Primary care blood tests show lipid profile changes in pre-symptomatic amyotrophic lateral sclerosis.

Multiple sources of evidence suggest that changes in metabolism may precede the onset of motor symptoms in amyotrophic lateral sclerosis. This study aimed to seek evidence for alterations in the levels of blood indices collected routinely in the primary care setting prior to the onset of motor symptoms in amyotrophic lateral sclerosis. Premorbid data, measured as part of routine health screening, for total cholesterol, high-density and low-density lipoprotein cholesterol, triglyceride, glycated haemoglobin A1c and creatinine were collected retrospectively from (i) a cohort of amyotrophic lateral sclerosis patients attending a specialist clinic (n = 143) and (ii) from primary care-linked data within UK Biobank. Data were fitted using linear mixed effects models with linear b-splines to identify inflection points, controlling for age and sex. In specialist amyotrophic lateral sclerosis clinic cases, models indicated decreasing levels of total and low-density lipoprotein cholesterol prior to an inflection point in the years before symptom onset (total cholesterol 3.25 years, low-density lipoprotein cholesterol 1.25 years), after which they stabilized or rose. A similar pattern was observed in amyotrophic lateral sclerosis cases within UK Biobank, occurring several years prior to diagnosis (total cholesterol 7 years, low-density lipoprotein cholesterol 7.25 years), differing significantly from matched controls. High-density lipoprotein cholesterol followed a similar pattern but was less robust to sensitivity analyses. Levels of triglyceride remained stable throughout. Glycated haemoglobin temporal profiles were not consistent between the clinic and biobank cohorts. Creatinine level trajectories prior to amyotrophic lateral sclerosis did not differ significantly from controls but decreased significantly in the symptomatic period after an inflection point of 0.25 years after symptom onset (clinic cohort) or 0.5 years before diagnosis (UK Biobank). These data provide further evidence for a pre-symptomatic period of dynamic metabolic change in amyotrophic lateral sclerosis, consistently associated with alterations in blood cholesterols. Such changes may ultimately contribute to biomarkers applicable to population screening and for pathways guiding the targeting of preventative therapy.

Genetic testing in motor neurone disease.

A minority (10%-15%) of cases of amyotrophic lateral sclerosis (ALS), the most common form of motor neurone disease (MND), are currently attributable to pathological variants in a single identifiable gene. With the emergence of new therapies targeting specific genetic subtypes of ALS, there is an increasing role for routine genetic testing for all those with a definite diagnosis. However, potential harm to both affected individuals and particularly to asymptomatic relatives can arise from the indiscriminate use of genetic screening, not least because of uncertainties around incomplete penetrance and variants of unknown significance. The most common hereditary cause of ALS, an intronic hexanucleotide repeat expansion in C9ORF72, may be associated with frontotemporal dementia independently within the same pedigree. The boundary of what constitutes a possible family history of MND has therefore extended to include dementia and associated psychiatric presentations. Notwithstanding the important role of clinical genetics specialists, all neurologists need a basic understanding of the current place of genetic testing in MND, which holds lessons for other neurological disorders.

Fit for purpose? A cross-sectional study to evaluate the acceptability and usability of HeadUp, a novel neck support collar for neurological neck weakness.

The HeadUp collar (previously known as the Sheffield Support Snood) provides support for neck weakness caused by amyotrophic lateral sclerosis (ALS) and has shown to be superior to alternative options in a small cohort of patients from one single center. Here we report the assessment of the HeadUp collar in a larger cohort of patients, exploring the use in other neurological conditions and expanding to other centers across the UK and Ireland. An interventional cross-sectional study design was implemented to investigate the usability and acceptability of the HeadUp collar. A total of 139 patients were recruited for the study, 117 patients had a diagnosis of ALS and 22 patients presented with neck weakness due to other neurological conditions. Participants were assessed at baseline, fitted a HeadUp collar and followed-up one month later. The performance of the HeadUp collar was rated favorably compared to previously worn collars in terms of the ability to eat, drink and swallow. Findings suggest that the collar also permitted a more acceptable range of head movements whilst maintaining a good level of support. We conclude that the HeadUp collar is a suitable option for patients with neck weakness due to ALS and other neurological conditions.

The use of biotelemetry to explore disease progression markers in amyotrophic lateral sclerosis.

OBJECTIVE: To explore novel, real-world biotelemetry disease progression markers in patients with amyotrophic lateral sclerosis (ALS) and to compare with clinical gold-standard measures. Methods: This was an exploratory, non-controlled, non-drug 2-phase study comprising a variable length Pilot Phase (n = 5) and a 48-week Core study Phase (n = 25; NCT02447952). Patients with mild or moderate ALS wore biotelemetry sensors for ∼3 days/month at home, measuring physical activity, heart rate variability (HRV), and speech over 48 weeks. These measures were assessed longitudinally in relation to ALS Functional Rating Scale-Revised (ALSFRS-R) score and forced vital capacity (FVC); assessed by telephone [monthly] and clinic visits [every 12 weeks]). Results: Pilot Phase data supported progression into the Core Phase, where a decline in physical activity from baseline followed ALS progression as measured by ALSFRS-R and FVC. Four endpoints showed moderate or strong between-patient correlations with ALSFRS-R total and gross motor domain scores (defined as a correlation coefficient of ≥0.5 or >0.7, respectively): average daytime active; percentage of daytime active; total daytime activity score; total 24-hour activity score. Moderate correlations were observed between speech endpoints and ALSFRS-R bulbar domain scores; HRV data quality was insufficient for reliable assessment. The sensor was generally well tolerated; 6/25 patients reported mostly mild or moderate intensity skin and subcutaneous tissue disorder adverse events. Conclusions: Biotelemetry measures of physical activity in this Pilot Study tracked ALS progression over time, highlighting their potential as endpoints for future clinical trials. A larger, formally powered study is required to further support activity endpoints as novel disease progression markers.

Objectively Monitoring Amyotrophic Lateral Sclerosis Patient Symptoms During Clinical Trials With Sensors: Observational Study.

BACKGROUND: Objective symptom monitoring of patients with Amyotrophic Lateral Sclerosis (ALS) has the potential to provide an important source of information to evaluate the impact of the disease on aspects of real-world functional capacity and activities of daily living in the home setting, providing useful objective outcome measures for clinical trials. OBJECTIVE: This study aimed to investigate the feasibility of a novel digital platform for remote data collection of multiple symptoms-physical activity, heart rate variability (HRV), and digital speech characteristics-in 25 patients with ALS in an observational clinical trial setting to explore the impact of the devices on patients' everyday life and to record tolerability related to the devices and study procedures over 48 weeks. METHODS: In this exploratory, noncontrolled, nondrug study, patients attended a clinical site visit every 3 months to perform activity reference tasks while wearing a sensor, to conduct digital speech tests and for conventional ALS monitoring. In addition, patients wore the sensor in their daily life for approximately 3 days every month for the duration of the study. RESULTS: The amount and quality of digital speech data captured at the clinical sites were as intended, and there were no significant issues. All the home monitoring sensor data available were propagated through the system and were received as expected. However, the amount and quality of physical activity home monitoring data were lower than anticipated. A total of 3 or more days (or partial days) of data were recorded for 65% of protocol time points, with no data collected for 24% of time points. At baseline, 24 of 25 patients provided data, reduced to 13 of 18 patients at Week 48. Lower-than-expected quality HRV data were obtained, likely because of poor contact between the sensor and the skin. In total, 6 of 25 patients had mild or moderate adverse events (AEs) in the skin and subcutaneous tissue disorders category because of skin irritation caused by the electrode patch. There were no reports of serious AEs or deaths. Most patients found the sensor comfortable, with no or minimal impact on daily activities. CONCLUSIONS: The platform can measure physical activity in patients with ALS in their home environment; patients used the equipment successfully, and it was generally well tolerated. The quantity of home monitoring physical activity data was lower than expected, although it was sufficient to allow investigation of novel physical activity end points. Good-quality in-clinic speech data were successfully captured for analysis. Future studies using objective patient monitoring approaches, combined with the most current technological advances, may be useful to elucidate novel digital biomarkers of disease progression.

A risk stratifying tool to facilitate safe late-stage percutaneous endoscopic gastrostomy in ALS.

BACKGROUND: The safety of percutaneous endoscopic gastrostomy (PEG) insertion in amyotrophic lateral sclerosis (ALS) patients with significant respiratory compromise has been questioned. OBJECTIVES: To review the characteristics of an ALS clinic patient cohort undergoing PEG, and the introduction of a risk stratification tool with procedural adaptations for higher-risk individuals. METHODS: Patients undergoing PEG insertion were analysed (n = 107). Cases stratified as higher-risk underwent insertion in a semi-recumbent position, minimising sedation, with the option of nasal non-invasive ventilation. RESULTS: All underwent successful PEG. One-third had pre-procedure FVC ≤50% (mean, 64 ± 22%). Of those who underwent PEG insertion after introduction of risk stratification (n = 58), 39 (67%) met criteria for being higher risk, 16 (41%) of whom had FVC ≤50% (p = 0.005). High-risk patients received lower sedative doses vs. the low-risk group (midazolam 2.1 ± 1.1 vs.2.8 ± 0.95mg, p = 0.021; fentanyl 42 ± 16 vs. 60 ± 21µg, p = 0.015). Four deaths occurred within one month of insertion (attributable to the natural disease course). CONCLUSIONS: Risk stratification identified a greater number of patients with evidence of respiratory compromise than using the sole criterion of FVC ≤50%. A modified PEG procedure enabled safe insertion despite respiratory compromise, in those who might not have tolerated attempted insertion by alternative means such as radiologically-inserted gastrostomy.

Nutritional pathway for people with motor neurone disease.

This paper provides an overview of the nutritional management and care of people living with motor neurone disease (MND) in a specialist nutrition clinic. A specialist pathway of care has been developed to enable people living with MND to undergo a percutaneous endoscopic gastrostomy (PEG) procedure in a safe way; the pathway incorporates attendance at a dedicated nutrition clinic, a stratification tool to identify patients with a high periprocedural risk and a PEG insertion team with significant experience in the MND population. Since this pathway has been in place, gastrostomies have been successfully placed in patients with a forced vital capacity (FVC) of less than 50%; previously, this would not have been possible.

The diagnostic pathway and prognosis in bulbar-onset amyotrophic lateral sclerosis.

BACKGROUND: Despite the inevitability of disease progression in amyotrophic lateral sclerosis, there is a high degree of prognostic heterogeneity in all subtypes. Some bulbar-onset (BO) patients may develop rapid anarthria yet remain ambulant for a prolonged period, whereas others progress rapidly, with early generalisation of motor weakness to the limbs and respiratory muscles. Diagnostic delay is a common occurrence in ALS, and many BO patients report having attended other specialist clinics prior to diagnosis. METHODS: A retrospective descriptive study of BO ALS patients seen in a tertiary clinic over a six year period. RESULTS: Forty-nine BO ALS patients were studied. Median survival from symptom onset was 27 months (range 6-84). 63% of subjects were female and the mean age at symptom onset was 68 years. Half had been referred to another speciality prior to diagnosis, either otolaryngology or stroke clinics, but this did not influence diagnostic latency or survival. Emotionality was reported in 45% of patients. Neurophysiological assessment was performed in 80%, brain imaging recorded in 69%, and antibody testing for myasthenia gravis in 22%. The median time to symptomatic progression beyond the bulbar region was approximately 1 year, with equal proportions progressing to the upper or lower limbs. The median interval from onset to anarthria was 18 months, and to loss of ambulation 22 months. There was a close correlation between the two (r(2)=0.6) and median survival from loss of ambulation was only 3 months. Gastrostomy was carried out in 78% of patients with a median time of 13 months from symptom onset, and 3 months from diagnosis. Median survival from gastrostomy was 10 months. CONCLUSIONS: Survival in bulbar-onset ALS is highly variable. Half of the patients were referred to an inappropriate clinic prior to diagnosis. The time interval to the development of anarthria predicted the timing of subsequent loss of ambulation accurately from which survival may then be only a few months.

Discussing sexuality with patients in a motor neurone disease clinic.

Sexual relationships remain an important aspect of life for people living with motor neurone disease. This article explores the use of the Extended-PLISSIT model when discussing relationships and sexual function with patients and their partners in a motor neurone disease clinic. The model provides a structured approach to assist discussions with patients as well as promoting reflection and exchange of knowledge in the multidisciplinary team. It is a useful model when addressing issues that are sometimes difficult to discuss.

Pattern of spread and prognosis in lower limb-onset ALS.

Our objective was to establish the pattern of spread in lower limb-onset ALS (contra- versus ipsi-lateral) and its contribution to prognosis within a multivariate model. Pattern of spread was established in 109 sporadic ALS patients with lower limb-onset, prospectively recorded in Oxford and Sheffield tertiary clinics from 2001 to 2008. Survival analysis was by univariate Kaplan-Meier log-rank and multivariate Cox proportional hazards. Variables studied were time to next limb progression, site of next progression, age at symptom onset, gender, diagnostic latency and use of riluzole. Initial progression was either to the contralateral leg (76%) or ipsilateral arm (24%). Factors independently affecting survival were time to next limb progression, age at symptom onset, and diagnostic latency. Time to progression as a prognostic factor was independent of initial direction of spread. In a regression analysis of the deceased, overall survival from symptom onset approximated to two years plus the time interval for initial spread. In conclusion, rate of progression in lower limb-onset ALS is not influenced by whether initial spread is to the contralateral limb or ipsilateral arm. The time interval to this initial spread is a powerful factor in predicting overall survival, and could be used to facilitate decision-making and effective care planning.