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).

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.

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.

Hammersmith Functional Motor Scale and Motor Function Measure-20 in non ambulant SMA patients.

The aim of this prospective longitudinal multi centric study was to evaluate the correlation between the Hammersmith Functional Motor Scale and the 20 item version of the Motor Function Measure in non ambulant SMA children and adults at baseline and over a 12 month period. Seventy-four non-ambulant patients performed both measures at baseline and 49 also had an assessment 12 month later. At baseline the scores ranged between 0 and 40 on the Hammersmith Motor function Scale and between 3 and 45 on the Motor Function Measure 20. The correlation between the two scales was 0.733. The 12 month changes ranged between -11 and 4 for the Hammersmith and between -11 and 7 for the Motor Function Measure 20. The correlation between changes was 0.48. Our results suggest that both scales provide useful information although they appeared to work differently at the two extremes of the spectrum of abilities. The Hammersmith Motor Function Scale appeared to be more suitable in strong non ambulant patients, while the Motor Function Measures appeared to be more sensitive to capture activities and possible changes in the very weak patients, including more items capturing axial and upper limb activities. The choice of these measures in clinical trials should therefore depend on inclusion criteria and magnitude of expected changes.

Somatropin treatment of spinal muscular atrophy: a placebo-controlled, double-blind crossover pilot study.

In preclinical studies growth hormone and its primary mediator IGF-1 have shown potential to increase muscle mass and strength. A single patient with spinal muscular atrophy reported benefit after compassionate use of growth hormone. Therefore we evaluated the efficacy and safety of growth hormone treatment for spinal muscular atrophy in a multicenter, randomised, double-blind, placebo-controlled, crossover pilot trial. Patients (n = 19) with type II/III spinal muscular atrophy were randomised to receive either somatropin (0.03 mg/kg/day) or placebo subcutaneously for 3 months, followed by a 2-month wash-out phase before 3 months of treatment with the contrary remedy. Changes in upper limb muscle strength (megascore for elbow flexion and hand-grip in Newton) were assessed by hand-held myometry as the primary measure of outcome. Secondary outcome measures included lower limb muscle strength, motor function using the Hammersmith Functional Motor Scale and other functional tests for motor function and pulmonary function. Somatropin treatment did not significantly affect upper limb muscle strength (point estimate mean: 0.08 N, 95% confidence interval (CI:-3.79;3.95, p = 0.965), lower limb muscle strength (point estimate mean: 2.23 N, CI:-2.19;6.63, p = 0.302) or muscle and pulmonary function. Side effects occurring during somatropin treatment corresponded with well-known side effects of growth hormone substitution in patients with growth hormone deficiency. In this pilot study, growth hormone treatment did not improve muscle strength or function in patients with spinal muscular atrophy type II/III.

Six minute walk test in type III spinal muscular atrophy: a 12month longitudinal study.

The aim of our longitudinal multicentric study was to establish the changes on the 6min walk test (6MWT) in ambulant SMA type III children and adults over a 12month period. Thirty-eight ambulant type III patients performed the 6MWT at baseline and 12months after baseline. The distance covered in 6min ranged between 75 and 510m (mean 294.91, SD 127) at baseline and between 50 and 611m (mean 293.41m, SD 141) at 12months. The mean change in distance between baseline and 12months was -1.46 (SD 50.1; range: -183 to 131.8m). The changes were not correlated with age or baseline values (p>.05) even though younger patients reaching puberty, had a relatively higher risk of showing deterioration of more than 30m compared to older patients. Our findings provide the first longitudinal data using the 6MWT in ambulant SMA patients.

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.

Peripheral neuropathy as the sole initial finding in three children with infantile metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is a progressive white matter disease caused by arylsulfatase A deficiency. Demyelination in the nervous system is detected by cerebral magnetic resonance imaging (MRI) and neurophysiological studies. We present three children with infantile MLD, who had difficulties in standing and walking with absent reflexes. Protein levels in cerebral spinal fluid (CSF) were elevated and nerve conduction studies revealed slowing down of motor nerve conduction velocity. Initial cerebral MRIs showed no white matter changes. Consecutively, all three children developed clinical symptoms of neurodegenerative disease. Follow-up MRI and arylsulfatase A testing led to diagnosis of MLD. We conclude, that in young children who present with an acute/subacute demyelinating polyneuropathy, MLD is a differential diagnosis.

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.

Further evidence for a somatic KRAS mutation in a pilocytic astrocytoma.

Astrocytomas are the most common brain tumors of childhood. However, knowledge of the molecular etiology of astrocytomas WHO grade I and II is limited. Germline mutations in the Ras-guanosine triphosphatase-activating protein, neurofibromin, in individuals with neurofibromatosis type I predispose to pilocytic astrocytomas. This association suggests that constitutive activation of the Ras signaling pathway plays a fundamental role in astrocytoma development. We screened 25 WHO I and II astrocytomas for mutations of PTPN11, NRAS, KRAS, and HRAS genes and identified the somatic G12A KRAS mutation in one pilocytic astrocytoma. These data suggest that Ras is rarely mutated in these tumors. Analyzed astrocytomas without mutations in Ras or neurofibromin may harbor mutations in other proteins of this pathway leading to hyperactive Ras signaling.

Clinical presentation and course of childhood Guillain-Barré syndrome: a prospective multicentre study.

Presenting symptoms, clinical course and paraclinical findings in childhood Guillain-Barré syndrome (GBS) have rarely been investigated prospectively. We performed a multicentre study in GBS diagnosed according to international criteria. Clinical findings were recorded using an ordinal GBS score and additional scores for arm, cranial nerve and vegetative function, and pain. Electrophysiological and CSF investigations followed individual procedures in the local hospitals. Ninety-five children with a median age of 6.2 years were registered over 40 months (53 boys, 42 girls). 70 had suffered an infection and 8 had been vaccinated during the previous 6 weeks. The first symptom was usually a disturbance of gait or neuropathic pain. The symptoms progressed for a median of 7 days. At the height of the disease, 60% of patients were unable to walk and 24% could not use their arms. 46% showed cranial nerve involvement, and 51% autonomous dysfunction. 13% required artificial ventilation. 79% complained of neuropathic pain, half of them to a severe degree. Electrophysiological examination showed demyelination in 74%, and 26% of these presented with very low amplitude compound action potentials. Purely axonal changes were found in 11%. All but eight were treated with I.V. immunoglobulin. Improvement began on day 13 after the first symptom (median). Ability to walk unaided returned after 27 days. In the children observed over the long-term, it took 118 days for them to be free of symptoms. Transient deterioration after immunoglobulin treatment occurred in seven patients, two suffered relapsing GBS, and three developed CIDP. At the end of the observation period (288 days), 75% of patients were free of symptoms. 21% suffered residual symptoms having no effect on daily functioning. The more severely disabled 4% either suffered from CIDP or concurrent myelitis. With this prospective study, the results of earlier retrospective investigations are confirmed. Besides pareses and respiratory compromise, severe neuropathic pain frequently is a therapeutic challenge during the acute phase of the disease. The long-term prognosis is good for most children. However, a change to CIDP and concurrent myelitis can give rise to a worse prognosis.

Prospective study on anti-ganglioside antibodies in childhood Guillain-Barré syndrome.

BACKGROUND: Antiganglioside antibodies have been reported to play a part in the pathophysiology of Guillain-Barré syndrome (GBS). AIMS: To investigate the prevalence and correlation of anti-ganglioside antibodies with clinical data in children with GBS in a multicentre clinical trial. METHODS: Immunoglobin (Ig)G and IgM to GM1, GM1b, GD1a, GalNAc-GD1a, GD1b, GT1a, and GQ1b were measured by ELISA in sera obtained before treatment. In addition, serological testing for Campylobacter jejuni was carried out. In parallel, a group of adults with GBS and a control group of children without GBS or other inflammatory diseases were evaluated. RESULTS: Sera from 63 children with GBS, 36 adults with GBS and 41 children without GBS were evaluated. Four of the children with GBS showed positive IgG to GM1, in one case combined with anti-GalNAc-GD1a and in one with anti-GD1b. Two others showed isolated positive IgG to GD1b and GT1a. One showed increased anti-GalNAc-GD1a IgM. In 5 of the 63 children, serological evidence of a recent infection with C jejuni was found, and this correlated significantly with the raised antibodies (p = 0.001). In the control group without GBS, no child showed positive IgG, but one showed anti-GalNAc-GD1a IgM. Compared with the adults with GBS, the frequency of antibodies in children was insignificantly lower. In our study, patients with positive antibodies did not show a more severe GBS course or worse outcome than those who were seronegative, and we could not show an increased incidence of axonal dysfunction. CONCLUSIONS: In some children with GBS, one can detect raised IgG against various gangliosides, similar to that in adults. A recent infection with C jejuni is markedly associated with the presence of these antibodies. However, in contrast with what has been reported in adults, in this study we were unable to show a negative effect of these findings on the clinical course.

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.

Echocardiographic and electrocardiographic findings of cardiomyopathy in Duchenne and Becker-Kiener muscular dystrophies.

We assessed the cardiac findings in Duchenne muscular dystrophy (DMD) and Becker-Kiener muscular dystrophy (BMD) patients in the large outpatient group of our single-center institution. The analysis included the revision of patient records (retrospectively) and current echocardiography, electrocardiogram (ECG), and Holter ECG data (prospectively). Reduced left ventricular fraction shortening (FS) < 25% was found in 24% of all patients (50 DMD, 12.1 +/- 4.7 years: 20 BMD, 17.1 +/- 8.5 years). Median age of onset of FS < 25% was 16.8 +/- 1.0 in DMD and 30.4 +/- 3.4 in BMD; (p < 0.05). Holter ECG in DMD demonstrated sinus tachycardia in 26% deprivation of circadian rhythm in 31%, and reduced heart rate variability in 51%. For these reasons, we recommend carrying out echocardiography annually in DMD and BMD > 10 years. Because the rate of disturbances in the cardiac autonomic nervous system is high in DMD, we also recommend Holter ECG annually. Further investigation should be conducted to determine if treatment with ss-blockers and ACE inhibitors in combination reduces cardiac autonomic nervous imbalance, thus improving patient outcome in DMD.

Recruitment of the sensorimotor cortex--a developmental FMRI study.

INTRODUCTION: The growing mastery of motor tasks is one of the most visible changes in the developing child. The cortex is known to play a central role in learning, planning, and performance of motor tasks. We investigated the age dependency of motor cortex activation using functional magnetic resonance imaging (fMRI). METHODS: Thirty-two right-handed subjects were studied: 11 children (median age 9 years, range 6 - 10 years), 10 adolescents (median age 13 years, range 11 - 15 years), and 11 adults (median age 27 years, range 23 - 42 years). The subjects performed a simple, paced unilateral motor task (repetitive squeezing of a ball with the right hand). Also, we set up a control experiment (visual stimulation using an alternating checkerboard pattern) in which no age-related differences were expected. RESULTS: Compared to children, adults showed significantly increased activation of the bilateral sensorimotor cortex, parietal areas, the supplementary motor area, and the cerebellum. In the visual stimulation experiment there were no age-related differences. CONCLUSION: Children show a significant difference in the degree of cortical activation compared to adults when performing a simple motor task. The change in fMRI activation patterns may reflect a maturation process of primary and secondary motor areas.

Low level of intracortical inhibition in children shown by transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is an established neurophysiological tool to evaluate the integrity and maturation of the corticospinal tract. TMS was used in this study to compare intracortical inhibition (ICI) in children, adolescents, and adults. The paired-pulse technique of TMS with interstimulus intervals of 2 ms was used to determine the ratio of conditioned (cMEP) and unconditioned amplitudes (ucMEP) that measures ICI. In experiment 1 (Exp 1) stimulus intensity was adapted to motor threshold (50 healthy subjects; 24 male, 26 female, median age 13.5 years, range 6.3 - 34 years) and in experiment 2 (Exp 2) stimulus intensity was adapted to the ucMEP (200 - 400 microV). Children (quotient of cMEP and ucMEP: Exp. 1: 0.71 +/- 0.41, Exp. 2: 0.82 +/- 0.25) had significantly less ICI compared to adults (Exp. 1: 0.21 +/- 0.19, mean +/- STD, Exp. 2: 0.35 +/- 0.22, in both experiments p < 0.001). Recently, ICI has been linked to the regulating function of GABAergic cortical interneurons on practice-dependent neuronal plasticity. Therefore, the lower ICI in children points to maturation processes that may have implications for the greater capacity of practice-dependent neuronal plasticity in children.