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.

Risdiplam therapy in adults with 5q-SMA: observational study on motor function and treatment satisfaction.

BACKGROUND: We aimed to describe the experience of a single neuromuscular center in Germany in treating adult spinal muscular atrophy (SMA) patients with risdiplam and to analyze motor function and treatment satisfaction during a follow-up period up to 20 months. METHODS: Fourteen patients with type 2 or 3 SMA (seven with SMA type 2, six with SMA type 3; age range: 18-51) were included. The Revised Upper Limb Module (RULM) and the Hammersmith Functional Motor Scale Expanded (HFMSE) were recorded at baseline and at follow-up (month 4, 8, 12, 16, 20). Treatment adverse events were collected at every follow-up visit. Patients' treatment satisfaction was assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM). RESULTS: Half of the patients reached the 20-month follow-up. Based on the HFMSE score, no patients had clinically meaningful improvement. Twelve remained stable (92.3%), two showed transient clinically meaningful deterioration (15.4%) and one experienced lasting clinically meaningful deterioration (7.7%). Based on the RULM scores, seven patients were either stable or demonstrated clinically meaningful improvement (53.8%) and six showed clinically meaningful deterioration (46.2%). There was no treatment withdrawal during the follow-up. The most common adverse events were skin rash/increased skin sensitivity to sunlight (n = 3), diarrhea (n = 3), aphthous ulcer (n = 3) and abdominal pain (n = 2). Most patients stated to be at least "satisfied" with the medication. CONCLUSIONS: Risdiplam was well tolerated. Half of the patients remained stable or improved after risdiplam initiation. Larger and multicentric studies are needed to better understand the long-term effects of risdiplam in adult SMA.

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.

Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

An observational cohort study on pulmonary function in adult patients with 5q-spinal muscular atrophy under nusinersen therapy.

BACKGROUND: Few studies assessed the effect of nusinersen on respiratory function in adult patients with spinal muscular atrophy (SMA). The aim of this single-center study was to analyze pulmonary function and its association with muscle function and quality of life (QoL) in adult patients with 5q-SMA under nusinersen. METHODS: We recorded forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and peak expiratory flow (PEF) during nusinersen treatment in 38 adult SMA patients. Revised Upper Limb Module (RULM), Hammersmith Functional Motor Scale Expanded (HFMSE), 36-Item Short Form Health Survey (SF-36) questionnaire and Fatigue Severity Scale (FSS) were recorded and correlations between muscle function, QoL, fatigue and respiratory parameters were analyzed. RESULTS: No differences were detected between mean FVC, FEV1, PEF at different timepoints versus baseline. Ambulatory patients showed significant improvement in mean PEF at month 30, compared to non-ambulatory patients (+ 0.8 ± 0.5 vs. - 0.0 ± 0.5, p < 0.05). Patients with fatigue at baseline showed significant improvement in mean PEF at month 10, compared to patients without fatigue at baseline (+ 0.6 ± 0.9 vs. - 0.4 ± 0.5, p < 0.05). Physical domains of SF-36 positively correlated with the change in FVC and FEV1. FSS negatively correlated with the change in mean PEF. CONCLUSION: Mean pulmonary function remained stable during nusinersen treatment over a period of up to 30 months. Improvement in pulmonary function was associated with improvement in motor function, fatigue and QoL, early after nusinersen initiation.

Improvement of muscle strength in specific muscular regions in nusinersen-treated adult patients with 5q-spinal muscular atrophy.

Real-world data have shown mild improvement of overall motor function in adult patients treated with nusinersen, the first approved therapy for 5q-spinal muscular atrophy (SMA). However, knowledge about preferably targeted muscle functions is sparse. The aim of this study was to evaluate strength of distinct muscles and body regions in adult SMA patients in the early course of nusinersen therapy. 72 muscles of 15 patients were tested on the Medical Research Council (MRC) 0-10 scale (translated into MRC %) from nusinersen start to 14 months of treatment. The whole body muscular strength improved slightly or remained stable in 80% of SMA patients with a median improvement of + 2%. However, relevant increases of muscle strength of distinct regions were identified in the proximal upper limbs and shoulder girdle (median + 8%) and in muscle groups with a preserved function pre-treatment, even in more advanced diseased SMA patients. MRC grading was additionally performed in seven patients enrolled during ongoing treatment. Here, further improvement of muscle strength until month 18-26 was seen with the highest increases in the proximal upper and lower limbs. Our findings suggest that sole evaluation of the overall muscle strength might underestimate nusinersen therapy benefits.

Cranial nerve involvement in patients with immune-mediated neuropathy: An observational blink reflex study.

OBJECTIVE: This study aimed to assess cranial nerve involvement in a large adult cohort of patients with immune-mediated neuropathy undergoing immunoglobulin treatment by measuring blink reflex R1 latency prolongation in correlation with clinical findings and nerve conduction studies. METHODS: 104 patients underwent blink reflex examination and ulnar nerve conduction studies and were assessed by the Inflammatory Neuropathy Cause and Treatment disability score, the revised Amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) and focused clinical examination. RESULTS: Prolonged R1 latencies were identified in 23 of 104 patients (22.1 %). These patients had more severe functional impairments according to the ALSFRS-R, yet only five clinically presented with bulbar dysfunction, facial- or trigeminal nerve impairment. Overall R1 latency was inversely correlated to ulnar motor conduction velocity. In preliminary follow-up assessments under continuous immunoglobulin treatment, prolonged R1 latencies partially improved. CONCLUSIONS: Cranial nerve involvement is a common feature in immune-mediated neuropathies and is associated with a more severe disease stage. Here, R1 prolongation was detected less frequently compared to previously reported untreated cohorts. SIGNIFICANCE: Blink reflex studies can detect subclinical cranial nerve involvement in immune-mediated neuropathies. Further studies are needed to evaluate the clinical utility of measuring R1 latency.

Health-Related Quality of Life in Spinal Muscular Atrophy Patients and Their Caregivers-A Prospective, Cross-Sectional, Multi-Center Analysis.

Spinal muscular atrophy (SMA) is a disabling disease that affects not only the patient's health-related quality of life (HRQoL), but also causes a high caregiver burden (CGB). The aim of this study was to evaluate HRQoL, CGB, and their predictors in SMA. In two prospective, cross-sectional, and multi-center studies, SMA patients (n = 39) and SMA patient/caregiver couples (n = 49) filled in the EuroQoL Five Dimension Five Level Scale (EQ-5D-5L) and the Short Form Health Survey 36 (SF-36). Caregivers (CGs) additionally answered the Zarit Burden Interview (ZBI) and the Hospital Anxiety and Depression Scale (HADS). Patients were clustered into two groups with either low or high HRQoL (EQ-5D-5L index value <0.259 or >0.679). The latter group was mostly composed of ambulatory type III patients with higher motor/functional scores. More severely affected patients reported low physical functioning but good mental health and vitality. The CGB (mean ZBI = 22/88) correlated negatively with patients' motor/functional scores and age. Higher CGB was associated with a lower HRQoL, higher depression and anxiety, and more health impairments of the CGs. We conclude that patient and CG well-being levels interact closely, which highlights the need to consider the health of both parties while evaluating novel treatments.

Prevalence of Anti-Adeno-Associated Virus Serotype 9 Antibodies in Adult Patients with Spinal Muscular Atrophy.

5q-associated spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that leads to progressive muscle atrophy and weakness. The disease is caused by a homozygous deletion or mutation in the survival of motor neuron 1 (SMN1) gene, resulting in insufficient levels of SMN protein. Onasemnogene abeparvovec-xioi (OA) is a nonreplicating vector based on adeno-associated virus serotype 9 (AAV9) that contains the full-length human SMN1 gene. Recently, OA was approved for the treatment of SMA by the U.S. Food and Drug Administration and the European Medicines Agency. Because the presence of neutralizing antibodies caused by previous natural exposure to wild-type adeno-associated viruses (AAVs) may impair the efficiency of AAV-mediated gene transfer and thus reduce the therapeutic benefit of the gene therapy, an AAV9-binding antibody titer of >1:50 was defined as a surrogate exclusion criterion in pivotal OA clinical trials. However, these studies were exclusively conducted in infants and children. Because data on anti-AAV9 antibody titers in adults are generally sparse and not available for adult patients with SMA, we determined the prevalence of anti-AAV9 antibodies in sera of adult individuals with SMA to evaluate the feasibility of AAV9-mediated gene therapy in this cohort. In our study population of 69 adult patients with SMA type 2 and type 3 from four German academic sites, only 3 patients (4.3%) had an elevated anti-AAV9 antibody titer of >1:50. The prevalence of anti-AAV9 antibodies did not increase with age. The low and age-independent prevalence of anti-AAV9 antibodies in our cohort provides evidence that gene therapy with intravenous administered recombinant AAV9 vectors (rAAV9) might be feasible in adult patients with SMA, regardless of the patients' sex, SMA type, walking ability, or ventilatory status. This could also apply to the treatment of other inherited neurological diseases with rAAV9.

Glial fibrillary acidic protein in cerebrospinal fluid of patients with spinal muscular atrophy.

OBJECTIVE: Activated astroglia is involved in the pathophysiology of neurodegenerative diseases and has also been described in animal models of spinal muscular atrophy (SMA). Given the urgent need of biomarkers for treatment monitoring of new RNA-modifying and gene replacement therapies in SMA, we examined glial fibrillary acidic protein concentrations in cerebrospinal fluid (cGFAP) as a marker of astrogliosis in SMA. METHODS: 58 adult patients and 21 children with genetically confirmed 5q-associated SMA from four German motor neuron disease specialist care centers and 30 age- and sex-matched controls were prospectively included in this study. cGFAP was measured and correlated to motor performance and disease severity. Additionally, we compared cGFAP with neurofilament light chain concentrations in cerebrospinal fluid (cNfL). RESULTS: cGFAP concentrations did not differ from controls but showed higher levels in more severely affected patients after adjustment for patients' age. Normalized cNfL values were associated with disease severity. Within 14 months of nusinersen treatment, cGFAP concentrations did not change, while cNfL decreased significantly. INTERPRETATION: cGFAP is not an outstanding biomarker in SMA, but might support the hypothesis that glial activation is involved in SMA pathology. Unlike previously suggested, cNfL may be a promising biomarker also in adult patients with SMA, which should be subject to further investigations.

Validity and reliability of the German multidimensional fatigue inventory in spinal muscular atrophy.

OBJECTIVE: Fatigue is a common and burdensome symptom of spinal muscular atrophy. Given its complex interactions, different dimensions of fatigue need to be investigated. The Multidimensional Fatigue Inventory is a widely used instrument that captures five distinct dimensions. The aim of this study was to investigate the validity and reliability of the German Multidimensional Fatigue Inventory in spinal muscular atrophy and to evaluate the presence of clinically relevant fatigue. METHODS: One hundred and forty adult spinal muscular atrophy patients completed the Multidimensional Fatigue Inventory in a nationwide, multicenter, cross-sectional study. Structural validity was explored using principal component analysis. Cronbach's α was calculated to evaluate internal consistency. Convergent validity was assessed by correlation with a Visual Analog Scale for fatigue and the EuroQol-Five Dimension-Five Level Scale as a measure of quality of life. RESULTS: The original five-component model of the questionnaire constituted an acceptable fit. Internal consistency and convergent validity of general, physical, mental fatigue, and reduced activity were good. We observed a floor effect for mental fatigue. While physical fatigue exceeded the cutoff for clinically relevant fatigue, all dimensions but reduced motivation correlated negatively with quality of life. Age, depression, and ≥4 copies of the survival motor neuron 2 gene were associated with higher general/physical fatigue; unemployed participants reported higher scores for reduced activity/motivation. INTERPRETATION: The Multidimensional Fatigue Inventory is a valid and reliable instrument to assess different dimensions of fatigue in spinal muscular atrophy. Fatigue is a relevant problem in spinal muscular atrophy and its assessment should be incorporated into standard care.

Costs and Health-Related Quality of Life in Patients With NMO Spectrum Disorders and MOG-Antibody-Associated Disease: CHANCENMO Study.

BACKGROUND AND OBJECTIVES: To evaluate costs and health-related quality of life (HRQoL) of neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). METHODS: In this multicenter cross-sectional study, data on consumption of medical and nonmedical resources and work ability were assessed via patient questionnaires. Costs were analyzed in Euros for 2018 from the societal perspective. HRQoL was captured by the EuroQoL Group 5 Dimension 5 Level Scale (EQ-5D-5L) questionnaire. Clinical data were retrieved from the Neuromyelitis Optica Study Group (NEMOS) database. RESULTS: Two hundred twelve patients (80% women, median age 50 [19-83] years, median disease duration 7 [0-43] years, median Expanded Disability Status Scale [EDSS] score 3.5 [0-8.5], 66% aquaporin-4 immunoglobulin G [IgG] positive, 22% MOG IgG positive, 12% double seronegative) were analyzed. The mean total annual per capita cost of illness accounted for €59,574 (95% CI 51,225-68,293 or US dollars [USD] 70,297, 95% CI 60,445-80,586), and the mean index value of the EQ-5D-5L was 0.693 (95% CI 0.65-0.73). The most important cost drivers were informal care costs (28% of total costs), indirect costs (23%), and drugs (16%), especially immunotherapeutics. Costs showed a positive correlation with disease severity (ρ = 0.56, 95% CI 0.45-0.65); in the EDSS score 6.5 to 8.5 subgroup, the mean annual costs were €129,687 (95% CI 101,946-160,336 or USD 153,031, 95% CI 120,296-189,196). The HRQoL revealed a negative correlation to disease severity (ρ = -0.69, 95% CI -0.76 to -0.61); in the EDSS score 6.5 to 8.5 subgroup, the EQ-5D-5L mean index value was 0.195 (95% CI 0.13-0.28). Neither antibody status nor disease duration influenced the total annual costs or HRQoL. DISCUSSION: These German data from the era without approved preventive immunotherapies show enormous effects of the diseases on costs and quality of life. An early and cost-effective therapy should be provided to prevent long-term disability and to preserve quality of life.

Health-related Quality of Life and Satisfaction with German Health Care Services in Patients with Charcot-Marie-Tooth Neuropathy.

BackgroundCharcot-Marie-Tooth (CMT) neuropathies entail a large group of diseases with different gene mutation patterns, which produce heterogeneous phenotypes. Although health-related quality of life (HRQOL) is significantly impaired, a comprehensive assessment of HRQOL in CMT patients in Germany considering phenotypical heterogeneity represented a research gap.ObjectiveThe aim was to assess HRQOL and the satisfaction with health care in CMT patients in Germany.MethodsCMT patients > 15 years with a genetically confirmed CMT subtype were recruited through a national CMT patient registry. HRQOL was assessed using the EQ-5D-5L questionnaire. Furthermore, subjective impairments in daily or work activities and satisfaction with health care were assessed using 4-point scales.ResultsHRQOL in CMT patients (n = 385) was impaired compared to the German population. Most patients reported problems in the dimension mobility (89.6%), pain/discomfort (89.4%) and usual activities (81.0%). Except for patients with hereditary neuropathy with liability to pressure palsy (HNPP), we found no differences in HRQOL between the CMT subtypes. 72.0%of CMT patients were satisfied with available health care services. However, patients reported to expect more CMT-specific knowledge and support as well as easier prescription and cost coverage procedures from health professionals and insurances.ConclusionsThe patient-reported outcomes in the assessed CMT cohort elucidate the need for more specific health care services that also address the heterogeneous phenotypes. Although the assessment has been limited to the German health services setting, insights may be applicable to CMT-specific care in other national settings.

Informal Caregiving in Amyotrophic Lateral Sclerosis (ALS): A High Caregiver Burden and Drastic Consequences on Caregivers' Lives.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients' informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers' burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients' CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients' functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King's Stages for ALS. The caregivers' burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers' burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients' functional status (rp = -0.555, p < 0.001, n = 242). It was influenced by the CGs' own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], p < 0.001), patients' wheelchair dependency (+9.30, 95% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs' depression (rp = 0.627, p < 0.001, n = 234), anxiety (rp = 0.550, p < 0.001, n = 234), and poorer physical condition (rp = -0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients' impairment in daily routine (rs = -0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs' lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs' work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.

Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy.

BACKGROUND: Studies regarding the impact of (neuro)inflammation and inflammatory response following repetitive, intrathecally administered antisense oligonucleotides (ASO) in 5q-associated spinal muscular atrophy (SMA) are sparse. Increased risk of hydrocephalus in untreated SMA patients and a marginal but significant increase of the serum/CSF albumin ratio (Qalb) with rare cases of communicating hydrocephalus during nusinersen treatment were reported, which confirms the unmet need of an inflammatory biomarker in SMA. The aim of this study was to investigate the (neuro)inflammatory marker chitotriosidase 1 (CHIT1) in SMA patients before and following the treatment with the ASO nusinersen. METHODS: In this prospective, multicenter observational study, we studied CSF CHIT1 concentrations in 58 adult and 21 pediatric patients with SMA type 1, 2 or 3 before treatment initiation in comparison to age- and sex-matched controls and investigated its dynamics during nusinersen treatment. Concurrently, motor performance and disease severity were assessed. RESULTS: CHIT1 concentrations were elevated in treatment-naïve SMA patients as compared to controls, but less pronounced than described for other neurodegenerative diseases such as amyotrophic lateral sclerosis. CHIT1 concentration did not correlate with disease severity and did not distinguish between clinical subtypes. CHIT1 concentration did show a significant increase during nusinersen treatment that was unrelated to the clinical response to nusinersen therapy. CONCLUSIONS: CHIT1 elevation in treatment-naïve SMA patients indicates the involvement of (neuro)inflammation in SMA. The lacking correlation of CHIT1 concentration with disease severity argues against its use as a marker of disease progression. The observed CHIT1 increase during nusinersen treatment may indicate an immune response-like, off-target reaction. Since antisense oligonucleotides are an establishing approach in the treatment of neurodegenerative diseases, this observation needs to be further evaluated.

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.

Serum creatine kinase and creatinine in adult spinal muscular atrophy under nusinersen treatment.

OBJECTIVE: To determine whether serum creatine kinase activity (CK) and serum creatinine concentration (Crn) are prognostic and predictive biomarkers for disease severity, disease progression, and nusinersen treatment effects in adult patients with 5q-associated spinal muscular atrophy (SMA). METHODS: Within this retrospective, multicenter observational study in 206 adult patients with SMA, we determined clinical subtypes (SMA types, ambulatory ability) and repeatedly measured CK and Crn and examined disease severity scores (Hammersmith Functional Motor Scale Expanded, Revised Upper Limb Module, and revised Amyotrophic Lateral Sclerosis Functional Rating Scale). Patients were followed under nusinersen treatment for 18 months. RESULTS: CK and Crn differed between clinical subtypes and correlated strongly with disease severity scores (e.g., for Hammersmith Functional Motor Scale Expanded: (CK) ρ = 0.786/ (Crn) ρ = 0.558). During the 18 months of nusinersen treatment, CK decreased (∆CK = -17.56%, p < 0.0001), whereas Crn slightly increased (∆Crn = +4.75%, p < 0.05). INTERPRETATION: Serum creatine kinase activity and serum creatinine concentration reflect disease severity of spinal muscular atrophy and are promising biomarkers to assess patients with spinal muscular atrophy during disease course and to predict treatment response. The decrease of creatine kinase activity, combined with the tendency of creatinine concentration to increase during nusinersen treatment, suggests reduced muscle mass wasting with improved muscle energy metabolism.

Nusinersen Wearing-Off in Adult 5q-Spinal Muscular Atrophy Patients.

The antisense oligonucleotide nusinersen was the first drug treatment available for all types of 5q-spinal muscular atrophy (SMA). The dosing regime has been derived from pivotal clinical trials in infants and children. The efficacy of nusinersen in severely affected adult SMA patients is still questionable, as no placebo-controlled trials have been conducted. In the present study, we systematically examined wearing-off phenomena during nusinersen maintenance dosing using a patient-centered approach. We found that adult SMA patients perceived wearing-off after nearly half of 51 investigated nusinersen administrations, primarily within the last month prior to the next administration. Symptoms and functions affected were mainly general strength and arm and leg muscle function next to endurance and independence in daily routine. Lack of walking ability and higher body mass index were characteristic phenotypic features in patients with consistent wearing-off effects. We assume that specific SMA phenotypes might benefit from higher dosing, shorter treatment intervals, change of treatment administration or a combination of all. Efforts towards treatment optimization may result in higher efficacy in distinct phenotypes.

A Nation-Wide, Multi-Center Study on the Quality of Life of ALS Patients in Germany.

Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (ß = -1.96 per increase of one point in the ALSFRS-R score, p < 0.001). "Limb-onset" ALS (lALS) was associated with a better QoL than "bulbar-onset" ALS (bALS) (mean ALSAQ-5 total score 55.46 versus 60.99, p = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (ß = -7.60, p = 0.001), being tracheostomized (ß = -14.80, p = 0.004) and using non-invasive ventilation (ß = -5.71, p = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (ß = 5.95, p = 0.007), and increasing age (ß = 0.18, p = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care.