Analyse der Versorgungsrealität von gegenwärtigen Behandlungsoptionen in den drei Dimensionen Beatmungsversorgung, Ernährungsversorgung und Hilfsmittelversorgung bei der Amyotrophen Lateralsklerose

Die Amyotrophe Lateralsklerose (ALS) ist eine schwerwiegende neurodegenerative Er-krankung, die bei Erhalt intellektueller Funktionen durch fortschreitenden Verlust der Willkürmotorik einschließlich der Atemmuskulatur zum Tod innerhalb von 3-5 Jahren führt. Da eine Heilung gegenwärtig nicht möglich ist, konzentrieren sich die Therapie-möglichkeiten auf die Behandlungsziele Symptomkontrolle, Teilhabe und Überleben. Hierfür kommen Medikamente, Heil- und Hilfsmittel sowie eine Ernährungs- und Beatmungsversorgung zum Einsatz. Die Dissertation fokussiert sich auf die 3 Studien, die offene Forschungsfragen der Hilfsmittel-, Ernährungs- und Beatmungsversorgung adressieren. Ziel der Beatmungsversorgung sind Symptomkontrolle und Lebenszeitverlängerung. 28 % der ALS-Patienten erhalten eine nicht-invasive (18 %) oder invasive (10 %) Beat-mungstherapie. Zunehmend werden Ärzte mit dem Wunsch des Patienten zum Thera-pieabbruch der Beatmungstherapie konfrontiert. Studie 1 (Kettemann et al.) untersucht erstmalig die klinischen Merkmale derjenigen Patienten, die eine Beendigung der Beat-mungstherapie (BBT) realisieren. Dabei wurden 49 ALS-Patienten (nichtinvasiv, n=13; invasiv n=36) und zwei unterschiedliche Behandlungspfade (intensivierte Symptomkontrolle, ISK; tiefe Sedierung, TS) der Palliativversorgung untersucht. Die BBT war mit dem Entstehen einer Ophthalmoplegie (41%) und dem damit verbundenen Verlust der Kommunikationsfähigkeit sowie mit einem hohen motorischen Funktionsverlust assoziiert. Der Sterbeprozess mit ISK war protrahiert (32 Stunden), während die verbleibende Lebensspanne in TS (0,3 h) signifikant verkürzt war. Ernährungsversorgung dient der Kompensation einer ALS-assoziierten Dysphagie und der Abwendung einer Malnutrition. Studie 2 (Dorst et al.) untersucht die Versorgung mit einer perkutanen endoskopischen Gastrostomie (PEG) bei 89 Patienten aus 9 ALS-Zentren über 3 Jahre. In dieser Studie konnte gezeigt werden, dass die frühzeitige, vor Gewichtsverlust von mehr als 5 kg, angelegte PEG unter einmaliger („single shot“) Antibiotikatherapie eine sichere Methode darstellt, die mit einer hochkalorischen Nahrungszufuhr mit einer Verbesserung des Überlebens verbunden ist. Die Hilfsmittelversorgung ist ein wesentliches Element der ALS-Behandlung, die auf eine verbesserte Symptomkontrolle und Teilhabe abzielt. Studie 3 (Funke et al.) untersucht über 3 Jahre die Versorgungsrealität von 1479 ALS-Patienten aus 4 deutschen 2 ALS-Zentren, die mit 3.313 Hilfsmitteln aus den Bereichen Orthesen, unterstütze Kommunikation, therapeutische Bewegungsgeräte und Elektrorollstühle versorgt wurden. Nur 64 % der ärztlich indizierten Hilfsmittel erreichten die Patienten, bedingt durch Ablehnungen von Patienten (9,8%) und Kostenträgern. Die Versorgungslatenzen und die Leistungsunterschiede innerhalb der Krankenkassen waren erheblich. Alle 3 Studien bilden die Versorgungsrealität aus Teilbereichen der gegenwärtigen Be-handlungsoption bei der ALS ab. In der Studie 1 wurden zwei unterschiedliche Behand-lungspfade der Palliativversorgung definiert und charakterisiert. Studie 2 und 3 generieren konkrete Handlungsempfehlungen in der klinischen Versorgung von ALS-Patienten. Die Ergebnisse der 3 Studien werden dazu beitragen, Behandlungsstandards und Leitlinien der ALS-Versorgung weiterzuentwickeln.Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive loss of motor function including respiratory muscles, leading to death within 3 to 5 years, while cognitive functions mostly remain unimpaired. Since cure is currently not achievable, therapy is focussed on treatment of symptoms, partici-pation and survival. Means to accomplish these goals comprise medication, physiotherapy/logopedics/occupational therapy, artificial ventilation, nutrition, and assisting devices. This thesis is focussed on three studies addressing scientific issues regarding assisting devices, nutrition, and artificial ventilation. Treatment goals of ventilation encompass control of symptoms and survival. Twentyeight percent of ALS patients either receive non-invasive (18%) or invasive (10%) ventilation. Physicians are increasingly confronted with patient’s requests for termination of ventilation. For the first time, study 1 (Kettemann et al.) examined the clinical characteristics of patients putting such a termination into effect. In 49 patients (13 on non-inva-sive, 36 on invasive ventilation) two different approaches of palliative care were ana-lyzed: intensified control of symptoms (ICS) and deep sedation (DS). The request for termination was associated with both, evolving ophthalmoplegia (41%) depriving pa-tients of their capability to communicate, and severe loss of motor function. The process of dying was rather protracted with ICS (32 hrs), while DS significantly shortened this period (0.3 hrs). Artificial nutrition compensates for ALS-associated dysphagia and prevents malnutrition. Study 2 (Dorst et al.) examined the course (3yrs) in 89 patients (9 centers) who received a percutaneous endoscopic gastrostomy (PEG). It was demonstrated that early (i.e., weight loss ≤ 5 kg) PEG application with a single shot of antibiotics and subsequent slow but high-caloric feed charge is safe and improves survival. Supply of ALS patients with assisting devices is a crucial element of treatment and is mainly focussed on symptom control and participation. Study 3 (Funke et al.) examined reallife technical support in 1479 patients from 4 German centers who were prescribed a total of 3.313 devices comprising 4 areas: orthoses, assisted communication, motion devices, and electric wheelchairs. Only 64% of prescribed aids eventually reached the patients, due to refusal by patients in almost 10%, while refusal by health insurance funds was responsible in the majority of cases. Furthermore, latencies before provision of aids and the scope of service significantly differed among health care providers. The studies demonstrate the reality of health care in subdomains of current treatment options for ALS. Thus, these studies may contribute to future standards of care and guidelines

Patient-Reported Outcome of Physical Therapy in Amyotrophic Lateral Sclerosis: Observational Online Study

Background: Physical therapy is an essential component of multidisciplinary treatment in amyotrophic lateral sclerosis (ALS). However, the meaning of physical therapy beside preservation of muscular strength and functional maintenance is not fully understood. Objective: The purpose of this study was to examine patients’ perception of physical therapy during symptom progression using an internet assessment approach. Methods: A prospective, longitudinal, observational study was performed. Recruitment took place in an ALS center in Berlin, Germany. Online self-assessment was established on a case management platform over 6 months. Participants self-assessed the progression of the disease with the ALS Functional Rating Scale-Revised (ALSFRS-R) and tracked the efficacy of targeted physical therapy using Measure Yourself Medical Outcome Profile (MYMOP). We used the net promoter score (NPS) to inquire into recommendation levels of physical therapy. Results: Forty-five participants with ALS were included in the study. Twenty-seven (60.0%) started the online assessment. The mean duration of physical therapy sessions per week was 142.7 minutes (SD 60.4) with a mean frequency of 2.9 (SD 1.2) per week. As defined by MYMOP input, the most concerning symptoms were reported in the legs (62.2%), arms (31.1%), and less frequently in the torso (6.7%). As expected for a progressive disease, there was a functional decline of 3 points in the ALSFRS-R at the end of the observation period (n=20). Furthermore, the MYMOP showed a significant loss of 0.8 in the composite score, 0.9 in the activity score and 0.8 in the targeted symptom. In spite of functional decline, the recommendation for physical therapy jumped from a baseline value of 20 NPS points to a very high 50 points at the end of study (P=.05). Conclusions: Physical therapy is perceived as an important treatment method by patients with ALS. Despite functional deterioration, patients are satisfied with physical therapy and recommend this intervention. The results also underline how the meaning of physical therapy changes throughout the disease. Physical therapy in ALS has to be regarded as a supportive and palliative health care intervention beyond functional outcome parameters

Real world experience of patients with amyotrophic lateral sclerosis (ALS) in the treatment of spasticity using tetrahydrocannabinol:cannabidiol (THC:CBD)

Background: Treatment of spasticity poses a major challenge in amyotrophic lateral sclerosis (ALS) patient management. Delta-9-tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (THC:CBD), approved for the treatment of spasticity in multiple sclerosis, serves as a complementary off-label treatment option in ALS-related spasticity. However, few structured data are available on THC:CBD in the treatment of spasticity in ALS. Method: A retrospective mono-centric cohort study was realised in 32 patients that meet the following criteria: 1) diagnosis of ALS, 2) ALS-related spasticity; 3) treatment with THC:CBD. Spasticity was rated using the Numeric Rating Scale (NRS). Patient’s experience with THC:CBD was assessed using the net promoter score (NPS) and treatment satisfaction questionnaire for medication (TSMQ-9) as captured through telephone survey or online assessment. Results: The mean dose THC:CBD were 5.5 daily actuations (range<1 to 20). Three subgroups of patients were identified: 1) high-dose daily use (≥ 7 daily actuations, 34%, n = 11), 2) low-dose daily use (< 7 daily actuations, 50%, n = 16), 3) infrequent use (< 1 daily actuation, 16%, n=5). Overall NPS was + 4.9 (values above 0 express a positive recommendation to fellow patients). Remarkably, patients with moderate to severe spasticity (NRS ≥ 4) reported a high recommendation rate (NPS: +29) in contrast to patients with mild spasticity (NRS<4; NPS: − 44). For the three main domains of TSQM-9 high mean satisfaction levels were found (maximum value 100): effectiveness 70.5 (±22.3), convenience 76.6 (±23.3) and global satisfaction 75.0 (±24.7). Conclusion: THC:CBD is used in a wide dose range suggesting that the drug was applied on the basis of individual patients’ needs and preferences. Contributing to this notion, moderate to severe spasticity was associated with an elevated number of daily THC:CBD actuations and stronger recommendation rate (NPS) as compared to patients with mild spasticity. Overall, treatment satisfaction (TSQM-9) was high. The results suggest that THC:CBD may serve as a valuable addition in the spectrum of symptomatic therapy in ALS. However, prospective studies and head-to-head comparisons to other spasticity medications are of interest to further explore the effectiveness of THC:CBD in the management of spasticity, and other ALS-related symptoms

Non‐invasive and tracheostomy invasive ventilation in amyotrophic lateral sclerosis: Utilization and survival rates in a cohort study over 12 years in Germany

Background and purpose: The aim of this study was to investigate utilization rates, treatment pathways and survival prognosis in patients with amyotrophic lateral sclerosis (ALS) undergoing non-invasive (NIV) and tracheostomy invasive ventilation (TIV) in a real-world setting. Methods: A prospective cohort study using a single-centre register of 2702 ALS patients (2007 to 2019) was conducted. Utilization of NIV/TIV and survival data were analysed in three cohorts: (i) non-NIV; (ii) NIV (NIV without subsequent TIV); and (iii) TIV (including TIV preceded by NIV). Results: A total of 1720 patients with available data were identified, 72.0% of whom (n = 1238) did not receive ventilation therapy. NIV was performed in 20.8% of patients (n = 358). TIV was performed in 9.5% of patients (n = 164), encompassing both primary TIV (7.2%, n = 124) and TIV with preceding NIV (2.3%, n = 40). TIV was more often utilized without previous NIV (25.7% vs. 8.3% of all ventilated patients), demonstrating that primary TIV was the prevailing pathway for invasive ventilation. The median (range) survival was significantly longer in the NIV cohort (40.8 [37.2–44.3] months) and the TIV cohort (82.1 [68.7–95.6] months) as compared to the non-NIV cohort (33.6 [31.6–35.7] months). Conclusions: Although NIV represents the standard of care, its utilization rate was low. TIV was mainly started without preceding NIV, suggesting that TIV may not be confined to NIV treatment escalation. However, TIV was pursued in a minority of patients who had previously undergone NIV. The survival benefit observed in the patients with NIV was equal to that reported in a controlled pivotal trial, but the prognosis with TIV is highly variable. The determinants of utilization of NIV/TIV and of survival (bulbar syndrome, availability of ventilation-related home nursing, cultural factors) warrant further investigation

Acceptance of Enhanced Robotic Assistance Systems in People With Amyotrophic Lateral Sclerosis–Associated Motor Impairment: Observational Online Study

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive paresis of the extremities and the loss of manual functioning. Due to the severe functional impairment that the disease entails, ALS requires the provision of comprehensive nursing care and a complex set of assistive technology devices. To relieve caregivers and promote autonomy of people with ALS, robotic assistance systems are being developed. This trial aims to evaluate the acceptance of technology, in general, and of robotic arm assistance among people with ALS in order to lay the groundwork for the development of a semiautomatic robotic arm that can be controlled by humans via a multimodal user interface and that will allow users to handle objects and attend to their own bodies. Objective: The aim of this study was to perform a systematic analysis of technology commitment and acceptance of robotic assistance systems from the perspective of physically limited people living with ALS. Methods: The investigation was conducted as a study of a prospective cohort. Participants were only included if they had received a medical diagnosis of ALS. Data collection took place via an online questionnaire on the Ambulanzpartner Soziotechnologie internet platform. Technological commitment was measured using the Neyer short scale. Furthermore, a multidimensional questionnaire was specially developed to analyze participant acceptance of robotic arm assistance: the Acceptance Measure of Robotic Arm Assistance (AMRAA). This questionnaire was accompanied by a video introducing the robot arm. ALS severity was ascertained using the ALS Functional Rating Scale–Extended (ALSFRS-EX). Results: A total of 268 people with ALS participated in the survey. Two-thirds of the participants were male. The overall mean ALS severity score was 42.9 (SD 11.7) points out of 60 on the ALSFRS-EX, with the most relevant restrictions on arms and legs (<60% of normal functioning). Technological commitment ranked high, with the top third scoring 47.2 points out of 60. Younger participants and males showed significantly higher values. The AMRAA score was, again, significantly higher among younger participants. However, the gender difference within the overall cohort was not significant. The more limited the arm functioning of participants according to the ALSFRS-EX subscale, the higher the acceptance rate of robotic assistance. This relationship proved significant. Conclusions: People with ALS display high technological commitment and feel positive about using technological assistance systems. In our study, younger participants were more open to technology use, in general, and robotic assistance, in particular. Self-appraisal of technology acceptance, competence, and control conviction were generally higher among men. However, any presumed gender difference vanished when users were asked to rate the anticipated usefulness of the technology, in particular the robotic arm. The acceptance was also reflected in users’ increased willingness to use a robotic arm as the functionality of their own arms decreased. From the perspective of people with ALS, robotic assistance systems are critical to promoting individual autonomy. Another key consideration in the development of future assistive technologies should be the reduction of caregiver burden. Trial Registration: German Clinical Trials Register DRKS00012803; https://tinyurl.com/w9yzduh

Treatment expectations and perception of therapy in adult patients with spinal muscular atrophy receiving nusinersen

Background and purpose: This was an investigation of treatment expectations and of the perception of therapy in adult patients with 5q-associated spinal muscular atrophy (5q-SMA) receiving nusinersen. Methods: A prospective, non-interventional observational study of nusinersen treatment in adult 5q-SMA patients was conducted at nine SMA centers in Germany. The functional status, treatment expectations and perceived outcomes were assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale-extended (ALS-FRS-ex), the Measure Yourself Medical Outcome Profile (MYMOP2), the Treatment Satisfaction Questionnaire for Medication (TSQM-9) and the Net Promoter Score (NPS). Results: In all, 151 patients were included with a median age of 36 years (15-69 years). SMA type 3 (n = 90, 59.6%) prevailed, followed by type 2 (33.8%) and type 1 (6.6%). In SMA types 1-3, median ALS-FRS-ex scores were 25, 33 and 46 (of 60 scale points), respectively. MYMOP2 identified distinct treatment expectations: head verticalization (n = 13), bulbar function (n = 16), arm function (n = 65), respiration (n = 15), trunk function (n = 34), leg function (n = 76) and generalized symptoms (n = 77). Median symptom severity decreased during nusinersen treatment (median observational period 6.1 months, 0.5-16 months) from 3.7 to 3.3 MYMOP2 score points (p < 0.001). The convenience of drug administration was critical (49.7 of 100 TSQM-9 points, SD 22); however, the overall treatment satisfaction was high (74.3, SD 18) and the recommendation rating very positive (NPS +66). Conclusions: Nusinersen was administered across a broad range of ages, disease durations and motor function deficits. Treatment expectations were highly differentiated and related to SMA type and functional status. Patient-reported outcomes demonstrated a positive perception of nusinersen therapy in adult patients with 5q-SMA

Safety and efficacy of rasagiline as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomised, double-blind, parallel-group, placebo-controlled, phase 2 trial

Background Rasagiline, a monoamine oxidase B inhibitor with neuroprotective potential in Parkinson's disease, has shown a disease-modifying effect in the SOD1-Gly93Ala low-expressing mouse model of amyotrophic lateral sclerosis, both alone and in combination with riluzole. We sought to test whether or not rasagiline 1 mg/day can prolong survival in patients with amyotrophic lateral sclerosis also receiving riluzole. Methods Patients with possible, probable, or definite amyotrophic lateral sclerosis were enrolled to our randomised, placebo-controlled, parallel-group, double-blind, phase 2 trial from 15 German network for motor neuron diseases (MND-NET) centres (university hospitals or clinics). Eligible patients were aged at least 18 years, had onset of progressive weakness within the 36 months before the study, had disease duration of more than 6 months and less than 3 years, and had a best-sitting slow vital capacity of at least 50%. After a 4-week screening period, eligible patients were randomly assigned (1:1) to receive either rasagiline (1 mg/day) or placebo in addition to riluzole (100 mg/day), after stratification for site of onset (bulbar or spinal) and study centre. Patients and all personnel assessing outcome parameters were masked to treatment allocation. Patients were followed up 2, 6, 12, and 18 months after randomisation. The primary endpoint was survival time, defined as the time to death or time to study cutoff date (ie, the last patient's last visit plus 14 days). Analyses of primary outcome and safety measures were done in all patients who received at least one dose of trial treatment (intention-to-treat population). The trial is registered with ClinicalTrials.gov, number NCT01879241. Findings Between July 2, 2013, and Nov 11, 2014, 273 patients were screened for eligibility, and 252 patients were randomly assigned to receive rasagiline (n=127) or placebo (n=125). 126 patients taking rasagiline and 125 taking placebo were included in the intention-to-treat analysis. For the primary outcome, the survival probability at the end of the study was 0.43 (95% CI 0.25-0.59) in the rasagiline group (n=126) and 0.53 (0.43-0.62) in the placebo group (n=125). The estimated effect size (hazard ratio) was 0.91 (one-sided 97.5% CI -infinity to 1.34; p=0.31). Rasagiline was well tolerated, and most adverse events were due to amyotrophic lateral sclerosis disease progression rather than treatment; the most frequent of these were dysphagia (32 [25%] taking rasagiline vs 24 [19%] taking placebo) and respiratory failure (25 [20%] vs 31 [25%]). Frequency of adverse events were comparable between both groups. Interpretation Rasagiline was safe in patients with amyotrophic lateral sclerosis. There was no difference between groups in the primary outcome of survival, although post-hoc analysis suggested that rasagiline might modify disease progression in patients with an initial slope of Amyotrophic Lateral Sclerosis Functional Rating Scale Revised greater than 0.5 points per month at baseline. This should be confirmed in another clinical trial. Copyright (C) 2018 Elsevier Ltd. All rights reserved

Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis: The TUDCA-ALS trial protocol

Background: Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative rare disease that affects motor neurons in the brain, brainstem, and spinal cord, resulting in progressive weakness and atrophy of voluntary skeletal muscles. Although much has been achieved in understanding the disease pathogenesis, treatment options are limited, and in Europe, riluzole is the only approved drug. Recently, some other drugs showed minor effects. Methods: The TUDCA-ALS trial is a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The study aims to enroll 320 patients in 25 centers across seven countries in Europe. Enrolled patients are randomized to one of two treatment arms: TUDCA or identical placebo by oral route. The study measures disease progression during the treatment period and compares it to natural progression during a no-treatment run-in phase. Clinical data and specific biomarkers are measured during the trial. The study is coordinated by a consortium composed of leading European ALS centers. Conclusion: This trial is aimed to determine whether TUDCA has a disease-modifying activity in ALS. Demonstration of TUDCA efficacy, combined with the validation of new biomarkers, could advance ALS patient care