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.

A De Novo Dominant Negative Mutation in DNM1L Causes Sudden Onset Status Epilepticus with Subsequent Epileptic Encephalopathy.

Mitochondrial dynamics such as fission and fusion play a vital role in normal brain development and neuronal activity. DNM1L encodes a dynamin-related protein 1 (Drp1), which is a GTPase essential for proper mitochondrial fission. The clinical phenotype of DNM1L mutations depends on the degree of mitochondrial fission deficiency, ranging from severe encephalopathy and death shortly after birth to initially normal development and then sudden onset of refractory status epilepticus with very poor neurologic outcome. We describe a case of a previously healthy 3-year-old boy with a mild delay in speech development until the acute onset of a refractory status epilepticus with subsequent epileptic encephalopathy and very poor neurologic outcome. The de novo missense mutation in DNM1L (c.1207C > T, p.R403C), which we identified in this case, seems to determine a unique clinical course, strikingly similar to four previously described patients in literature with the identical de novo heterozygous missense mutation in DNM1L.

[Neuronal plasticity and neuromodulation in pediatric neurology]. / Neuronale Plastizität und Neuromodulation in der Kinderneurologie.

BACKGROUND: Neuronal plasticity is a core mechanism for learning and memory. Abnormal neuronal plasticity has emerged as a key mechanism in many neurological and neuropediatric diseases. OBJECTIVE: Chances and perspectives of neuromodulation techniques in neurological and neuropediatric diseases with altered neuronal plasticity. MATERIAL AND METHODS: Presentation and discussion of own results of neuronal plasticity investigations in patients with neurodevelopmental disorders including RASopathies, autism spectrum disorders (ASD) and Gilles de la Tourette syndrome (GTS). RESULTS: The results of neuronal plasticity studies in patients with RASopathies, ASD and GTS underline the pathophysiological relevance of abnormal neuronal plasticity in these diseases. Transcranial magnetic stimulation (TMS) is a useful tool to examine and also induce neuronal plasticity in these patients. CONCLUSION: Neuronal plasticity appears to be an important pathophysiological factor in neuronal developmental disorders and can be investigated using TMS. New and innovative techniques may offer novel approaches for individualized TMS applications, particularly in children with neuropediatric conditions.

[Acoustic reflexes of children with and without central auditory processing disorders]. / Stapediusreflexe von Kindern mit und ohne auditive Verarbeitungs- und Wahrnehmungsstörungen.

BACKGROUND: According to international standards, determination of acoustic reflex thresholds (ART) is one of the established objective measurements in the diagnostic workup of central auditory processing disorders (CAPD). However, there is still no evidence for the significance of ART in CAPD diagnosis. PATIENTS AND METHODS: This study tested 57 children with proven CAPD and 50 healthy children (control group) with regard to group differences in mean ART (sine tones or bandpass-filtered noise). Additionally, it was investigated whether there were group differences between the mean dissociations of ART for sine tones or bandpass filtered noise. RESULTS: Neither ipsi- nor contralaterally were significant clinically relevant group differences (p < 0.050) between the mean ART of children with and without CAPD found. After Bonferroni correction, a significant group difference in the percentage of non-triggered reflexes was only observed with left-sided contralateral 2 kHz stimuli. Concerning the number of dissociations ≥20 dB, no significant group differences (p < 0.050) were detected either ipsi- or contralaterally (Fisher's test). CONCLUSION: The results of the study seem to indicate no clinically relevant ability of ART measurements to distinguish between children with and without CAPD. This renders the benefit of ART measurements for CAPD diagnosis questionable.

[Hypersalivation - inauguration of the S2k Guideline (AWMF) in short form]. / Hypersalivation - Ersterstellung der S2k-Leitlinie (AWMF) in gekürzter Darstellung.

Hypersalivation describes a relatively excessive salivary flow, which wets the patient himself and his surroundings. It may result because of insufficient oro-motor function, dysphagia, decreased central control and coordination. This reduces social interaction chances and burdens daily care. Multidisciplinary diagnostic and treatment evaluation is recommended already at early stage and focus on dysphagia, and saliva aspiration. Therefore, a multidisciplinary S2k guideline was developed. Diagnostic tools such as fiberoptic endoscopic evaluation of swallowing and videofluoroscopic swallowing studies generate important data on therapy selection and control. Especially traumatic and oncologic cases profit from swallowing therapy programmes in order to activate compensation mechanisms. In children with hypotonic oral muscles, oralstimulation plates can induce a relevant symptom release because of the improved lip closure. In acute hypersalivation, the pharmacologic treatment with glycopyrrolate and scopolamine in various applications is useful but its value in long-term usage critical. The injection of botulinum toxin into the salivary glands has shown safe and effective results with long lasting saliva reduction. Surgical treatment should be reserved for isolated cases. External radiation is judged as ultima ratio. Therapy effects and symptom severity has to be followed, especially in neurodegenerative cases. The resulting xerostomia should be critically evaluated by the responsible physician regarding oral and dental hygiene.

A practical guide to diagnostic transcranial magnetic stimulation: report of an IFCN committee.

Transcranial magnetic stimulation (TMS) is an established neurophysiological tool to examine the integrity of the fast-conducting corticomotor pathways in a wide range of diseases associated with motor dysfunction. This includes but is not limited to patients with multiple sclerosis, amyotrophic lateral sclerosis, stroke, movement disorders, disorders affecting the spinal cord, facial and other cranial nerves. These guidelines cover practical aspects of TMS in a clinical setting. We first discuss the technical and physiological aspects of TMS that are relevant for the diagnostic use of TMS. We then lay out the general principles that apply to a standardized clinical examination of the fast-conducting corticomotor pathways with single-pulse TMS. This is followed by a detailed description of how to examine corticomotor conduction to the hand, leg, trunk and facial muscles in patients. Additional sections cover safety issues, the triple stimulation technique, and neuropediatric aspects of TMS.

Hip lateralisation in children with bilateral spastic cerebral palsy treated with botulinum toxin type A: a 2-year follow-up.

We investigated the effect of BoNT/A injection on hip lateralisation in children with bilateral spastic cerebral palsy and bilateral adductor spasticity. Pelvic radiographs using Reimers' migration index (MI) were evaluated from 27 children (n=9 females, n=18 males; mean age 5.2 ± 1.96 years; range: 2-10 years; initial MI <50%) with bilateral spastic cerebral palsy over a time period of 2 years. All received injections of BoNT/A (Dysport) every 12 weeks with a dose of 30 Units per kilogram body weight into adductor and medial hamstring muscles on both sides. The MI was calculated before treatment and after 1 and 2 years. The mean MI increased from 25.5% (range: 0-48) to 26.7% (+1.2%, range: 0-79) on the right side and from 28.0% (range: 0-40) to 30.6% (+2.6%, range: 3-84) on the left side over 2 years, respectively. Hips of one patient dislocated bilaterally. The mean MI remained stable over 2 years. Although a specific BoNT/A effect cannot be proven because of the open design of this study, we provide strong evidence that the MI can be kept stable for a time period of 2 years under non-surgical management including therapy with BoNT/A even in CP patients with a high risk for hip dislocation.

Do patients with congenital hemiparesis and ipsilateral corticospinal projections respond differently to constraint-induced movement therapy?

This study investigates whether the type of corticospinal reorganization (identified by transcranial magnetic stimulation) influences the efficacy of constraint-induced movement therapy (CIMT). Nine patients (five males, four females; mean age 16y [SD 6y 5mo], range 11-30y) controlling their paretic hand via ipsilateral corticospinal projections from the contralesional hemisphere and seven patients (three males, four females; mean age 17y [SD 7y], range 10-30y) with preserved crossed corticospinal projections from the affected hemisphere to the paretic hand underwent 12 consecutive days of CIMT. A Wolf motor function test applied before and after CIMT revealed a significant improvement in the quality of upper extremity movements in both groups. Only in patients with preserved crossed projections, however, was this amelioration accompanied by a significant gain in speed, whereas patients with ipsilateral projections tended to show speed reduction. These data, although preliminary, suggest that patients with congenital hemiparesis and ipsilateral corticospinal projections respond differently to CIMT.

Cortical neuromodulation by constraint-induced movement therapy in congenital hemiparesis: an FMRI study.

OBJECTIVE: The aim of this study was to assess neuromodulative effects of CIMT in congenital hemiparesis. PATIENTS AND METHODS: Ten patients (age range: 10-30 years) with congenital hemiparesis due to unilateral cortico-subcortical infarctions in the middle cerebral artery territory, and with preserved cortico-spinal projections from the affected hemisphere to the paretic hand, were included. After a twelve-day period of constraint-induced movement therapy (CIMT), all showed a significant improvement of paretic hand function. Immediately before and after therapy, functional MRI during active and passive hand movements was performed to monitor cortical activation. RESULTS: Four patients showed consistent increases in cortical activation during movements of the paretic hand in the primary sensorimotor cortex of the affected hemisphere. Of the remaining six patients, three showed similar changes, but these results were potentially contaminated by an improved task performance after therapy. No significant alteration in activation was observed in two patients, and one showed movement artifacts. CONCLUSIONS: Even a short period of CIMT can induce changes of cortical activation in congenital hemiparesis. In our sample, increases in fMRI activation were consistently observed in the primary sensorimotor cortex of the affected hemisphere. Thus, the potential for neuromodulation is preserved in the affected hemisphere after early brain lesions.

Modulation of soleus H-reflexes during gait in healthy children.

During locomotion spinal short latency reflexes are rhythmically modulated and depressed compared to rest. In adults this modulation is severely disturbed after bilateral spinal lesions indicating a role for supra-spinal control. Soleus reflex amplitudes are large in the stance phase and suppressed in the swing phase contributing to the reciprocal muscle activation pattern required for walking. In early childhood the EMG pattern during gait underlies an age-dependent process changing from co-contraction of agonists and antagonists to a reciprocal pattern at the age of 5-7 years. It is unknown whether at this stage apart from the EMG also reflexes are modulated, and if so, whether the reflex modulation is fully mature or still underlies an age-dependent development. This may give important information about the maturation of CNS structures involved in gait control. Soleus Hoffmann H-reflexes were investigated in 36 healthy children aged 7-16 years during treadmill walking at 1.2 km/h and 3.0 km/h. At 7 years old a rhythmic modulation similar to adults was observed. The H-reflex size during the stance phase decreased significantly with age while the maximum H-reflex (H (max)) at rest remained unchanged. At 3.0 km/h H-reflexes were significantly larger during the stance phase and smaller during the swing phase as compared to 1.2 km/h but the age-dependent suppression was observed at both walking velocities. In conclusion H-reflex modulation during gait is already present in young children but still underlies an age-dependent process independent of the walking velocity. The finding that the rhythmic part of the modulation is already present at the age of 7 years may indicate that the supra-spinal structures involved mature earlier than those involved in the tonic reflex depression. This may reflect an increasing supra-spinal control of spinal reflexes under functional conditions with maturation.

The Spastic Paraplegia Rating Scale (SPRS): a reliable and valid measure of disease severity.

OBJECTIVE: To develop and evaluate a clinical Spastic Paraplegia Rating Scale (SPRS) to measure disease severity and progression. METHODS: A 13-item scale was designed to rate functional impairment occurring in pure forms of spastic paraplegia (SP). Additional symptoms constituting a complicated form of SP are recorded in an inventory. Two independent patient cohorts were evaluated in a two-step validation procedure. RESULTS: Application of SPRS requires less than 15 minutes and does not require any special equipment, so it is suitable for an outpatient setting. Interrater agreement of SPRS was high (intraclass correlation coefficient = 0.99). Reliability was further supported by high internal consistency (Cronbach alpha = 0.91). SPRS values were almost normally distributed without apparent floor or ceiling effect. Construct validity was shown by high correlation of SPRS to Barthel Index and the International Cooperative Ataxia Rating Scale (convergent validity) and low correlation to Mini-Mental Status Examination (discriminant validity). CONCLUSION: The Spastic Paraplegia Rating Scale is a reliable and valid measure of disease severity.

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.

Methylphenidate enhances both intracortical inhibition and facilitation in healthy adults.

Transcranial magnetic stimulation was used to investigate the effect of the psychostimulant drug methylphenidate (MPH) on motor cortex excitability in healthy adults (n = 12) in a placebo-controlled, crossover design study. MPH caused an enhancement of intracortical inhibition as well as intracortical facilitation. Enhancement of both of these TMS parameters was unexpected and suggests that MPH exerts its action on the motor cortex not only through the dopaminergic neurotransmitter system.

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.

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.

Medium-term functional benefits in children with cerebral palsy treated with botulinum toxin type A: 1-year follow-up using gross motor function measure.

One of the main goals when treating spasticity is to relieve pain and improve function. Intramuscular injection of botulinum toxin type A (BTX-A) has gained widespread acceptance in the treatment of spastic cerebral palsy. Several studies have clearly shown the short-term functional benefit of BTX-A treatment. Information is limited, however, on the efficacy of medium and long-term regimens, using repeated injection of BTX-A. The aim of the present open-label, prospective study was to evaluate functional outcome in children with spastic cerebral palsy after 1 year of treatment with BTX-A, using the Gross Motor Function Measure (GMFM) as a validated outcome measure. Patients (n=25, age 1.5--15.5 years) were treated with BTX-A for adductor spasm (n=12) or pes equinus (n=13). The local effect was evaluated using passive range of motion and modified Ashworth Scale. Apart from a significant improvement in joint mobility and reduction of spasticity compared to pretreatment values (P < 0.01), we demonstrated a significant improvement of gross motor function after 12 months of treatment, with a median gain of 6% in total and goal scores (P < 0.001). An increase in GMFM scores was particularly evident in younger and moderately impaired children (Gross Motor Function Classification System level III). Whether the observed improvement in gross motor function in children with cerebral palsy is specifically related to therapy with BTX-A or represents at least in part the natural course of motor development still needs clarification.

CNS lipoma in patients with epidermal nevus syndrome.

Epidermal nevus syndrome (ENS) is a congenital neurocutaneous disorder characterized by linear nevus with a significant involvement of the nervous, ophthalmological and skeletal systems. Clinical manifestations of ENS include neurological features such as mental retardation, seizures, and movement disorders which are caused by a wide range of neuropathological lesions. We describe three patients with ENS, all of whom had in addition to the characteristic features of ENS intracranial and/or intraspinal lipomas. In one patient the lipoma extended from the thoracal vertebra 8 to the 4th ventricle; in the second patient it was localized on T9, and in the third patient an intracranial lipoma was located at the right cerebellopontine angle. The intraspinal lipomas caused a significant spastic movement disorder. So far, CNS lipomas have not been described as typical neuropathological findings in ENS. The differential diagnosis to encephalocraniocutaneous lipomatosis with the typical finding of CNS lipoma is discussed.

An SNP map of human chromosome 22.

The human genome sequence will provide a reference for measuring DNA sequence variation in human populations. Sequence variants are responsible for the genetic component of individuality, including complex characteristics such as disease susceptibility and drug response. Most sequence variants are single nucleotide polymorphisms (SNPs), where two alternate bases occur at one position. Comparison of any two genomes reveals around 1 SNP per kilobase. A sufficiently dense map of SNPs would allow the detection of sequence variants responsible for particular characteristics on the basis that they are associated with a specific SNP allele. Here we have evaluated large-scale sequencing approaches to obtaining SNPs, and have constructed a map of 2,730 SNPs on human chromosome 22. Most of the SNPs are within 25 kilobases of a transcribed exon, and are valuable for association studies. We have scaled up the process, detecting over 65,000 SNPs in the genome as part of The SNP Consortium programme, which is on target to build a map of 1 SNP every 5 kilobases that is integrated with the human genome sequence and that is freely available in the public domain.