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.

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.

Provision of assistive technology devices among people with ALS in Germany: a platform-case management approach.

OBJECTIVE: The procurement of assistive technology devices (ATD) is an essential component of managed care in ALS. The objective was to analyze the standards of care for ATD and to identify challenges in the provision process. METHODS: A cohort study design was used. We investigated the provision of 11,364 ATD in 1494 patients with ALS at 12 ALS centers in Germany over four years. Participants were patients that entered a case management program for ATD including systematic assessment of ATD on a digital management platform. RESULTS: Wheelchairs (requested in 65% of patients), orthoses (52%), bathroom adaptations (49%), and communication devices (46%) were the most needed ATD. There was a wide range in the number of indicated ATD per patient: 1 to 4 ATD per patient in 45% of patients, 5 to 20 ATD in 48%, and >20 ATD in 7% of patients. Seventy percent of all requested ATD were effectively delivered. However, an alarming failure rate during procurement was found in ATD that are crucial for ALS patients such as powered wheelchairs (52%), communication devices (39%), or orthoses (21%). Leading causes for not providing ATD were the refusal by health insurances, the decision by patients, and the death of the patient before delivery of the device. CONCLUSIONS: The need for ATD was highly prevalent among ALS patients. Failed or protracted provision posed substantial barriers to ATD procurement. Targeted national strategies and the incorporation of ATD indication criteria in international ALS treatment guidelines are urgently needed to overcome these barriers.

An eye-tracking controlled neuropsychological battery for cognitive assessment in neurological diseases.

Traditional cognitive assessment in neurological conditions involving physical disability is often prevented by the presence of verbal-motor impairment; to date, an extensive motor-verbal-free neuropsychological battery is not available for such purposes. We adapted a set of neuropsychological tests, assessing language, attentional abilities, executive functions and social cognition, for eye-tracking (ET) control, and explored its feasibility in a sample of healthy participants. Thirty healthy subjects performed a neuropsychological assessment, using an ET-based neuropsychological battery, together with standard "paper and pencil" cognitive measures for frontal (Frontal Assessment Battery-FAB) and working memory abilities (Digit Sequencing Task) and for global cognitive efficiency (Montreal Cognitive Assessment-MoCA). Psychological measures of anxiety (State-Trait Anxiety Inventory-Y-STAI-Y) and depression (Beck Depression Inventory-BDI) were also collected, and a usability questionnaire was administered. Significant correlations were observed between the "paper and pencil" screening of working memory abilities and the ET-based neuropsychological measures. The ET-based battery also correlated with the MoCA, while poor correlations were observed with the FAB. Usability aspects were found to be influenced by both working memory abilities and psychological components. The ET-based neuropsychological battery developed could provide an extensive assessment of cognitive functions, allowing participants to perform tasks independently from the integrity of motor or verbal channels. Further studies will be aimed at investigating validity and usability components in neurological populations with motor-verbal impairments.

Cognitive assessment in Amyotrophic Lateral Sclerosis by means of P300-Brain Computer Interface: a preliminary study.

OBJECTIVE: To investigate the use of P300-based Brain Computer Interface (BCI) technology for the administration of motor-verbal free cognitive tests in Amyotrophic Lateral Sclerosis (ALS). METHODS: We recruited 15 ALS patients and 15 age- and education-matched healthy subjects. All participants underwent a BCI-based neuropsychological assessment, together with two standard cognitive screening tools (FAB, MoCA), two psychological questionnaires (BDI, STAI-Y) and a usability questionnaire. For patients, clinical and respiratory examinations were also performed, together with a behavioural assessment (FBI). RESULTS: Correlations were observed between standard cognitive and BCI-based neuropsychological assessment, mainly concerning execution times in the ALS group. Moreover, patients provided positive rates concerning the BCI perceived usability and subjective experience. Finally, execution times at the BCI-based neuropsychological assessment were useful to discriminate patients from controls, with patients achieving lower processing speed than controls regarding executive functions. CONCLUSIONS: The developed motor-verbal free neuropsychological battery represents an innovative approach, that could provide relevant information for clinical practice and ethical issues. Its use for cognitive evaluation throughout the course of ALS, currently not available by means of standard assessment, must be addressed in further longitudinal validation studies. Further work will be aimed at refining the developed system and enlarging the cognitive spectrum investigated.

Ex post facto assessment of diffusion tensor imaging metrics from different MRI protocols: preparing for multicentre studies in ALS.

Diffusion tensor imaging (DTI) for assessing ALS-associated white matter alterations has still not reached the level of a neuroimaging biomarker. Since large-scale multicentre DTI studies in ALS may be hampered by differences in scanning protocols, an approach for pooling of DTI data acquired with different protocols was investigated. Three hundred and nine datasets from 170 ALS patients and 139 controls were collected ex post facto from a monocentric database reflecting different scanning protocols. A 3D correction algorithm was introduced for a combined analysis of DTI metrics despite different acquisition protocols, with the focus on the CST as the tract correlate of ALS neuropathological stage 1. A homogenous set of data was obtained by application of 3D correction matrices. Results showed that a fractional anisotropy (FA) threshold of 0.41 could be defined to discriminate ALS patients from controls (sensitivity/specificity, 74%/72%). For the remaining test sample, sensitivity/specificity values of 68%/74% were obtained. In conclusion, the objective was to merge data recorded with different DTI protocols with 3D correction matrices for analyses at group level. These post processing tools might facilitate analysis of large study samples in a multicentre setting for DTI analysis at group level to aid in establishing DTI as a non-invasive biomarker for ALS.

Live and let die: existential decision processes in a fatal disease.

Decisions and determinants of decisions to prolong or shorten life in the course of fatal diseases like ALS are poorly understood. Decisions and desire for hastened death of N = 93 ALS patients were investigated in a prospective longitudinal approach three times in the course of 1 year. Determinants of decisions were evaluated: quality of life (QoL), depression, feeling of being a burden, physical function, social support and cognitive status. More than half of patients had a positive attitude towards life-sustaining treatments and they had a low desire for hastened death. Of those with undecided or negative attitude, 10 % changed attitudes towards life-sustaining treatments in the course of 1 year. Patients' desire to hasten death was low and decreased significantly within 1 year despite physical function decline. Those with a high desire for hastened death decided against invasive therapeutic treatments. QoL, depression and social support were not predictors for vital decisions and remained stable. Feeling of being a burden was a predictor for decisions against life-supporting treatments. Throughout physical function loss, decisions to prolong life are flexibly adapted while desire to shorten life declines. QoL was stable and not a predictor for vital decisions, even though anticipated low QoL has been reported to be the reason to request euthanasia. In contrast, feeling of being a burden in decision making needs more attention in clinical counselling. Considering a patient's possible adaptation processes in the course of a fatal disease is necessary.

The use of P300-based BCIs in amyotrophic lateral sclerosis: from augmentative and alternative communication to cognitive assessment.

The use of augmentative and alternative communication (AAC) tools in patients with amyotrophic lateral sclerosis (ALS), as effective means to compensate for the progressive loss of verbal and gestural communication, has been deeply investigated in the recent literature. The development of advanced AAC systems, such as eye-tracking (ET) and brain-computer interface (BCI) devices, allowed to bypass the important motor difficulties present in ALS patients. In particular, BCIs could be used in moderate to severe stages of the disease, since they do not require preserved ocular-motor ability, which is necessary for ET applications. Furthermore, some studies have proved the reliability of BCIs, regardless of the severity of the disease and the level of physical decline. However, the use of BCI in ALS patients still shows some limitations, related to both technical and neuropsychological issues. In particular, a range of cognitive deficits in most ALS patients have been observed. At the moment, no effective verbal-motor free measures are available for the evaluation of ALS patients' cognitive integrity; BCIs could offer a new possibility to administer cognitive tasks without the need of verbal or motor responses, as highlighted by preliminary studies in this field. In this review, we outline the essential features of BCIs systems, considering advantages and challenges of these tools with regard to ALS patients and the main applications developed in this field. We then outline the main findings with regard to cognitive deficits observed in ALS and some preliminary attempts to evaluate them by means of BCIs. The definition of specific cognitive profiles could help to draw flexible approaches tailored on patients' needs. It could improve BCIs efficacy and reduce patients' efforts. Finally, we handle the open question, represented by the use of BCIs with totally locked in patients, who seem unable to reliably learn to use such tool.

The economic costs of progressive supranuclear palsy and multiple system atrophy in France, Germany and the United Kingdom.

Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are progressive disabling neurological conditions usually fatal within 10 years of onset. Little is known about the economic costs of these conditions. This paper reports service use and costs from France, Germany and the UK and identifies patient characteristics that are associated with cost. 767 patients were recruited, and 760 included in the study, from 44 centres as part of the NNIPPS trial. Service use during the previous six months was measured at entry to the study and costs calculated. Mean six-month costs were calculated for 742 patients. Data on patient sociodemographic and clinical characteristics were recorded and used in regression models to identify predictors of service costs and unpaid care costs (i.e., care from family and friends). The mean six-month service costs of PSP were €24,491 in France, €30,643 in Germany and €25,655 in the UK. The costs for MSA were €28,924, €25,645 and €19,103 respectively. Unpaid care accounted for 68-76%. Formal and unpaid costs were significantly higher the more severe the illness, as indicated by the Parkinson's Plus Symptom scale. There was a significant inverse relationship between service and unpaid care costs.