for newborn screening?] / Spinale Muskelatrophie : Zeit für das Neugeborenenscreening?

The most common neurodegenerative disease in childhood is spinal muscular atrophy (SMA). The severe infantile type 1 (Werdnig-Hoffman disease) makes 60% of SMA in total. These children usually die within 18 months without ventilation. New therapeutic approaches have led from the theoretical concept to randomized controlled clinical trials in patients. For the first time, a pharmacological treatment of SMA has been approved. The early detection of the disease is decisive for the success of therapy. All previous data suggest starting treatment early and when possible prior to the onset of symptoms considerably improves the outcome in comparison to a delayed start. The goal must be the presymptomatic diagnosis in order to initiate treatment before motor neuron degeneration. Technical and ethical prerequisites for a molecular genetic newborn screening are given.

Early-Onset Myopathies: Clinical Findings, Prevalence of Subgroups and Diagnostic Approach in a Single Neuromuscular Referral Center in Germany.

BACKGROUND: Early-onset myopathies are a heterogeneous group of neuromuscular diseases with broad clinical, genetic and histopathological overlap. The diagnostic approach has considerably changed since high throughput genetic methods (next generation sequencing, NGS) became available. OBJECTIVE: We present diagnostic subgroups in a single neuromuscular referral center and describe an algorithm for the diagnostic work-up. METHODS: The diagnostic approach of 98 index patients was retrospectively analysed. In 56 cases targeted sequencing of a known gene was performed, in 44 patients NGS was performed using large muscle specific panels, and in 12 individuals whole exome sequencing (WES) was undertaken. One patient was diagnosed via array CGH. Clinical features of all patients are provided. RESULTS: The final diagnosis could be found in 63 out of 98 patients (64%) with molecular genetic analysis. In 55% targeted gene sequencing could establish the genetic diagnosis. However, this rate largely depended on the presence of distinct histological or clinical features. NGS (large myopathy-related panels and WES) revealed genetic diagnosis in 58.5% (52% and 67%, respectively). The genes detected by WES in our cohort of patients were all covered by the panels. Based on our findings we propose an algorithm for a practical diagnostic approach.Prevalences:MTM1- and LAMA2-patients are the two biggest subgroups, followed by SEPN1-, RYR1- and Collagen VI-related diseases. 31% of genetically confirmed cases represents a group with overlap between "congenital myopathies (CM)" and "congenital muscular dystrophies (CMD)". In 36% of the patients a specific genetic diagnosis could not be assigned. CONCLUSIONS: A final diagnosis can be confirmed by high throughput genetic analysis in 58.5% of the cases, which is a higher rate than reported in the literature for muscle biopsy and should in many cases be considered as a first diagnostic tool. NGS cannot replace neuromuscular expertise and a close discussion with the geneticists on NGS is mandatory. Targeted candidate gene sequencing still plays a role in selected cases with highly suspicious clinical or histological features. There is a relevant clinical and genetic overlap between the entities CM and CMD.

[Multiple sclerosis in childhood and adolescence : Complex, chronic and differentiated]. / Multiple Sklerose im Kindes- und Jugendalter : Komplex, chronisch, differenziert.

Pediatric multiple sclerosis (MS) is one of the most important acquired neurological disorders in childhood and adolescence. A timely recognition, diagnosis and treatment are of utmost importance. This article highlights the current state of knowledge on the etiology, pathogenesis, diagnosis, clinical presentation and treatment in childhood. Although the rate of progression of disability in the early years is slower in younger patients compared to adults, a disease-modifying therapy should be started once MS is diagnosed.

Proximal muscular atrophy and weakness: An unusual adverse effect of deferasirox iron chelation therapy.

Deferasirox is a standard treatment for chronic transfusional iron overload. Adverse effects of deferasirox have been reported in large prospective studies. We report two cases of monozygotic twins manifesting with proximal muscular atrophy and weakness under deferasirox. Discontinuation of deferasirox resulted in symptom improvement and ultimately in complete remission five months after successful haematopoietic stem cell transplantation. Broad diagnostic work-up could not bring evidence of another aetiology of muscular weakness. Iron overload or beta thalassemia itself as a cause is considered unlikely in our patients because the chronological coincidence of muscular symptoms was contra-directional to serum ferritin levels and significant clinical improvement was observed promptly after cessation of deferasirox even before transplantation. These observations suggest that the development of muscular weakness in patients on deferasirox should be recognised as a possible adverse effect of the drug.

Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibodies have been recently described in children with acute disseminating encephalomyelitis (ADEM), but the clinical and neuroradiological characterisation of this subgroup is lacking. OBJECTIVE: To compare the clinical and neuroradiological features of paediatric ADEM with and without MOG antibodies. METHODS: Clinical course, cerebrospinal fluid (CSF)-, MRI studies, outcome and MOG status of 33 paediatric ADEM prospectively studied were reviewed. RESULTS: MOG antibodies (median 1:2560; range 1:160-1:20 480) were detected in 19 children with ADEM. The majority of children showed a decline of serum MOG-IgG titres over time. Children with MOG antibodies did not differ in their age at presentation, sex ratio, the presence of oligoclonal bands, clinical symptoms or initial severity, apart from a higher CSF cell count (p=0.038), compared with children without MOG antibodies. In addition, further relapsing demyelinating episodes associated with MOG antibodies were observed only in children with MOG antibodies. All 19 children with MOG antibodies had a uniform MRI pattern, characterised by large, hazy and bilateral lesions and the absence of atypical MRI features (eg, mainly small lesions, well-defined lesions), which was significantly different compared to that of children without MOG antibodies (p=0.003; and p=0.032, respectively). In addition, children with MOG antibodies had involvement of more anatomical areas (p=0.035) including the myelon characterised by a longitudinally extensive transverse myelitis (p=0.003), more often a complete resolution of lesions (p=0.036) and a better outcome (p=0.038). CONCLUSIONS: Patients with ADEM with MOG antibodies in our cohort had a uniform MRI characterised by large, bilateral and widespread lesions with an increased frequency of longitudinal extensive transverse myelitis and a favourable clinical outcome in contrast to children lacking MOG antibodies.

Muscle ultrasound in classic infantile and adult Pompe disease: a useful screening tool in adults but not in infants.

A cohort of 4 infantile and 15 adult Pompe patients has been investigated regarding correlation between strength and ultrasound of skeletal musculature. In adults, muscle ultrasound is useful to assess clinical and subclinical involvement of muscles. In this study, visible sonographic changes were found in every clinically affected muscle, using a modified Heckmatt scale. In some muscles morphologic changes preceded weakness. Regarding the anatomical pattern of involvement, our findings do not support the hypothesis of a specific pattern with a higher vulnerability of vastus intermedius than rectus femoris, which has been postulated before. A frequent sparing of triceps brachii could be confirmed. Intramuscular abnormalities occurred in a focal, a diffuse, or an intermediate pattern, with characteristics of both. In contrast to muscular dystrophies, bone echogencity was not markedly decreased in Pompe disease even in an advanced stage. In infants, muscle ultrasound showed no distinct pathology even in clinically severely affected children and should not be used as a screening method for infantile Pompe disease.

Early white matter changes in childhood multiple sclerosis: a diffusion tensor imaging study.

BACKGROUND AND PURPOSE: Loss of integrity in nonlesional white matter occurs as a fundamental feature of multiple sclerosis in adults. The purpose of our study was to evaluate DTI-derived measures of white matter microstructure in children with MS compared with age- and sex-matched controls by using tract-based spatial statistics. MATERIALS AND METHODS: Fourteen consecutive pediatric patients with MS (11 female/3 male; mean age, 15.1 ± 1.6 years; age range, 12-17 years) and age- and sex-matched healthy subjects (11 female/3 male; mean age, 14.8 ± 1.7 years) were included in the study. After we obtained DTI sequences, data processing was performed by using tract-based spatial statistics. RESULTS: Compared with healthy age- and sex-matched controls, children with multiple sclerosis showed a global decrease in mean fractional anisotropy (P ≤ .001), with a concomitant increase in mean (P < .001), radial (P < .05), and axial diffusivity (P < .001). The most pronounced fractional anisotropy value decrease in patients with MS was found in the splenium of the corpus callosum (P < .001). An additional decrease in fractional anisotropy was identified in the right temporal and right and left parietal regions (P < .001). Fractional anisotropy of the white matter skeleton was related to disease duration and may, therefore, serve as a diagnostic marker. CONCLUSIONS: The microstructure of white matter is altered early in the disease course in childhood multiple sclerosis.

Persisting myelin oligodendrocyte glycoprotein antibodies in aquaporin-4 antibody negative pediatric neuromyelitis optica.

BACKGROUND: Recently we showed that antibodies to myelin oligodendrocyte glycoprotein (MOG) can be found in aquaporin-4 (AQP4)-immunoglobulin (IgG) seronegative pediatric and adult patients with definite and high-risk neuromyelitis optica (NMO). OBJECTIVE: The purpose of this study was to describe the clinical characteristics and temporal dynamics of MOG-IgG in AQP4-IgG seronegative pediatric patients presenting with definite NMO. METHODS: Children with definite NMO who were referred for further testing of serum antibodies for AQP4 and MOG with a cell-based assay were included in this study. Clinical disease course, cerebrospinal fluid and magnetic resonance imaging (MRI) studies of these patients were reviewed. RESULTS: Between 2008 and 2012 eight children who fulfilled the diagnostic criteria of definite NMO were recruited. Two children with definite NMO tested positive for AQP4-IgG but were negative for MOG-IgG antibodies. Three children had an absence of AQP4-IgG and MOG-IgG antibodies. Three children with definite NMO had high titers of serum MOG-IgG antibodies (≥1: 160), but no AQP4-directed humoral immune response. Longitudinal analysis of serum samples of the latter three children showed persisting high MOG-IgG titers over time. CONCLUSION: Pediatric patients presenting with clinical symptoms and MRI findings highly suggestive of NMO but with high and persisting MOG-IgG antibody titers are most likely to represent a distinct subgroup of acute demyelinating diseases with important clinical and therapeutic implications.

Ten-year follow-up in a case series of integrative botulinum toxin intervention in adolescents with chronic daily headache and associated muscle pain.

INTRODUCTION: A total of 83% of children report headache during a 6-month period. The estimated 1-year prevalence of chronic daily headache (CDH) in children is at least 1 to 2%. Muscle pain is associated with headache severity and chronicity. Muscle pain can be associated with active muscular trigger points, a functional concept still remaining a controversy. An integrated approach including bio-behavioral management is accepted as standard treatment but does not provide sufficient pain relief in all patients. OBJECTIVE: We report the individual clinical course of five adolescents with treatment-refractory CDH associated with focal muscle pain. We describe a concept of short-term integrative intervention including botulinum toxin (StiBo) in a personalized "follow the referred pain pattern" injection regimen with the focus on long-term follow-up. RESULTS: StiBo showed short-term efficacy on headache frequency and severity. In the long-term follow-up, CDH was not existent in any of the patients. CONCLUSION: The treatment may have enabled the patients to draw attention away from a repeated circle of muscle-triggered pain and withdrawal of daily activities toward self-driven activities, thereby potentially preventing the development of further chronification. To prove this hypothesis, a prospective, placebo-controlled study in young adolescents with CDH should be initiated including objective outcome parameters on muscular level.

Familial Mediterranean fever-associated mutation pyrin E148Q as a potential risk factor for multiple sclerosis.

BACKGROUND: Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease caused by mutations in the MEFV gene and characterized by recurrent febrile polyserositis. A possible association of FMF and multiple sclerosis (MS) has been suggested in cohorts from Turkey and Israel. OBJECTIVE: The objective of this study was to investigate the prevalence of MEFV mutations in subjects with MS and in controls in Germany. METHODS: One-hundred and fifty seven MS patients with at least one symptom or without symptoms suggestive of FMF from our outpatient clinic were investigated for mutations in exons 2, 3, and 10 of the MEFV gene (group 1). 260 independent MS patients (group 2) and 400 unrelated Caucasian controls (group 3) were screened selectively for the low-penetrance pyrin mutations E148Q and K695R RESULTS: In group 1, 19 MS patients (12.1%) tested positive for a mutation in the MEFV gene, mainly the E148Q (n=7) substitution. Fifteen of the 19 mutation-positive individuals reported at least one symptom suggestive of FMF. In three cases, we could identify additional family members with MS. In these pedigrees, the E148Q exchange co-segregated with MS (p=0.026). Frequencies of the pyrin E148Q and K695R mutations were not statistically different between MS group 2 and controls but they occurred with a surprisingly high frequency in the German population. CONCLUSION: The MEFV gene appears to be another immunologically relevant gene locus which contributes to MS susceptibility. In particular, the pyrin E148Q mutation, which co-segregated with disease in three MS families, is a promising candidate risk factor for MS that should be further explored in larger studies.

Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis.

OBJECTIVE: To study the longitudinal dynamics of anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies in childhood demyelinating diseases. METHODS: We addressed the kinetics of anti-MOG immunoglobulins in a prospective study comprising 77 pediatric patients. This was supplemented by a cross-sectional study analyzing 126 pediatric patients with acute demyelination and 62 adult patients with multiple sclerosis (MS). MOG-transfected cells were used for detection of antibodies by flow cytometry. RESULTS: Twenty-five children who were anti-MOG immunoglobulin (Ig) positive at disease onset were followed for up to 5 years. Anti-MOG antibodies rapidly and continuously declined in all 16 monophasic patients with acute disseminated encephalomyelitis and in one patient with clinically isolated syndrome. In contrast, in 6 of 8 patients (75%) eventually diagnosed with childhood MS, the antibodies to MOG persisted with fluctuations showing a second increase during an observation period of up to 5 years. Antibodies to MOG were mainly IgG 1 and their binding was largely blocked by pathogenic anti-MOG antibodies derived from a spontaneous animal model of autoimmune encephalitis. The cross-sectional part of our study elaborated that anti-MOG Ig was present in about 25% of children with acute demyelination, but in none of the pediatric or adult controls. Sera from 4/62 (6%) adult patients with MS had anti-MOG IgG at low levels. CONCLUSIONS: The persistence or disappearance of antibodies to MOG may have prognostic relevance for acute childhood demyelination.

Concurrent TNFRSF1A R92Q and pyrin E230K mutations in a child with multiple sclerosis.

We report a 16-year-old female patient with a severe course of multiple sclerosis and concomitant symptoms suggestive of a hereditary autoinflammatory disease. Genetic analyses revealed that she inherited a TNFRSF1A R92Q mutation from her mother and a pyrin E230K mutation from her father. To our knowledge, this is the first report of a patient with severe childhood multiple sclerosis and mutations in two genes which predispose to hereditary autoinflammatory disorders. We speculate that these mutations contribute to early multiple sclerosis manifestation and enhance the inflammatory damage inflicted by the autoimmune response.

Sustainability of motor performance after robotic-assisted treadmill therapy in children: an open, non-randomized baseline-treatment study.

AIM: The aim of the study was to investigate the sustainability of motor improvements achieved after a three week trial of robotic assisted treadmill therapy in children and adolescents with central gait disorders within a follow up period of about six months. METHODS: Open, non-randomized, baseline-treatment study. Fourteen patients (mean age 8.2+/-5.4) underwent a trial of 12 sessions of robotic-assisted treadmill therapy using the Lokomat over a period of three weeks. Outcome measures were the dimensions D (standing) and E (walking) of the Gross Motor Function Measure, the ten meter walking test and the six minute walking test. Outcome variables were evaluated immediately before and after the trial and at a follow up of about six months. RESULTS: Improvements after the trial in the dimension D from 49.5% to 54.4% (P=0.008) and from 38.9% to 42.3% (P=0.012) in the dimension E of the GMFM were seen and are within the same range of previously published results. The mean score at the follow up after six months was 56.8% and 43.3% for dimension D and E, respectively. Gait speed improved from 0.80 m/s to 1.01 m/s (P=0.006) after the trial and was 1.11 m/s at the follow-up visit at six months. Similar results were obtained for endurance. CONCLUSION: The improvements of motor function after a three-week trial of robotic-assisted treadmill therapy appear to be sustained after a mean period of six months.

[Is there an association between the reduced school years in grammar schools and headache and other health complaints in adolescent students?]. / Besteht ein Zusammenhang zwischen der verkürzten Gymnasialzeit und Kopfschmerzen und gesundheitlichen Belastungen bei Schülern im Jugendalter?

BACKGROUND: The reduction of school years in grammar schools from 9 to 8 years (G9 vs. G8) is supposed to exhibit increased impairments of health of the latter group of students. Aim of the present study was to investigate whether G8-students are exposed to more stress and report more headaches and other health complaints than G9-students. PARTICIPANTS: 1 260 formers of grammar schools in Munich (10 (th) vs. 11 (th) form). METHODS: In a survey, the frequency of headache and other health complaints, experience of chronic stress and health-related quality of life were assessed with a questionnaire and compared between the two groups of different grammar-school durations (G8 vs. G9). RESULTS: 83.1% of all formers reported to suffer from headache at least once per month. Further frequently reported health complaints were back pain (47.7%), excessive need for sleep (45.6%) and pain in neck or shoulder (45.0%). 20.4% of the formers reported high exposure to stress. The greatest reductions in quality of life were found with respect to school-related and physical wellbeing. As the only significant differences, formers of G8 reported fewer daily leisure time and that available leisure time was not sufficient for recreation. CONCLUSIONS: The high prevalence of pain, health complaints and stress indicates high demands to all grammar scholars. High demands due to the reduction of school years in grammar school, however, are not reflected in increased health impairments in these formers, but rather in limited leisure time activities.

Clinical outcome of children presenting with a severe manifestation of acute disseminated encephalomyelitis.

BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is an acute, inflammatory-demyelinating disorder of the CNS with a favourable outcome in the majority of cases. OBJECTIVE: The aim of this study was to examine the long-term outcome of children with an initially severe form of ADEM. METHODS: Children with ADEM according to the criteria of the International Pediatric MS Study Group (IPMSSG) referred to the rehabilitation centre Vogtareuth were included. Neurological impairment was evaluated with a standardized telephone-based interview assessing the EDSS score. Neuropsychological outcome was assessed with review of the medical records and a standardized parental questionnaire (KOPKIJ). RESULTS: Twelve children (1 year 9 months to 13 years of age) were included. All children had focal-neurological signs and changes in mental status at presentation and an MRI of the brain showing a range of white and gray matter lesions. 11/12 patients with a mean follow-up of 6.2 years (2-13.6 years) had a monophasic course of the disease. One child had a multiphasic ADEM. Two children had an EDSS score of 0, three an EDSS of 2, five an EDSS between 3 and 5 and two children had an EDSS score of 6 and 9. Results of a standardized parental questionnaire (KOPKIJ) revealed that 7 children had deficits in the categories alertness, memory, school performance, visual-spatial skills and/or impulse control. CONCLUSION: The results of our study indicate that children with an initially severe manifestation of ADEM continue to have in the majority of cases neurological and neuropsychological handicaps.

[Primary headache in children]. / Wann und wie müssen Sie eingreifen?

Primary idiopathic headache in childhood can usually be reliably diagnosed on the basis of a comprehensive anamnesis and neurological examination. Wherever necessary, an individualized work-up (including imaging procedures) may be needed to exclude secondary headache. Overall, treatment of headaches is integrative and multimodal, and includes pharmacotherapy, psychological interventional measures, modification. of the daily routine (e.g. drinking, sleeping) and trigger point-based physiotherapy. Fundamental to the treatment of migraine in children is a rapid and appropriate administration of analgesics. In the case of tension headache, the main therapeutic thrust is directed towards adaptation of behavior.