Long-term efficacy and safety of nusinersen in adults with 5q spinal muscular atrophy: a prospective European multinational observational study.

Background: Evidence for the efficacy of nusinersen in adults with 5q-associated spinal muscular atrophy (SMA) has been demonstrated up to a period of 16 months in relatively large cohorts but whereas patients reach a plateau over time is still to be demonstrated. We investigated the efficacy and safety of nusinersen in adults with SMA over 38 months, the longest time period to date in a large cohort of patients from multiple clinical sites. Methods: Our prospective, observational study included adult patients with SMA from Germany, Switzerland, and Austria (July 2017 to May 2022). All participants had genetically-confirmed, 5q-associated SMA and were treated with nusinersen according to the label. The total Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores, and 6-min walk test (6 MWT; metres), were recorded at baseline and 14, 26, and 38 months after treatment initiation, and pre and post values were compared. Adverse events were also recorded. Findings: Overall, 389 patients were screened for eligibility and 237 were included. There were significant increases in all outcome measures compared with baseline, including mean HFMSE scores at 14 months (mean difference 1.72 [95% CI 1.19-2.25]), 26 months (1.20 [95% CI 0.48-1.91]), and 38 months (1.52 [95% CI 0.74-2.30]); mean RULM scores at 14 months (mean difference 0.75 [95% CI 0.43-1.07]), 26 months (mean difference 0.65 [95% CI 0.27-1.03]), and 38 months (mean difference 0.72 [95% CI 0.25-1.18]), and 6 MWT at 14 months (mean difference 30.86 m [95% CI 18.34-43.38]), 26 months (mean difference 29.26 m [95% CI 14.87-43.65]), and 38 months (mean difference 32.20 m [95% CI 10.32-54.09]). No new safety signals were identified. Interpretation: Our prospective, observational, long-term (38 months) data provides further real-world evidence for the continuous efficacy and safety of nusinersen in a large proportion of adult patients with SMA. Funding: Financial support for the registry from Biogen, Novartis and Roche.

Remote digital assessment of amyotrophic lateral sclerosis functional rating scale - a multicenter observational study.

OBJECTIVE: Remote self-assessment of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) using digital data capture was investigated for its feasibility as an add-on to ALSFRS-R assessments during multidisciplinary clinic visits. METHODS: From August 2017 to December 2021, at 12 ALS centers in Germany, an observational study on remote assessment of the ALSFRS-R was performed. In addition to the assessment of ALSFRS-R during clinic visits, patients were offered a digital self-assessment of the ALSFRS-R - either on a computer or on a mobile application ("ALS-App"). RESULTS: An estimated multicenter cohort of 4,670 ALS patients received care at participating ALS centers. Of these patients, 971 remotely submitted the ALSFRS-R, representing 21% of the multicenter cohort. Of those who opted for remote assessment, 53.7% (n = 521) completed a minimum of 4 ALSFRS-R per year with a mean number of 10.9 assessments per year. Different assessment frequencies were found for patients using a computer (7.9 per year, n = 857) and mobile app (14.6 per year, n = 234). Patients doing remote assessments were more likely to be male and less functionally impaired but many patients with severe disability managed to complete it themselves or with a caregiver (35% of remote ALSFRS-R cohort in King's Stage 4). CONCLUSIONS: In a dedicated ALS center setting remote digital self-assessment of ALSFRS-R can provide substantial data which is complementary and potentially an alternative to clinic assessments and could be used for research purposes and person-level patient management. Addressing barriers relating to patient uptake and adherence are key to its success.

Clinical Ethics Consultation in Neurology - a case series.

BACKGROUND: The concept of clinical ethics consultation (CECs) was implemented to provide support in ethical controversies in clinical settings and are offered in at least every second hospital in Germany. Neurological disorders often require complex decision-making. The aims of this study were to determine which situations lead to CEC in neurology and to investigate the influence of the individual patient's wishes on the recommendation. METHODS: Standardised CEC protocols in the years 2011 to 2017 at the University Hospitals of Goettingen and Jena were retrospectively surveyed. The contents were categorised along existing protocol templates of CEC scenarios and subsequently paraphrased and reduced to significant meanings. RESULTS: 27 CEC scenarios which were facilitated by various professional disciplines were reviewed. Stroke was the most frequent underlying condition. Nearly all patients were not able to consent. Mostly, the relatives acted as representatives or health advocates. In 67 % of cases, a sense of conflict triggered a CEC; in 33 % a sense of uncertainty was the reason for the CEC request. In 21 CEC scenarios, a recommendation was reached in consensus with all parties involved. In 59 % of cases, a decision was made to continue medical therapy. In seven cases, the patient's wishes led to a limitation of therapy, while in just two cases this decision was made primarily relying on the patient's best interest. In only 13 % of cases, a valid advance directive led to respective therapeutic consequences. CONCLUSIONS: CEC is feasible for consensus-finding not only in conflicts, but also in situations of therapeutic uncertainty in neurology. There is a special importance of the patient's wishes in decision-making in neurology. However, only in a few cases were advance directives precise and specific enough to have sufficient and decisive weight in therapeutic decision-making.

[Undergraduate palliative care teaching in times of COVID-19]. / Palliativmedizinische Lehre im Querschnittsbereich 13 unter dem Einfluss von COVID-19.

BACKGROUND: Due to the coronavirus disease 2019 (COVID-19) pandemic classroom teaching was largely discontinued at all German medical faculties in the summer semester (SS) 2020. This also affected undergraduate education in palliative care, which is established with an average of 22 teaching units. Teachers were asked to rapidly develop digital teaching and assessment tools. OBJECTIVE: The aim of this survey was to map the teaching situation in QB13 palliative medicine in SS 2020 under the influence of COVID-19 and from this to derive the need for networking and support for the coming semesters. MATERIAL AND METHODS: The key persons involved in palliative care education in all 41 medical faculties in Germany were identified and invited by the coordination office of the German Society for Palliative Medicine (DGP) to participate in an online survey using SurveyMonkey®. The questionnaire consisted of 15 items dealing with the evaluation of the past semester and the need for support for the coming semester. RESULTS: Out of 41 contacted teachers 16 participated in the survey. Most of them described the challenge of teaching in SS 2020 as successful. Support from the faculties was provided primarily in the form of digital teaching structures. A digital teaching design is also planned for the coming semester. Power point slides with sound and the conference tool Zoom® are often used. CONCLUSION: The design of examinations in SS 2020 is rated worse in the self-evaluation than the teaching design. Multiple choice questions were often used in classroom examinations. Lecturers would like the DGP to create and collect teaching and assessment materials centrally.

Challenges and opportunities for Multi-National Investigator-Initiated clinical trials for ALS: European and United States collaborations.

An inherent challenge to clinical trials that aim to test the efficacy of experimental therapeutics for patients with amyotrophic lateral sclerosis (ALS) is the relative rarity of the disease. A promising solution to this problem is a multi-center approach that ideally includes sites distributed across a broad geographic area. In support of such an approach, the European E-RARE program and the United States National Institutes of Health (NIH) partnered to support the investigator-initiated ROCK-ALS trial (Eudra-CT-Nr.: 2017-003676-31, NCT03792490) as a multi-national collaboration between centers in Europe and North America that is led by European investigators. During the set-up of this international trial, however, a number of unanticipated legal, administrative, and financial complexities emerged that required significant adaptation of the proposed trial scheme. Here, we report our experience navigating these obstacles and describe the potential solutions that we explored. Our experience may inform future efforts to implement multi-national investigator-initiated trials that involve both European and United States centers.

[Status of palliative care education in Germany : A survey of medical faculties in 2018]. / Stand der palliativmedizinischen Lehre in Deutschland : Bestandsaufnahme an den medizinischen Fakultäten im Jahr 2018.

BACKGROUND: To investigate the development in palliative care education in Germany, numerous surveys have been conducted since 2006. They showed differences of palliative care education between the faculties before and after the implementation of palliative care as a mandatory subject. The present study aims to document the status of palliative care education at German medical faculties in 2018. MATERIALS AND METHODS: Using an online questionnaire with 19 questions, the structure, organization, content, and assessment of palliative care education of German medical faculties were assessed. RESULTS: Of the 37 participating faculties, 30 reported improvements in terms of structural aspects, e.g., there were more palliative care units and full professorships. Due to increasing opportunities for final year rotations and innovative, practical teaching, students can now deepen their knowledge, skills, and attitude in palliative care. CONCLUSION: This study showed clear progression in palliative care education. Nevertheless, there is still room for improvement in terms of examination formats and professorships. Complementary surveys with students would be helpful to evaluate the education outcome.

Triage of Amyotrophic Lateral Sclerosis Patients during the COVID-19 Pandemic: An Application of the D50 Model.

Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease, the management of which requires the continuous provision of multidisciplinary therapies. Owing to the novel coronavirus disease (COVID-19) pandemic, regular contact with ALS patients at our center was severely restricted and patient care was at risk by delay of supportive therapies. We established a triage system based on the D50 disease progression model and were thus able to identify a prospective cohort with high disease aggressiveness (D50 < 30). Thirty-seven patients with highly aggressive disease were actively offered follow-up, either via telephone or on-site, depending on their disease-specific needs and abilities. We describe here the procedures, obstacles, and results of these prescient efforts during the restrictions caused by COVID-19 in the period between March and June 2020. In conclusion, four patients with highly aggressive disease were initiated with non-invasive ventilation and two received a gastrostomy. We could show that a comparable amount of advanced care was induced in a retrospective cohort within a similar time period one year prior to the COVID-19 outbreak. Our workflow to identify high-risk patients via D50 model metrics can be easily implemented and integrated within existing centers. It helped to maintain a high quality of advanced care planning for our ALS patients.

[Implementing the Cross-Disciplinary Subject Palliative Care - Lecture's Perspective]. / Implementierung des Q13 Palliativmedizin ­ Sicht der Lehrbeauftragten.

Introduction In 2009, palliative care was introduced as a mandatory subject in the undergraduate medical curriculum in Germany. Despite all efforts to integrate this subject into the curriculum, research suggests substantial differences and deficits in the quality of education between the medical schools. The aim of this research was to find out promoting as well as impedimental aspects of implementing palliative care in the medical training program. By this, a suitable framework in terms of content and structure for palliative care teaching should be extracted. Methods We performed guided interviews with 15 of the in total 36 lecturers responsible for the implementation of palliative care teaching at their respective medical schools. We focused on content, design and methods of implementation within the palliative care curriculum. Data was evaluated by content analysis according to Meuser and Nagel. Results We found that a lack of recognition of this subject within the medical faculties, coupled with entrenched structures of an already packed syllabus, were considered to be most relevant for the given heterogeneity in the implementation process. Deficits in personnel, financial and time resources also contributed to the perceived deficits. Faced with these difficulties, inner- and cross-faculty teamwork and support, extracurricular activities as well as external funds have proven to be important resources. Discussion To promote the implementation process, medical faculties need established palliative care structures that meet the interests and needs of the students more effectively. Analysis of structural needs (for instance, the amount of apprenticeships and teachings units) would be an important step to prove political claims. Moreover, the development of suitable and resource-saving teaching and assessment methods should be promoted.

Undergraduate education in palliative medicine in Germany: a longitudinal perspective on curricular and infrastructural development.

BACKGROUND: In 2009, palliative medicine became an integrated and compulsory part of undergraduate training in Germany by legislation. After a transitional period, all medical faculties were required to provide adequate teaching with an according examination and certification procedure. In parallel, we conducted bi-annual surveys on all medical faculties in Germany to examine for potential discrepancies between the implementation process and their intended consequences on teaching time and content. METHODS: Four consecutive bi-annual surveys (2006, 2008, 2010, 2012) of all 36 medical faculties in Germany were performed, using purposively for this study developed questionnaires. Likert scales and closed questions were analyzed descriptively. RESULTS: Medical Faculty response rate increased from 50 % in 2006 to 88.9 % in 2012. Teaching coordinators in palliative medicine primarily had an anesthesiology or internal medicine background. There was a noted increase over time of the involvement of specialized palliative care units (PCUs) as providing the setting for education. The number of faculties that were able to offer a complete 16 weeks of training in palliative medicine during the "final year" rose steadily. In addition, increased patient-centered teaching formats have been implemented over time. The faculties which offered innovative teaching formats with actors as patients (standardized patient interaction) increased, as did the total number of mandatory examinations. The number of faculties that provided compulsory teaching in a condensed manner within a single academic year increased sharply from 3 of 31 responding faculties in 2010 to 19 of 32 responding faculties in 2012. CONCLUSIONS: Until now, teaching conditions and structures in palliative medicine in Germany have proven to be extraordinarily heterogeneous. Although professorships ("Chairs") in palliative medicine proved to be particularly beneficial and supportive in curricular and structural development, only a minority of faculties provide leading academic positions in palliative medicine.

Susceptibility-weighted imaging provides insight into white matter damage in amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disorder, characterised by widespread white matter damage. There is growing evidence that disturbances in iron metabolism contribute to white matter alterations. MATERIALS & METHODS: We analysed the data of susceptibility-weighted imaging (SWI) of white matter in a cohort of 27 patients with ALS and 30 healthy age-matched controls. RESULTS: Signal alterations were found on SWI in the corpus callosum; along the corticospinal tract (subcortical motor cortex, posterior limb of the internal capsule and brainstem levels) and in the subgyral regions of frontal, parietal, temporal, occipital and limbic lobes. Alterations of white matter in the corpus callosum correlated with disease severity as assessed by the revised ALS functional rating scale. CONCLUSION: SWI is capable of indicating iron and myelin disturbances in white matter of ALS patients. The SWI patterns observed in this study suggest that widespread alterations due to iron disturbances occur in patients with ALS and correlate with disease severity.

Voxel-based MRI intensitometry reveals extent of cerebral white matter pathology in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of upper and lower motor neurons. Advanced MRI techniques such as diffusion tensor imaging have shown great potential in capturing a common white matter pathology. However the sensitivity is variable and diffusion tensor imaging is not yet applicable to the routine clinical environment. Voxel-based morphometry (VBM) has revealed grey matter changes in ALS, but the bias-reducing algorithms inherent to traditional VBM are not optimized for the assessment of the white matter changes. We have developed a novel approach to white matter analysis, namely voxel-based intensitometry (VBI). High resolution T1-weighted MRI was acquired at 1.5 Tesla in 30 ALS patients and 37 age-matched healthy controls. VBI analysis at the group level revealed widespread white matter intensity increases in the corticospinal tracts, corpus callosum, sub-central, frontal and occipital white matter tracts and cerebellum. VBI results correlated with disease severity (ALSFRS-R) and patterns of cerebral involvement differed between bulbar- and limb-onset. VBI would be easily translatable to the routine clinical environment, and once optimized for individual analysis offers significant biomarker potential in ALS.