A. Sebastian Schroeder

Muscle biopsy substantiates long-term MRI alterations one year after a single dose of botulinum toxin injected into the lateral gastrocnemius muscle of healthy volunteers†

Despite numerous clinical and experimental studies on botulinum toxin type A (BoNT/A), long‐term alterations of muscle texture and fine structure following BoNT/A treatment have thus far not been studied in normal human skeletal muscle. After obtaining institutional review board approval, we performed a prospective, placebo‐controlled, double‐blinded follow‐up study on two healthy adults using magnetic resonance imaging (MRI) and muscle biopsy to visualize long‐term alterations after a single BoNT/A injection into the lateral head of the gastrocnemius muscle. MRI disclosed a high‐signal‐intensity pattern in short tau inversion recovery sequences, and a reduction of the cross‐sectional area in the BoNT/A‐injected, but not in the saline‐injected contralateral control muscle (at 6 to 9 months in volunteer A: 73%, in B: 62%; at 12 months in A: 88%, and in B: 78%). Enzyme histochemistry, 12 months after injection, confirmed neurogenic atrophy of muscle fibers only in the BoNT/A‐injected muscle. Electron microscopy revealed additional degenerative changes at the neuromuscular junction. The data confirm that MRI is a suitable tool to monitor the long‐term effect of BoNT/A on skeletal muscle. Neurogenic muscle atrophy following a single BoNT/A injection should be taken into consideration when repeated BoNT/A injections into the same muscles are proposed.

Secondary non-response due to antibody formation in a child after three injections of botulinum toxin B into the salivary glands

Botulinum toxin (BTX) offers a new treatment option to reduce drooling in adults and children. Antibody formation against BTX is known to be one reason for clinical secondary non‐response to this treatment. This is a case report on the development of secondary non‐response to BTX type B (BTX‐B) in a 15‐year‐old male, with bilateral dyskinetic cerebral palsy (Gross Motor Function Classification System Level IV) with additional learning disability* and microcephaly, treated for the indication of drooling. After three successful treatment sessions, the fourth and fifth injections showed no clinical response. This was associated with the presence of antibodies against BTX‐B as determined using the mouse diaphragm assay. Thus, formation of neutralizing antibodies against BTX‐B appears to be an important issue, not only in patients treated for cervical dystonia but also in children treated for drooling. Subsequent injections with an adequate dose of BTX type A (BTX‐A) did not show any clinical response either, although no antibodies to BTX‐A were detected. Besides the unanswered questions of dosing and distribution, a second possible explanation could be that BTX‐B gave rise to non‐neutralizing antibodies that cross‐react with BTX‐A. The resulting immune complexes could be taken up by phagocytes and, thereby, impede clinical response.

When it comes to botulinum toxin, children and adults are not the same: Multimuscle option for children with cerebral palsy

to be palatopharyngeal myoclonus/tremor and posited a direct relationship to metoclopramide. The drug was stopped and her symptoms subsided over approximately 8 hours. Palatopharyngeal myoclonus is typically a slow form of tremor at 1 to 4 Hz. It can involve the pharynx, larynx, diaphragm, and extend to involve even eye muscles. The rhythmic movement can occur both during phonation and at rest. Voice tremor and clicking or popping sounds can be associated with the movement. The disorder is usually secondary to an interruption in the central tegmental tract from brainstem infarct or from idiopathic degeneration. Treatment may include serotonin precursors, carbamazepine, and clonazepam, but in general the condition is resistant to treatment. Previously described adverse reactions to metoclopramide include several conditions associated with more typical neuroleptic agents: acute dystonias, parkinsonian symptoms, including perioral, jaw, and extremity rest tremors, akathisia, tardive dyskinesia in several clinical forms, and neuroleptic malignant syndrome.1,2 The risk of developing metoclopramide-induced movement disorders has been found to increase with age, female sex, and some coexistent illnesses.1,3 Diabetes mellitus appears to confer additional risk for extrapyramidal symptoms.4 There is a 2:1 risk ratio for tardive dyskinesia in diabetics compared to nondiabetics.5 Diabetics who have been treated with metoclopramide also have a significantly greater severity of tardive dyskinesia than nondiabetics who have been treated with metoclopramide.5 We alert colleagues to our observation because we have not found other reports of metoclopramide-induced palatopharyngeal myoclonus/tremor, and because the patient responded fully and promptly to metoclopramide cessation.

Migraine-related vertigo and somatoform vertigo frequently occur in children and are often associated.

Migraine-related syndromes are a common cause of episodic vertigo and dizziness in children. Somatoform vertigo (SV) is an important cause of chronic dizziness, especially in adolescents. Our aim was to elucidate the comorbidity of migraine and SV. Three diagnostic groups were defined: migraine-related vertigo (MRV), SV, and combined migraine-related and SV (MSV). A retrospective analysis was performed on patient data (demographics, diagnosis, neuro-orthoptic and neurologic status, and results of vestibular and balance testing) from 168 patients who were presented to the German Center for Vertigo and Balance Disorders (IFB) over a 2.5-year period. Mean age of patients was 12 ± 4 years (range: 1.4 to 18 years). The most frequent diagnosis was MRV (28%), followed by MSV (19%) and SV (14%). MSV occurred most frequently in adolescent girls (25%). MRV was the most common cause of dizziness in our cohort. MSV ranked second overall but ranked first in adolescent girls, followed by isolated SV. SV was most prevalent in adolescent girls. MRV, MSV, and SV account for about 60% of diagnoses established in our tertiary referral center. Competent care of childhood migraine should include skill in detecting both the clinical symptoms of vertigo and overlapping somatoform symptoms.

How doctors think – and treat with botulinum toxin

Here we add a note about botulinum toxin type A (BoNT-A), a substance used worldwide in applications ranging from (child) neurology to aesthetics, contributing to significantly improved medical care in one field and generating big business in the other. BoNT-A injections are performed thousands of times every day worldwide. Based on the evidence accumulated in over 10 000 publications (PubMed search under ‘botulinum toxin’) there is general consensus that the clinical effect of BoNT-A lasts for about 3–6 months. Therefore, in keeping with clinical

Use of intrathecal baclofen in children and adolescents: interdisciplinary consensus table 2013.

In recent years, intrathecal baclofen (ITB) has attained an important role in the treatment of severe spasticity and dystonia in children. There are principal differences between the use of ITB in children and its use in neurology and oncology in adults. Here, we present a consensus report on best practice for the treatment of severe spastic and dystonic movement disorders with ITB. Using a problem-orientated approach to integrate theories and methods, the consensus was developed by an interdisciplinary group of experienced ITB users and experts in the field of movement disorders involving 14 German centers. On the basis of the data pooled from more than 400 patients, the authors have summarized their experience and supporting evidence in tabular form to provide a concise, but still a comprehensive information base that represents our current understanding regarding ITB treatment options in children and adolescents.

Seizures and stupor during intravenous mannose therapy in a patient with CDG syndrome type 1b (MPI-CDG).

MPI-CDG (formally called CDG 1b), caused by phosphomannose isomerase (MPI) deficiency, leads to hypoglycaemia, protein losing enteropathy, hepatopathy, and thrombotic events, whereas neurologic development remains unaffected. Dietary supplementation of mannose can reverse clinical symptoms by entering the N-glycosylation pathway downstream of MPI. When oral intake of mannose in patients with MPI-CDG is not possible, e.g. due to surgery, mannose has to be given intravenously. We report a patient with MPI-CDG on intravenous mannose therapy that showed severe depression of consciousness and seizures without apparent cause. EEG and cranial MRI findings were compatible with metabolic coma whereas extended laboratory examinations including repeated blood glucose measurements were normal. Importantly, an intravenous bolus of glucose immediately led to clinical recovery and EEG improvement. Mannose did not interfere with glucose measurement in our assay. We suggest that in patients with MPI-CDG, intravenous mannose infusion can lead to intracellular ATP deprivation due to several mechanisms: (1) in MPI deficiency, mannose 6-P cannot be isomerised to fructose 6-P and therefore is unavailable for glycolysis; (2) animal data has shown that accumulating intracellular mannose 6-P inhibits glycolysis; and (3) elevated intracellular mannose 6-P may induce an ATP wasting cycle of dephosphorylation and rephosphorylation (“honey bee effect”). The mannose-induced metabolic inhibition may be overcome by high-dose glucose treatment. We caution that, in patients with MPI-CDG, life-threatening central nervous system disturbances may occur with intravenous mannose treatment. These may be due to intracellular energy failure. Clinical symptoms of energy deficiency should be treated early and aggressively with intravenous glucose regardless of blood glucose levels.

Muscle Atrophy Beyond the Clinical Effect After a Single Dose of OnabotulinumtoxinA Injected in the Procerus Muscle: A Study with Magnetic Resonance Imaging

Background Botulinum toxin is a powerful and often used agent to treat dynamic rhytides. Focal and reversible neurogenic atrophy is considered to be the relevant mechanism of action. Objective To investigate the loss and regain of muscular volume in relation to clinical wrinkle severity as assessed using standardized scales. Methods The facial procerus and corrugator supercilii muscles were injected in two drug‐naïve men with 20 U of onabotulinumtoxinA at five injection points (onA). Two men served as controls (one with the same volume of placebo injection using saline solution, one without any intervention). All subjects underwent 3 Tesla magnetic resonance imaging before and after the injection and 1, 4, 6, 10, and 12 months after the injection. Standardized photographs were taken at each test point. Results Volumetric muscle analysis revealed a 46% to 48% reduction in procerus muscle volume lasting for 12 months after a single dose of onA; glabellar line severity returned to the drug‐naïve status after 6 to 10 months. Conclusion The gap between long‐term focal muscular atrophy and regained function remains to be elucidated. Future studies will be needed to investigate the complex interaction between focal neurogenic atrophy and potential compensatory functional muscle changes.

German Translation of the Caregiver Priorities and Child Health Index of Life with Disabilities Questionnaire: Test–Retest Reliability and Correlation with Gross Motor Function in Children with Cerebral Palsy

We aimed to translate the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) questionnaire into German and to evaluate its reliability and validity by studying the association between CPCHILD scores and gross motor function as measured by the gross motor function classification system (GMFCS) in children with cerebral palsy (CP). The original CPCHILD questionnaire and manual were translated and back translated. It was administered to primary caregivers of persons with CP (GMFCS levels III-V) and was completed a second time 2 weeks after the first to measure test-retest reliability (n = 17). Primary caregivers of 68 children with CP; GMFCS level III (n = 14), level IV (n = 28), and level V (n = 26) completed the questionnaire. Mean total CPCHILD scores across GMFCS levels were 67.1 ± 14.9 for GMFCS level III, 56.6 ± 11.8 for level IV, and 44.3 ± 12.9 for level V. Good correlation (r =  - 0.56) was observed between GMFCS and total scores test-retest reliability showed intraclass correlation coefficients between 0.4 and 0.9. The German CPCHILD yielded similar test-retest reliability and score distributions across the GMFCS level as the original version. The best correlations were observed for domains that are close to the functional deficits.

Split-screen video demonstration of sonography-guided muscle identification and injection of botulinum toxin.

A standardization of injection procedures for the various botulinum toxin (BoNT) indications has not been achieved to date. One established option to guide the therapists needle is sonography guidance. It provides real‐time visualization of the injection process, which is quick, allows perfect precision, and the procedure as such is painless. To demonstrate these qualities, we have recorded six split‐screen video segments that show the handling of the probe and the needle during BoNT injections concurrently with the respective cross‐sectional sonography recordings. The video sequences show differentiation of the pollicis longus muscle and individual finger flexor fascicles, needle tracking, and real‐time sonography‐guided injection of the gastrocnemius, rectus femoris, and iliopsoas muscles. We hope this short presentation will help to encourage a more widespread use of the technique as well as further research on sonography guidance for precise delivery of BoNT injections to various target muscles.