Safety Profile and Lack of Immunogenicity of IncobotulinumtoxinA in Pediatric Spasticity and Sialorrhea: A Pooled Analysis.

IncobotulinumtoxinA, a pure botulinumtoxinA formulation, is free of accessory proteins. This analysis provides pooled safety data from phase 3 trials of children/adolescents (2-17 years), investigating incobotulinumtoxinA for the treatment of spasticity associated with cerebral palsy (at doses ≤20 U/kg (max. 500 U) per injection cycle (IC) for ≤6 ICs; three trials) or sialorrhea associated with neurologic disorders (at total doses of 20-75 U per IC for ≤4 ICs; one trial) for ≤96 weeks. Safety endpoints included the incidences of different types of treatment-emergent adverse events (TEAEs) and immunogenicity. IncobotulinumtoxinA dose groups were combined. Of 1159 patients (mean age 7.3 years, 60.4% males) treated with incobotulinumtoxinA, 3.9% experienced treatment-related TEAEs, with the most common being injection site reactions (1.3%) (both indications), muscular weakness (0.7%) (spasticity), and dysphagia (0.2%) (sialorrhea). Two patients (0.2%) experienced a treatment-related treatment-emergent serious adverse event, and 0.3% discontinued the study due to treatment-related TEAEs. No botulinumtoxinA-naïve patients developed neutralizing antibodies (NAbs) after incobotulinumtoxinA. All children/adolescents with known pre-treatment status and testing positive for Nabs at final visit (n = 7) were previously treated with a botulinumtoxinA other than incobotulinumtoxinA. IncobotulinumtoxinA was shown to be safe, with very few treatment-related TEAEs in a large, diverse cohort of children/adolescents with chronic conditions requiring long-term treatment and was without new NAb formation in treatment-naïve patients.

[Stroke alarm-Arterial ischemic stroke as one of the most time-critical emergencies in children and adolescents]. / Notfall-Neuropädiatrie ­ Der arteriell ischämische Schlaganfall als einer der zeitkritischsten Notfälle bei Kindern und Jugendlichen.

Arterial ischemic stroke in childhood and adolescence is one of the most time-critical emergencies in pediatrics. Nevertheless, it is often diagnosed with a considerable time delay which may be associated with low awareness, the sometimes nonspecific clinical presentation with a wide variety of differential diagnoses, and less established 'acute care structures'. The revascularisation strategies in adult stroke care are also potential and promising treatment options for children, even if available evidence is still limited. In the post-acute phase, the etiological work-up is complex due to the multitude of risk factors to be considered. But it is essential to identify each child's individual risk profile as it determines secondary prevention, risk of recurrence and outcome. Long-term care in a multiprofessional, interdisciplinary team must take into account the bio-psycho-social aspects to integrate the child into its social and educational, and later professional environment.

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.

Three by three weeks of robot-enhanced repetitive gait therapy within a global rehabilitation plan improves gross motor development in children with cerebral palsy - a retrospective cohort study.

AIM: To assess the improvement in gross motor function following three blocks of a three-week, intensive robot-enhanced treadmill therapy (ROBERT-Program). METHOD: retrospective chart review in a before-after interventional trial in children with cerebral palsy attending a university hospital outpatient rehabilitation centre. Patients received three blocks of a three-week, 12 sessions ROBERT-Program over a mean period of 24 months. Outcome measures were block specific and cumulative improvement in GMFM 66, D and E. Longterm GMFM 66 improvements were compared to the individuals' expected increment as derived from previously published GMFM-66 percentiles. 95% confidence intervals (CI) and paired t-test were calculated. RESULTS: 20 children (8 GMFCS Level II; 12 GMFCS Level III, mean age 5.9 years (CI: [5.0; 6.7])) were treated. For each block a significant increase in motor performance in similar size could be observed without deterioration between blocks. The cumulative improvement during 21 months observation period was: 6.5 (CI: [4.8; 8.2]) in GMFM 66, which represents a clinically meaningful effect size of 3.6 (CI: [1.4; 5.8]) above the expected improvement. INTERPRETATION: Progressive clinically meaningful improvement in motor performance for three blocks of ROBERT-Program was observed. Cumulative GMFM 66 improvements exceeded the individuals' age-specific expected course.

[Developmental neurology - networked medicine and new perspectives]. / Entwicklungsneurologie ­ vernetzte Medizin und neue Perspektiven.

Developmental neurology is one of the major areas of neuropediatrics and is among other things (legally) responsible for monitoring the motor, cognitive and psychosocial development of all infants using standardized monitoring investigations. The special focus is on infants born at risk and/or due to premature birth before 32 weeks of gestation or a birth weight less than 1500 g. Early diagnosis of deviations from normal, age-related development is a prerequisite for early interventions, which may positively influence development and the long-term biopsychosocial prognosis of the patients. This article illustrates the available methods in developmental neurology with a focus on recent developments. Particular attention is paid to the predictive value of general movements (GM). The current development of markerless automated detection of spontaneous movements using conventional depth imaging cameras is demonstrated. Differences in spontaneous movements in infants at the age of 12 weeks are illustrated and discussed exemplified by three patients (healthy versus genetic syndrome versus cerebral palsy).

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.

Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice.

Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson's disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock-in (KI) mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6months, by 12months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over-expressing mutant LRRK2. Via in vivo microdialysis measurement of basal and drug-evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S KI mice, which are consistent with mitochondrial fission arrest. We anticipate that this G2019S mouse line will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression.

Prospective controlled cohort study to evaluate changes of function, activity and participation in patients with bilateral spastic cerebral palsy after Robot-enhanced repetitive treadmill therapy.

BACKGROUND: Robot-enhanced therapies are increasingly being used to improve gross motor performance in patients with cerebral palsy. AIM: To evaluate gross motor function, activity and participation in patients with bilateral spastic cerebral palsy (BS-CP) after Robot-enhanced repetitive treadmill therapy (ROBERT) in a prospective, controlled cohort study. METHODS: Participants trained for 30-60 min in each of 12 sessions within a three-week-period. Changes in Gross Motor Function Measure (GMFM 66) scores, standardized walking distance, self-selected and maximum walking speed (ICF domain "Activity"), and Canadian Occupational Performance Measure (COPM; "Participation") were measured. Outcome measures were assessed three weeks in advance (V1), the day before (V2) as well as the day after, and 8 weeks after ROBERT (V3 + V4). RESULTS: 18 patients with BS-CP participated; age 11.5 (mean, range: 5.0-21.8) years, body weight 36.4 (15.0-72.0) kg. GMFCS levels I-IV were: n = 4; 5; 8; 1. There was no significant difference comparing V1 and V2. GMFM 66 (total +2.5 points, Dimension D +3.8 and E +3.2) and COPM (Performance +2.1 points, Satisfaction +1.8 points) showed statistically significant improvements for V3 or V4 compared to V1 or V2 representing clinically meaningful effect sizes. Age, GMFCS level, and repeated ROBERT blocks correlated negatively with GMFM improvement, but not with COPM improvement. INTERPRETATION: Following ROBERT, this prospective controlled cohort study showed significant and clinically meaningful improvements of function in ICF domains of "activity" and "participation" in patients with BS-CP. Further assessment in a larger cohort is necessary to allow more specific definition of factors that influence responsiveness to ROBERT program.

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.

Vertigo and dizziness in childhood - update on diagnosis and treatment.

Vertigo and balance disorders are not uncommon in children. The prevalence of vestibular vertigo in 10-year-Dolds is estimated to be 5.7%. The most common cause is vestibular migraine which accounts for almost 40% of the diagnoses. In adolescents, the incidence of somatoform vertigo syndromes increases. Vestibular function can be reliably evaluated at the bedside by the head-impulse test for vestibulo-ocular reflex function, ocular motor testing of the central vestibular system, and balance tests for vestibulo-spinal function. Vestibular migraine is treated by behavioural and drug therapies. Somatoform vertigo improves if information about the disorder and behavioual advice are provided. Sometimes psychotherapy is useful; drug therapy is recommended in severe cases. Other common vestibular disorders in children include benign positioning nystagmus and labyrinthitis. In summary, the underlying causes of vertigo and dizziness in children can be diagnosed on the basis of patient history and clinical bedside testing. Reponses to caloric irrigation of the ears, rotational chair testing, posturography, and video-oculography can be used to ascertain the diagnosis. Brain imaging is indicated in patients presenting with subacute central vestibular signs. The majority of syndromes have a favourable prognosis and can be successfully treated.

Post-mortem tissue donation at the Institute of Legal Medicine in Hamburg: talking to the next of kin guidelines and first experiences.

While building up a tissue donation program at the Institute of Legal Medicine in Hamburg we had to organize the contact to the deceased's close relatives and to develop guidelines for an appropriate approach. Loosing a family member may cause intense psychological reactions as an Acute Stress Disorder (ICD-10F43.0). An "Informed Consent", according to the German Tissue Law, requires a good emotional contact, enough time and a detailed discussion on donation between the tissue coordinator and the contacted next of kin. A reliable decision for tissue donation can activate the coping strategies of the deceased s family.

Botulinum toxin treatment of children with cerebral palsy - a short review of different injection techniques.

The intramuscular application of botulinum toxin type A (BoNT/A) has emerged to be an established treatment option to reduce muscular hyperactivity due to spasticity in children with cerebral palsy. Accurate injection is a prerequisite for efficient and safe treatment with BoNT/A. So far, treatment procedures have not been standardized. This paper is a short review of different injection techniques, i.e., manual needle placement as well as guidance by electromyography, electrical stimulation, and ultrasound. Advantages and disadvantages of the different injection techniques are discussed with a focus on needle positioning within the targeted muscle, injection close to the neuromuscular junction and diffusion of BoNT/A within the target muscles and through fascia. The additional information gained by each injection technique is weighed in terms of the clinical impact for children with cerebral palsy.