Musculoskeletal pain: a new algorithm for differential diagnosis of a cardinal symptom in pediatrics.

Musculoskeletal pain (MSP) is a common childhood complaint associated with multiple differential diagnoses, including cancer. Considering the expanding spectrum of diagnostics, evaluat-ing a young patient with MSP is a challenge today, particularly for non-specialists in a primary care setting. Since childhood cancer is rare and most cardinal symptoms mimic rather non-serious diseases, misdiagnosis is not uncommon, but of significant prognostic relevance. To build the appropriate bridge between primary and secon-dary care for a child presenting with MSP, thereby preventing treatment delay and longterm sequelae, initial evaluation should follow a comprehensive, multidisciplinary, systematic and stepwise approach, which unites the patient's individual anamnestic, psychosocial, and clinical charac-teristics. After a systematic review of the literature, we generated multidisciplinarily quality-assured recommendations for efficient, rational and cost-effective primary care assessment of pediatric MSP. The algorithm promotes the identification and structured interpretation of the patient's individual clinical clues. It should serve the primary care physician to recognize when further intervention, rather than reassurance and follow-up, is needed using the minimum amount of testing to make an appropriate, prompt diagnosis in the clinical situation "child presenting with MSP". A German version of this algorithm has been published in the Guideline-Portal of The Association of the Scientific Medical Societies ("Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften", AWMF) in November 2013.

The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy.

Disorganization of the neurofilament network is a prominent feature of several neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy and axonal Charcot-Marie-Tooth disease. Giant axonal neuropathy (GAN, MIM 256850), a severe, autosomal recessive sensorimotor neuropathy affecting both the peripheral nerves and the central nervous system, is characterized by neurofilament accumulation, leading to segmental distension of the axons. GAN corresponds to a generalized disorganization of the cytoskeletal intermediate filaments (IFs), to which neurofilaments belong, as abnormal aggregation of multiple tissue-specific IFs has been reported: vimentin in endothelial cells, Schwann cells and cultured skin fibroblasts, and glial fibrillary acidic protein (GFAP) in astrocytes. Keratin IFs also seem to be alterated, as most patients present characteristic curly or kinky hairs. We report here identification of the gene GAN, which encodes a novel, ubiquitously expressed protein we have named gigaxonin. We found one frameshift, four nonsense and nine missense mutations in GAN of GAN patients. Gigaxonin is composed of an amino-terminal BTB (for Broad-Complex, Tramtrack and Bric a brac) domain followed by a six kelch repeats, which are predicted to adopt a beta-propeller shape. Distantly related proteins sharing a similar domain organization have various functions associated with the cytoskeleton, predicting that gigaxonin is a novel and distinct cytoskeletal protein that may represent a general pathological target for other neurodegenerative disorders with alterations in the neurofilament network.

Assessing quality of life in long-term survivors after ¹²5I brachytherapy for low-grade glioma in childhood.

Quality of life (QOL) is important for the survivors of malignancies. We investigated health-related QOL in 51 patients treated with iodine-125 (¹²5I) brachytherapy for childhood low-grade gliomas. Instruments included a questionnaire on life situation, German versions of PEDQOL (8-18 years), EORTC QLQ-30 and head and neck module H&N-35 (>18 years), strength and difficulties questionnaire, "Fertigkeitsskala Münster Heidelberg", and an adapted Rankin score. The time lapsed since ¹²5I-brachytherapy was 134 months (median, range: 29-293 months). 57% of the patients were over 18 years of age, 34% were 11-17 years old and 8% were younger. 14 had undergone other treatments after ¹²5I brachytherapy. Over half of the >18 year olds reported residual problems; 68% were disabled, 38% to a severe degree. Many of the young adults still lived with their parents and 17% were jobless. 43% of the children/adolescents needed rehabilitative treatment, 20% visited special schools and 71% were disabled, 33% severely. The patients and their caregivers rated their QOL as not different from that of the normal population. However, many QOL dimensions correlated to the severity of disability. Comparison of QOL outcomes between different treatment measures would require a prospective study controlling for the most important factors of influence.

Incidence of vasculopathy in children with hypothalamic/chiasmatic gliomas treated with brachytherapy.

INTRODUCTION: External brain irradiation in children can cause cognitive decline, endocrine dysfunctions and second malignancies. A rare complication is cerebral vasculopathy, which occurs most often in patients with neurofibromatosis type 1. Interstitial radiotherapy using transient Iodine-125 implants is a radiotherapy option, called brachytherapy, offering excellent survival rates, but little is known on treatment-related morbidity, especially long time vascular changes. PATIENTS AND METHODS: Thirteen children with low-grade hypothalamic gliomas, four of them with neurofibromatosis type 1, were diagnosed and treated at the University Hospital Freiburg, Germany. They belong to a larger group of 44 children with suprasellar low-grade gliomas, treated with transient Iodine-125 seeds and include those who attended all routine follow-up examinations in Freiburg. After written informed consent from the parents or caregivers all patients underwent magnetic resonance imaging with angiographic techniques in 2001, 3 to 13 years after treatment. RESULTS AND DISCUSSION: Six out of 13 revealed cerebral vasculopathies, only one of them revealed symptoms of intermittent cerebral ischemia. Neurofibromatosis type 1 was present in one affected patient. The aetiology of the cerebral vascular changes is not fully understood so far. Tumour encasement, surgical damage and brachytherapy may contribute as a single risk factor or in combination. To get more information, we recommend MRA for artery vasculopathy at follow-up in all patients with suprasellar brain tumours irrespectively to their former treatment or presence of cerebrovascular symptoms.

Compound heterozygosity of the protein S-gene as a cause of severe cerebral sinovenous thrombosis in a 7-year-old child.

The genotype-phenotype relationship of compound heterozygous protein S-deficiency in a 7-year-old girl with reduced protein S-levels and a severe cerebral sinovenous thrombosis is illustrated. In this patient we identified a novel deletion in the protein S-gene causing a compound heterozygous state and subsequently a symptomatic protein S-deficiency. In case of thrombosis analysis of protein S is recommended. Low levels of protein S should be further investigated by molecular diagnostics.

Diagnosis and treatment of Guillain-Barré Syndrome in childhood and adolescence: An evidence- and consensus-based guideline.

This evidence- and consensus-based practical guideline for the diagnosis and treatment of Guillain-Barré Syndrome (GBS) in childhood and adolescence has been developed by a group of delegates from relevant specialist societies and organisations; it is the result of an initiative by the German-Speaking Society of Neuropediatrics (GNP), and is supported by the Association of Scientific Medical Societies (AWMF, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften). A systematic analysis of the literature revealed that only a few adequately-controlled studies exist for this particular age group, while none carries a low risk of bias. For this reason, the diagnostic and therapeutic recommendations largely rely on findings in adult patients with GBS, for which there are a higher number of suitable studies available. Consensus was established using a written, multi-step Delphi process. A high level of consensus could be reached for the crucial steps in diagnosis and treatment. We recommend basing the diagnostic approach on the clinical criteria of GBS and deriving support from CSF and electrophysiological findings. Repetition of invasive procedures that yield ambiguous results is only recommended if the diagnosis cannot be ascertained from the other criteria. For severe or persistently-progressive GBS treatment with intravenous immunoglobulin (IVIG) is recommended, whereas in cases of IVIG intolerance or inefficacy we recommended treatment with plasmapheresis. Corticosteroids are ineffective for GBS but can be considered when acute onset chronic inflammatory demyelinating polyneuropathy (A-CIDP) is suspected due to a prolonged disease course. The full German version of the Guideline is available on the AWMF website (https://www.awmf.org/leitlinien/detail/ll/022-008.html).

Phenotypic variability in siblings with calpainopathy (LGMD2A).

Calpainopathy is an autosomal-recessive limb girdle muscular dystrophy (LGMD2A) characterized by selective atrophy and weakness of proximal limb girdle muscles. The clinical phenotype of the disease is highly variable inter-familial, but little is known about intra-familial variability. This study reports the phenotypic variability in eight sibling pairs with genetically proven LGMD2A. Although siblings with identical mutations were often similarly affected, in some families the age of onset and the clinical course varied considerably.

German registry of paediatric deep brain stimulation in patients with childhood-onset dystonia (GEPESTIM).

BACKGROUND: Data on paediatric deep brain stimulation (DBS) is limited, especially for long-term outcomes, because of small numbers in single center series and lack of systematic multi-center trials. OBJECTIVES: We seek to systematically evaluate the clinical outcome of paediatric patients undergoing DBS. METHODS: A German registry on paediatric DBS (GEPESTIM) was created to collect data of patients with dystonia undergoing DBS up to the age of 18 years. Patients were divided into three groups according to etiology (group 1 inherited, group 2 acquired, and group 3 idiopathic dystonia). RESULTS: Data of 44 patients with a mean age of 12.8 years at time of operation provided by 6 German centers could be documented in the registry so far (group 1 n = 18, group 2 n = 16, group 3 n = 10). Average absolute improvement after implantation was 15.5 ± 18.0 for 27 patients with pre- and postoperative Burke-Fahn-Marsden Dystonia Rating scale movement scores available (p < 0.001) (group 1: 19.6 ± 19.7, n = 12; group 2: 7.0 ± 8.9, n = 8; group 3: 19.2 ± 20.7, n = 7). Infection was the main reason for hardware removal (n = 6). 20 IPG replacements due to battery expiry were necessary in 15 patients at 3.7 ± 1.8 years after last implantation. DISCUSSION: Pre- and postoperative data on paediatric DBS are very heterogeneous and incomplete but corroborate the positive effects of DBS on inherited and acquired dystonia. Adverse events including relatively frequent IPG replacements due to battery expiry seem to be a prominent feature of children with dystonia undergoing DBS. The registry enables collaborative research on DBS treatment in the paediatric population and to create standardized management algorithms in the future.

Facing the genetic heterogeneity in neuromuscular disorders: linkage analysis as an economic diagnostic approach towards the molecular diagnosis.

The identification of an ever increasing number of gene defects in patients with neuromuscular disorders has disclosed both marked phenotype and genotype variability and considerable disease overlap. In order to offer an economic strategy to characterise the molecular defect in patients with unclassified neuromuscular disorders, we designed DNA marker sets for linkage analysis of 62 distinct neuromuscular disorders gene loci, including all known muscular dystrophies, congenital myopathies, congenital myasthenic syndromes and myotonias. Genotyping of marker loci of 140 clinically well-characterised families with unclassified neuromuscular disorders reduced the number of candidates to one or two genes in 49 % of the families. Subsequent mutation analysis and genome-wide scans enabled the determination of the genetic defect in 31 % of the families including the identification of a new gene and a new mutation in an unexpected candidate gene. This highlights the effective application of this approach both for diagnostic strategies as well as for the identification of new loci and genes.

Identification of seven novel mutations in the GAN gene.

Giant axonal neuropathy (GAN) is a severe early onset neurodegenerative disorder affecting both the peripheral nerves and the central nervous system. The diagnosis is based on the presence of characteristic giant axons on nerve biopsy. In GAN, the integrity of the intermediate filament network is altered. Indeed, abnormal accumulation of the intermediate filaments has been reported in different cell types, including in the swollen axons, which are filled with neurofilaments. We identified the defective protein, gigaxonin, of unknown function, and reported fourteen distinct mutations in twelve families of various origins. Two additional mutations have been recently reported. In the present study, we analysed the GAN gene in 6 families, and identified seven novel mutations: three nonsense and two missense mutations and two deletions. In addition, the molecular result for an already reported family was re-evaluated. In this family, the R269Q "polymorphism" is in fact the pathogenic mutation.

Dopa-responsive dystonia: mutation analysis of GCH1 and analysis of therapeutic doses of L-dopa. German Dystonia Study Group.

Analysis of the gene GCH1 in 58 patients with dystonia and a positive response to L-dopa revealed mutations in 30 individuals from 22 families. Thirteen of the mutations observed were familial, three occurred de novo, and inheritance could not be determined in six cases. There was no mutation in the promoter region of GCH1 in any patient. The doses of L-dopa given to members of the two groups were not significantly different.

Probable Opitz trigonocephaly C syndrome with medulloblastoma.

We report on a patient with trigonocephaly, biparietal widening as a result of metopic synostosis, strabismus, upslanted palpebral fissures, apparently low-set ears with abnormal helices, deeply furrowed palate, postaxial polysyndactyly of the feet, ankle flexion deformities, cryptorchidism, loose skin, and severe mental retardation, findings compatible with a diagnosis of the Opitz trigonocephaly C syndrome (OTS). At the age of 12 years this patient presented with symptoms of raised intracranial pressure. A biopsy showed findings diagnostic of a medulloblastoma WHO Grade IV, an unprecedented finding in OTS. The possibility of coincidence should not prevent continued surveillance of OTS patients in the future for the occurrence of malignancy.

Botulinum toxin treatment in cerebral palsy: evidence for a new treatment option.

Intramuscular injections of botulinum toxin type A (BTX-A) have increasingly been used to reduce spasticity in specific muscle groups in children with cerebral palsy. Targets of therapeutic efforts are improvement of gross motor function, alleviation of pain or facilitation of hygienic care. Placebo-controlled studies have shown the local and functional effectiveness of BTX-A for the treatment of dynamic pes equinus. Whether long-term treatment with BTX-A improves motor development and delays contractures is still under investigation.

Inhibitory conditioning stimulus in transcranial magnetic stimulation reduces the number of excited spinal motor neurons.

OBJECTIVE: To study the mechanisms of amplitude attenuation caused by a transcranial magnetic conditioning stimulus. Both conventional MEPs and the recently described triple stimulation technique (TST) were applied; the latter to improve the quantification of the response size decrease. METHODS: TST uses a peripheral collision method to eliminate the effects of desynchronization of the transcranial magnetic stimulation (TMS) induced spinal motor neuron discharges. The attenuation of motor evoked potentials (MEPs) and responses to TST was studied in 10 healthy volunteers using the conditioning-test paradigm with 2 ms interstimulus intervals. RESULTS: Conventional MEPs and responses to TST demonstrated a marked attenuation by the preceding conditioning stimulus in all subjects. The ratio of MEP to TST amplitudes was the same in conditioned and unconditioned responses. CONCLUSIONS: Our findings suggest that the transcranial conditioning stimulus does not change the degrees of desynchronization of spinal motor neuron discharges, but results in a reduced number of excited alpha motor neurons. This reduction can be estimated by both MEPs and TST.

Exclusively intracranial cranial fasciitis in a child. Case report.

The authors present a case of an intracranial tumor in a 7-year-old girl leading to increasing hemiparesis. The lesion arose from the dura and consisted of fibroblasts in a myxoid matrix. The diagnosis of cranial fasciitis was made. The histological, immunohistological, and ultrastructural features of the tumor are described and the differential diagnosis is discussed.

Increased urinary excretion of tubular enzymes and proteins in children with epilepsy.

Cross-sectional analysis of children undergoing treatment with anti-epileptic drugs has shown an increased urinary excretion of tubular enzymes and proteins. This has usually been interpreted as a consequence of subclinical renal-tubular damage or enzyme induction. We measured excretion of tubular enzymes and proteins in 29 children who suffered from epileptic seizures and in 27 control children. Investigations were undertaken at diagnosis before the start of treatment and 3-4 months later. At diagnosis we found a slightly, but statistically significant increased excretion of N-acetyl-beta-glucosaminidase and alpha1-microglobulin. There was no significant difference between patients with an idiopathic and symptomatic aetiology of seizures or between patients with different seizure types. At the second investigation, in children treated with carbamazepine or valproate, no further increase occurred. We conclude that the increased excretion of tubular enzymes and proteins in children with epilepsy is most probably not due to a side-effect of the anti-epileptic drugs, but to a physiological alteration associated with the epilepsy itself. While the cause is unknown, the influence of serotonin metabolism is discussed.

Evaluation of botulinum toxin A therapy in children with adductor spasm by gross motor function measure.

Intramuscular injection of botulinum neurotoxin A is a relatively new method for treating spastic movement disorders in children. One major goal of any therapy for patients with movement disorders is to improve gross motor function. In this study, 18 patients with adductor spasm were treated with botulinum neurotoxin A. Treatment effect was determined with the Gross Motor Function Measure, a standardized, validated instrument designed to assist in assessment of gross motor function. Spastic muscle hyperactivity and joint mobility were evaluated by the modified Ashworth Scale and by range of motion, respectively. Compared to pretreatment values, significant improvement in gross motor function (P < .010), decrease in the modified Ashworth Scale, and increase in the range of motion (P < .010) were achieved. Patients with moderate impairment of gross motor function (classed at level III and level IV in the Gross Motor Function Classification System) benefited most from treatment. In patients with severe handicap (level V), only one of five treated patients showed improvement in gross motor function. Nevertheless, all patients in this subgroup benefited from improved ease in hygienic care. In conclusion, we have demonstrated that for most children with moderate functional impairment, the Gross Motor Function Measure is a useful instrument for objective documentation of improvements of gross motor function following treatment with botulinum neurotoxin A.

Axonal neuropathy and predominance of type II myofibers in infantile spinal muscular atrophy.

Two affected siblings with infantile spinal muscular atrophy (SMA I) presented with generalized muscular hypotonia, which progressed to early death. Quadriceps muscle biopsy did not show the typical neurogenic pattern of spinal muscular atrophy. The histochemical fiber type determination revealed a predominance of type II fibers without type I hypertrophy, an unprecedented finding in spinal muscular atrophy. Sural nerve biopsy exhibited findings typical for axonal neuropathy. In one patient, electrical stimulation of peripheral nerves showed an inexcitability of motor and sensory nerves. Genetic studies revealed homozygous deletions of the telomeric survival motor neuron (SMN) gene and the neuronal apoptosis inhibitory protein (NAIP) gene in the affected children. This is the second case report of molecular genetically proven spinal muscular atrophy associated with axonal neuropathy. We conclude atypical findings on muscle biopsy and evidence of axonal neuropathy are compatible with the diagnosis of infantile spinal muscular atrophy.

Rare combination of Becker muscular dystrophy and Klinefelter's syndrome in one patient.

Becker muscular dystrophy (BMD) was diagnosed in a male patient with Klinefelter's syndrome (47, XXY karyotype). The BMD was confirmed by (i) immunohistological methods and Western blotting, showing decreased quantity of dystrophin in muscle biopsy specimen and (ii) molecular genetic analysis which demonstrated a homozygous deletion of exons 45-47 within the dystrophin gene on both X-chromosomes. The same deletion was found on one of the X-chromosomes in the patient's mother. It can be deduced therefore that Klinefelter's syndrome in this patient is most likely due to a non-disjunctional error which occurred either during the second maternal meiotic division or during early postzygotic mitotic divisions.

Efficacy of lamotrigine and vigabatrin in drug-resistant epilepsies of childhood.

It was the purpose of this study to compare the efficacy and side effects of lamotrigine (LTG) and vigabatrin (VGB) as add-on therapy in epilepsies of childhood resistant to conventional drugs. Retrospective analysis of the medical charts and electroencephalograms of 134 children (LTG 57, VGB 77) was performed considering the various epileptic seizures and syndromes. In general, LTG and VGB had similar efficacy, with 30-40 % of patients demonstrating significant improvement. Few differences according to seizure type and epileptic syndrome were observed. Primary generalized tonic-clonic seizures more frequently improved and less frequently worsened with LTG than with VGB. In tonic seizures the treatment results were significantly more favorable with VGB. Only insignificantly better results occurred with LTG in the generalized group and with VGB in the localization-related group. VGB was significantly more effective in symptomatic than in idiopathic and cryptogenic syndromes. The frequency of adverse reactions with both drugs was close to 60%. However, treatment had to be discontinued because of severe rashes in only a few patients taking LTG or because of behavior disturbances in patients taking VGB.