David Czell

Outcomes of percutaneous endoscopic gastrostomy tube insertion in respiratory impaired amyotrophic lateral sclerosis patients under noninvasive ventilation.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) tube placement in amyotrophic lateral sclerosis (ALS) patients with impaired respiratory function is associated with an increased risk of peri-procedural and post-interventional complications. It was the aim of the study to analyze peri- and post-interventional complications and survival after PEG tube placement under noninvasive ventilation (NIV) in ALS patients with various degrees of respiratory impairment. METHODS: Twenty-six subjects were included in this retrospective case study. Prior to PEG tube placement, training with ventilatory support via an oronasal mask was performed with ALS subjects on the pneumology ward. PEG placement was then performed under continuous NIV. FVC, sniff nasal inspiratory pressure, and demographic data were assessed. Complication rates and 1-month and overall survival rates were analyzed. RESULTS: There were no deaths within 24 hours after PEG placement. One subject died within the first month. The mean survival rate after PEG was 12 ± 10 months (range 0.6–42 months). There was no difference in post-PEG survival between subjects with moderately (> 50%) and severely (< 50%) impaired FVC. CONCLUSIONS: In this case series, PEG tube insertion was associated with minimal peri- and post-procedural complications. The low complication rate might be due to the systematic use of procedural NIV in ALS subjects.

C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: A genome-wide meta-analysis

Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP‐43 inclusions have been found in both ALS and FTD cases (FTD‐TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS‐FTD.

H63D polymorphism in HFE is not associated with amyotrophic lateral sclerosis

The H63D polymorphism in HFE has frequently been associated with susceptibility to amyotrophic lateral sclerosis (ALS). Regarding the role of HFE in iron homeostasis, iron accumulation is considered an important process in ALS. Furthermore, novel therapeutic strategies are being developed targeting this process. Evidence for this genetic association is, however, limited to several small studies. For this reason we studied the H63D polymorphism in a large European cohort including 3962 ALS patients and 5072 control subjects from 7 countries. After meta-analysis of previous studies and current findings we conclude that the H63D polymorphism in HFE is not associated with susceptibility to ALS, age at disease onset, or survival.

Progressive aphasia as the presenting symptom in a patient with amyotrophic lateral sclerosis with a novel mutation in the OPTN gene

Progressive aphasia as the presenting symptom in a patient with amyotrophic lateral sclerosis with a novel mutation in the OPTN gene

The role of the SenseWear device and ghrelin for metabolism in amyotrophic lateral sclerosis

Initially, pathological abnormalities in amyotrophic lateral sclerosis (ALS) were thought to be restricted to motor neurons, but in the past few years it has become apparent that also the nutritional state, energy intake and energy expenditure are altered (1–3). Metabolism and nutritional status are very important prognostic factors for survival in patients with ALS (4). However, to date it has been challenging to reliably predict energy expenditure during the disease course (5,6). The SenseWear Armband is a bracelet device to accurately measure resting energy expenditure (REE) in healthy subjects (7–9). It has been validated against the double labelled water method (dLW) (10). Ghrelin and leptin, which regulate appetite and metabolism, were recently found to have a neuroprotective effect in neurodegenerative diseases (11,12). In this study we evaluated the SenseWear armband for measuring REE, measured ghrelin, leptin and determined caloric intake and nutritional status in patients with amyotrophic lateral sclerosis (ALS). First energy expenditure (EE) and caloric intake were measured over three days in 10 healthy controls. EE over 24 h was very stable in all subjects, not exceeding 3% day-to-day variability. The main problem of this study was recruitment of patients; that patients had to move to a different building for ghrelin and leptin measurements after a regular 2-h consultation was too burdensome for most of the patients. However, in two patients (P1, P2) and their spouses (C1, C2) EE and caloric intake could be measured over 48 h twice with an interval of six months. Total ghrelin was 30% lower in ALS patients (P1, P2) compared to spouses (C1, C2) and normal values. Comparing EE between consecutive days revealed reliable measurements (P1: 2064 and 2124 kcal/day, P2: 2020 and 1969 kcal/day, C1: 1740 and 1599 kcal/day, C2: 1569 and 1422 kcal/day). Despite balanced EE and caloric intake both patients had profound weight loss over time (P1 74.5 kg vs. 68.4 kg, P2 76 kg vs. 71 kg). Both patients also had a higher EE at night six months after the first measurement (P1 744 vs. 1186, P2 854 vs. 1029). This suggests an increasing resting expenditure as the disease progresses, which is in line with other studies demonstrating hypermetabolism of the order of about 10% in ALS patients compared to a healthy population (13,14). Interestingly, ghrelin levels were lower in patients compared to control subjects and published normal values (15). Ghrelin is a hormone that leads to hunger and stimulates appetite (16). Weight loss causes a higher release of ghrelin, yet the appetite in both patients was reduced as described in other studies (17). Low ghrelin levels may also have an influence on the protection of the motor neurons. A possible effect of ghrelin on glutamate excitotoxicity has been reported earlier (12). Despite all its limitations this study supports the hypothesis that ghrelin plays a key role in the metabolism of patients with ALS (12). The study shows that the SenseWear Armband is easy to use, not only for healthy subjects as in previous studies (7–9), but also for ALS patients with neurological problems and focal neurological deficits. Novel tubes are now available that allow blood to be taken on site without further immediate processing. This may help to recruit patients into such studies.

Further analysis of KIFAP3 gene in ALS patients from Switzerland and Sweden

Abstract A series of studies suggests that susceptibility to ALS may be influenced by variants in multiple genes. While analyses of the 10% of cases of familial origin have identified more than 33 monogenic ALS-causing genetic defects, little is known about genetic factors that influence susceptibility or phenotype in sporadic ALS (SALS). We and others conducted a genome-wide association study (GWAS) in a cohort of 1014 ALS cases from Western Europe, England and the United States, and identified an intronic single nucleotide polymorphism (SNP) rs1541160 in the KIFAP3 gene that was statistically associated with improved survival. We have now completed an additional survival analysis examining the impact of the rs1541160 genotype in a cohort of 264 ALS and progressive bulbar palsy (PBP) cases. In the combined cohort of 264 patients, the CC, CT and TT genotypes for rs1541160 were detected, respectively, in 8.3% (22), 41.7% (110) and 50.0% (132). This study does not show an influence of KIFAP3 variants on survival in the studied Swiss and Swedish cohort. There was a difference in survival between the US and English patients and the patients from the Netherlands. The effect of KIFAP3 variants may be population specific, or the rs1541160 association reported previously may have been a false-positive.

Daytime Mouthpiece Ventilation Plus Nighttime Noninvasive Ventilation Improves Quality of Life in Patients With Neuromuscular Disease

Respiratory failure due to respiratory muscle dysfunction is a common problem in neuromuscular diseases,[1][1] and respiratory muscle weakness can be reversible, relapsing, or progressive.[2][2] In amyotrophic lateral sclerosis (ALS), the respiratory muscle dysfunction is not reversible, and

Exercise-induced myalgia and rhabdomyolysis in a patient with the rare m.3243A>T mtDNA mutation

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes comprises a number of mitochondrial disorders with a wide range of clinical presentations. We present the case of a 32-year-old patient with an m.3243A>T mitochondrial DNA mutation who presented with rhabdomyolysis after 2 days of excessive physical work. The case presented here demonstrates a new clinical phenotype associated with this pathogenic mtDNA mutation.

In-vivo evaluation of neuronal and glial changes in amyotrophic lateral sclerosis with diffusion tensor spectroscopy

Diffusion tensor spectroscopy (DTS) combines features of magnetic resonance spectroscopy and diffusion tensor imaging and permits evaluating cell-type specific properties of microstructure by probing the diffusion of intracellular metabolites. This exploratory study investigates for the first time microstructural changes in the neuronal and glial compartments of the brain of patients with amyotrophic lateral sclerosis (ALS) using DTS. To this end, the diffusion properties of the neuronal metabolite tNAA (N-acetylaspartate + N-acetylaspartylglutamate) and the predominantly glial metabolites tCr (creatine + phosphocreatine) and tCho (choline-containing compounds) were evaluated in the primary motor cortex of 24 ALS patients and 27 healthy controls. Significantly increased values in the diffusivities of all three metabolites were found in ALS patients relative to controls. Further analysis revealed more pronounced microstructural alterations in ALS patients with limb onset than with bulbar onset relative to controls. This observation may be related to the fact that the spectroscopic voxel was positioned in the part of the motor cortex where the motor functions of the limbs are represented. The higher diffusivities of tNAA may reflect neuronal damage and/or may be a consequence of mitochondrial dysfunction in ALS. Increased diffusivities of tCr and tCho are in line with reactive microglia and astrocytes surrounding degenerating motor neurons in the primary motor cortex of ALS patients. This pilot study demonstrates for the first time that cell-type specific microstructural alterations in the brain of ALS patients may be explored in vivo and non-invasively with DTS. In conjunction with other microstructural magnetic resonance imaging techniques, DTS may provide further insights into the pathogenic mechanisms that underlie neurodegeneration in ALS.

Platform Session – Electromyography: Large inter-rater variation on revised El Escorial and Awaji diagnostic criteria for amyotrophic lateral sclerosis

Introduction The revised El Escorial Criteria (rEEC) from 2000 and their amendment, the Awaji Criteria (AC) from 2008, are widely used diagnostic criteria for amyotrophic lateral sclerosis (ALS) and their sensitivity and specificity have been evaluated in several studies, however, reproducibility among different raters has not been studied. This study was undertaken to assess inter-rater agreement on rEEC and AC. Methods Eight experienced physicians from seven different countries independently classified 399 patients referred for ALS according to the rEEC and the AC. Clinical and electrophysiological data were presented in standardised forms. Agreement was evaluated by Kappa coefficients. Diagnostic sensitivity and specificity were calculated from the majority diagnosis of the eight physicians for 349 cases with follow-up data. Results Kappa coefficients differed among the diagnostic categories for rEEC (“Definite”: 0.50, CI:0.39–0.60, “Probable”: 0.36, CI:0.31–0.41, “Probable Laboratory Supported”: 0.25,CI:0.18–0.34, “Possible”: 0.14, CI:0.09–0.20, and “Not-ALS”: 0.59, CI:0.51–0.65) as well as for AC (“Definite”: 0.44, CI:0.37–0.51, “Probable”: 0.34, CI:0.29–0.39, “Possible”: 0.33, CI:0.26–0.40, and “Not-ALS”: 0.65, CI:0.58–0.72). The only significant difference in agreement between rEEC and AC was for the category “Possible”. A large fraction of cases classified as “Probable” using the rEEC were upgraded to “Definite” using the AC, however, many cases classified as “Probable Laboratory Supported” by rEEC were downgraded to “Possible” by the AC. Sensitivity for “Definite/Probable” versus “Possible/Not-ALS” did not differ between rEEC (0.64, CI:0.58–0.69) and AC (0.63, CI:0.58–0.69). Similarly, there was no difference in specificity between rEEC (0.91, CI:0.74–0.98) and AC (0.85, CI:0.67–0.94). Conclusion There is a large inter-rater variation on rEEC and AC most pronounced for the “Probable Laboratory Supported” and “Possible” categories. The sensitivity was rather low compared to other studies and was not significantly increased using AC, probably due to omission of the “Probable Laboratory Supported” category. However, in trials including patients with possible disease AC may be advantageous. Inter-rater variation may be due to (1) a high complexity of the rEEC, which is also inherited in the AC, including definition of four body regions, interpretation of clinical findings (upper/lower motor neuron signs), significance of rostral/caudal signs, and significance of EMG findings (acute/chronic signs), and (2) the need to apply rEEC together with AC. However, pre-study training and quality control at individual laboratories may reduce variation and improve sensitivity and specificity. The results indicate that there is a need for initiatives to develop more simple and reproducible criteria.