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.

Correction to: Advanced Robotic Therapy Integrated Centers (ARTIC): an international collaboration facilitating the application of rehabilitation technologies.

The original article [1] contains a small mistake concerning the ARTIC Team members mentioned in the Acknowledgements. The team member, Rocco Salvatore Calabrò had their name presented incorrectly. This has now been corrected in the original article.

Intrathecal Baclofen therapy in Germany: Proceedings of the IAB-Interdisciplinary Working Group for Movement Disorders Consensus Meeting.

Continuous intrathecal Baclofen application (ITB) through an intracorporeal pump system is widely used in adults and children with spasticity of spinal and supraspinal origin. Currently, about 1200 new ITB pump systems are implanted in Germany each year. ITB is based on an interdisciplinary approach with neurologists, rehabilitation specialists, paediatricians and neurosurgeons. We are presenting the proceedings of a consensus meeting organised by IAB-Interdisciplinary Working Group for Movement Disorders. The ITB pump system consists of the implantable pump with its drug reservoir, the refill port, an additional side port and a flexible catheter. Non-programmable pumps drive the Baclofen flow by the reservoir pressure. Programmable pumps additionally contain a radiofrequency control unit, an electrical pump and a battery. They have major advantages during the dose-finding phase. ITB doses vary widely between 10 and 2000 µg/day. For spinal spasticity, they are typically in the order of 100-300 µg/day. Hereditary spastic paraplegia seems to require particularly low doses, while dystonia and brain injury require particularly high ones. Best effects are documented for tonic paraspasticity of spinal origin and the least effects for phasic muscle hyperactivity disorders of supraspinal origin. Oral antispastics are mainly effective in mild spasticity. Botulinum toxin is most effective in focal spasticity. Myotomies and denervation operations are restricted to selected cases of focal spasticity. Due to its wide-spread distribution within the cerebrospinal fluid, ITB can tackle wide-spread and severe spasticity.

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.

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.

Botulinum toxin assessment, intervention and follow-up for paediatric upper limb hypertonicity: international consensus statement.

The primary objective of this paper was to evaluate the published evidence of efficacy and safety of botulinum neurotoxin (BoNT) injections in paediatric upper limb hypertonia (PULH). Secondary objectives included the provision of clinical context, based on evidence and expert opinion, in the areas of assessment, child and muscle selection, dosing, and adjunctive treatment. A multidisciplinary panel of authors systematically reviewed, abstracted, and classified relevant literature. Recommendations were based on the American Academy of Neurology (AAN) evidence classification. Following a literature search, 186 potential articles were screened for inclusion, and 15 of these met the criteria and were reviewed. Grade A evidence was found to support the use of BoNT to reach individualized therapeutic goals for PULH. There is grade B evidence (probably effective) for tone reduction following BoNT injections and grade U evidence (inconclusive) for improvement in upper limb (UL) activity and function. BoNT injections were generally found to be safe and well tolerated with the most common side effect identified as a transient decrease in grip strength.

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.

Return to participation - significant improvement after bilateral pallidal stimulation in rapidly progressive DYT-1 dystonia.

We report the case of an 8-year-old girl who developed progressive generalized dystonia, rendering her unable to walk and sit within months despite medical therapy with dopamine and anti-cholinergic agents. She was found to have a 9q34.1 GAG-deletion, which is known to cause DYT1-dystonia. DYT-1 dystonia is an autosomal dominant condition with incomplete penetrance that usually starts in childhood. It is known to be refractory to pharmacotherapy. Reports on deep brain stimulation in this condition reveal marked benefits of the treatment in the pediatric and adult populations. The patient underwent bilateral stimulation of the internal globus pallidus 18 months after symptom onset. Postoperatively, her clinical status improved significantly as measured by the Burke-Fahn-Marsden dystonia rating scale and the resolution of a unilateral hip dislocation. Normal participation was regained.

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.

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.

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.

Sonography-guided injection of botulinum toxin A in children with cerebral palsy.

Visual identification of muscles and depth control of needle placement are the key features of sonography-guided injection that lead to improved targeting and safety of BoNT/A injections. This method may be especially helpful to validate already established injection techniques or when learning the correct injection technique. We recommend sonography-guided injection as a simple and painless "add-on" to the currently used standard procedure of palpation. The additional expenditure for sonography-guided injection is more than offset by the improved reliability in correct needle placement.

Regression of left ventricular hypertrophy in hemodialysis patients is possible.

Regression of left ventricular hypertrophy in hemodialysis patients is possible. Left ventricular hypertrophy represents the major risk factor for cardiac morbidity and mortality. Therefore, their regression is mandatory. Since the causes of uremia-associated left ventricular hypertrophy are multifactorial, various therapeutic options can be considered: optimal control of arterial hypertension and volume status, optimal correction of metabolic acidosis, best possible correction of hypoalbuminemia and severe secondary hyperparathyroidism, modern pharmacotherapeutic strategy for the treatment of heart failure (use of angiotensin-converting enzyme inhibitors in combination with angiotensin II receptor blockers and beta-blockers) and total correction of renal anemia. Following the proposed therapeutic strategies we could, by using echocardiography, distinguish in 100 hemodialysis patients the following 3 groups (on the average after 1.5 years): 36 patients with initially normal left ventricular mass index (LVMI (g/m2), F < 110; M < 130) maintained normal (group 1); in 31 patients with moderately increased LVMI full regression resulted (group 2); 33 patients with severely increased LVMI (group 3) had to be further divided into 2 sub-groups: 22 patients with significant improvement of LVMI, 11 patients with no, regression. For the first time we were able to show that it is possible to maintain initially normal LVMI during long-term treatment and to achieve complete regression and significant improvement of LVMI in our patients. However, since LVMI requires a long time to develop, a similarly long time must be estimated for its regression. However, 11 patients remained therapeutically resistant. In this group, severe heart diseases were often combined and highly prevalent, including ischemic heart and valve diseases and end-stage dilatative cardiomyopathy. These patients had to be transferred to cardiac surgery. Anemia is considered to be one of the most important factors for the development of left ventricular hypertrophy. Therefore, total correction of renal anemia has to be strongly recommended in addition to other measures of our therapeutic strategy to maintain full or significant regression of left ventricular hypertrophy.

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.

Development of the corticospinal system and hand motor function: central conduction times and motor performance tests.

Maturation of the corticospinal (CS) tract and hand motor function provide paradigms for central nervous system development. In this study, involving 112 participants (aged from 0.2 to 30 years), we evaluated central motor conduction times (CMCT) obtained with transcranial magnetic stimulation (TMS) during preinnervation conditions of facilitation and relaxation. Auditory reaction time, velocity of a ballistic movement of the arm, finger tapping, diadochokinesis, and fine motor visuomanual tracking were also examined. The maturation profiles for every parameter were calculated. CMCTs for the different preinnervation conditions reached adult values at different times and this could be explained by maturation of excitability at the cortical and spinal level. A stable phase for CMCTs and reaction time was reached during childhood. Parameters which measured motor speed and skill indicated that the development of these continued into adulthood. The maturation of the fast CS tract seems to be completed before the acquisition of the related motor performance has been accomplished. In conclusion, we could demonstrate that data from several neurophysiological methods can be combined and used to study the maturation of the function of the nervous system. This approach could allow appraisal of pathological conditions that show parallels with omissions or lack of developmental progress.

How can hemodialysis-associated hypotension and dialysis-induced symptoms be explained and controlled--particularly in diabetic and arteriosclerotic patients?

Patients with diabetes and/or severe arteriosclerosis are often unable to tolerate volume removal during hemodialysis (HD) and develop hemodialysis-induced symptoms. These problems can be omitted by well-balanced correction of the acid/base status. We compared 20 high-risk patients which were either treated with standard HD (dialysate bicarbonate 33 mmol/l, treatment A) or treated with standard HD and additional administration of NaHCO3 (120-160 ml 8.4% NaHCO3 solution over the venous line during HD) to correct the metabolic acidosis to upper normal values (treatment B). The following parameters were compared: 1. Acid/base status; 2. EEG monitoring and clinical observation of dialysis-induced symptoms; 3. Invasive monitoring of circulation by Swan-Ganz thermodilution; 4. Ventilation, oxygen consumption and lactate production. Optimal correction of acid/base values resulted in symptom-free hemodialysis sessions with stable PaCO2 in the normal range, cardiovascular stability assessed by invasive monitoring, normal ventilation and higher oxygen consumption and decreased lactate production. Optimal correction of acid/base balance further led to the absence of EEG alterations and of dialysis-induced symptoms during treatment B as compared to treatment A. The baroreceptor response in these patients is usually disturbed due to sclerosis of the pressosensible vessels, especially the aortic arch and the pulmonary arteries impairing a compensatory increase of heart rate upon volume removal. However, chemoreceptors are able to increase sympathetic tone with preservation of blood pressure in this situation. In addition a decrease of PaO2 during volume removal can only be answered by an early increase of ventilation response due to stimulation of chemoreceptors provided that PaCO2 is maintained normal. Furthermore, normal cerebral blood flow also depends on a normal PaCO2. Based on these pathophysiological mechanisms the therapeutic strategy of additional bicarbonate administration to correct the acid/base status guarantees a stable normal PaCO2 and facilitates a symptom-free HD in high-risk patients.