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.

Neurofilament light-chain response during therapy with antisense oligonucleotide tofersen in SOD1-related ALS: Treatment experience in clinical practice.

INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1-ALS), the antisense oligonucleotide tofersen had been investigated in a phase III study (VALOR) and subsequently introduced in an expanded access program. In this study we assess neurofilament light chain (NfL) before and during tofersen treatment. METHODS: In six SOD1-ALS patients treated with tofersen at three specialized ALS centers in Germany, NfL in cerebrospinal fluid (CSF-NfL) and/or serum (sNfL) were investigated using the ALS Functional Rating Scale Revised (ALSFRS-R) and ALS progression rate (ALS-PR), defined by monthly decline of ALSFRS-R. RESULTS: Three of the six SOD1-ALS patients reported a negative family history. Three patients harbored a homozygous c.272A > C, p.(Asp91Ala) mutation. These and two other patients showed slower progressing ALS (defined by ALS-PR <0.9), whereas one patient demonstrated rapidly progressing ALS (ALS-PR = 2.66). Mean treatment duration was 6.5 (range 5 to 8) months. In all patients, NfL decreased (mean CSF-NfL: -66%, range -52% to -86%; mean sNfL: -62%, range -36% to -84%). sNfL after 5 months of tofersen treatment was significantly reduced compared with the nearest pretreatment measurement (P = .017). ALS-PR decreased in two patients, whereas no changes in ALSFRS-R were observed in four participants who had very low ALS-PR or ALSFRS-R values before treatment. DISCUSSION: In this case series, the significant NfL decline after tofersen treatment confirmed its value as response biomarker in an expanded clinical spectrum of SOD1-ALS. Given the previously reported strong correlation between sNfL and ALS progression, the NfL treatment response supports the notion of tofersen having disease-modifying activity.

Performance of serum neurofilament light chain in a wide spectrum of clinical courses of amyotrophic lateral sclerosis-a cross-sectional multicenter study.

BACKGROUND AND PURPOSE: The objective was to assess the performance of serum neurofilament light chain (sNfL) in amyotrophic lateral sclerosis (ALS) in a wide range of disease courses, in terms of progression, duration and tracheostomy invasive ventilation (TIV). METHODS: A prospective cross-sectional study at 12 ALS centers in Germany was performed. sNfL concentrations were age adjusted using sNfL Z scores expressing the number of standard deviations from the mean of a control reference database and correlated to ALS duration and ALS progression rate (ALS-PR), defined by the decline of the ALS Functional Rating Scale. RESULTS: In the total ALS cohort (n = 1378) the sNfL Z score was elevated (3.04; 2.46-3.43; 99.88th percentile). There was a strong correlation of sNfL Z score with ALS-PR (p < 0.001). In patients with long (5-10 years, n = 167) or very long ALS duration (>10 years, n = 94) the sNfL Z score was significantly lower compared to the typical ALS duration of <5 years (n = 1059) (p < 0.001). Furthermore, in patients with TIV, decreasing sNfL Z scores were found in correlation with TIV duration and ALS-PR (p = 0.002; p < 0.001). CONCLUSIONS: The finding of moderate sNfL elevation in patients with long ALS duration underlined the favorable prognosis of low sNfL. The strong correlation of sNfL Z score with ALS-PR strengthened its value as progression marker in clinical management and research. The lowering of sNfL in correlation with long TIV duration could reflect a reduction either in disease activity or in the neuroaxonal substrate of biomarker formation during the protracted course of ALS.

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.

Use and subjective experience of the impact of motor-assisted movement exercisers in people with amyotrophic lateral sclerosis: a multicenter observational study.

Motor-assisted movement exercisers (MME) are devices that assist with physical therapy in domestic settings for people living with ALS. This observational cross-sectional study assesses the subjective experience of the therapy and analyzes users' likelihood of recommending treatment with MME. The study was implemented in ten ALS centers between February 2019 and October 2020, and was coordinated by the research platform Ambulanzpartner. Participants assessed symptom severity, documented frequency of MME use and rated the subjective benefits of therapy on a numerical scale (NRS, 0 to 10 points, with 10 being the highest). The Net Promotor Score (NPS) determined the likelihood of a participant recommending MME. Data for 144 participants were analyzed. Weekly MME use ranged from 1 to 4 times for 41% of participants, 5 to 7 times for 42%, and over 7 times for 17%. Particularly positive results were recorded in the following domains: amplification of a sense of achievement (67%), diminution of the feeling of having rigid limbs (63%), diminution of the feeling of being immobile (61%), improvement of general wellbeing (55%) and reduction of muscle stiffness (52%). Participants with more pronounced self-reported muscle weakness were more likely to note a beneficial effect on the preservation and improvement of muscle strength during MME treatment (p < 0.05). Overall, the NPS for MME was high (+ 61). High-frequency MME-assisted treatment (defined as a minimum of five sessions a week) was administered in the majority of participants (59%) in addition to physical therapy. Most patients reported having achieved their individual therapeutic objectives, as evidenced by a high level of satisfaction with MME therapy. The results bolster the justification for extended MME treatment as part of a holistic approach to ALS care.

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

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive paresis of the extremities and the loss of manual functioning. Due to the severe functional impairment that the disease entails, ALS requires the provision of comprehensive nursing care and a complex set of assistive technology devices. To relieve caregivers and promote autonomy of people with ALS, robotic assistance systems are being developed. This trial aims to evaluate the acceptance of technology, in general, and of robotic arm assistance among people with ALS in order to lay the groundwork for the development of a semiautomatic robotic arm that can be controlled by humans via a multimodal user interface and that will allow users to handle objects and attend to their own bodies. OBJECTIVE: The aim of this study was to perform a systematic analysis of technology commitment and acceptance of robotic assistance systems from the perspective of physically limited people living with ALS. METHODS: The investigation was conducted as a study of a prospective cohort. Participants were only included if they had received a medical diagnosis of ALS. Data collection took place via an online questionnaire on the Ambulanzpartner Soziotechnologie internet platform. Technological commitment was measured using the Neyer short scale. Furthermore, a multidimensional questionnaire was specially developed to analyze participant acceptance of robotic arm assistance: the Acceptance Measure of Robotic Arm Assistance (AMRAA). This questionnaire was accompanied by a video introducing the robot arm. ALS severity was ascertained using the ALS Functional Rating Scale-Extended (ALSFRS-EX). RESULTS: A total of 268 people with ALS participated in the survey. Two-thirds of the participants were male. The overall mean ALS severity score was 42.9 (SD 11.7) points out of 60 on the ALSFRS-EX, with the most relevant restrictions on arms and legs (<60% of normal functioning). Technological commitment ranked high, with the top third scoring 47.2 points out of 60. Younger participants and males showed significantly higher values. The AMRAA score was, again, significantly higher among younger participants. However, the gender difference within the overall cohort was not significant. The more limited the arm functioning of participants according to the ALSFRS-EX subscale, the higher the acceptance rate of robotic assistance. This relationship proved significant. CONCLUSIONS: People with ALS display high technological commitment and feel positive about using technological assistance systems. In our study, younger participants were more open to technology use, in general, and robotic assistance, in particular. Self-appraisal of technology acceptance, competence, and control conviction were generally higher among men. However, any presumed gender difference vanished when users were asked to rate the anticipated usefulness of the technology, in particular the robotic arm. The acceptance was also reflected in users' increased willingness to use a robotic arm as the functionality of their own arms decreased. From the perspective of people with ALS, robotic assistance systems are critical to promoting individual autonomy. Another key consideration in the development of future assistive technologies should be the reduction of caregiver burden. TRIAL REGISTRATION: German Clinical Trials Register DRKS00012803; https://tinyurl.com/w9yzduhd.

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.

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

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

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

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

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

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

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.

Clinical characteristics and course of dying in patients with amyotrophic lateral sclerosis withdrawing from long-term ventilation.

Non-invasive ventilation (NIV) or tracheotomy with invasive ventilation (TIV) are treatment options in ALS. However, a proportion of patients receiving long-term ventilation decide to have it withdrawn. The objective of this study was to analyse the clinical characteristics and palliative approaches in ALS patients withdrawing from long-term ventilation (WLTV). In a cohort study, two different palliative concepts in WLTV were studied: (1) augmented symptom control (ASC; sedation not intended) in patients with ventilator-free tolerance; (2) continuous deep sedation (CDS; sedation intended) in patients without ventilator-free tolerance. Results showed that WLTV was realised in 49 ALS patients (NIV = 13; TIV = 36). Mean daily ventilation was 23.4 h. The ALS Functional Rating Scale (ALSFRS-R) was low (5.6 of 48). Forty-one per cent of patients (n = 20) presented with ophthalmoplegia. ASC was performed in 20 patients, CDS in 29 patients. The mean time to death following disconnection was 32 (0.3-164) h during ASC and 0.3 (0.2-0.6) h in CDS. In conclusion, a low ALSFRS-R, high incidence of ophthalmoplegia and extended ventilator dependency were found before WLTV. The presence or absence of ventilator-free tolerance determined the approach to the management of symptoms, the setting for immediate end-of-life care and the course of dying in WLTV.

Interleukin-1 Antagonist Anakinra in Amyotrophic Lateral Sclerosis--A Pilot Study.

UNLABELLED: Preclinical studies show that blocking Interleukin-1 (IL-1) retards the progression of Amyotrophic Lateral Sclerosis (ALS). We assessed the safety of Anakinra (ANA), an IL-1 receptor antagonist, in ALS patients. In a single arm pilot study we treated 17 ALS patients with ANA (100 mg) daily for one year. We selected patients with dominant or exclusive lower motor neuron degeneration (LMND) presentation, as peripheral nerves may be more accessible to the drug. Our primary endpoint was safety and tolerability. Secondary endpoints included measuring disease progression with the revised ALS functional rating scale (ALSFRSr). We also quantified serum inflammatory markers. For comparison, we generated a historical cohort of 47 patients that fit the criteria for enrollment, disease characteristics and rate of progression of the study group. Only mild adverse events occurred in ALS patients treated with ANA. Notably, we observed lower levels of cytokines and the inflammatory marker fibrinogen during the first 24 weeks of treatment. Despite of this, we could not detect a significant reduction in disease progression during the same period in patients treated with ANA compared to controls as measured by the ALSFRSr. In the second part of the treatment period we observed an increase in serum inflammatory markers. Sixteen out of the 17 patients (94%) developed antibodies against ANA. This study showed that blocking IL-1 is safe in patients with ALS. Further trials should test whether targeting IL-1 more efficiently can help treating this devastating disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT01277315.

Combining micro computed tomography and three-dimensional registration to evaluate local strains in shape memory scaffolds.

Appropriate mechanical stimulation of bony tissue enhances osseointegration of load-bearing implants. Uniaxial compression of porous implants locally results in tensile and compressive strains. Their experimental determination is the objective of this study. Selective laser melting is applied to produce open-porous NiTi scaffolds of cubic units. To measure displacement and strain fields within the compressed scaffold, the authors took advantage of synchrotron radiation-based micro computed tomography during temperature increase and non-rigid three-dimensional data registration. Uniaxial scaffold compression of 6% led to local compressive and tensile strains of up to 15%. The experiments validate modeling by means of the finite element method. Increasing the temperature during the tomography experiment from 15 to 37°C at a rate of 4 K h(-1), one can locally identify the phase transition from martensite to austenite. It starts at ≈ 24°C on the scaffolds bottom, proceeds up towards the top and terminates at ≈ 34°C on the periphery of the scaffold. The results allow not only design optimization of the scaffold architecture, but also estimation of maximal displacements before cracks are initiated and of optimized mechanical stimuli around porous metallic load-bearing implants within the physiological temperature range.

Severe loss of appetite in amyotrophic lateral sclerosis patients: online self-assessment study.

BACKGROUND: Undesirable loss of weight is a major challenge in amyotrophic lateral sclerosis (ALS). However, little is known about loss of appetite in ALS patients. OBJECTIVE: We investigated loss of appetite in ALS patients by means of an online self-assessment and whether ALS-related symptoms were associated with it. METHODS: Loss of appetite in 51 ALS patients was assessed using the Council on Nutrition Appetite Questionnaire (CNAQ). Loss of appetite is defined as a CNAQ-score of 28 or less with a predicted weight loss of at least 5% within 6 months. We developed an Internet portal to facilitate self-assessment. RESULTS: Approximately half of the ALS patients (47%, 24/51) suffered from severe loss of appetite; after 6 months this increased to nearly two-thirds (65%, 22/34). An average weight loss of 5% was found in the group with severe loss of appetite as compared to only 2% of patients with normal appetite. Interestingly, loss of appetite was associated with respiratory dysfunction (P=.001, R(2)=.223). CONCLUSIONS: Loss of appetite was more common and more severe than expected. It was found to be an independent risk factor for unintended weight loss and may be related to dyspnea. The impact of severe loss of appetite on survival and quality of life should be established in further studies.

Online assessment of ALS functional rating scale compares well to in-clinic evaluation: a prospective trial.

Self-assessment of symptom progression in chronic diseases is of increasing importance in clinical research, patient management and specialized outpatient care. Against this background, we developed a secure internet platform (ALShome.de) that allows online assessment of the revised ALS Functional Rating Scale (ALSFRS-R) and other established self-assessment questionnaires. We developed a secure and closed internet portal to assess patient reported outcomes. In a prospective, controlled and stratified study, patients conducted a web-based self-assessment of ALSFRS-R compared to on-site assessment. On-site and online assessments were compared at baseline (n = 127) and after 3.5 months (n = 81, 64%). Results showed that correlation between on-site evaluation and online testing of ALSFRS-R was highly significant (r = 0.96; p < 0.001). The agreement of both capturing methods (online vs. on-site) was excellent (mean interval, 8.8 days). The adherence to online rating was high; 75% of patients tested on-site completed a follow-up online visit (mean 3.5 months, SD 1.7). We conclude that online self-assessment of ALS severity complements the well-established face-to-face application of the ALSFRS-R during on-site visits. The results of our study support the use of online administration of ALSFRS-R within clinical trials and for managing the care of ALS patients.

Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients.

BACKGROUND: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. OBJECTIVE: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. METHODS: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). RESULTS: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of ≤ 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades ≤ 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions ≥ 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. CONCLUSION: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.

Identification of novel Angiogenin (ANG) gene missense variants in German patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease characterized by the selective death of motor neurons in the motor cortex, brain stem and spinal cord. Recently, missense variants in the angiogenin gene (ANG), an angiogenic factor expressed in ventral horn motor neurons that is up-regulated by hypoxia, have been found in ALS patients of Irish/Scottish, North American, Italian, French and Dutch descent. To investigate the role of ANG in the German population, we screened for mutations by sequencing the entire coding region of the ANG gene in a large sample of 581 German ALS cases and 616 sex- and age-matched healthy controls. We identified two heterozygous missense variants, F(-13)L and K54E, in two German sporadic ALS cases but not in controls. Both missense variants are novel and have not been previously found in ALS cases. Our results suggest that missense variants in the ANG gene play a role in ALS in the German population and provide further evidence to support the hypothesis that angiogenic factors up-regulated by hypoxia are involved in the pathophysiology of ALS.

Heterozygous S44L missense change of the spastin gene in amyotrophic lateral sclerosis.

The authors present a 50-year-old patient with adult-onset amyotrophic lateral sclerosis (ALS) that was rapidly progressing. Screening of the spastin gene revealed a heterozygous missense change S44L. We excluded the involvement of the ALS-linked gene for copper/zinc superoxide dismutase (SOD1). This unusual phenotype shows that allelic variants of spastin may predispose bearers to a greater spectrum of motor neuron disorders including ALS.