André Maier

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

Abstract 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.

Thalidomide causes sinus bradycardia in ALS

ObjectiveNeuroinflammation contributes to motor neuron degeneration in ALS. Thalidomide (THL) shows potent anti-inflammatory properties and increased the lifespan in ALS transgenic mice. Thalidomide was therefore suggested as atherapeutic intervention for the treatment of ALS.We conducted a pilot, randomized clinical trial of THL in patients with ALS to assess safety, feasibility, and preliminary estimates of treatment efficacy.MethodsPatients were randomized to THL in combination with riluzole (n = 18) or riluzole alone (n = 19). THL was initiated at 100 mg per day for 6 weeks. Thereafter, the dose was increased every week by 50 mg until reaching the dose of 400 mg per day and planned to continue for another 12 weeks.ResultsWithin 12 weeks of THL treatment, nine THL patients (50%) developed bradycardia defined as a heart rate below 60 beats per minute (bpm) and ranged from 46 to 59 bpm. Mean heart rate dropped by 17 bpm with THL treatment. Severe symptomatic bradycardia of 30 bpm occurred in one patient. A further patient died from sudden unexpected death. The study was terminated prematurely for safety concerns. The secondary outcome variables showed similar results for both groups.ConclusionBradycardia was the most common adverse event of THL treatment in ALS. THL-related bradycardia does not appear to be ALS-specific. It is conceivable, however, that the unexpected frequency and severity of THL-induced bradycardia may be related to subclinical involvement of the autonomic nervous system in ALS. The cardiac toxicity discourages further clinical trials and compassionate use of THL in ALS. ClinicalTrials.gov Identifier: NCT00231140.

De novo partial deletion in GRID2 presenting with complicated spastic paraplegia.

Introduction: Complex forms of spastic paraplegia (SPG) are rare and genetically heterogeneous. In apparently sporadic cases, analysis of known SPG genes often fails to reveal a mutation. Methods: We report a 24‐year‐old patient with a syndrome of spastic paraplegia, ataxia, frontotemporal dementia, and lower motor neuron involvement. Results: Screening of the patients genome for copy number variation identified a novel 276 kb deletion spanning the first exon of the GRID2 gene. MRI scan showed atrophy of the cerebellum, and electromyography revealed a chronic disorder of motor neurons or their axons. A deletion in GRID2, coding for the glutamate receptor delta‐2 subunit precursor protein, was excluded in either parent, suggesting that the deletion in the index patient occurred de novo. Conclusions: We hypothesize that the deletion identified here is the cause of our patients clinical presentation, due to the resemblance to the GRID2 mutation phenotype in mouse models. Muscle Nerve 49: 289–292, 2014

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

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 enrolment, 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

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, R2=.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.

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

Abstract 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.

[Provision of assistive devices in amyotrophic lateral sclerosis. Analysis of 3 years case management in an internet-based supply network].

BACKGROUND The provision of assistive devices (PAD) is a key element of care in amyotrophic lateral sclerosis (ALS). Since 2011, assistive devices (AD) have been coordinated in an internet-supported care network at university-based ALS centers in Berlin, Bochum, Hannover and Jena. The digitization of PAD processes has facilitated the evaluation of real-life ALS care. OBJECTIVES Orthotics (OT), augmentative and alternative communication (AAC), supported treadmill (ST) and powered wheelchair (PW) were the PAD groups analyzed for delivery rates (proportion of delivered AD vs. medically indicated AD), rejection by patients and payers and latency of provision of care. RESULTS Between June 2011 and October 2014 a total of 1479 patients and 12,478 AD were coordinated, among which 3313 PAD were related to OT, AAC, ST or EM. The median delivery rate was 64.3 %. The mean rejection rate by patients was 9.8 % (OT 5.4 %, AAC 9.8 %, ST 10.2 % and PW 15.6 %). Marked differences were noted in the rejection rate by payers and in care provision latency: OT (16.2 %, 68 days, n = 734), AAC (30.4 %, 96 days, n = 392), ST (34.8 %, 113 days, n = 164) and PW (35.6 %, 129 days, n = 259). Analysis of rejection rates showed significant differences among insurers. CONCLUSION Only two thirds of the medically indicated AD reached the patients. Rejection rates by patients and payers and latency of provision of care were high. The PAD can substantially vary among health insurance companies. The establishment of consented criteria for PAD and their integration into treatment regimens and guidelines are crucial tasks for the future.

Disturbance of verticality perception and postural dysfunction in Parkinson's disease

Verticality perception is known to be abnormal in Parkinsons disease (PD), but in which stage respective dysfunctions arise and how they relate to postural disorders remains to be settled. These issues were studied with respect to different dimensions of the subjective visual vertical (SVV) in relation to clinical parameters of postural control.

Hilfsmittelversorgung bei der amyotrophen Lateralsklerose

BACKGROUND The provision of assistive devices (PAD) is a key element of care in amyotrophic lateral sclerosis (ALS). Since 2011, assistive devices (AD) have been coordinated in an internet-supported care network at university-based ALS centers in Berlin, Bochum, Hannover and Jena. The digitization of PAD processes has facilitated the evaluation of real-life ALS care. OBJECTIVES Orthotics (OT), augmentative and alternative communication (AAC), supported treadmill (ST) and powered wheelchair (PW) were the PAD groups analyzed for delivery rates (proportion of delivered AD vs. medically indicated AD), rejection by patients and payers and latency of provision of care. RESULTS Between June 2011 and October 2014 a total of 1479 patients and 12,478 AD were coordinated, among which 3313 PAD were related to OT, AAC, ST or EM. The median delivery rate was 64.3 %. The mean rejection rate by patients was 9.8 % (OT 5.4 %, AAC 9.8 %, ST 10.2 % and PW 15.6 %). Marked differences were noted in the rejection rate by payers and in care provision latency: OT (16.2 %, 68 days, n = 734), AAC (30.4 %, 96 days, n = 392), ST (34.8 %, 113 days, n = 164) and PW (35.6 %, 129 days, n = 259). Analysis of rejection rates showed significant differences among insurers. CONCLUSION Only two thirds of the medically indicated AD reached the patients. Rejection rates by patients and payers and latency of provision of care were high. The PAD can substantially vary among health insurance companies. The establishment of consented criteria for PAD and their integration into treatment regimens and guidelines are crucial tasks for the future.

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

Abstract 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.