Muskelzentrum/ALS Clinic

Sir, Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by adult-onset loss of motor neurons. Five to 10% of all ALS cases are familial ALS. To date, more than 20 genes have been implicated in causing familial ALS, with the discovery of mutations in CHCHD10 (Bannwarth et al. , 2014) and TBK1 (Cirulli et al. , 2015; Freischmidt et al. , 2015) representing the latest examples for monogenic causes of ALS. Most recently, whole exome sequencing of ALS patients suggested an association of heterozygous loss-of-function mutations in NEK1 with ALS. However, this observation was made in a cohort of mostly sporadic patients, and the result was only significant in a combined analysis of the discovery and the replication cohort (Cirulli et al. , 2015), making further validation essential. To assess the association between NEK1 variants and familial ALS we analysed whole exome sequence data of 265 familial ALS index patients and 827 control individuals. A subset of these exome sequence data has recently led to the discovery of mutations in TBK1 as a cause for ALS in an exome-wide mutational burden analysis (Freischmidt et al. , 2015). The patients with familial ALS were selected from families with two or more affected individuals from European countries (Germany, Sweden, Finland, Denmark, Switzerland, and Portugal) following a negative screen for SOD1 and C9orf72 mutations as described previously (Freischmidt et al. , 2015). In-house control exomes ( n = 827) from Germany were used to compare the variant burden in NEK1 . All ALS patients were diagnosed according to the EFNS Consensus criteria (Andersen et al. , 2012). Control subjects were comprised of healthy parents of children with various diseases, healthy control tissues of individuals with tumour diseases and 200 individuals of the KORA study. With informed written consent and approval by …

mutations, treatment with the α-miSOD1 antibody delayed the onset of motor symptoms, extended survival by up to 2 months, and reduced aggregation of misfolded SOD1 and motor neuron degeneration. These effects were obtained whether α-miSOD1 antibody treatment was administered by direct brain infusion or peripheral administration. These results support the further development of α-miSOD1 antibody as a candidate treatment for ALS involving misfolding of SOD1.

BACKGROUND: Muscle cramps can occur anywhere and for many reasons. Quinine has been used to treat cramps of all causes. However, controversy continues about its efficacy and safety. This review was first published in 2010 and searches were updated in 2014. OBJECTIVES: To assess the efficacy and safety of quinine-based agents in treating muscle cramps. SEARCH METHODS: On 27 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE and EMBASE. We searched reference lists of articles up to 2014. We also searched for ongoing trials in November 2014. SELECTION CRITERIA: Randomised controlled trials of people of all ages with muscle cramps in any location and of any cause, treated with quinine or its derivatives. DATA COLLECTION AND ANALYSIS: Three review authors independently selected trials for inclusion, assessed risk of bias and extracted data. We contacted study authors for additional information. For comparisons including more than one trial, we assessed the quality of the evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). MAIN RESULTS: We identified 23 trials with a total of 1586 participants. Fifty-eight per cent of these participants were from five unpublished studies. Quinine was compared to placebo (20 trials, n = 1140), vitamin E (four trials, n = 543), a quinine-vitamin E combination (three trials, n = 510), a quinine-theophylline combination (one trial, n = 77), and xylocaine injections into the gastrocnemius muscle (one trial, n = 24). The most commonly used quinine dosage was 300 mg/day (range 200 to 500 mg). We found no new trials for inclusion when searches were updated in 2014.The risk of bias in the trials varied considerably. All 23 trials claimed to be randomised, but only a minority described randomisation and allocation concealment adequately.Compared to placebo, quinine significantly reduced cramp number over two weeks by 28%, cramp intensity by 10%, and cramp days by 20%. Cramp duration was not significantly affected.A significantly greater number of people suffered minor adverse events on quinine than placebo (risk difference (RD) 3%, 95% confidence interval (CI) 0% to 6%), mainly gastrointestinal symptoms. Overdoses of quinine have been reported elsewhere to cause potentially fatal adverse effects, but in the included trials there was no significant difference in major adverse events compared with placebo (RD 0%, 95% CI -1% to 2%). One participant suffered from thrombocytopenia (0.12% risk) on quinine.A quinine-vitamin E combination, vitamin E alone, and xylocaine injections into gastrocnemius were not significantly different to quinine across all outcomes, including adverse effects. Based on a single trial comparison, quinine alone was significantly less effective than a quinine-theophylline combination but with no significant differences in adverse events. AUTHORS' CONCLUSIONS: There is low quality evidence that quinine (200 mg to 500 mg daily) significantly reduces cramp number and cramp days and moderate quality evidence that quinine reduces cramp intensity. There is moderate quality evidence that with use up to 60 days, the incidence of serious adverse events is not significantly greater than for placebo in the identified trials, but because serious adverse events can be rarely fatal, in some countries prescription of quinine is severely restricted.Evidence from single trials suggests that theophylline combined with quinine improves cramps more than quinine alone, and the effects of xylocaine injections into gastrocnemius are not significantly different to quinine across all outcomes. Low or moderate quality evidence shows no significant difference between quinine and vitamin E or quinine and quinine-vitamin E mixture. Further research into these alternatives, as well other pharmacological and non-pharmacological treatments, is thus warranted.There is no evidence to judge optimal dosage or duration of quinine treatment. Further studies using different dosages and measurement of serum quinine levels will allow a therapeutic range to be defined for muscle cramp. Because serious adverse events are not common, large population studies are required to more accurately inform incidence. Longer lengths of follow-up in future trials will help determine the duration of action following cessation of quinine as well as long-term adverse events. The search for new therapies, pharmacological and nonpharmacological, should continue and further trials should compare vitamin E, quinine-vitamin E combination, and quinine-theophylline mixture with quinine.

Spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease which affects 1 in 6,000-10,000 live births, caused by loss of the survival motor neuron 1 gene (SMN1). A major focus of therapeutic developments has been on increasing the full-length SMN protein by increasing the inclusion of exon 7 in SMN2 transcripts, enhancing SMN2 gene expression, stabilizing the SMN protein or replacing the SMN1 gene.In June 2017, FDA and EMA have approved the antisense oligonucleotide Nusinersen as the first treatment for all SMA subtypes without age restriction. While prominent treatment effects have been observed in the earlier stages of the disease and in patients up to 15 years of age, there is only limited data from clinical trials in adult SMA patients. First real-world data from neuromuscular clinical centers suggest a therapeutic benefit of nusinersen with a favourable safety profile also in adult SMA patients: in several cases, relevant improvements of motor function is achieved, which might lead to enhanced autonomy in daily life activities and improved quality of life. Systematic follow-up of the motor status with validated instruments is crucial for an adequate monitoring of the therapeutic effects but most of the widely used scales and scores have been developed and evaluated for the pediatric population only. International neuromuscular experts have met in Frankfurt/Main, Germany in May 2019 to discuss relevant aspects of the diagnostic pathway and patient management in adult SMA. The recommendations and challenges in this patient population are discussed.

Repeat expansion in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Expanded sense and antisense repeat RNA transcripts in C9orf72 are translated into five dipeptide-repeat proteins (DPRs) in an AUG-independent manner. We previously identified the heterogeneous ribonucleoprotein (hnRNP) A3 as an interactor of the sense repeat RNA that reduces its translation into DPRs. Furthermore, we found that hnRNPA3 is depleted from the nucleus and partially mislocalized to cytoplasmic poly-GA inclusions in C9orf72 patients, suggesting that poly-GA sequesters hnRNPA3 within the cytoplasm. We now demonstrate that hnRNPA3 also binds to the antisense repeat RNA. Both DPR production and deposition from sense and antisense RNA repeats are increased upon hnRNPA3 reduction. All DPRs induced DNA double strand breaks (DSB), which was further enhanced upon reduction of hnRNPA3. Poly-glycine-arginine and poly-proline-arginine increased foci formed by phosphorylated Ataxia Telangiectasia Mutated (pATM), a major sensor of DSBs, whereas poly-glycine-alanine (poly-GA) evoked a reduction of pATM foci. In dentate gyri of C9orf72 patients, lower nuclear hnRNPA3 levels were associated with increased DNA damage. Moreover, enhanced poly-GA deposition correlated with reduced pATM foci. Since cytoplasmic pATM deposits partially colocalized with poly-GA deposits, these results suggest that poly-GA, the most frequent DPR observed in C9orf72 patients, differentially causes DNA damage and that poly-GA selectively sequesters pATM in the cytoplasm inhibiting its recruitment to sites of DNA damage. Thus, mislocalization of nuclear hnRNPA3 caused by poly-GA leads to increased poly-GA production, which partially depletes pATM, and consequently enhances DSB.

BACKGROUND: Cramps are painful, involuntary muscle contractions. They commonly affect people with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) at all stages of the disease. To date, the treatment of muscle cramps in ALS has been largely empirical without any evidence from randomised controlled trials. OBJECTIVES: To systematically assess the effect of interventions on muscle cramps as a primary or secondary endpoint or adverse event in people with ALS/MND. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (14 February 2011), the Cochrane Central Register of Controlled Trials (Issue 1, 2011 in The Cochrane Library), MEDLINE (January 1966 to January 2011) and EMBASE (January 1980 to January 2011) and reference lists of articles searched using the terms motor neuron disease, motor neurone disease, motoneuron disease or amyotrophic lateral sclerosis. We contacted authors of trials for further information. SELECTION CRITERIA: We included all randomised and quasi-randomised trials of oral medications in people with ALS which assessed cramps as a primary or secondary outcome measure or as an adverse event. We also included trials using subcutaneous or intravenous medications or physical therapy. DATA COLLECTION AND ANALYSIS: All authors applied the selection criteria and assessed study quality independently, and all authors performed independent data extraction. MAIN RESULTS: Twenty studies including 4789 participants were identified. Only one trial, of tetrahydrocannabinol (THC), assessed cramps as the primary endpoint. Thirteen studies assessed cramps as a secondary endpoint. The medications comprised vitamin E, baclofen, riluzole, L-threonine, xaliproden, indinavir, and memantine. Six studies assessed cramps as an adverse event. The medications comprised creatine, gabapentin, dextromethorphan, quinidine, and lithium. In all 20 studies no favourable effect for the treatment of cramps in ALS/MND could be demonstrated, but many studies were underpowered to draw a definite conclusion. A meta-analysis of two small studies showed a statistically nonsignificant result for the amino acid L-threonine for the treatment of cramps in ALS/MND. No study was identified using physical therapy as a therapeutic intervention for cramps. AUTHORS' CONCLUSIONS: There is no evidence to support the use of any intervention for muscle cramps in ALS/MND. More and larger randomised controlled trials evaluating treatments for muscle cramps in ALS/MND are needed.

OBJECTIVES: In Switzerland, assisted suicide (AS) is legal, provided that the person seeking assistance has decisional capacity and the person assisting is not motivated by reasons of self-interest. However, in this particular setting nothing is known about patients' and their caregivers' attitudes toward AS and life-prolonging measures. METHODS: Data was retrieved through validated questionnaires and personal interviews in 33 patients and their caregivers covering the following domains: physical function according to the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), demographic data, quality of life, anxiety, depression, social situation, spirituality, burden of disease, life-prolonging, and life-shortening acts. RESULTS: In patients the median time after diagnosis was 9 months (2-90) and the median Amyotrophic Lateral Sclerosis (ALS) FRS-R score was 37 (22-48). The majority of patients (94%; n = 31) had no desire to hasten death. Patients' and caregivers' attitudes toward Percutaneous Endoscopic Gastrostomy (PEG) and Non-Invasive Ventilation (NIV) differed. Significantly more patients than caregivers (21.2 versus 3.1%) stated that they were against NIV (p = 0.049) and against PEG (27.3 versus 3.1%; p = 0.031). Answers regarding tracheotomy were not significantly different (p = 0.139). Caregivers scored significantly higher levels of "suffering" (p = 0.007), "loneliness" (p = 0.006), and "emotional distress" answering the questionnaires (p < 0.001). Suffering (p < 0.026) and loneliness (p < 0.016) were related to the score of the Hospital Anxiety and Depression Scale (HADS) in patients. CONCLUSION: A liberal legal setting does not necessarily promote the wish for AS. However, the desire to discuss AS is prevalent in ALS patients. There is a higher level of suffering and loneliness on the caregivers' side. A longitudinal study is warranted.

'DU bist Radio' (DBR) is an award winning [DBR has been awarded with the "Catholic Media Award of the German Bishops Conference, Prädikat WERTvoll" (2011), the Suisse "Media Prize Aargau/Solothurn" (2010), the German "Alternative Media Award" (2009) and was nominated for the "Prix Europa" (2009)] monthly radio format that goes on air on three Swiss radio stations. The purpose of this program which was first broadcast in 2009 is the development of a new media format which--without applying any journalistic (or other) filter and influence--conveys authenticity of expression amongst society's most vulnerable fellow citizens such as patients, clients and the socially deprived. So-called marginal groups are encouraged to speak for themselves, as a possible paradigm case for encouraging the inclusion of patients' and relatives' "unfiltered" voices in general and in clinical ethics as well. Before handing over the microphone to the groups in focus, a team of journalists, educated in medical ethics, over a period of 4 days, teaches them on-site radio skills and craft. Once this task is completed and the actual production of the broadcast begins, the media crew does not exert any influence whatsoever on the content of the 1-h program. Thus, the final product is solely created and accounted for by the media-inexperienced participants, leading to unforeseen and often surprising results. It is discussed that the DBR approach of fostering authenticity of expression can serve as an enhancement to today's respect and autonomy oriented field of medical ethics.

The heterogeneity among the amyotrophic lateral sclerosis (ALS)/MND patient population is well recognized but not well understood. Such heterogeneity may represent a significant confound in our current and prior clinical trials as certain subgroups of patients might have a selective response (or resistance) to a novel therapeutic. The basis on which to segregate the patient population is, however, unclear. The ALS/MND Committee of the World Federation of Neurology (WFN) convened a symposium to discuss various strategies that might be considered for separating (stratifying) the population to further study. The results of that conference are presented here as a white paper, reflecting current understanding of several of the various criteria that could be implemented to divide the patient population as presented and discussed at that meeting. Consideration of grouping patients based on phenotype, cognitive involvement, imaging, or electrophysiology is presented here.

Severe paresis of the neck muscles, dystonia or an increased activation of the head flexor can lead to dropped-head syndrome. It can be based on various neurological diseases. We present a patient with amyotrophic lateral sclerosis with severe paresis of the head extensor muscles, which led to a dropped-head syndrome. Usual advices did not permit an adequate swallowing and breathing. The new developed device (head-up) can be adjusted on the individual needs which lead to a marked improvement in quality of life of the patient. Especially for ambulatory patients with Dropped-head syndrome is the «head-up» a very good solution.

Verkrampfungen im Gesichts- und Mundbereich stellen häufig eine differenzialdiagnostische Herausforderung dar. Eine seltene Ursache ist der Spasmus hemilingualis bei dem es analog zum Spasmus hemifacialis – mit Betroffenheit des Nervus facialis – zu einer Kompression des Nervus hypoglossus kommt. In unserer Kasuistik berichten wir über einen Patienten mit Spasmus hemilingualis bei welchen ein Kontakt des Nervus hypoglossus durch die Arteria vertebralis und die Arteria cerebelli posterior inferior nachgewiesen werden konnte. An Therapieoptionen stehen wie beim Spasmus hemifacialis die Behandlung mit Antikonvulsiva (Carbamazepin, Pregabalin, Gabapentin), Botulinumtoxin und die dekomprimierende Operation zur Auswahl. Unser Patient konnte durch das Kauen von Kaugummi seine Beschwerden lindern. Mögliche pathophysiologische Mechanismen hierzu werden diskutiert.

Neuromuskuläre Erkrankungen (NMD) können das Leben von betroffenen Kindern und Erwachsenen schwer beeinträchtigen. Die Behandlung ist oft komplex und involviert viele professionelle und informelle Dienste. Um diese Personengruppe bestmöglich zu unterstützen, wurde ein Tätigkeitsprofil für ein Care Management (CM) entwickelt. Mittels Mixed-Methods Design wurde die aktuelle Versorgungssituation von Menschen mit NMD in der Schweiz untersucht. Es wurden Versorgungslücken und Erwartungen an ein CM beschrieben. Auf der Basis dieser Erkenntnisse folgte die Entwicklung eines Tätigkeitsprofils im Rahmen eines zyklischem Co-design Prozesses mit Betroffenen, Angehörigen und Fachpersonen. Es resultierte ein umfassendes Anforderungs- und Kompetenzprofil sowie Schulungsprogramm für ein NMD CM, welches die pädiatrische sowie die adulte Versorgung miteinschliesst. Das Tätigkeitsprofil beinhaltet drei Leistungsbereiche: 1) die direkte klinische Praxis, 2) die interprofessionelle Zusammenarbeit und 3) die Fachentwicklung und Netzwerkarbeit. Das CM wurde infolgedessen in acht ambulanten Teams in drei Sprachregionen implementiert und diese werden derzeit wissenschaftlich evaluiert. Der Bedarf für ein NMD CM wurde evaluiert und in ein sehr gut fundiertes Konzept integriert. Der Einbezug von Betroffenen förderte die Qualität des Tätigkeitsprofils. Weitere Untersuchungen sind erforderlich, um die Umsetzbarkeit und Auswirkungen der neuen Rollen beurteilen zu können.

Die Borreliose spielt in der Schweiz eine grosse Rolle und ist in den letzten Jahren teilweise auch eine Art «Modediagnose» für unklare Fälle geworden. Mit der vorliegenden Arbeit versuchen wir, ein wenig mehr Klarheit zu schaffen und einen Überblick über den aktuellen Stand der Diagnostik und Therapie der Neuroborreliose zu geben. Die Grundpfeiler der Diagnostik sind die typische Anamnese und die Lumbalpunktion mit Bestimmung der entsprechenden Antikörper. Bei der Therapie stehen vor allem die intravenöse Gabe von Ceftriaxon und das für die ambulante Therapie besser geeignete perorale Doxycyclin zur Verfügung. Zur Veranschaulichung des theoretischen Teils werden zwei Patienten mit Neuroborreliose, die in unserer Klinik behandelt wurden, vorgestellt.

Teilweise verlaufen auch Behandlungen von Krankheitsbildern, deren Symptomatik den behandelnden Ärzten bekannt sein sollte, nicht optimal. Aus didaktischen Gründen wird der Fall eines 67-jährigen Patienten vorgestellt, der nach einer Meningeomoperation im Bereich der hinteren Schädelgrube einen Hydrocephalus malresorptivus und nach Shuntanlage ein Überdrainagesyndrom mit Ausbildung von Hygromen entwickelte. Trotz gut geschildeter Symptomatik wurde die jeweilige Diagnose relativ spät gestellt und dadurch der Genesungsprozess verzögert. Der Fall demonstriert beispielhaft wie wichtig eine sorgfältige Anamneseerhebung ist, um eine optimale und komplikationslose Behandlung zu erreichen.

Die Versorgung von Menschen mit neuromuskulären Erkrankungen (NMD) ist komplex und erfordert einen koordinierten, interprofessionellen Ansatz. NMD Care Managerinnen können Betroffene und Angehörige durch Beratung und Koordination unterstützen und die interprofessionelle Zusammenarbeit im Behandlungsteam fördern. Ziel dieser Studie ist es die Zufriedenheit mit dem im 2023 implementierten Care Management (CM) in acht ambulanten Teams in der Schweiz zu beurteilen. Daten wurden im Rahmen einer wiederholten Querschnittstudie durch einen online Fragebogen vor und 1 Jahr nach der Implementation des CM erhoben (2021, 2024). Die Zufriedenheit und Qualität der Versorgung wurde mittels Fragen auf einer Skala 0-100 bewertet. Die Daten wurden mittels Analysesoftware SPSS statistisch analysiert. Insgesamt nahmen 254 Betroffene und 184 Angehörige an der Umfrage teil. Die Zufriedenheit der Betroffenen mit der Versorgung war in der Umfrage 2024 höher als 2021. Die Implementation des CM wurde positiv bewertet. Auch die Angehörigen waren mit dem Angebot und der ambulanten Versorgung sehr zufrieden. Ein spezialisiertes Care Management hat das Potential die Zufriedenheit von NMD-Betroffenen und ihren Angehörigen zu verbessern. Weitere Untersuchungen sind erforderlich, um die Auswirkungen des CM auf das interprofessionelle Team und die Lebensqualität der Betroffenen zu evaluieren.

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Die bisher gängigen neuropsycho­logischen Tests zur Untersuchung fronto-temporaler Funktionen bei ALS wurden nicht eigens für die ALS-Erkrankten entwickelt und weisen dadurch keine ­An­­passung an die besonderen, körperlichen Einschränkungen dieser Patienten auf. Die Durchführung und Auswertung wird hierdurch erschwert oder gar verunmöglicht. Mit dem ECAS wurde ein schnell und einfach anwendbares klinisches Screening-Tool entwickelt.