J. Raaphorst

The ALS-FTD-Q A new screening tool for behavioral disturbances in ALS

Objective: The assessment of behavioral disturbances in amyotrophic lateral sclerosis (ALS) is important because of the overlap with the behavioral variant of frontotemporal dementia (ALS-bvFTD). Motor symptoms and dysarthria are not taken into account in currently used behavioral questionnaires. We examined the clinimetric properties of a new behavioral questionnaire for patients with ALS (Amyotrophic Lateral Sclerosis-Frontotemporal Dementia-Questionnaire [ALS-FTD-Q]). Methods: In addition to other clinimetric properties, we examined reliability, clinical validity, and construct validity of the ALS-FTD-Q, using data from patients with ALS (n = 103), ALS-bvFTD (n = 10), bvFTD (n = 25), muscle disease control subjects (n = 39), and control subjects (n = 31). Construct validity of the ALS-FTD-Q was assessed using the Frontal Systems Behavior scale (FrSBe), Frontal Behavioral Inventory (FBI), Hospital Anxiety and Depression Scale, ALS Functional Rating Scale−Revised, Frontal Assessment Battery, Mini-Mental State Examination, and a fluency index. In addition, the point prevalence of behavioral disturbances according to the ALS-FTD-Q was compared with those obtained with the FrSBe and FBI. Results: The internal consistency of the ALS-FTD-Q was good (Cronbach α = 0.92). The ALS-FTD-Q showed construct validity because it correlated highly with other behavioral measures (r = 0.80 and 0.79), moderately with measures of frontal functions and global cognitive functioning (r = 0.37; r = 0.32), and poorly with anxiety/depression and motor impairment (r = 0.18 for both). The ALS-FTD-Q discriminated between patients with ALS-bvFTD, patients with ALS, and control subjects. The point prevalence of behavioral disturbances in patients with ALS measured with the ALS-FTD-Q was lower than that for the FrSBe and FBI. Conclusion: The ALS-FTD-Q is a feasible and clinimetrically validated instrument for the screening of behavioral disturbances in ALS.

RYR1‐related myopathies: a wide spectrum of phenotypes throughout life

Although several recent studies have implicated RYR1 mutations as a common cause of various myopathies and the malignant hyperthermia susceptibility (MHS) trait, many of these studies have been limited to certain age groups, confined geographical regions or specific conditions. The aim of the present study was to investigate the full spectrum of RYR1‐related disorders throughout life and to use this knowledge to increase vigilance concerning malignant hyperthermia.

Tau Rather than TDP-43 Proteins are Potential Cerebrospinal Fluid Biomarkers for Frontotemporal Lobar Degeneration Subtypes: A Pilot Study

BACKGROUNDnFrontotemporal dementia (FTD) is a heterogeneous disease both at the clinical, genetic, and pathobiological level. The underlying pathological spectrum (termed FTLD, frontotemporal lobar degeneration) is in most cases defined by accumulation of either tau (FTLD-tau) or TDP-43 proteins (FTLD-TDP). Biomarkers to differentiate these subtypes are not yet available, whereas these are essential requirements to study the natural course of disease and for homogeneous inclusion of patients in clinical studies.nnnOBJECTIVEnTo study if a combination of total (t-) and phosphorylated (p-)tau, and t-TDP-43 and p-TDP-43 proteins in cerebrospinal fluid (CSF) is suitable to discriminate FTLD-tau and FTLD-TDP subtypes.nnnMETHODSnWe developed immunoassays for the quantification of t-TDP-43 and p-TDP-43 proteins and used commercially available assays for the quantification of t-tau and p-tau proteins. We quantified these proteins in ventricular CSF samples from neuropathologically defined FTLD-tau and FTLD-TDP cases to study the reflection of underlying brain pathology in CSF composition, and in lumbar CSF samples from FTLD-tau and FTLD-TDP patients to study the diagnostic potential of CSF biomarkers.nnnRESULTSnIn ventricular CSF, t-TDP-43 and t-tau levels, when combined into one model, were significantly different between neuropathologically-defined FTLD-tau and FTLD-TDP cases. In a pilot study using lumbar CSF, the p-tau/t-tau ratio, but not t-TDP-43 levels, were significantly different between FTLD-TDP and FTLD-tau patients.nnnCONCLUSIONnWe conclude that with current available methods, CSF tau, rather than TDP-43 proteins, may have diagnostic value in the differentiation of FTLD patients with either tau or TDP-43 pathology.

The predictive value of respiratory function tests for non-invasive ventilation in amyotrophic lateral sclerosis

BackgroundNon-invasive ventilation (NIV) improves survival and quality of life in amyotrophic lateral sclerosis (ALS) patients. The timing of referral to a home ventilation service (HVS), which is in part based on respiratory function tests, has shown room for improvement. It is currently unknown which respiratory function test predicts an appropriate timing of the initiation of NIV.MethodsWe analysed, retrospectively, serial data of five respiratory function tests: forced vital capacity (FVC), peak cough flow (PCF), maximum inspiratory and expiratory pressure (MIP and MEP) and sniff nasal inspiratory pressure (SNIP) in patients with ALS. Patients who had had at least one assessment of respiratory function and one visit at the HVS, were included. Our aim was to detect the test with the highest predictive value for the need for elective NIV in the following 3xa0months. We analysed time curves, currently used cut-off values for referral, and respiratory function test results between ‘NIV indication’ and ‘no-NIV indication’ patients.ResultsOne hundred ten patients with ALS were included of whom 87 received an NIV indication; 11.5% had one assessment before receiving an NIV indication, 88.5% had two or more assessments. The NIV indication was based on complaints of hypoventilation and/or proven (nocturnal) hypercapnia. The five respiratory function tests showed a descending trend during disease progression, where SNIP showed the greatest decline within the latest 3xa0months before NIV indication (meanxa0=xa0−22%). PCF at the time of referral to the HVS significantly discriminated between the groups ‘NIV-indication’ and ‘no NIV-indication yet’ patients at the first HVS visit: 259 (±92) vs. 348 (±137) L/min, pxa0=xa00.019. PCF and SNIP showed the best predictive characteristics in terms of sensitivity.ConclusionSNIP showed the greatest decline prior to NIV indication and PCF significantly differentiated ‘NIV-indication’ from ‘no NIV-indication yet’ patients with ALS. Currently used cut-off values might be adjusted and other respiratory function tests such as SNIP and PCF may become part of routine care in patients with ALS in order to avoid non-timely initiation of (non-invasive) ventilation.

The cognitive profile of myotonic dystrophy type 1: A systematic review and meta-analysis

OBJECTIVEnTo examine the cognitive profile of patients with myotonic dystrophy type 1 (DM1) on the basis of a systematic review and meta-analysis of the literature.nnnMETHODSnEmbase, Medline and PsycInfo were searched for studies reporting ≥1 neuropsychological test in both DM1 patients and healthy controls. Search, data extraction and risk of bias analysis were independently performed by two authors to minimize error. Neuropsychological tests were categorized into 12 cognitive domains and effect sizes (Hedges g) were calculated for each domain and for tests administered in ≥5 studies.nnnRESULTSnDM1 participants demonstrated a significantly worse performance compared to controls in all cognitive domains. Effect sizes ranged from -.33 (small) for verbal memory to -1.01 (large) for visuospatial perception. Except for the domains global cognition, intelligence and social cognition, wide confidence intervals (CIs) were associated with moderate to marked statistical heterogeneity that necessitates careful interpretation of results. Out of the individual tests, the Rey-Osterrieth complex figure-copy (both non-verbal memory and visuoconstruction) showed consistent impairment with acceptable heterogeneity.nnnCONCLUSIONnIn DM1 patients, cognitive deficits may include a variable combination of global cognitive impairment with involvement across different domains, including social cognition, memory and visuospatial functioning. Although DM1 is a heterogeneous disorder, our study shows that meta-analysis is feasible, contributes to the understanding of brain involvement and may direct bedside testing. The protocol for this study has been registered in PROSPERO (International prospective register of systematic reviews) under ID: 42016037415.

Combined N-of-1 trials to investigate mexiletine in non-dystrophic myotonia using a Bayesian approach; study rationale and protocol

BackgroundTo obtain evidence for the clinical and cost-effectiveness of treatments for patients with rare diseases is a challenge. Non-dystrophic myotonia (NDM) is a group of inherited, rare muscle diseases characterized by muscle stiffness. The reimbursement of mexiletine, the expert opinion drug for NDM, has been discontinued in some countries due to a lack of independent randomized controlled trials (RCTs). It remains unclear however, which concessions can be accepted towards the level 1 evidence needed for coverage decisions, in rare diseases. Considering the large number of rare diseases with a lack of treatment evidence, more experience with innovative trial designs is needed. Both NDM and mexiletine are well suited for an N-of-1 trial design. A Bayesian approach allows for the combination of N-of-1 trials, which enables the assessment of outcomes on the patient and group level simultaneously.Methods/DesignWe will combine 30 individual, double-blind, randomized, placebo-controlled N-of-1 trials of mexiletine (600 mg daily) vs. placebo in genetically confirmed NDM patients using hierarchical Bayesian modeling. Our results will be compared and combined with the main results of an international cross-over RCT (mexiletine vs. placebo in NDM) published in 2012 that will be used as an informative prior. Similar criteria of eligibility, treatment regimen, end-points and measurement instruments are employed as used in the international cross-over RCT.DiscussionThe treatment of patients with NDM with mexiletine offers a unique opportunity to compare outcomes and efficiency of novel N-of-1 trial-based designs and conventional approaches in producing evidence of clinical and cost-effectiveness of treatments for patients with rare diseases.Trial registrationClinicalTrials.gov Identifier: NCT02045667

The cognitive profile of behavioural variant FTD and its similarities with ALS: a systematic review and meta-analysis

Approximately 30% of patients with amyotrophic lateral sclerosis (ALS) have cognitive impairment and 8%–14% fulfil the criteria for behavioural variant frontotemporal dementia (bv-FTD). The cognitive profiles of ALS and bv-FTD have been reported to be comparable, but this has never been systematically investigated. We aimed to determine the cognitive profile of bv-FTD and examine its similarities with that of ALS, to provide evidence for the existence of a cognitive disease continuum encompassing bv-FTD and ALS. We therefore systematically reviewed neuropsychological studies on bv-FTD patients and healthy volunteers. Neuropsychological tests were divided in 10 cognitive domains and effect sizes were calculated for all domains and compared with the cognitive profile of ALS by means of a visual comparison and a Pearson’s r correlation coefficient. We included 120 studies, totalling 2425 bv-FTD patients and 2798 healthy controls. All cognitive domains showed substantial effect sizes, indicating cognitive impairment in bv-FTD patients compared to healthy controls. The cognitive domains with the largest effect sizes were social cognition, verbal memory and fluency (1.77–1.53). The cognitive profiles of bv-FTD and ALS (10 cognitive domains, 1287 patients) showed similarities on visual comparison and a moderate correlation 0.58 (p=0.13). When social cognition, verbal memory, fluency, executive functions, language and visuoperception were considered, i.e. the cognitive profile of ALS, Pearson’s r was 0.73 (p=0.09), which raised to 0.92 (p=0.03), when language was excluded in this systematic analysis of patients with a non-language subtype of FTD. The cognitive profile of bv-FTD consists of deficits in social cognition, verbal memory, fluency and executive functions and shows similarities with the cognitive profile of ALS. These findings support a cognitive continuum encompassing ALS and bv-FTD.

Quality of life in inflammatory neuropathies : the IN-QoL

Background No consensus exists which quality of life (QoL) measure should be used in patients with inflammatory neuropathies. Moreover, most QoL measures are ordinal-based scales with their known deficiencies. Objectives To establish a new disease-specific interval-based QoL questionnaire in inflammatory neuropathies (IN-QoL) using the Rasch model and evaluate its scientific properties (validity, reliability and responsiveness). Methods 264 patients with inflammatory neuropathies completed six commonly used QoL questionnaires. The obtained data were stacked and subjected to Rasch analysis. Responsiveness was determined by using the concept of minimum clinically important differences related to varying individually obtained SEs (responsiveness definition: MCID-SE≥1.96u2009after 1-year follow-up compared with baseline). Results The IN-QoL fulfilled all Rasch’s model requirements with high internal reliability values (patient separation index of 0.94), except being multidimensional. Additional factor analysis resulted in two (functional and mental) subsets that were unidimensional on their own. The IN-QoL showed good correlation with the EuroQol-health quality visual analogue scale (EQ-VAS) (Spearman’s rho 0.72). It demonstrated acceptable responsiveness in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), as did the EQ-VAS. In patients with monoclonal gammopathy-related neuropathy and multifocal motor neuropathy, hardly any changes were seen over time. Conclusion The IN-QoL questionnaire fulfils modern clinimetric requirements and correlates strongly with a patient’s self-assessment of their own quality of health, while also showing responsiveness in patients with GBS and CIDP. We propose using the IN-QoL and the EQ-VAS for assessing the QoL of patients with inflammatory neuropathies in future studies.

Falls and resulting fractures in Myotonic Dystrophy: Results from a multinational retrospective survey

Myotonic Dystrophy type 1 multisystem involvement leads to functional impairment with an increased risk of falling. This multinational study estimates the prevalence of falls and fall-associated fractures. A web-based survey among disease-specific registries (Germany, UK and The Netherlands) was carried out among DM1 ambulant adults with a total of 573 responses retrieved. Results provided a risk ratio estimation of 30%-72% for falls and of 11%-17% for associated fractures. There was no significant difference for falls between male and female, but there was for fall-related fractures with a higher prevalence in women. Balance and leg weakness were the most commonly reported causes for falling. This study is based on a voluntary retrospective survey with naturally inherent limitations; however, the sample size allows for robust comparisons. The estimated risk of falls in this cohort with a mean age of 46 years compares to a previous estimation for a healthy population of over 65 years of age. These results suggest a premature-ageing DM1 phenotype with an increased risk of falling depending on age and disease severity that, so far, might have been underestimated. This may have clinical implications for the development of care guidelines and when testing new interventions in this population.

Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands

Few reliable data exist on the prevalence of skeletal muscle channelopathies. We determined the minimum point prevalence of genetically-defined skeletal muscle channelopathies in the Netherlands and report their mutation spectrum. Minimum point prevalence rates were calculated as number of genetically-confirmed skeletal muscle channelopathy patients (CLCN1, SCN4A, CACNA1S and KCNJ2 gene mutations) in the Netherlands (1990-2015) divided by the total number of at-risk individuals. Rates were expressed as cases/100.000 and 95% confidence intervals were calculated based on Poisson distribution. Results of standardized genetic diagnostic procedures were used to analyze mutation spectra. We identified 405 patients from 234 unrelated pedigrees, resulting in a minimum point prevalence of 2.38/100.000 (95% CI 2.16-2.63) for skeletal muscle channelopathies in the Netherlands. Minimum point prevalence rates for the disease groups, non-dystrophic myotonia and periodic paralysis, were 1.70/100.000 and 0.69/100.000 respectively. Sixty-one different CLCN1 mutations (including 12 novel mutations) were detected in myotonia congenita. Twenty-eight different SCN4A missense mutations (including three novel mutations) were identified in paramyotonia congenita/sodium channel myotonia, hypokalemic periodic paralysis and hyperkalemic periodic paralysis. Four different CACNA1S missense mutations were detected in hypokalemic periodic paralysis and five KCNJ2 missense mutations in Andersen-Tawil syndrome. The minimum point prevalence rates for genetically-defined skeletal muscle channelopathies confirm their rare disease status in the Netherlands. Rates are almost twice as high as in the UK and more in line with pre-genetic prevalence estimates in parts of Scandinavia. Future diagnostic and therapeutic studies may benefit from knowledge of the mutation spectrum of skeletal muscle channelopathies.