Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis. METHODS: ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18-80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6-24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed. FINDINGS: Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1·00 (95% CI 0·91 to 1·00) with placebo, 1·00 (0·89 to 1·00) with fasudil 30 mg, and 1·00 (0·90 to 1·00) with fasudil 60 mg; the difference in proportions was 0·00 (95% CI -0·11 to 0·10; p>0·99) for fasudil 30 mg versus placebo and 0·00 (-0·10 to 0·10; p>0·99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0·93 (95% CI 0·81 to 0·99) with placebo, 1·00 (0·90 to 1·00) with fasudil 30 mg, and 0·90 (0·76 to 0·97) with fasudil 60 mg; the difference in proportions was 0·07 (95% CI -0·05 to 0·20; p=0·25) for fasudil 30 mg versus placebo, and -0·03 (-0·18 to 0·10; p=0·70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group. INTERPRETATION: Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug. FUNDING: Framework of the E-Rare Joint Transnational Call 2016 "Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases".

Comparative analysis of neurofilaments and biomarkers of muscular damage in amyotrophic lateral sclerosis.

Diagnosis of the fatal neurodegenerative disease amyotrophic lateral sclerosis is challenging. Neurofilaments, indicative of neuronal damage, along with creatine kinase, creatinine, myoglobin, and troponin T, representing muscular damage, have been identified as promising fluid biomarkers. This study aims to comprehensively assess and compare their diagnostic and prognostic potential in a 'real-world' cohort of patients with amyotrophic lateral sclerosis. About 77 patients with amyotrophic lateral sclerosis and its clinical variants, and 26 age- and sex-matched controls with various neuromuscular and neurodegenerative diseases, were retrospectively included in this monocentric, cross-sectional study. Neurofilaments in cerebrospinal fluid and biomarkers of muscular damage in serum were measured and correlated with demographic features, motor function, survival time, clinical phenotypes, and the extent of upper and lower motor neuron involvement. Neurofilament, myoglobin, and troponin T concentrations were higher in patients with amyotrophic lateral sclerosis compared to disease controls. Higher neurofilament levels correlated with lower motor function and faster disease progression rate, while higher creatine kinase and creatinine concentrations were linked to preserved motor function. In contrast, troponin T elevation indicated poorer fine and gross motor functions. Increased neurofilament levels were associated with shorter survival, whereas biomarkers of muscular damage lacked survival correlation. Neurofilament concentrations were higher in classical amyotrophic lateral sclerosis than in progressive muscular atrophy, while myoglobin and troponin T levels were elevated in progressive muscular atrophy compared to primary lateral sclerosis. Neurofilaments were predominantly linked to upper motor neuron involvement. Our findings confirmed the robust diagnostic and prognostic value of neurofilaments in amyotrophic lateral sclerosis. Elevated neurofilament concentrations were associated with higher disease severity, faster disease progression, shorter survival, and predominant upper motor neuron degeneration. Biomarkers of muscular damage were inferior in distinguishing amyotrophic lateral sclerosis from other neuromuscular and neurodegenerative diseases. However, they may serve as complementary biomarkers and support in discriminating clinical variants of amyotrophic lateral sclerosis.

SOD1 gene screening in ALS - frequency of mutations, patients' attitudes to genetic information and transition to tofersen treatment in a multi-center program.

Objective: To report the frequency of pathogenic SOD1 gene variants in a screening program in amyotrophic lateral sclerosis (ALS), and the clinical practice of transition to an expanded access program (EAP) of tofersen treatment. Methods: From October 2021 to February 2024, at 11 ALS centers in Germany genetic testing for SOD1, FUS, TARDBP, and C9orf72 was performed. Patients were offered to opt for notification either about all genetic variants or SOD1 variants relevant for tofersen therapy. The transition to the EAP with tofersen was assessed. Results: 1935 patients were screened (94.7% sporadic ALS). 48.8% (n = 928) opted for notification of treatment-relevant information. Genetic variants were found as follows: SOD1 (likely) pathogenic variants (class 4/5) 1.8% (n = 34), variants of unknown significance (class 3) 0.8% (n = 16), FUS (class 4/5) 0.9% (n = 17), TARDBP (class 4/5) 1.3% (n = 25), C9orf72 hexanucleotide repeat expansion 7.0% (n = 135). In SOD1-ALS (encompassing class 3-5 variants, n = 50), 68.0% (n = 34) reported a negative family history. 74.0% (n = 37) of SOD1-ALS patients - which represent 1.9% of all participants of the screening program - were transitioned to tofersen. Median duration from start of genetic testing to treatment was 94 days (57 to 295 days). Eight patients declined treatment whereas five individuals died before initiation of therapy. Conclusion: The finding of SOD1 variants in patients with a negative family history underscores the need for a broad genetic screening in ALS. In SOD1-ALS, the treatment option with tofersen was mostly utilized. The wide range in the transition time to tofersen calls for a SOD1-ALS management program.

Smartphone-Based Assessment of Mobility and Manual Dexterity in Adult People with Spinal Muscular Atrophy.

Background: More responsive, reliable, and clinically valid endpoints of disability are essential to reduce size, duration, and burden of clinical trials in adult persons with spinal muscular atrophy (aPwSMA). Objective: The aim is to investigate the feasibility of smartphone-based assessments in aPwSMA and provide evidence on the reliability and construct validity of sensor-derived measures (SDMs) of mobility and manual dexterity collected remotely in aPwSMA. Methods: Data were collected from 59 aPwSMA (23 walkers, 20 sitters and 16 non-sitters) and 30 age-matched healthy controls (HC). SDMs were extracted from five smartphone-based tests capturing mobility and manual dexterity, which were administered in-clinic and remotely in daily life for four weeks. Reliability (Intraclass Correlation Coefficients, ICC) and construct validity (ability to discriminate between HC and aPwSMA and correlations with Revised Upper Limb Module, RULM and Hammersmith Functional Scale - Expanded HFMSE) were quantified for all SDMs. Results: The smartphone-based assessments proved feasible, with 92.1% average adherence in aPwSMA. The SDMs allowed to reliably assess both mobility and dexterity (ICC > 0.75 for 14/22 SDMs). Twenty-one out of 22 SDMs significantly discriminated between HC and aPwSMA. The highest correlations with the RULM were observed for SDMs from the manual dexterity tests in both non-sitters (Typing, ρ= 0.78) and sitters (Pinching, ρ= 0.75). In walkers, the highest correlation was between mobility tests and HFMSE (5 U-Turns, ρ= 0.79). Conclusions: This exploratory study provides preliminary evidence for the usability of smartphone-based assessments of mobility and manual dexterity in aPwSMA when deployed remotely in participants' daily life. Reliability and construct validity of SDMs remotely collected in real-life was demonstrated, which is a pre-requisite for their use in longitudinal trials. Additionally, three novel smartphone-based performance outcome assessments were successfully established for aPwSMA. Upon further validation of responsiveness to interventions, this technology holds potential to increase the efficiency of clinical trials in aPwSMA.

Patients' and caregivers' perception of multidimensional and palliative care in amyotrophic lateral sclerosis - protocol of a German multicentre study.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an inevitably fatal condition that leads to a progressive loss of physical functioning, which results in a high psychosocial burden and organizational challenges related to medical care. Multidimensional and multiprofessional care is advised to meet the complex needs of patients and their families. Many healthcare systems, including Germany, may not be able to meet these needs because non-medical services such as psychological support or social counselling are not regularly included in the care of patients with ALS (pwALS). Specialised neuropalliative care is not routinely implemented nor widely available. Caregivers of pwALS are also highly burdened, but there is still a lack of support services for them. METHODS: This project aims to assess the perceptions and satisfaction with ALS care in Germany in pwALS and their caregivers. This will be achieved by means of a cross-sectional, multicentre survey. The examination will assess, to which extend the patients' needs in the six domains of physical, psychological, social, spiritual, practical and informational are being met by current care structures. This assessment will be linked to mental well-being, subjective quality of life, attitudes toward life-sustaining measures and physician-assisted suicide, and caregiver burden. The study aims to recruit 500 participants from nationwide ALS centres in order to draw comprehensive conclusions for Germany. A total of 29 centres, mostly acquired via the clinical and scientific German Network for Motor Neuron Diseases (MND-NET), will take part in the project, 25 of which have already started recruitment. PERSPECTIVE: It is intended to provide data-based starting points on how current practice of care in Germany is perceived pwALS and their caregivers and how it can be improved according to their needs. Planning and initiation of the study has been completed. TRIAL REGISTRATION: The study is registered at ClinicalTrails.gov; NCT06418646.

Clinical and patient-reported outcomes and neurofilament response during tofersen treatment in SOD1-related ALS-A multicenter observational study over 18 months.

INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (SOD1-ALS), tofersen received accelerated approval in the United States and is available via expanded access programs (EAP) outside the United States. This multicenter study investigates clinical and patient-reported outcomes (PRO) and serum neurofilament light chain (sNfL) during tofersen treatment in an EAP in Germany. METHODS: Sixteen SOD1-ALS patients receiving tofersen for at least 6 months were analyzed. The ALS progression rate (ALS-PR), as measured by the monthly change of the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity (SVC), and sNfL were investigated. PRO included the Measure Yourself Medical Outcome Profile (MYMOP2), Treatment Satisfaction Questionnaire for Medication (TSQM-9), and Net Promoter Score (NPS). RESULTS: Mean tofersen treatment was 11 months (6-18 months). ALS-PR showed a mean change of -0.2 (range 0 to -1.1) and relative reduction by 25%. Seven patients demonstrated increased ALSFRS-R. SVC was stable (mean 88%, range -15% to +28%). sNfL decreased in all patients except one heterozygous D91A-SOD1 mutation carrier (mean change of sNfL -58%, range -91 to +27%, p < .01). MYMOP2 indicated improved symptom severity (n = 10) or yet perception of partial response (n = 6). TSQM-9 showed high global treatment satisfaction (mean 83, SD 16) although the convenience of drug administration was modest (mean 50, SD 27). NPS revealed a very high recommendation rate for tofersen (NPS +80). DISCUSSION: Data from this EAP supported the clinical and sNfL response to tofersen in SOD1-ALS. PRO suggested a favorable patient perception of tofersen treatment in clinical practice.

Analysis and occurrence of biallelic pathogenic repeat expansions in RFC1 in a German cohort of patients with a main clinical phenotype of motor neuron disease.

Biallelic pathogenic repeat expansions in RFC1 were recently identified as molecular origin of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) as well as of one of the most common causes of adult-onset ataxia. In the meantime, the phenotypic spectrum has expanded massively and now includes mimics of multiple system atrophy or parkinsonism. After identifying a patient with a clinical diagnosis of amyotrophic lateral sclerosis (ALS) as a carrier of biallelic pathogenic repeat expansions in RFC1, we studied a cohort of 106 additional patients with a clinical main phenotype of motor neuron disease (MND) to analyze whether such repeat expansions are more common in MND patients. Indeed, two additional MND patients (one also with ALS and one with primary lateral sclerosis/PLS) have been identified as carrier of biallelic pathogenic repeat expansions in RFC1 in the absence of another genetic alteration explaining the phenotype, suggesting motor neuron disease as another extreme phenotype of RFC1 spectrum disorder. Therefore, MND might belong to the expanding phenotypic spectrum of pathogenic RFC1 repeat expansions, particularly in those MND patients with additional features such as sensory and/or autonomic neuropathy, vestibular deficits, or cerebellar signs. By systematically analyzing the RFC1 repeat array using Oxford nanopore technology long-read sequencing, our study highlights the high intra- and interallelic heterogeneity of this locus and allows the identification of the novel repeat motif 'ACAAG'.

Serum neurofilament light chain in distinct phenotypes of amyotrophic lateral sclerosis: A longitudinal, multicenter study.

OBJECTIVE: To assess the performance of serum neurofilament light chain (sNfL) in clinical phenotypes of amyotrophic lateral sclerosis (ALS). METHODS: In 2949 ALS patients at 16 ALS centers in Germany and Austria, clinical characteristics and sNfL were assessed. Phenotypes were differentiated for two anatomical determinants: (1) upper and/or lower motor involvement (typical, typMN; upper/lower motor neuron predominant, UMNp/LMNp; primary lateral sclerosis, PLS) and (2) region of onset and propagation of motor neuron dysfunction (bulbar, limb, flail-arm, flail-leg, thoracic onset). Phenotypes were correlated to sNfL, progression, and survival. RESULTS: Mean sNfL was - compared to typMN (75.7 pg/mL, n = 1791) - significantly lower in LMNp (45.1 pg/mL, n = 413), UMNp (58.7 pg/mL n = 206), and PLS (37.6 pg/mL, n = 84). Also, sNfL significantly differed in the bulbar (92.7 pg/mL, n = 669), limb (64.1 pg/mL, n = 1305), flail-arm (46.4 pg/mL, n = 283), flail-leg (53.6 pg/mL, n = 141), and thoracic (74.5 pg/mL, n = 96) phenotypes. Binary logistic regression analysis showed highest contribution to sNfL elevation for faster progression (odds ratio [OR] 3.24) and for the bulbar onset phenotype (OR 1.94). In contrast, PLS (OR 0.20), LMNp (OR 0.45), and thoracic onset (OR 0.43) showed reduced contributions to sNfL. Longitudinal sNfL (median 12 months, n = 2862) showed minor monthly changes (<0.2%) across all phenotypes. Correlation of sNfL with survival was confirmed (p < 0.001). CONCLUSIONS: This study underscored the correlation of ALS phenotypes - differentiated for motor neuron involvement and region of onset/propagation - with sNfL, progression, and survival. These phenotypes demonstrated a significant effect on sNfL and should be recognized as independent confounders of sNfL analyses in ALS trials and clinical practice.

Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS.

Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)-both putative products of the Parkinson's disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.

Troponin T is elevated in a relevant proportion of patients with 5q-associated spinal muscular atrophy.

Troponin T concentration (TNT) is commonly considered a marker of myocardial damage. However, elevated concentrations have been demonstrated in numerous neuromuscular disorders, pointing to the skeletal muscle as a possible extracardiac origin. The aim of this study was to determine disease-related changes of TNT in 5q-associated spinal muscular atrophy (SMA) and to screen for its biomarker potential in SMA. We therefore included 48 pediatric and 45 adult SMA patients in this retrospective cross-sequential observational study. Fluid muscle integrity and cardiac markers were analyzed in the serum of treatment-naïve patients and subsequently under disease-modifying therapies. We found a TNT elevation in 61% of SMA patients but no elevation of the cardiospecific isoform Troponin I (TNI). TNT elevation was more pronounced in children and particularly infants with aggressive phenotypes. In adults, TNT correlated to muscle destruction and decreased under therapy only in the subgroup with elevated TNT at baseline. In conclusion, TNT was elevated in a relevant proportion of patients with SMA with emphasis in infants and more aggressive phenotypes. Normal TNI levels support a likely extracardiac origin. Although its stand-alone biomarker potential seems to be limited, exploring TNT in SMA underlines the investigation of skeletal muscle integrity markers.

'Reading the palm' - A pilot study of grip and finger flexion strength as an outcome measure in 5q spinal muscular atrophy.

BACKGROUND: Innovative RNA modifying and gene replacement therapies are currently revolutionizing the therapeutic landscape in 5q-associated spinal muscular atrophy (SMA). In order to provide individual recommendations for choice of treatment and therapy (dis-) continuation, objective outcome measures are needed. The purpose of this study was to determine whether maximum isometric voluntary grip and finger flexion strength is a useful sensitive outcome measure in children and adult patients with SMA. METHODS: In this non-interventional, longitudinal pilot study, we assessed grip and finger flexion strength on 39 patients with SMA II and III (n = 16 children, mean age = 10.0; n = 23 adults, mean age = 38.4) using the Weber hand and finger dynamometer HFD 200. Grip and finger flexion strength, clinical examinations and motor function scores (Revised Upper Limb Module, Hammersmith Functional Motor Scale Expanded) were assessed over a 12-month treatment period concurrent with the nusinersen treatment. RESULTS: Grip and finger flexion strength was highly associated with motor function and disease severity, SMA type and SMN2 copy number. During nusinersen treatment, grip and finger flexion strength significantly increased in children and adults with SMA. CONCLUSION: Grip and finger flexion strength measured with the HFD 200 is a promising sensitive outcome measure for SMA.

5qSMA: standardised retrospective natural history assessment in 268 patients with four copies of SMN2.

Newborn screening for 5qSMA offers the potential for early, ideally pre-symptomatic, therapeutic intervention. However, limited data exist on the outcomes of individuals with 4 copies of SMN2, and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of SMN2 from the SMArtCARE registry in Germany, Austria and Switzerland. Inclusion criteria required comprehensive baseline data and diagnosis outside of newborn screening. Only data prior to initiation of disease-modifying treatment were included. The median age at disease onset was 3.0 years, with a mean of 6.4 years. Significantly, 55% of patients experienced symptoms before the age of 36 months. 3% never learned to sit unaided, a further 13% never gained the ability to walk independently and 33% of ambulatory patients lost this ability during the course of the disease. 43% developed scoliosis, 6.3% required non-invasive ventilation and 1.1% required tube feeding. In conclusion, our study, in line with previous observations, highlights the substantial phenotypic heterogeneity in SMA. Importantly, this study provides novel insights: the median age of disease onset in patients with 4 SMN2 copies typically occurs before school age, and in half of the patients even before the age of three years. These findings support a proactive approach, particularly early treatment initiation, in this subset of SMA patients diagnosed pre-symptomatically. However, it is important to recognize that the register will not include asymptomatic individuals.

Macrophage inclusions in cerebrospinal fluid following treatment initiation with antisense oligonucleotide therapies in motor neuron diseases.

5q-associated spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are two distinct neurological disorders leading to degeneration of lower motor neurons. The antisense oligonucleotides (ASOs) nusinersen and tofersen are novel disease-modifying agents for these diseases, respectively. In the context of ASO treatment, the cytological characteristics and composition of cerebrospinal fluid (CSF) have recently garnered particular interest. This report presents a case series of CSF cytology findings in two patients with SMA and ALS revealing comparable unspecified macrophage inclusions following treatment initiation with nusinersen and tofersen. Yet, the presence of these "asophages" in the treatment course of two different ASOs is of unclear significance. While both treatments have been well tolerated, this phenomenon warrants attention, given the long-term nature of these treatments.

Effects of tofersen treatment in patients with SOD1-ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program.

Background: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated. Methods: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events. Findings: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported. Interpretation: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction. Funding: No funding was received towards this study.

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.

Impairment of oculomotor functions in patients with early to advanced amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) can result into an incomplete locked in state (iLIS), in which communication depends on eye tracking computer devices. Oculomotor function impairments in ALS have been reported, but there is little research, particularly with respect to patients in iLIS. In the present study, we compared reflexive and executive oculomotor function by means of an eye tracking test battery between three groups: advanced ALS patients in iLIS (n = 22), patients in early to middle ALS stages (n = 44) and healthy subjects (n = 32). Patients with ALS showed significant deteriorations in oculomotor functions, with stronger impairments in iLIS. More specifically, ALS patients produced visually guided prosaccades with longer latencies and more frequent hypometria compared to healthy subjects. Longest latencies were obtained in iLIS patients, with a stronger prolongation for vertical than for horizontal prosaccades. ALS patients made more antisaccade errors and generated antisaccades with longer latencies. Smooth pursuit was also impaired in ALS. In the earlier ALS stages, bulbar onset patients presented stronger antisaccade and smooth pursuit deficits than spinal onset patients. Our findings reveal a relevant deterioration of important oculomotor functions in ALS, which increases in iLIS. It includes impairments of reflexive eye movements to loss of executive inhibitory control, indicating a progressing pathological involvement of prefrontal, midbrain and brainstem areas. The assessment of oculomotor functions may therefore provide clinically relevant bio- and progression marker, particularly in advanced ALS.

[Psychologically guided group meetings for family caregivers of ALS patients]. / Psychologisch geleitete Gruppentreffen für Angehörige von ALS-Patient*innen.

BACKGROUND: The course of amyotrophic lateral sclerosis (ALS,) associated with progressive physical limitations, is a challenge to the patients themselves and also to their family caregivers, who have to deal with psychosocial, socio-medical and organizational issues. Caregivers are often closely involved and heavily burdened themselves, which is why specific support is recommended. The aim of this study was to investigate the feasibility and acceptance of psychologically guided supportive group meetings for family caregivers in a specialist ALS outpatient clinic. METHODS: Over a period of two years, data were collected from a total of 26 caregivers of ALS patients in order to evaluate the relevance, usefulness and criticisms of open-topic meetings that took place every three months. RESULTS: Topics discussed in the meetings included mainly psychosocial issues such as self-care, dealing with emotions or with conflicts with the patients and third parties, as well as practical and organizational matters. The meetings were predominantly rated as helpful, well understandable and personally relevant and the exchange in a "community of destiny" was perceived as emotionally relieving. DISCUSSION: The ALS caregiver group meetings in the described format were easy to carry out and well accepted. Supportive interventions, such as the one reported here, might be a valuable component of ALS care, to relieve the highly burdened caregivers of ALS-patients by providing them with social, emotional and practical support. However, the quantitative verification of the intervention's effectiveness is challenging - both methodologically and due to the caregivers' complex life situation. Psychosocial support services for ALS caregivers are feasible with little effort and should be an integral part of the standard ALS care based on a multi-dimensional, palliative care concept.

Classifying flow cytometry data using Bayesian analysis helps to distinguish ALS patients from healthy controls.

Introduction: Given its wide availability and cost-effectiveness, multidimensional flow cytometry (mFC) became a core method in the field of immunology allowing for the analysis of a broad range of individual cells providing insights into cell subset composition, cellular behavior, and cell-to-cell interactions. Formerly, the analysis of mFC data solely relied on manual gating strategies. With the advent of novel computational approaches, (semi-)automated gating strategies and analysis tools complemented manual approaches. Methods: Using Bayesian network analysis, we developed a mathematical model for the dependencies of different obtained mFC markers. The algorithm creates a Bayesian network that is a HC tree when including raw, ungated mFC data of a randomly selected healthy control cohort (HC). The HC tree is used to classify whether the observed marker distribution (either patients with amyotrophic lateral sclerosis (ALS) or HC) is predicted. The relative number of cells where the probability q is equal to zero is calculated reflecting the similarity in the marker distribution between a randomly chosen mFC file (ALS or HC) and the HC tree. Results: Including peripheral blood mFC data from 68 ALS and 35 HC, the algorithm could correctly identify 64/68 ALS cases. Tuning of parameters revealed that the combination of 7 markers, 200 bins, and 20 patients achieved the highest AUC on a significance level of p < 0.0001. The markers CD4 and CD38 showed the highest zero probability. We successfully validated our approach by including a second, independent ALS and HC cohort (55 ALS and 30 HC). In this case, all ALS were correctly identified and side scatter and CD20 yielded the highest zero probability. Finally, both datasets were analyzed by the commercially available algorithm 'Citrus', which indicated superior ability of Bayesian network analysis when including raw, ungated mFC data. Discussion: Bayesian network analysis might present a novel approach for classifying mFC data, which does not rely on reduction techniques, thus, allowing to retain information on the entire dataset. Future studies will have to assess the performance when discriminating clinically relevant differential diagnoses to evaluate the complementary diagnostic benefit of Bayesian network analysis to the clinical routine workup.

Impaired diaphragmatic motility in treatment-naive adult patients with spinal muscular atrophy improved during nusinersen treatment.

INTRODUCTION/AIMS: The leading clinical feature of 5q-associated spinal muscular atrophy (SMA) is symmetric, proximal muscle weakness. Muscles involved in ventilation exhibit a specific pattern of denervation: intercostal muscles are severely atrophic, whereas the diaphragm muscle is less affected. The aim of this study was to investigate the involvement of diaphragmatic function by ultrasound imaging in adult patients with SMA and to quantify dynamics of diaphragmatic function during nusinersen treatment. METHODS: Diaphragmatic thickness, thickening, and excursion during quiet breathing were assessed in 24 adult patients with SMA type 2 and 3 by diaphragm ultrasound imaging before and during nusinersen treatment and were correlated with spirometric parameters. RESULTS: Diaphragm thickness was not reduced, but increased in a remarkable proportion of patients, whereas diaphragm thickening and excursion were reduced in about 20% to 30% of nusinersen-naive, adult patients with SMA types 2 and 3. During 26 months of nusinersen treatment, diaphragm thickening fraction and excursion improved. DISCUSSION: Diaphragm ultrasound imaging can provide disease- and treatment-relevant information that is not identified during routine clinical assessments and may therefore be a valuable complementary outcome measure.

Economic evaluation of Motor Neuron Diseases: a nationwide cross-sectional analysis in Germany.

BACKGROUND AND OBJECTIVES: Motor Neuron Diseases (MND) are rare diseases but have a high impact on affected individuals and society. This study aims to perform an economic evaluation of MND in Germany. METHODS: Primary patient-reported data were collected including individual impairment, the use of medical and non-medical resources, and self-rated Health-Related Quality of Life (HRQoL). Annual socio-economic costs per year as well as Quality-Adjusted Life Years (QALYs) were calculated. RESULTS: 404 patients with a diagnosis of Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA) or Hereditary Spastic Paraplegia (HSP) were enrolled. Total annual costs per patient were estimated at 83,060€ in ALS, 206,856€ in SMA and 27,074€ in HSP. The main cost drivers were informal care (all MND) and disease-modifying treatments (SMA). Self-reported HRQoL was best in patients with HSP (mean EuroQoL Five Dimension Five Level (EQ-5D-5L) index value 0.67) and lowest in SMA patients (mean EQ-5D-5L index value 0.39). QALYs for patients with ALS were estimated to be 1.89 QALYs, 23.08 for patients with HSP and 14.97 for patients with SMA, respectively. Cost-utilities were estimated as follows: 138,960€/QALY for ALS, 525,033€/QALY for SMA, and 49,573€/QALY for HSP. The main predictors of the high cost of illness and low HRQoL were disease progression and loss of individual autonomy. CONCLUSION: As loss of individual autonomy was the main cost predictor, therapeutic and supportive measures to maintain this autonomy may contribute to reducing high personal burden and also long-term costs, e.g., care dependency and absenteeism from work.