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.

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 However, a proportion of patients receiving long-term ventilation decide to have it withdrawn.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 (71= 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.

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.

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

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.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.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.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.

ABSTRACTIntroduction: 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 patient's 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 patient's clinical presentation, due to the resemblance to the GRID2 mutation phenotype in mouse models. Muscle Nerve 49: 289–292, 2014

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.

Patients suffering from amyotrophic lateral sclerosis (ALS) require comprehensive aids for mobility, communication, nutrition, ventilation and other care elements. They receive support from a variety of stakeholders. Coordination of the various partners is a complex matter and subject to high barriers. AmbulanzPartner (AP) provides persons afflicted with ALS and all players involved with a network for the coordinated provision of assistive devices and therapies combining case management and the internet portal AmbulanzPartner. de in a hybrid product concept. AP reduces the existing interfaces in ALS care. The internet portal AmbulanzPartner. de serves as an "electronic health record" and "management platform" liaising between patients, next of kin, doctors and providers while making all care processes discernible. AP is designed to facilitate the provision of assistive devices and therapies and to avoid inappropriate health care. The management portal has been in operation since April 2011. Up to March 2 013, 2 363 patients and 15 867 assistive devices and therapies have been coordinated. The captured data are designated for health-care research and off er an insight into care processes for different clinical and sociomedical constellations as well as a comparative consideration of arrays of assistive devices and insurance companies. Use of the internet portal AmbulanzPartner. de is based on a "shared value" principle revenue model: patients, next of kin, doctors and sociomedical partners, may use of the portal free of charge whereas the entrepreneurial stakeholders (e.g., providers of assistive devices) are integrated into a licensing model. AP embraces a generic approach and scalability so that - based on ALS - transferability to other complex neurological conditions is given.

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.

We report a patient with Guillain–Barré syndrome (GBS), characterized by severe tetraparesis, bulbar syndrome, and ophthalmoparesis. The nadir was reached within 1 day, followed by respiratory insufficiency requiring mechanical ventilation. Molecular analysis revealed a duplication at chromosome 17p11.2‐12, which is a known genetic cause of Charcot–Marie–Tooth disease type 1A (CMT1A). We suggest that this genotype may comprise a previously unrecognized genetic risk factor for GBS. Muscle Nerve, 2007

Background: Some patients with diabetes mellitus (DM) develop a peripheral neuropathy indistinguishable from chronic demyelinating polyneuropathy (CIDP). Immune-mediated mechanisms are involved in the pathogenesis of demyelinating neuropathy in DM and in CIDP. Immunotherapy, including intravenous immunoglobulin (IVIg) is effective in idiopathic CIDP and CIDP-DM. Despite treatment with IVIg, CIDP may remain clinically active. It has been reported that CIDP may respond to Rituximab (RTX), a chimeric humanized monoclonal antibody against CD20+ antigen on B-lymphocytes. We reported a patient with CIDP associated with DM increasingly less responsive to IVIg who was treated with RTX.

Objectives – Mutations in the p150 subunit of the axonal transport protein dynactin (DCTN1) have been reported in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Given the common features of neurodegeneration in multiple sclerosis (MS), FTD and ALS, sequence variants of the DCTN1 gene may be a contributory factor to neurodegeneration in MS. Methods – We investigated a total of 200 MS patients and 200 controls. A total of 100 patients had a relapsing–remitting form of MS, 100 cases were primary progressive. Sequence alterations were screened for in the coding region of DCTN1 using heteroduplex and sequence analyses. Results – Two heterozygous missense mutations (T1249I, I196V) were found in two healthy control subjects. No mutations were identified in 200 MS patients. The frequency of a known single nucleotide polymorphism (R495Q) was not significantly different between patients and controls. Conclusion – The results indicate that the DCTN1 gene is probably not influencing susceptibility to neurodegeneration in MS.

The authors report a 57-year-old patient with chronic inflammatory demyelinating polyneuropathy (CIDP) associated with diabetes mellitus (DM) who was treated successfully with rituximab. The B lymphocyte suppression using rituximab was followed 4 weeks later by neurological improvement and a stable disease course of over 10 months. We suggest that rituximab may be a treatment option in CIDP increasingly less responsive to intravenous immunoglobulin, particularly in patients with concurrent DM.

Multiple sclerosis (MS) is a multifactorial disease in which mostly unidentified genetic factors in conjunction with environmental agents affect its clinical expression. Neurodegeneration has emerged as a significant contributor to CNS lesions in MS. Genetic susceptibility of the neuron may determine the degree of ensuing neurodegeneration after an inflammatory attack. We have recently described mutations in the p150 subunit of the molecular motor dynactin (DCTN1) in amyotrophic lateral slerosis (ALS) and frontotemporal dementia (FTD) that may predispose different neuron types to degeneration. Given the common features of neurodegeneration in MS, ALS and FTD, we raised the question whether genetic variants in the DCTN1 gene may constitute a risk factor for MS. We conducted a DCTN1 mutation analysis in 192 patients with MS (96 patients with relapsing-remitting MS and 96 with primary progressive MS) and the same number of unrelated controls. In MS, no mutations in the DCTN1 gene have been found. Three novel heterozygous sequence variants (R532L, T1249I, I196V) of the DTCN1 gene were detected in four controls. However, no significant genetic association of the three sequence alterations with the absence of MS has been found. We conclude that DCTN1 may not contribute to the genetic background of neurodegeneration in MS. Our findings support the notion that the DCTN1 gene is highly heterogeneous. DCTN1 sequence variants are also found under normal conditions and their pathogenetic relevance is far from being completely understood.

Medial-to-lateral somatotopy is a well-established feature of the human primary somatosensory cortex (SI); however, it is unknown whether, similarly to non-human primates, a rostral-to-caudal somatotopic arrangement exists as well. Therefore, in this functional magnetic resonance imaging (fMRI) study on eight healthy human subjects, five circumscribed skin areas sequentially located on the third finger and the palm of the hand were stimulated with innocuous electrical pulses. Within area 3b of contralateral SI, successive cortical representation sites ordered in a rostral-to-caudal fashion were seen in the group analysis and in six individual subjects. The fingertip was located most rostrally, whereas the proximal parts of the finger as well as the distal palm were represented at more caudal locations. Within area 1, the group analysis revealed a similar pattern of discrete representations. However, in contrast to area 3b, the fingertip was located most caudally, whereas the more proximal parts of the finger were found to be represented rostrally within area 1. Thus, the representation pattern of area 1 appeared as a ‘mirror image’ of that of area 3b. In comparison to the representations of the finger and the distal palm, the proximal palm was found to be represented at a more medial position of the postcentral gyrus.

Cortical signal intensity changes due to brief (1 s) innocuous electrical stimuli applied to the second and fifth finger of the right hand were measured by means of fMRI at 1.5 T. The activation pattern in this event-related fMRI approach closely resembled that obtained in recent block-design studies. Activations were found in contralateral primary (SI) and bilaterally in secondary (SII) somato-sensory cortex as well as in posterior parietal cortex, insula, and supplementary motor area (SMA). In SI, the somatotopic organization of the hand area is demonstrated, more clearly to be seen in area 3b than in area 1 and 2. In conclusion, the feasibility to employ event-related somatosensory stimulation paradigms in fMRI studies is demonstrated.

This fMRI study investigated the human somatosensory system, especially the secondary somatosensory cortex (SII), with respect to its potential somatotopic organization. Eight subjects received electrical stimulation on their right second finger, fifth finger and hallux. Within SII, the typical finding for both fingers was a representation site within the contralateral parietal operculum roughly halfway between the lip of the lateral sulcus and its fundus, whereas the representation site of the hallux was found more medially to this position at the fundus of the lateral sulcus, near the posterior pole of the insula. Somatotopy in SII seems to be less fine-grained than in primary somatosensory cortex (SI), as, in contrast to SI, no separate representations of the two fingers in SII were observed. A similar somatotopic representation pattern between fingers and the hallux was also observed within ipsilateral SII, indicating somatotopy of contra- as well as ipsilateral SII using unilateral stimulation. Further areas exhibiting activation were found in the superior and inferior parietal lobule, in the supplementary and cingulate motor area, and in the insula.