Amyotrophic Lateral Sclerosis and Pain: A Narrative Review from Pain Assessment to Therapy.

Amyotrophic lateral sclerosis (ALS) is the most frequent neurodegenerative disease of the motor system that affects upper and lower motor neurons, leading to progressive muscle weakness, spasticity, atrophy, and respiratory failure, with a life expectancy of 2-5 years after symptom onset. In addition to motor symptoms, patients with ALS have a multitude of nonmotor symptoms; in fact, it is currently considered a multisystem disease. The purpose of our narrative review is to evaluate the different types of pain, the correlation between pain and the disease's stages, the pain assessment tools in ALS patients, and the available therapies focusing above all on the benefits of cannabis use. Pain is an underestimated and undertreated symptom that, in the last few years, has received more attention from research because it has a strong impact on the quality of life of these patients. The prevalence of pain is between 15% and 85% of ALS patients, and the studies on the type and intensity of pain are controversial. The absence of pain assessment tools validated in the ALS population and the dissimilar study designs influence the knowledge of ALS pain and consequently the pharmacological therapy. Several studies suggest that ALS is associated with changes in the endocannabinoid system, and the use of cannabis could slow the disease progression due to its neuroprotective action and act on pain, spasticity, cramps, sialorrhea, and depression. Our research has shown high patients' satisfaction with the use of cannabis for the treatment of spasticity and related pain. However, especially due to the ethical problems and the lack of interest of pharmaceutical companies, further studies are needed to ensure the most appropriate care for ALS patients.

Cannabis for the treatment of amyotrophic lateral sclerosis: What is the patients' view?

Cannabis may have therapeutic benefits to relieve symptoms of amyotrophic lateral sclerosis (ALS) thanks to its pleiotropic pharmacological activity. This study is the first to present a large questionnaire-based survey about the "real-life" situation regarding cannabis use in the medical context in ALS patients in France. There were 129 respondents and 28 reported the use of cannabis (21.7%) to relieve symptoms of ALS. Participants mostly reported the use of cannabidiol (CBD) oil and cannabis weed and declared benefits both on motor (rigidity, cramps, fasciculations) and non-motor (sleep quality, pain, emotional state, quality of life, depression) symptoms and only eight reported minor adverse reactions (drowsiness, euphoria and dry mouth). Even if cannabis is mostly used outside medical pathways and could expose patients to complications (street and uncontrolled drugs, drug-drug interactions, adverse effects…), most of the participants reported "rational" consumption (legal cannabinoids, with only few combustion and adverse reactions). Despite some limitations, this study highlights the need for further research on the potential benefits of cannabis use for the management of ALS motor and non-motor symptoms. Indeed, there is an urgent need and call for and from patients to know more about cannabis and secure its use in a medical context.

Randomized double-blind personalized N-of-1 clinical trial to test the safety and potential efficacy of TJ-68 for treating muscle cramps in amyotrophic lateral sclerosis (ALS): study protocol for a TJ-68 trial.

INTRODUCTION/AIMS: Muscle cramps are a common and often disabling symptom in amyotrophic lateral sclerosis (ALS), a devastating and incurable neurodegenerative disorder. To date, there are no medications specifically approved for the treatment of muscle cramps. Ameliorating muscle cramps in ALS may improve and sustain quality of life. A widely prescribed traditional Japanese (Kampo) medicine against muscle cramps, shakuyakukanzoto (TJ-68), has been studied in advanced liver disease, spinal stenosis, kidney failure, and diabetic neuropathy. The Japanese ALS Management Guideline mentions TJ-68 for difficult muscle cramps in ALS. Therefore, the rationale of our trial is to investigate the safety and effectiveness of TJ-68 in treating painful and disabling muscle cramps in people with ALS outside of Japan. Accordingly, we are conducting a randomized clinical trial to test the safety and efficacy of TJ-68 in participants with ALS reporting frequent muscle cramps using an innovative, personalized N-of-1 design. If successful, TJ-68 may be used for muscle cramps in a broader population of people with ALS. METHODS: This is a two-site, double-blind, randomized personalized N-of-1 early clinical trial with TJ-68. At least 22 participants with ALS and daily muscle cramps will receive drug or placebo for 2 weeks (one treatment period) followed by a 1-week washout in a four-period cross-over design. While the primary objective is to evaluate the safety of TJ-68, the study has 85% power to detect a one-point shift on the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity of the Columbia Muscle Cramp Scale (MCS). Secondary outcomes include the full MCS score, a Cramp Diary, Clinical Global Impression of Changes, Goal Attainment Scale, quality of life scale and ALS functional rating scale-revised (ALSFRS-R). DISCUSSION: The study is underway. A personalized N-of-1 trial design is an efficient approach to testing medications that alleviate muscle cramps in rare disorders. If TJ-68 proves safe and efficacious then it may be used to treat cramps in ALS, and help to improve and sustain quality of life. TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov (NCT04998305), 8/9/2021.

The role of spirituality in people with amyotrophic lateral sclerosis and their caregivers: Scoping review.

BACKGROUND: There are few studies evaluating the role of spirituality and the role of spiritually integrated interventions in people with amyotrophic lateral sclerosis (PALS) and their caregivers. OBJECTIVES: A scoping review was conducted to examine the nature and breadth of peer-reviewed literature on the role of spirituality, interventions integrating spirituality, and outcomes for PALS and their caregivers. METHODS: A literature review was performed, following the methods from the Joanna Briggs Institute Reviewers, based on all articles published between January 2006 and April 2022, identified in the CINAHL Complete, MEDLINE Complete, MedicLatina, Psychology and Behavioral Sciences Collection, and SPORTDiscus with full-text databases using key terms. Extracted data included research aims, study design, population and characteristics, theme description, and measures or type of intervention. RESULTS: A total of 18 articles were included in this study: 14 qualitative, 3 quantitative, and 1 protocol of a quantitative study. Eight studies were based in Europe. The search identified different main themes related to spirituality for caregivers and patients, 2 spiritual measure scales, and one intervention. However, many studies were limited in sample size, generalizability, and transferability and used less sophisticated research designs. SIGNIFICANCE OF THE RESULTS: This scoping review illustrates the importance given to spirituality by caregivers and PALS and reveals a very heterogeneous response. Thus, experimental studies in the area of spirituality are needed to systematically explore the impact of spiritual interventions, and the results of these studies could advance practice and policy by enhancing the quality of life for PALS and their caregivers.

Prognostic Value of Regular Nutritional Treatment in Patients With Amyotrophic Lateral Sclerosis.

BACKGROUND: Malnutrition adversely affects the prognosis of amyotrophic lateral sclerosis (ALS). The aim of this study was to evaluate the effect of regular nutrition treatment and follow-up in clinical nutrition outpatient clinic (CNOC) on survival in ALS patients. MATERIALS AND METHODS: The study included 55 ALS patients who were admitted and followed up in CNOC. Malnutrition was diagnosed using ESPEN criteria and nutrition treatment was planned according to needs of each patient. Nutritional status was followed up by body mass index (BMI), bioelectrical impedence analysis, and serum albumin. During the follow-up, survivors and nonsurvivors were compared according to their nutrition treatment success and changes in the anthropometric and laboratory measurements. RESULTS: Body weight, BMI, and fat free mass were decreased during the follow-up in both survivors and nonsurvivors ( P <0.01). The decrease in the serum albumin and BMI were significantly higher in nonsurvivors ( P <0.01). Mortality rate was lower in those with higher adherence to nutrition treatment ( P <0.01) and patients with lower adherence to nutrition treatment showed more significant decrease in serum albumin levels ( P <0.01). CONCLUSION: A personalized nutrition treatment combined with increased nutritional adherence in CNOC can decrease mortality in ALS patients.

Effectiveness of herbal medicine on patients with amyotrophic lateral sclerosis: Analysis of the PRO-ACT data using propensity score matching.

BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) have restricted pharmacotherapy options and thus resort to herbal medicines (HMs), despite limited and conflicting evidence. Therefore, use of HMs needs to be assessed in patients with ALS. PURPOSE: This study aimed to evaluate the benefits of HMs in ALS and to describe the characteristics of HM users. STUDY DESIGN: The correlation between HMs and prognosis was determined based on data obtained from the largest ALS database with high-quality clinical trials. Propensity score (PS) matching was used to address confounding and selection bias. METHODS: In total, 321 and 231 HM users with at least a 4-week HM prescription were identified and PS-matched with non-HM users at a 1:1 ratio based on predefined confounders. Time-to-event models with censoring at 12 or 18 months were established for survival analyses. For evaluating activity limitation and respiratory function, 320 and 376 HM users were included, respectively, and analyzed using multivariate analysis of variance (MANOVA). RESULTS: The profiles of 321 HM users indicated a better condition compared with that of non-HM users before PS-matching, including higher weight (median [IQR], 77.90 [21.8] kg vs. 74.00 [21.2] kg, p < 0.01), higher body mass index (26.00 [5.4] vs. 25.20 [5.8], p < 0.01), more percentage of limb onset (261 [81.3%] vs. 2366 [67.2%], p < 0.01), and slower progression (0.47 [0.5] vs. 0.51 [0.5], p = 0.03). HM did not significantly affect survival at 12 months (adjusted hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.49-1.03; log-rank p = 0.069), but it significantly prolonged survival at 18 months (adjusted HR 0.74, 95% CI 0.56-0.98; log-rank p = 0.038). After imputation of missing data, MANOVA revealed significant effectiveness of HMs in improving activity limitation (Pillai trace, 0.0195; p = 0.03). CONCLUSION: PS-based methods eliminated baseline differences between HM and non-HM users. Overall, the use of HM to treat patients with ALS is favored based on their association with prolonged overall survival within 18 months and improved activity limitation.

Pseudobulbar affect in neurodegenerative diseases: A systematic review and meta-analysis.

BACKGROUND: Pseudobulbar affect (PBA) is characterized by uncontrolled episodes of crying and laughing which is associated with a variety of neurological diseases including traumatic brain injury, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), brain tumors, stroke, Parkinson's disease (PD), Alzheimer's disease (AD) and other dementias. However, there is a lack of exact estimated prevalence of PBA among neurological disorders. AIM: In this systematic review and meta-analysis study we aimed to assess the prevalence of PBA in four neurodegenerative diseases including ALS, MS, AD, and PD. METHODS: PubMed, Scopus, and Web of Science were searched in July 2021 for studies that reported the prevalence of PBA in ALS, MS, AD, and PD patients. The mean point of PBA prevalence and odds ratios were calculated as effect size (ES) using the random-effect model with a 95% confidence interval (CI). RESULTS: The summarized prevalence of PBA was of PBA in PD patients were ranged between 1% and 31% with an overall meta-analysis prevalence of 16.5% and high heterogeneity (I2: 98.7%, p: 0.000). Patients with ALS showed a PBA prevalence of 38.5%, which is higher than other neurodegenerative diseases (CI 95%: 31%-45%, I2: 61.4%, p: 0.034). Moreover, the prevalence of PBA in MS patients in the analysis was 23.3% ranging between 11% and 35% with high-level heterogeneity according to the I2 value (I2: 98.9%, p: 0.000). Also, our meta-analysis showed that the PBA prevalence in AD was 16.4% (CI 95%: 7%-25%) with high heterogeneity (I2: 97.8%, p: 0.000). CONCLUSION: This review showed that PBA is common in patients with neurodegenerative diseases including PD, AD, MS, and especially ALS. Due to the lack of proper recognition, medication and treatment would not be effective and sufficient. Therefore, it can dramatically lower the quality of life in PBA patients and decrease their social interactions.

ALSUntangled #61: melatonin.

ALSUntangled reviews alternative and off-label treatments for people with amyotrophic lateral sclerosis (ALS). Here we review melatonin. We show that it has plausible mechanisms, some positive (and some negative) pre-clinical studies, two cases in which cocktails of supplements including melatonin were associated with recovery of lost motor function, and a very small, flawed retrospective study suggesting that patients in the PRO-ACT database who reported taking melatonin progressed more slowly and lived longer compared to those who were not taking it. Melatonin appears safe, but an optimal dose and route of administration for ALS have not been determined. Based on all this, we support a pilot trial of melatonin in people with ALS but we cannot yet recommend it as a treatment.

Cannabinoids for the treatment of refractory neuropathic pruritus in amyotrophic lateral sclerosis: A case report.

BACKGROUND: Neuropathic symptoms have a wide variety of manifestations, ranging from pain to pruritus. Neuropathic pruritus is a type of chronic pruritus related to damaged small fibers. Cannabinoids have evidence to manage neuropathic symptoms. We present a case of refractory neuropathic pruritus that was successfully managed with the use of oral cannabinoids. CASE PRESENTATION: A 60-year-old male with amyotrophic lateral sclerosis with ongoing pruritus despite the use of standard neuropathic therapies. POSSIBLE COURSE OF ACTION: Sodium channel and N-methyl-D-aspartate receptor antagonists have evidence for neuropathic symptoms but can cause significant gastrointestinal side effects. Prescription cannabinoids such as nabiximol can be cost prohibitive to use in practice. Synthetic tetrahydrocannabinol products are dose limited by psychoactive side effects. FORMULATION OF A PLAN: A balanced oral cannabinoid from a licensed producer was preferred as it has evidence for neuropathic symptoms and is generally well tolerated. OUTCOME: The patient showed improvement to his pruritus score from 7/10 to 3/10. There was initial increased sedation but tolerance developed quickly. LESSONS LEARNED FROM CASE: Cannabinoids are possibly safe and effective in management of neuropathic pruritus. VIEW ON RESEARCH PROBLEMS: Additional research is needed to establish efficacy and safety.

Progressive Neurochemical Abnormalities in Cognitive and Motor Subgroups of Amyotrophic Lateral Sclerosis: A Prospective Multicenter Study.

OBJECTIVE: To evaluate progressive cerebral degeneration in amyotrophic lateral sclerosis (ALS) by assessing alterations in N-acetylaspartate (NAA) ratios in the motor and prefrontal cortex within clinical subgroups of ALS. METHODS: Seventy-six patients with ALS and 59 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium. Participants underwent serial clinical evaluations and magnetic resonance spectroscopy at baseline and 4 and 8 months using a harmonized protocol across 5 centers. NAA ratios were quantified in the motor cortex and prefrontal cortex. Patients were stratified into subgroups based on disease progression rate, upper motor neuron (UMN) signs, and cognitive status. Linear mixed models were used for baseline and longitudinal comparisons of NAA metabolite ratios. RESULTS: Patients with ALS had reduced NAA ratios in the motor cortex at baseline (p < 0.001). Ratios were lower in those with more rapid disease progression and greater UMN signs (p < 0.05). A longitudinal decline in NAA ratios was observed in the motor cortex in the rapidly progressing (p < 0.01) and high UMN burden (p < 0.01) cohorts. The severity of UMN signs did not change significantly over time. NAA ratios were reduced in the prefrontal cortex only in cognitively impaired patients (p < 0.05); prefrontal cortex metabolites did not change over time. CONCLUSIONS: Progressive degeneration of the motor cortex in ALS is associated with more aggressive clinical presentations. These findings provide biological evidence of variable spatial and temporal cerebral degeneration linked to the disease heterogeneity of ALS. The use of standardized imaging protocols may have a role in clinical trials for patient selection or subgrouping. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that MRS NAA metabolite ratios of the motor cortex are associated with more rapid disease progression and greater UMN signs in patients with ALS. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02405182.

Amyotrophic lateral sclerosis with speech apraxia, predominant upper motor neuron signs, and prominent iron accumulation in the frontal operculum and precentral gyrus.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease; transactivation response DNA-binding protein of 43 kDa (TDP-43) and iron accumulation are supposed to play a crucial role in the pathomechanism of the disease. Here, we report an unusual case of a patient with ALS who presented with speech apraxia as an initial symptom and upper motor neuron deficiencies. In the early clinical stages, single-photon emission computed tomography visualized focal hypoperfusion of the right frontal operculum, and magnetic resonance imaging identified a hypointense area along the frontal lobe on T2-weighted images. Neuropathological examination revealed that neuronophagia of Betz cells, gliosis, appearance of phosphorylated TDP-43 (p-TDP-43)-positive glial and neuronal inclusions, and prominent iron accumulation were frequently visible in the precentral gyrus. TDP-43 pathology and focal iron accumulation were also visible in the frontal operculum, but only a mild neuronal loss and a few p-TDP-43-positive neuronal and glial inclusions were found in the hypoglossal nucleus of the medulla oblongata and anterior horn of the spinal cord. Immunoblot analysis revealed an atypical band pattern for ALS. In our case, abnormal TDP-43 and iron accumulation might possibly have caused neurodegeneration of the frontal operculum, in tandem or independently; it might then have spread into the primary motor area. Our results suggest a causative association between TDP-43 and iron accumulation in the pathomechanisms of ALS presenting with upper motor neuron signs.

Neuromuscular magnetic stimulation counteracts muscle decline in ALS patients: results of a randomized, double-blind, controlled study.

The aim of the study was to verify whether neuromuscular magnetic stimulation (NMMS) improves muscle function in spinal-onset amyotrophic lateral sclerosis (ALS) patients. Twenty-two ALS patients were randomized in two groups to receive, daily for two weeks, NMMS in right or left arm (referred to as real-NMMS, rNMMS), and sham NMMS (sNMMS) in the opposite arm. All the patients underwent a median nerve conduction (compound muscle action potential, CMAP) study and a clinical examination that included a handgrip strength test and an evaluation of upper limb muscle strength by means of the Medical Research Council Muscle Scale (MRC). Muscle biopsy was then performed bilaterally on the flexor carpi radialis muscle to monitor morpho-functional parameters and molecular changes. Patients and physicians who performed examinations were blinded to the side of real intervention. The primary outcome was the change in the muscle strength in upper arms. The secondary outcomes were the change from baseline in the CMAP amplitudes, in the nicotinic ACh currents, in the expression levels of a selected panel of genes involved in muscle growth and atrophy, and in histomorphometric parameters of ALS muscle fibers. The Repeated Measures (RM) ANOVA with a Greenhouse-Geisser correction (sphericity not assumed) showed a significant effect [F(3, 63) = 5.907, p < 0.01] of rNMMS on MRC scale at the flexor carpi radialis muscle, thus demonstrating that the rNMMS significantly improves muscle strength in flexor muscles in the forearm. Secondary outcomes showed that the improvement observed in rNMMS-treated muscles was associated to counteracting muscle atrophy, down-modulating the proteolysis, and increasing the efficacy of nicotinic ACh receptors (AChRs). We did not observe any significant difference in pre- and post-stimulation CMAP amplitudes, evoked by median nerve stimulation. This suggests that the improvement in muscle strength observed in the stimulated arm is unlikely related to reinnervation. The real and sham treatments were well tolerated without evident side effects. Although promising, this is a proof of concept study, without an immediate clinical translation, that requires further clinical validation.

Electroencephalography-based endogenous brain-computer interface for online communication with a completely locked-in patient.

BACKGROUND: Brain-computer interfaces (BCIs) have demonstrated the potential to provide paralyzed individuals with new means of communication, but an electroencephalography (EEG)-based endogenous BCI has never been successfully used for communication with a patient in a completely locked-in state (CLIS). METHODS: In this study, we investigated the possibility of using an EEG-based endogenous BCI paradigm for online binary communication by a patient in CLIS. A female patient in CLIS participated in this study. She had not communicated even with her family for more than one year with complete loss of motor function. Offline and online experiments were conducted to validate the feasibility of the proposed BCI system. In the offline experiment, we determined the best combination of mental tasks and the optimal classification strategy leading to the best performance. In the online experiment, we investigated whether our BCI system could be potentially used for real-time communication with the patient. RESULTS: An online classification accuracy of 87.5% was achieved when Riemannian geometry-based classification was applied to real-time EEG data recorded while the patient was performing one of two mental-imagery tasks for 5 s. CONCLUSIONS: Our results suggest that an EEG-based endogenous BCI has the potential to be used for online communication with a patient in CLIS.

Elucidating the End-of-Life Experience of Persons With Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that occurs in 4 among 100 000 people in the United States. Individuals with ALS gradually lose their ability to control voluntary muscles, diminishing their ability to communicate. A comprehensive multidatabase search retrieved 31 qualitative research articles that addressed persons with end-of-life experiences with ALS. Inclusion/exclusion criteria were applied and a critical appraisal was applied for the final 8 included articles. First-person data extraction from the final articles represented emergence of 3 themes significant to persons with ALS: decisions for life-sustaining support, coping and fear of what is to come, and communication with providers. Tracheostomy and ventilation as a means of prolonging life were important considerations for individuals with ALS. Persons with ALS struggled emotionally with their sudden loss of control and facing their demise. Some facets in which they did exert control, such as living wills, were hindered by patient and health care provider communication. Effective communication in end-of-life circumstances is paramount to preserving patient autonomy and dignity. This can be achieved by the patients conveying their preferences with respect to end-of-life care in advance, as well the nurses and other health care providers supporting the patients emotionally as they cope with terminal illness. Understanding patients' views regarding end-of-life circumstances is pertinent to nurses and other health care providers as they plan for palliative care.

Relevancia del síndrome piramidal en la esclerosis lateral amiotrófica / Relevance of the pyramidal syndrome in amyotrophic lateral sclerosis

Introducción: Los signos piramidales (hiperreflexia, espasticidad, signo de Babinski) son fundamentales para el diagnóstico de esclerosis lateral amiotrófica (ELA). Sin embargo, no siempre están presentes al comienzo, pueden variar con el tiempo y es controvertido su papel en la evolución. El objetivo del estudio es describir qué signos piramidales están presentes inicialmente y cómo evolucionan en una cohorte de pacientes con ELA, así como su papel pronóstico. Métodos: Análisis retrospectivo de pacientes recogidos de manera prospectiva, diagnosticados de ELA en nuestro centro, desde 1990 hasta 2015. Resultados: Del total de 130 pacientes con ELA, 34 (26,1%) no presentaron inicialmente ningún signo piramidal, mientras que 15 (11,5%) presentaban un síndrome piramidal completo. De aquellos pacientes sin piramidalismo inicial, la mediana de aparición de los primeros signos fue de 4,5 meses. El signo de Babinski estaba presente en 64 (49,2%), la hiperreflexia en 90 (69,2%) y en 22 (16,9%) pacientes existía espasticidad. Los signos piramidales tendían a mantenerse inalterados en el tiempo, aunque existe un porcentaje de pacientes en el que aparecen tardíamente o desaparecen con el tiempo. No se encontró asociación entre supervivencia y la presencia o modificación de signos piramidales, aunque la disminución de la espasticidad se asociaba a mayor deterioro clínico (escala ALSFR) (p < 0,001). Conclusión: Una cuarta parte de pacientes con ELA no presentaron inicialmente ningún signo piramidal y, en algunos casos, estos desaparecen con el tiempo. Esto resalta la necesidad de la inclusión de herramientas para la valoración de la vía piramidal (AU)

Introduction: Pyramidal signs (hyperreflexia, spasticity, Babinski sign) are essential for the diagnosis of amyotrophic lateral sclerosis (ALS). However, these signs are not always present at onset and may vary over time, besides which their role in disease evolution is controversial. Our goal was to describe which pyramidal signs were present and how they evolved in a cohort of patients with ALS, as well as their role in prognosis. Methods: Retrospective analysis of prospectively collected patients diagnosed with ALS in our centre from 1990 to 2015. Results: Of a total of 130 patients with ALS, 34 (26.1%) patients showed no pyramidal signs at the first visit while 15 (11.5%) had a complete pyramidal syndrome. Of those patients without initial pyramidal signs, mean time of appearance of the first signs was 4.5 months. Babinski sign was positive in 64 (49.2%) patients, hyperreflexia in 90 (69.2%) and 22 (16.9%) patients had spasticity. Pyramidal signs tended to remain unchanged over time, although they seem to appear at later stages or even disappear with time in some patients. We found no association between survival and the presence of changes to pyramidal signs, although decreased spasticity was associated with greater clinical deterioration (ALSFR scale) (P < .001). Conclusion: A quarter of patients with ALS initially showed no pyramidal signs and in some cases they even disappear over time. These data support the need for tools that assess the pyramidal tract (AU)

Treatment of fatigue in amyotrophic lateral sclerosis/motor neuron disease.

BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is terminal, progressive neurological condition for which there are no curative treatments. Among people with ALS/MND, fatigue is a common and debilitating symptom, which is characterised by reversible motor weakness and whole-body tiredness that is only partially relieved by rest. The effectiveness of pharmacological or non-pharmacological treatments for fatigue in ALS/MND is not yet established. OBJECTIVES: To assess the effects of pharmacological and non-pharmacological interventions for fatigue in ALS/MND. SEARCH METHODS: We searched the following databases on 5 September 2017: Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL Plus, and ERIC. We also searched two clinical trials registries. SELECTION CRITERIA: We selected randomised and quasi-randomised controlled trials of any intervention which sought to reduce fatigue for people with ALS/MND. We included studies if reduction in fatigue was a primary or secondary outcome of the trial. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: We included one pharmacological (modafinil) study and three non-pharmacological studies (resistance exercise, respiratory exercise, and repetitive transcranial magnetic stimulation (rTMS)), involving a total of 86 participants with ALS/MND. None of the included studies were free from risk of bias. Since there was only one trial for each intervention, no meta-analysis was possible. All studies assessed fatigue using the Fatigue Severity Scale (FSS; scale from 9 to 63, higher scores indicate more fatigue). Information for assessing bias was often lacking in study reports, making the risk of bias unclear across several domains in all trials. Blinding of participants was not possible in exercise trials, but the outcome assessment was blinded.We found very low-quality evidence suggesting possible improvements in fatigue for modafinil treatment versus placebo (MD -11.00, 95% CI -23.08 to 1.08), respiratory exercise versus a sham intervention (MD -9.65, 95% CI -22.04 to 2.73), and rTMS versus sham rTMS (data not provided), which warrant further investigation to clarify the efficacy of these treatments for fatigue in ALS/MND. We found no clear improvements in fatigue for resistance exercise versus usual care (MD 0.20, 95% CI -10.98 to 11.38; very low-quality evidence).Three participants in the modafinil group dropped out of the modafinil study, two citing issues with headache and one with chest tightness; other adverse effects were anxiety, nausea, dizziness, and sialorrhoea (probably ALS-related). The trials reported no adverse effects of exercise or rTMS.We cannot be certain about the effects of any of the interventions studied because of imprecision (small numbers of participants, wide CI), and possible study limitations. AUTHORS' CONCLUSIONS: It is impossible to draw firm conclusions about the effectiveness of interventions to improve fatigue for people with ALS/MND as there are few randomised studies, and the quality of available evidence is very low.

Nutrition management methods effective in increasing weight, survival time and functional status in ALS patients: a systematic review.

Poor prognosis and decreased survival time correlate with the nutritional status of patients with amyotrophic lateral sclerosis (ALS). Various studies were reviewed which assessed weight, body mass index (BMI), survival time and ALS functional rating scale revised (ALSFRS-R) in order to determine the best nutrition management methods for this patient population. A systematic review was conducted using CINAHL, Medline, and PubMed, and various search terms in order to determine the most recent clinical trials and observational studies that have been conducted concerning nutrition and ALS. Four articles met criteria to be included in the review. Data were extracted from these articles and were inputted into the Data Extraction Tool (DET) provided by the Academy of Nutrition and Dietetics (AND). Results showed that nutrition supplementation does promote weight stabilisation or weight gain in individuals with ALS. Given the low risk and low cost associated with intervention, early and aggressive nutrition intervention is recommended. This systematic review shows that there is a lack of high quality evidence regarding the efficacy of any dietary interventions for promoting survival in ALS or slowing disease progression; therefore more research is necessary related to effects of nutrition interventions.

Detecting neuronal dysfunction of hand motor cortex in ALS: A MRSI study.

BACKGROUND: Although hand motor cortex (HMC) has been constantly used for identification of primary motor cortex in magnetic resonance spectroscopy (MRS) studies of amyotrophic lateral sclerosis (ALS), neurochemical profiles of HMC have never been assessed independently. As HMC has a constant location and the clinic-anatomic correlation between hand motor function and HMC has been established, we hypothesize that HMC may serve as a promising region of interest in diagnosing ALS. PATIENTS AND METHODS: Fourteen ALS patients and 14 age- and gender-matched healthy controls (HC) were recruited in this study. An optimized magnetic resonance spectroscopic imaging (MRSI) method was developed and for each subject bilateral HMC areas were scanned separately (two-dimensional multi-voxel MRSI, voxel size 0.56 cm3). N-acetyl aspartate (NAA)-creatine (Cr) ratio was measured from HMC and the adjacent postcentral gyrus. RESULTS: Compared with HC, NAA/Cr ratios from HMC and the postcentral gyrus were significantly reduced in ALS. However, in each group the difference of NAA/Cr ratios between HMC and the postcentral gyrus was not significant. Limb predominance of HMC was not found in either ALS or HC. In ALS, there was a significant difference in NAA/Cr ratio between the most affected HMC and the less affected HMC. A positive relationship between NAA/Cr ratio of HMC and the severity of hand strength (assessed by finger tapping speed) was demonstrated. CONCLUSION: Neuronal dysfunction of HMC can differentiate ALS patients from HC when represented as reduced NAA/Cr ratio. Postcentral gyrus could not serve as normal internal reference tissue in diagnosing ALS. Asymmetrical NAA/Cr ratios from bilateral HMC may serve as a promising diagnostic biomarker of ALS at the individual level.

Executive dysfunction affects word list recall performance: Evidence from amyotrophic lateral sclerosis and other neurodegenerative diseases.

The Rey Auditory Verbal Learning Test (RAVLT) is widely used in clinical practice to evaluate verbal episodic memory. While there is evidence that RAVLT performance can be influenced by executive dysfunction, the way executive disorders affect the serial position curve (SPC) has not been yet explored. To this aim, we analysed immediate and delayed recall performances of 13 non-demented amyotrophic lateral sclerosis (ALS) patients with a specific mild executive dysfunction (ALSci) and compared their performances to those of 48 healthy controls (HC) and 13 cognitively normal patients with ALS. Moreover, to control for the impact of a severe dysexecutive syndrome and a genuine episodic memory deficit on the SPC, we enrolled 15 patients with a diagnosis of behavioural variant of frontotemporal dementia (bvFTD) and 18 patients with probable Alzheimer's disease (AD). Results documented that, compared to cognitively normal subjects, ALSci patients had a selective mid-list impairment for immediate recall scores. The bvFTD group obtained low performances with a selectively increased forgetting rate for terminal items, whereas the AD group showed a disproportionately large memory loss on the primary and middle part of the SPC for immediate recall scores and were severely impaired in the delayed recall trial. These results suggested that subtle executive dysfunctions might influence the recall of mid-list items, possibly reflecting deficiency in control strategies at retrieval of word lists, whereas severer dysexecutive syndrome might also affect the recall of terminal items possibly due to attention deficit or retroactive interference.