EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis:, Peter M Andersen, Sharon Abrahams, Gian D Borasio, Mamede de Carvalho, Adriano Chio, Philip Van Damme, Orla Hardiman, Katja Kollewe, Karen E Morrison, Susanne Petri, Pierre-Francois Pradat, Vincenzo Silani, Barbara Tomik, Maria Wasner, Markus Weber
EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)--revised report of an EFNS task force.
Eur J Neurol. 2012 Mar;19(3):360-75. doi: 10.1111/j.1468-1331.2011.03501.x. Epub 2011 Sep 14.
Abstract/Text
BACKGROUND: The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak.
OBJECTIVES: To provide evidence-based or expert recommendations for the diagnosis and management of ALS based on a literature search and the consensus of an expert panel.
METHODS: All available medical reference systems were searched, and original papers, meta-analyses, review papers, book chapters and guidelines recommendations were reviewed. The final literature search was performed in February 2011. Recommendations were reached by consensus.
RECOMMENDATIONS: Patients with symptoms suggestive of ALS should be assessed as soon as possible by an experienced neurologist. Early diagnosis should be pursued, and investigations, including neurophysiology, performed with a high priority. The patient should be informed of the diagnosis by a consultant with a good knowledge of the patient and the disease. Following diagnosis, the patient and relatives/carers should receive regular support from a multidisciplinary care team. Medication with riluzole should be initiated as early as possible. Control of symptoms such as sialorrhoea, thick mucus, emotional lability, cramps, spasticity and pain should be attempted. Percutaneous endoscopic gastrostomy feeding improves nutrition and quality of life, and gastrostomy tubes should be placed before respiratory insufficiency develops. Non-invasive positive-pressure ventilation also improves survival and quality of life. Maintaining the patient's ability to communicate is essential. During the entire course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end-of-life care should be discussed early with the patient and carers, respecting the patient's social and cultural background.
© 2011 The Author(s). European Journal of Neurology © 2011 EFNS.
Matthew C Kiernan, Steve Vucic, Benjamin C Cheah, Martin R Turner, Andrew Eisen, Orla Hardiman, James R Burrell, Margaret C Zoing
Amyotrophic lateral sclerosis.
Lancet. 2011 Mar 12;377(9769):942-55. doi: 10.1016/S0140-6736(10)61156-7. Epub 2011 Feb 4.
Abstract/Text
Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease of the human motor system. In this Seminar, we summarise current concepts about the origin of the disease, what predisposes patients to develop the disorder, and discuss why all cases of ALS are not the same. In the 150 years since Charcot originally described ALS, painfully slow progress has been made towards answering these questions. We focus on what is known about ALS and where research is heading-from the small steps of extending longevity, improving therapies, undertaking clinical trials, and compiling population registries to the overarching goals of establishing the measures that guard against onset and finding the triggers for this neurodegenerative disorder.
Copyright © 2011 Elsevier Ltd. All rights reserved.
B R Brooks, R G Miller, M Swash, T L Munsat, World Federation of Neurology Research Group on Motor Neuron Diseases
El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis.
Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Dec;1(5):293-9.
Abstract/Text
Steve Vucic, Toby A Ferguson, Catherine Cummings, Michael T Hotchkin, Angela Genge, Robert Glanzman, Kasper C D Roet, Merit Cudkowicz, Matthew C Kiernan
Gold Coast diagnostic criteria: Implications for ALS diagnosis and clinical trial enrollment.
Muscle Nerve. 2021 Nov;64(5):532-537. doi: 10.1002/mus.27392. Epub 2021 Aug 24.
Abstract/Text
Diagnostic criteria for amyotrophic lateral sclerosis (ALS) are complex, incorporating multiple levels of certainty from possible through to definite, and are thereby prone to error. Specifically, interrater variability was previously established to be poor, thereby limiting utility as diagnostic enrollment criteria for clinical trials. In addition, the different levels of diagnostic certainty do not necessarily reflect disease progression, adding confusion to the diagnostic algorithm. Realizing these inherent limitations, the World Federation of Neurology, the International Federation of Clinical Neurophysiology, the International Alliance of ALS/MND Associations, the ALS Association (United States), and the Motor Neuron Disease Association convened a consensus meeting (Gold Coast, Australia, 2019) to consider the development of simpler criteria that better reflect clinical practice, and that could merge diagnostic categories into a single entity. The diagnostic accuracy of the novel Gold Coast criteria was subsequently interrogated through a large cross-sectional study, which established an increased sensitivity for ALS diagnosis when compared with previous criteria. Diagnostic accuracy was maintained irrespective of disease duration, functional status, or site of disease onset. Importantly, the Gold Coast criteria differentiated atypical phenotypes, such as primary lateral sclerosis, from the more typical ALS phenotype. It is proposed that the Gold Coast criteria should be incorporated into routine practice and clinical trial settings.
© 2021 Wiley Periodicals LLC.
横山徹爾, 土井由利子:平成20年患者調査による難病の受療状況データブック．平成22年度厚生労働科学研究費補助金難治性疾患克服研究事業特定疾患の疫学に関する研究班（研究代表者：永井正規）, 2011.
荻野美恵子：ALSにおける倫理的・社会的問題．神経治療学.2005;22：741‐745.
Tameko Kihira, Sohei Yoshida, Masaya Hironishi, Hideto Miwa, Kazusi Okamato, Tomoyoshi Kondo
Changes in the incidence of amyotrophic lateral sclerosis in Wakayama, Japan.
Amyotroph Lateral Scler Other Motor Neuron Disord. 2005 Sep;6(3):155-63. doi: 10.1080/14660820510030031.
Abstract/Text
In the 1960s, the incidence of amyotrophic lateral sclerosis (ALS) in the Kozagawa and Koza areas in Wakayama prefecture was much higher than that in other areas of the world. However, between 1980 and 1993, a gradual decrease in the incidence of the disease in these areas was reported. To ascertain whether the decreased incidence has persisted, we conducted a retrospective epidemiological study, and determined the average annual incidence of ALS in Wakayama prefecture from 1998 to 2002. The number of ALS cases encountered during the period was 134 (male 79, female 55). The crude average annual incidence in Wakayama prefecture in total was 2.50 (male 3.08, female 1.99) per 100,000. In the Kozagawa and Koza areas in Wakayama prefecture, where the senility rate rapidly increased in recent years, the average annual incidence of ALS in the present research was 10.56 (male 14.14, female 7.66). When the crude rate was standardized for both age and sex to the Japanese population in 1990, the expected value was 5.24 (male 7.34, female 3.18), which was lower than that of our previous survey. The prevalence in Wakayama prefecture at 31 December 2002 was 11.31 (male 14.40, female 8.53). In Kozagawa and Koza areas, the crude prevalence was 52.81 (male 70.70, female 38.28). These results indicated that the incidence of ALS in Wakayama prefecture, especially for females, steadily decreased compared to that in previous reports. However, a high incidence of ALS persisted among males in Wakayama prefecture, especially in the Kozagawa and Koza areas. Some environmental factors and gender specificity may be related to the decreased incidence of ALS in focus areas.
Yuriko Doi, Testuji Yokoyama, Toshiro Tango, Kunihiko Takahashi, Kenichi Fujimoto, Imaharu Nakano
Temporal trends and geographic clusters of mortality from amyotrophic lateral sclerosis in Japan, 1995-2004.
J Neurol Sci. 2010 Nov 15;298(1-2):78-84. doi: 10.1016/j.jns.2010.08.004.
Abstract/Text
The present study examined temporal trends and geographic clustering of amyotrophic lateral sclerosis (ALS) mortality in Japan, during 1995-2004, using vital statistics based on death certificates. ALS was usually diagnosed by neurologists according to clinical guidelines that complied with the El Escorial Criteria. The underlying cause of death for ALS was coded as G12.2A. Regression analysis was used to examine temporal trends. Spatial scan statistic was used to detect any area of elevated risk as a cluster. A total of 12,173 (6864 male and 5309 female) ALS deaths were reported. Annual crude mortality rate per 100,000 population was 1.07 (1.26 for males and 0.89 for females) in 2004. Although the overall temporal trend was stable, the trend increased in the 70+ years age group (p for trend, <0.001 in males and <0.05 in females), while it declined in the under 70 years age group (p for trend, <0.01 for both sexes). Male preponderance and M/F ratio remained nearly constant over time. Three clusters were detected: two (p<0.005 in males and p<0.05 in females) in northeast and one (p<0.05 in males) in west-central Japan. Further research is needed to clarify contributing factors for the observed trends and clusters in ALS mortality.
Copyright © 2010 Elsevier B.V. All rights reserved.
Benoît Marin, Philippe Couratier, Pierre-Marie Preux, Giancarlo Logroscino
Can mortality data be used to estimate amyotrophic lateral sclerosis incidence?
Neuroepidemiology. 2011;36(1):29-38. doi: 10.1159/000321930. Epub 2010 Nov 17.
Abstract/Text
BACKGROUND: Because studies of the incidence of amyotrophic lateral sclerosis (ALS) have uncertain feasibility and high costs, mortality rates are often used to provide an estimate. We performed a systematic review of the literature concerning mortality related to ALS. We aimed to use well-known criteria of good epidemiological practice to assess the methodological quality of the studies.
METHODS: A Medline and ScienceDirect literature search was performed to identify studies on ALS mortality published from 1971 to 2009. The literature was examined following 6 criteria.
RESULTS: Of the 29 studies examined, almost all presented a clear definition of the population at risk, but 55% of the papers did not report on the accuracy of death certificates, and the use of both 'underlying' and 'contributory' causes of death was identified in only 41% of cases. When comparing ALS mortality data between calendar dates, the codes from the International Classification of Diseases were consistent overall, except in 3 studies. A majority of articles that compared mortality patterns between geographical regions or ethnic groups discussed the key issues of comparability of health care and equality of access. Overall, among the 29 ALS mortality studies, only 3 complied with all the criteria. In 2 of them, the mortality rates were highly consistent with available incidence data.
CONCLUSION: Only few studies on mortality data followed a high-quality methodology. When studies complied with the criteria, they showed good accuracy with regard to incidence rates. The criteria used in this study could also be used to guide future studies based on mortality data.
Copyright © 2010 S. Karger AG, Basel.
Susan Byrne, Cathal Walsh, Catherine Lynch, Peter Bede, Marwa Elamin, Kevin Kenna, Russell McLaughlin, Orla Hardiman
Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis.
J Neurol Neurosurg Psychiatry. 2011 Jun;82(6):623-7. doi: 10.1136/jnnp.2010.224501. Epub 2010 Nov 3.
Abstract/Text
BACKGROUND: The population rate of familial amyotrophic lateral sclerosis (FALS) is frequently reported as 10%. However, a systematic review and meta-analysis of the true population based frequency of FALS has never been performed.
METHOD: A Medline literature review identified all original articles reporting a rate of FALS. Studies were grouped according to the type of data presented and examined for sources of case ascertainment. A systematic review and meta-analysis of reported rates of FALS was then conducted to facilitate comparison between studies and calculate a pooled rate of FALS.
RESULTS: 38 papers reported a rate of FALS. Thirty-three papers were included in analysis and the rate of FALS for all studies was 4.6% (95% CI 3.9% to 5.5%). Restricting the analysis to prospective population based registry data revealed a rate of 5.1% (95% CI 4.1% to 6.1%). The incidence of FALS was lower in southern Europe. There was no correlation between rate of FALS and reported SOD1 mutation rates.
CONCLUSION: The rate of FALS among prospective population based registries is 5.1% (CI 4.1 to 6.1%), and not 10% as is often stated. Further detailed prospective population based studies of familial ALS are required to confirm this rate.
バーナード・ロウ:医療の倫理ジレンマ 解決への手引き―患者の心を理解するために―. 北野喜良、中澤英之、小宮良輔監訳. 西村書店 .2003.
筋萎縮性側索硬化症患者の意向の尊重とケア（事前指示）に関する検討中間報告. 厚生労働科学研究費補助金難治性疾患克服研究事業「特定疾患患者の自立支援体制の確立に関する研究」班. 2011.
吉良潤一編：難病医療専門員による難病患者のための難病相談ガイドブック（改訂2版）. 九州大学出版会. 2011.
Mamede De Carvalho, Michael Swash
Awaji diagnostic algorithm increases sensitivity of El Escorial criteria for ALS diagnosis.
Amyotroph Lateral Scler. 2009 Feb;10(1):53-7. doi: 10.1080/17482960802521126.
Abstract/Text
We have tested the sensitivity of a recently published approach to combining clinical and EMG data in the 'research diagnosis' of ALS, in 55 consecutive patients clinically diagnosed with ALS. The application of this 'Awaji algorithm' to the revised El Escorial diagnostic criteria for diagnosis of ALS achieved a diagnostic sensitivity of 95% for definite ALS compared with 18% using the clinical El Escorial criteria and 53% when the EMG criteria as defined in the El Escorial criteria, were applied to the same dataset. This increased sensitivity was particularly relevant for bulbar onset patients (sensitivity improved from 38% to 87%) and for patients with El Escorial clinically possible ALS (from 50% to 86%). We suggest that, in future, investigators and triallists should use the Awaji algorithm superimposed onto the El Escorial criteria, in selecting patients for research studies.
Maarten Schrooten, Charlotte Smetcoren, Wim Robberecht, Philip Van Damme
Benefit of the Awaji diagnostic algorithm for amyotrophic lateral sclerosis: a prospective study.
Ann Neurol. 2011 Jul;70(1):79-83. doi: 10.1002/ana.22380. Epub 2011 Mar 17.
Abstract/Text
OBJECTIVE: Early and accurate diagnosis of amyotrophic lateral sclerosis (ALS) is important for patient care and for entry in clinical trials. Retrospective studies suggest that the use of the Awaji algorithm for the diagnosis of ALS is more sensitive for early diagnosis than the currently used revised El Escorial criteria.
METHODS: We prospectively compared the revised El Escorial criteria with the Awaji algorithm in patients seen with suspected ALS at the University Hospitals Leuven between January 2008 and April 2010.
RESULTS: Out of 200 patients referred for the diagnosis of ALS, 66% and 85% could be categorized to definite or probable ALS at first presentation according to the revised El Escorial and the Awaji algorithm, respectively (p < 5.6 × 10(-17) ). This corresponds to a >50% reduction of patients not eligible for clinical trial entry. Application of the Awaji algorithm made the diagnosis of ALS more likely by at least 1 diagnostic category in 25.7% of patients and identified at least 1 additional region with electrodiagnostic signs of ongoing lower motor neuron loss in 46.4% of electrodiagnostic investigations. Application of the Awaji algorithm did not result in a single false-positive diagnosis of ALS in this study.
INTERPRETATION: Our data demonstrate that the Awaji algorithm is significantly more sensitive compared to the revised El Escorial criteria, without resulting in false-positive diagnoses of ALS. It should therefore be used in clinical trials.
Copyright © 2011 American Neurological Association.
Yu-ichi Noto, Sonoko Misawa, Kazuaki Kanai, Kazumoto Shibuya, Sagiri Isose, Saiko Nasu, Yukari Sekiguchi, Yumi Fujimaki, Masanori Nakagawa, Satoshi Kuwabara
Awaji ALS criteria increase the diagnostic sensitivity in patients with bulbar onset.
Clin Neurophysiol. 2012 Feb;123(2):382-5. doi: 10.1016/j.clinph.2011.05.030. Epub 2011 Jul 20.
Abstract/Text
OBJECTIVE: To assess whether Awaji criteria improve the sensitivity of diagnosis for amyotrophic lateral sclerosis (ALS). In Awaji ALS criteria, fasciculation potentials are regarded as evidence of acute denervation in the presence of chronic neurogenic changes on needle electromyography.
METHODS: We reviewed clinical and neurophysiological data of 113 consecutive patients who were suspected as suffering ALS. The six muscles (trapezius, biceps, first dorsal interosseous, T10-paraspinalis, vastus lateralis, and tibialis anterior muscles) were examined by EMG, focusing on the presence of fasciculation potentials. The sensitivity of revised El Escorial (R-EEC) and Awaji criteria was compared.
RESULTS: Probable or definite ALS was diagnosed in 61% of the patients by R-EEC and 71% by Awaji criteria. By applying Awaji criteria; (1) 17 of the 44 patients categorized as possible ALS by R-EEC reached to probable/definite ALS, 11 of whom had bulbar onset, (2) in 48 patients with bulbar onset, the proportion of probable/definite ALS increased from 59% to 82%, (3) in 62 patients with limb onset, the proportion of probable/definite ALS was 61% (63% by R-EEC).
CONCLUSIONS: Awaji criteria improve the sensitivity of ALS diagnosis in patients with bulbar onset, but not in those with limb onset.
SIGNIFICANCE: Accepting fasciculation potentials as evidence of acute denervation increases the diagnostic sensitivity of ALS, particularly in patients with bulbar onset, and contributes to early diagnosis.
Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
G M Ringholz, S H Appel, M Bradshaw, N A Cooke, D M Mosnik, P E Schulz
Prevalence and patterns of cognitive impairment in sporadic ALS.
Neurology. 2005 Aug 23;65(4):586-90. doi: 10.1212/01.wnl.0000172911.39167.b6.
Abstract/Text
OBJECTIVE: To investigate the prevalence and nature of cognitive changes associated with sporadic amyotrophic lateral sclerosis (ALS) using a large scale study.
METHODS: Consecutive patients with sporadic ALS (n = 279) underwent comprehensive neurologic evaluation and neuropsychological testing. Testing data from normal controls (n = 129) were used for classification and comparison purposes.
RESULTS: On non-motor, non-speed-dependent tasks, 51% of patients with ALS had evidence of cognitive impairment compared to 5% of controls. Cluster analysis suggested four patient subgroups: 49% intact, 32% with mild impairment, 13% with moderate impairment, and 6% with severe impairment. Forty-one patients (15%) met criteria for frontotemporal dementia (FTD). ALS patient subgroups, excluding the intact group, performed significantly lower on tests of executive function and memory than normal controls. Patients with more severe disease also had deficits in confrontation naming. Although memory function declined with increasing severity of overall cognitive impairment, only two patients had the severe memory loss typical of Alzheimer disease. Cognitive impairment was correlated with clinical measures of word-finding, phrase length, and motor programming. Cognitive impairment was not correlated with depression scores or severity or duration of motor or bulbar symptoms. Patients with bulbar vs limb-onset ALS were not different in either level of impairment or pattern of performance.
CONCLUSIONS: These data confirm the presence of cognitive impairment in 50% of patients with ALS and particularly implicate executive dysfunction and mild memory decline in the disease process. More severe impairment occurs in a subset of patients with ALS and has features consistent with FTD.
M Witgert, A R Salamone, A M Strutt, A Jawaid, P J Massman, M Bradshaw, D Mosnik, S H Appel, P E Schulz
Frontal-lobe mediated behavioral dysfunction in amyotrophic lateral sclerosis.
Eur J Neurol. 2010 Jan;17(1):103-10. doi: 10.1111/j.1468-1331.2009.02801.x. Epub 2009 Oct 29.
Abstract/Text
BACKGROUND: Cognitive impairment secondary to frontal lobe atrophy exists in 40-60% of Amyotrophic Lateral Sclerosis (ALS) cases. We aimed to determine the prevalence of frontal-lobe mediated behavioral impairment in (ALS) and to ascertain its relationship to cognitive impairment.
METHODS: Two-hundred and twenty five patients diagnosed with sporadic ALS were evaluated for behavioral dysfunction using the Frontal Systems Behavior Scale (FrSBe), a validated measure used to examine frontal-lobe mediated behaviors, specifically apathy, executive dysfunction and disinhibition; a total behavior score is also provided. Additionally, a subset of patients also underwent a comprehensive neuropsychological evaluation.
RESULTS: Changes in the total FrSBe scores were observed in 24.4% of the patients and 39.6% of the patients had impairment in at least one behavioral domain with symptoms of Apathy being the most common (31.1%). Cognitively impaired ALS patients had worse total (P = 0.05) and apathy scores (P < 0.01); however, behavioral dysfunction was also present in 16% of the cognitively intact patients. Half of the behaviorally intact patients exhibited cognitive impairment. Significant correlations were observed for performance on certain neuropsychological tests (Animal fluency, Block Design, Logical Memory I and Verbal Series Attention Test) and severity of behavioral dysfunction on certain FrSBe sub scores.
CONCLUSIONS: Frontal-lobe mediated behavioral dysfunction appears to be common in ALS. Cognitively impaired ALS patients had greater behavioral dysfunction. Recognition of behavioral and cognitive dysfunction may assist health-care providers and care-givers recognize changes in decision-making capacity and treatment compliance of patients with ALS.
C Lomen-Hoerth, J Murphy, S Langmore, J H Kramer, R K Olney, B Miller
Are amyotrophic lateral sclerosis patients cognitively normal?
Neurology. 2003 Apr 8;60(7):1094-7.
Abstract/Text
BACKGROUND: Patients with ALS are often told that the disease spares cognition; however, recent evidence suggests deficits in frontal executive skills occur in a sizable minority of ALS patients. In many instances, the frontal executive deficits represent the co-occurrence of frontotemporal lobar dementia (FTLD) and ALS.
METHODS: Word generation, a simple frontal task that takes <2 minutes, was tested in 100 consecutive patients with ALS seen in the authors' multidisciplinary clinic. Any patient with a prior dementia diagnosis was excluded from the study. A subset of 44 patients agreed to undergo further neuropsychological testing and clinical interview to confirm or deny a diagnosis of dementia.
RESULTS: Diminished word generation was found in one-third. Of the patients with abnormal word generation who agreed to further evaluation, nearly all were shown to meet research criteria for FTLD. In addition, one-quarter of the patients with normal word generation who agreed to further evaluation met research criteria for FTLD; these patients had new-onset personality changes.
CONCLUSIONS: This study suggests that frontal executive deficits are present in half of ALS patients, many of whom meet strict research criteria for FTLD. Word generation tests are a useful screening tool in this cohort.
Joost Raaphorst, Marianne de Visser, Marie-José van Tol, Wim H J P Linssen, Anneke J van der Kooi, Rob J de Haan, Leonard H van den Berg, Ben Schmand
Cognitive dysfunction in lower motor neuron disease: executive and memory deficits in progressive muscular atrophy.
J Neurol Neurosurg Psychiatry. 2011 Feb;82(2):170-5. doi: 10.1136/jnnp.2009.204446. Epub 2010 Jun 18.
Abstract/Text
AIM: In contrast with findings in amyotrophic lateral sclerosis (ALS), cognitive impairments have as yet not been shown in the lower motor neuron variant of motor neuron disease, progressive spinal muscular atrophy (PMA). The objective of this study was to investigate cognitive function in PMA and to compare the cognitive profile with that of ALS. In addition, visuospatial functions were assessed comprehensively; these tests are underrepresented in earlier neuropsychological investigations in ALS.
METHODS: 23 PMA and 30 ALS patients (vital capacity >70% of predicted value) underwent a neuropsychological assessment adapted to motor impairments: global cognitive and executive functioning, psychomotor speed, memory, language, attention and visuospatial skills. The results were compared with age, education and sex matched controls and with normative data.
RESULTS: Compared with controls, PMA patients performed worse on attention/working memory (digit span backward), category fluency and the Mini-Mental State Examination. Compared with normative data, PMA patients most frequently showed impairment on three measures: letter-number sequencing, and immediate and delayed story recall. 17% of PMA patients showed cognitive impairment, defined as performance below 2 SDs from the mean of normative data on at least three neuropsychological tests. In ALS, similar but more extensive cognitive deficits were found. Visuospatial dysfunction was not found in PMA and ALS.
CONCLUSIONS: 17% of PMA patients have executive and memory impairments. PMA with cognitive impairment adds a formerly unknown phenotype to the existing classification of motor neuron diseases.
Laurie E Sterling, Ali Jawaid, Alicia R Salamone, Santosh B Murthy, Diane M Mosnik, Emily McDowell, Michael Wheaton, Adriana M Strutt, Ericka Simpson, Stanley Appel, Paul E Schulz
Association between dysarthria and cognitive impairment in ALS: A prospective study.
Amyotroph Lateral Scler. 2010;11(1-2):46-51. doi: 10.3109/17482960903207997.
Abstract/Text
Several studies have demonstrated impaired cognition in amyotrophic lateral sclerosis (ALS) patients, but it has been difficult to identify risk factors for this impairment. An association between cognitive changes and bulbar site of onset or dysarthria has been suggested, but the findings are variable. We tested for both associations in a large cohort of ALS patients. At the time of diagnosis of sporadic ALS, all patients (n=355) in this prospective study underwent comprehensive neuropsychological testing. In addition, a subset of 175 patients underwent a detailed assessment of dysarthria, which was quantified using the Appel ALS Score (AALSS). ALS patients with bulbar site of onset performed significantly worse than limb onset patients on a few timed ((VSAT-time, p<0.05), (Stroop Color, p<0.05), (Stroop Word, p<0.05)) tests of frontal lobe functions, but the significance could not be replicated when motor impairment was accommodated into the tests ((VSAT-errors, p=0.73), (Stroop interference, p=0.08)). ALS patients with dysarthria performed significantly worse than non-dysarthrics on multiple timed ((BD, p<0.05), (VSAT-time, p<0.05), (Stroop Color, p<0.05), (Stroop Word, p<0.05), (Trails A, p<0.05), (Trails B, p<0.05)) neuropsychological tests, and the significance was maintained when motor impairment was accommodated into one of these tests (Stroop interference, p<0.05). Additionally, dysarthrics performed significantly worse on two untimed measures of cognition ((Similarities, p<0.05), (Rey Copy, p<0.05)). Cognitive functioning in ALS does not associate with the site of onset and has a moderate association with dysarthria.
Ian Ra Mackenzie, Rosa Rademakers, Manuela Neumann
TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia.
Lancet Neurol. 2010 Oct;9(10):995-1007. doi: 10.1016/S1474-4422(10)70195-2.
Abstract/Text
Abnormal intracellular protein aggregates comprise a key characteristic in most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The seminal discoveries of accumulation of TDP-43 in most cases of ALS and the most frequent form of FTD, frontotemporal lobar degeneration with ubiquitinated inclusions, followed by identification of FUS as the novel pathological protein in a small subset of patients with ALS and various FTD subtypes provide clear evidence that these disorders are related. The creation of a novel molecular classification of ALS and FTD based on the identity of the predominant protein abnormality has, therefore, been possible. The striking functional and structural similarities of TDP-43 and FUS, which are both DNA/RNA binding proteins, imply that abnormal RNA metabolism is a pivotal event, but the mechanisms leading to TDP-43 and FUS accumulation and the resulting neurodegeneration are currently unknown. Nonetheless, TDP-43 and FUS are promising candidates for the development of novel biomarker assays and targeted therapies.
Copyright © 2010 Elsevier Ltd. All rights reserved.
Yasuhiro Watanabe, Mieko Ogino, Hiroo Ichikawa, Ritsuko Hanajima, Kenji Nakashima
The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) for Japanese ALS and FTD patients.
Amyotroph Lateral Scler Frontotemporal Degener. 2021 Feb;22(1-2):66-72. doi: 10.1080/21678421.2020.1801751. Epub 2020 Aug 6.
Abstract/Text
OBJECTIVE: Amyotrophic lateral sclerosis (ALS) patients might present with cognitive and behavioural abnormalities resembling frontotemporal dementia (FTD). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was developed as an easy to administer cognitive screen for detecting these symptoms. The aim of the present study was to develop and validate a Japanese version of the ECAS.
METHODS: In this single centre observational study, 35 ALS patients and 28 healthy controls were enrolled. Three patients in the ALS group fulfilled the criteria for behavioural variant FTD (ALS-FTD) and the rest were grouped as ALS without FTD. Participants were subjected to the Japanese version of the ECAS. ALS patients were also subjected to the Montreal Cognitive Assessment, Frontal Assessment Battery, ALS Functional Rating Scale-Revised, and respiratory function testing. Demographic and disease characteristics (e.g., sex, age at examination, and years of education) were also recorded.
RESULTS: Internal consistency and correlations with general cognitive screenings were sufficient in the Japanese adaptation. Executive functions were the most commonly affected ECAS domain, followed by fluency and language. Compared to control subjects, ALS patients without FTD had low scores in the ECAS ALS-specific functions but not in ALS-nonspecific functions. Meanwhile ALS-FTD patients markedly underperformed both in the ECAS ALS-specific and ALS-nonspecific functions. Furthermore, the Japanese ECAS score correlated positively with years of education and negatively with age at onset.
CONCLUSION: The Japanese version of the ECAS is a valid and useful screening tool to identify multiple types of cognitive impairment in ALS patients.
水町真知子, 若林佑子, 川上純子, 吉本佳預子：筋萎縮性側索硬化症のインフォームド・コンセント ALSとともに生きる人から見た現状と告知のあり方医療 2002；56（6）：338-343.
（荻野美恵子、荻野裕、川浪文、坂井文彦：ALSの告知のありかたについて―患者アンケート調査より―. 第44回日本神経学会総会 2003 (臨床神経学2003;43:1027)）.
G D Borasio, R Sloan, D E Pongratz
Breaking the news in amyotrophic lateral sclerosis.
J Neurol Sci. 1998 Oct;160 Suppl 1:S127-33.
Abstract/Text
Telling the diagnosis to patients with amyotrophic lateral sclerosis (ALS) is a daunting task for any neurologist. Obviously, breaking the news in ALS is not a standardizable procedure. However, proven techniques exist to reduce the trauma to the patient and ease the burden on the doctor, thus reducing the risk of burnout and the tendency to 'pull away' from the patient. Such communication skills are of fundamental importance to clinical practice and should be more prominent in medical teaching. The way the patient is told the diagnosis is now recognized to be the first and one of the most delicate steps in palliative care. Information is best offered in a stepwise fashion at the patient's pace with an emphasis on positive aspects, and in the presence of the patient's family. Reviewing available therapeutic options and current research efforts may foster hope for the future, while pointing out that almost all symptoms of ALS can be alleviated by palliative therapy may help to reduce fears. Encouraging patients to ask questions and disclose anxieties is important for their psychological wellbeing. Available options for mechanical ventilation should be reviewed early enough to allow for unhurried decision-making. We believe that the terminal phase of the disease should be discussed at the latest when dyspneic symptoms appear, in order to prevent unwarranted fears of 'choking to death'.
Leo McCluskey, David Casarett, Andrew Siderowf
Breaking the news: a survey of ALS patients and their caregivers.
Amyotroph Lateral Scler Other Motor Neuron Disord. 2004 Sep;5(3):131-5. doi: 10.1080/14660820410020772.
Abstract/Text
Breaking the news of the diagnosis of amyotrophic lateral sclerosis (ALS) is a formidable task. To evaluate the process from the perspective of patients and caregivers, we surveyed 94 patient-caregiver pairs, as well as 50 unpaired patients and 19 unpaired caregivers. We asked respondents to evaluate the physician who first broke the news of the diagnosis based on the time spent discussing the diagnosis, and six attributes of effective communication of bad news derived from the SPIKES protocol (setting, perception, invitation, knowledge, empathy, strategy). Fifty-six percent of patients rated the way the physician who broke the news as average (30.7), below average (8.6) or poor (16.4). Forty-eight percent of caregivers rated the physician as poor (14.4), below average (4.8) or average (28.8). Better performance on all attributes of effective communication as well as greater time spent discussing the diagnosis was correlated with higher patient/caregiver satisfaction. Our results suggest that there is room for improvement in breaking the news of the diagnosis of ALS. Greater adherence to certain attributes of effective communication of bad news may improve the way physicians perform this difficult task.
A Chiò, G Mora, M Leone, L Mazzini, D Cocito, M T Giordana, E Bottacchi, R Mutani, Piemonte and Valle d'Aosta Register for ALS (PARALS)
Early symptom progression rate is related to ALS outcome: a prospective population-based study.
Neurology. 2002 Jul 9;59(1):99-103.
Abstract/Text
OBJECTIVE: To define the factors related to ALS outcome in a population-based, prospective survey.
METHODS: The 221 patients (120 men and 101 women) listed in the Piemonte and Valle d'Aosta ALS Register between 1995 and 1996 were enrolled in the study. The patients were prospectively monitored with a standard evaluation form after diagnosis.
RESULTS: Mean age at onset was 62.8 (SD = 11.2) years. According to El Escorial diagnostic criteria (EEDC), 112 patients had definite ALS, 85 probable ALS, 18 possible ALS, and six suspected ALS. The median survival time from symptom onset was 915 days (95% CI = 790 to 1065). The median survival time from diagnosis was 580 days (95% CI = 490 to 670). In univariate analysis, outcome was significantly related to age, onset site, EEDC classification, and symptom progression rate (i.e., the rate of decline of muscle strength and bulbar and respiratory function in the 6 months after diagnosis). In the Cox multivariate model, age, progression rate of respiratory, bulbar, and lower limb symptoms, EEDC classification, percutaneous endoscopic gastrostomy, and treatment with riluzole were significantly related to outcome.
CONCLUSIONS: The rate of progression of symptoms in early ALS is predictive of disease outcome.
B J Traynor, M B Codd, B Corr, C Forde, E Frost, O M Hardiman
Clinical features of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria: A population-based study.
Arch Neurol. 2000 Aug;57(8):1171-6.
Abstract/Text
BACKGROUND: The El Escorial and the revised Airlie House diagnostic criteria for amyotrophic lateral sclerosis (ALS) classify patients into categories reflecting different levels of diagnostic certainty. We conducted a prospective, population-based study of the natural course of ALS in the Republic of Ireland during a 6-year period to examine the utility of these ALS diagnostic criteria.
METHODS: Using data from the Irish ALS Register, we studied the clinical features of all patients diagnosed as having ALS in Ireland throughout their illness.
RESULTS: Between 1993 and 1998, 388 patients were diagnosed as having ALS. Forty percent of patients reported bulbar-onset symptoms. Disease progression occurred over time: at last follow-up, 75% of all patients had bulbar signs, compared with 59% at diagnosis. When the El Escorial criteria were applied, more than half of patients (218 [56%]) had definite or probable ALS at diagnosis. Of the 165 possible and suspected ALS cases at diagnosis (trial ineligible), 110 (67%) were trial eligible at last follow-up. Of the 254 patients who had died, 229 (90%) had definite or probable ALS, whereas 25 patients (10%) remained trial ineligible at death. El Escorial category at diagnosis was not a significant prognostic indicator. Use of the Airlie House criteria had no effect on the median time from symptom onset to trial eligibility (12.9 vs 12.8 months).
CONCLUSIONS: The El Escorial and Airlie House diagnostic criteria are excessively restrictive. Furthermore, levels of diagnostic certainty cannot be used as prognostic indicators. Arch Neurol. 2000;57:1171-1176
Adriano Chiò, Andrea Calvo, Cristina Moglia, Letizia Mazzini, Gabriele Mora, PARALS study group
Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study.
J Neurol Neurosurg Psychiatry. 2011 Jul;82(7):740-6. doi: 10.1136/jnnp.2010.235952. Epub 2011 Mar 14.
Abstract/Text
BACKGROUND: Different amyotrophic lateral sclerosis (ALS) phenotypes have been recognised, marked by a varying involvement of spinal and bulbar upper and lower motor neurons. However, the differential characteristics of these phenotypes are still largely unknown.
OBJECTIVE: To define the epidemiology and outcome of ALS phenotypes in a population based setting.
METHODS: All ALS cases incident in two Italian regions were prospectively collected from 1995 to 2004 in an epidemiological register. Cases were classified according to established ALS phenotypes: classic, bulbar, flail arm, flail leg, pyramidal, respiratory, pure lower motor neuron (PLMN) and pure upper motor neuron (PUMN).
RESULTS: ALS phenotype were determined in 1332 out of 1351 incident patients (98.6%). Classic and bulbar phenotypes had similar mean annual incidence rates. Gender specific incidence rates showed a male preponderance in respiratory, flail arm, classic and PLMN phenotypes; in all other phenotypes, men and women had similar incidence rates. Age at onset was significantly lower in pyramidal, PLMN and PUMN phenotypes and higher in the bulbar phenotype. The best outcomes were observed in PUMN, pyramidal, PLMN and flail arm phenotypes and the worst in respiratory and bulbar phenotypes.
CONCLUSIONS: Our epidemiological findings suggest that ALS phenotypes carry distinctive and easily distinguishable clinical and prognostic characteristics, strongly related to a complex interplay between gender and age. The categorisation of ALS patients according to more homogenous clinical groups is relevant in identifying biological markers for ALS and should be considered for the design of clinical trials.
B Marin, J C Desport, P Kajeu, P Jesus, B Nicolaud, M Nicol, P M Preux, P Couratier
Alteration of nutritional status at diagnosis is a prognostic factor for survival of amyotrophic lateral sclerosis patients.
J Neurol Neurosurg Psychiatry. 2011 Jun;82(6):628-34. doi: 10.1136/jnnp.2010.211474. Epub 2010 Nov 19.
Abstract/Text
OBJECTIVES: The aims were to analyse changes in nutritional parameters from diagnosis of amyotrophic lateral sclerosis (ALS) to death and to assess their relationships with survival at the time of diagnosis and during follow-up.
METHODS: 92 ALS patients were included and clinically assessed every 3 months (ALS functional rating scale, manual muscular testing, forced vital capacity, weight, BMI, percentage weight loss). Bioimpedance was performed to evaluate body composition (fat-free mass, fat mass and hydration status) and phase angle. Survival analyses were performed from diagnosis to death or censoring date using a Cox model.
RESULTS: The evolution of nutritional parameters in ALS patients was marked by significant decreases in weight, BMI, fat-free mass and phase angle, and increased fat mass. The authors identified an adjusted 30% increased risk of death for a 5% decrease from usual weight at time of diagnosis (RR 1.30; 95% CI 1.08 to 1.56). During follow-up, the authors identified adjusted 34% (95% CI 18% to 51%) and 24% (95% CI 13% to 36%) increased risks of death associated with each 5% decrease in usual weight and each unit decrease in usual BMI, respectively (p<0.0001). Malnutrition during the course was related to a shorter survival (p=0.01), and fat mass level was associated with a better outcome (RR 0.90 for each 2.5 kg fat mass increment).
CONCLUSIONS: Nutritional parameters of ALS patients worsened during evolution of the disease, and worse nutritional status (at time of diagnosis or during the course) was associated with a higher mortality. This study offers some justification for studying the use of therapeutic nutritional intervention to modify the survival of ALS patients.
Chieko Fujimura-Kiyono, Fumiharu Kimura, Simon Ishida, Hideto Nakajima, Takafumi Hosokawa, Masakazu Sugino, Toshiaki Hanafusa
Onset and spreading patterns of lower motor neuron involvements predict survival in sporadic amyotrophic lateral sclerosis.
J Neurol Neurosurg Psychiatry. 2011 Nov;82(11):1244-9. doi: 10.1136/jnnp-2011-300141. Epub 2011 Sep 15.
Abstract/Text
OBJECTIVE: To define patterns of spread through the order of lower motor neuron involvement (first, second or third order), relationships between interval or sites of affected areas from onset to involvement of a second region, and prognosis, including 5 year survival, normal preservation of motor function at onset of respiratory symptoms and cumulative occurrence of each region and direction of spread.
METHOD: 150 patients with sporadic amyotrophic lateral sclerosis (ALS) underwent follow-up at 3 month intervals until the appearance of respiratory symptoms. Symptom appearances were determined using the revised version of the ALS Functional Rating Scale.
RESULT: Median survival with combined type onset (two regions simultaneously) was shorter (18 months) than with bulbar onset (26 months, p=0.01). The interval from onset to involvement of the second region correlated significantly with survival, independent of particular combinations. 5 year survival rate was 21% for lower limb onset, 18% for upper limb onset and 16% for bulbar onset. No patient with a rapid spread pattern (two regions within 3 months from onset) survived >5 years. Early manifestations of bulbar symptoms within 1 year were associated with worse survival (p<0.001) although no significant difference in survival was seen between groups with and without bulbar symptoms (p=0.51). In terms of cumulative occurrence, symptoms spread longitudinally to adjacent regions. Bulbar function remained preserved in 27%, lower limb function in 10% and upper limb function in 2.7%.
CONCLUSION: The interval between onset and involvement of the second region is an important predictor of survival. The data support the contiguous anatomical propagation of lower motor neuron involvement in sporadic ALS.
Martin R Turner, Alice Brockington, Jakub Scaber, Hannah Hollinger, Rachael Marsden, Pamela J Shaw, Kevin Talbot
Pattern of spread and prognosis in lower limb-onset ALS.
Amyotroph Lateral Scler. 2010 Aug;11(4):369-73. doi: 10.3109/17482960903420140.
Abstract/Text
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.
R K Olney, J Murphy, D Forshew, E Garwood, B L Miller, S Langmore, M A Kohn, C Lomen-Hoerth
The effects of executive and behavioral dysfunction on the course of ALS.
Neurology. 2005 Dec 13;65(11):1774-7. doi: 10.1212/01.wnl.0000188759.87240.8b.
Abstract/Text
OBJECTIVE: To determine whether patients with ALS-frontotemporal lobar dementia (FTLD) have a shorter survival and are less compliant with recommended treatments than those with ALS who have normal executive and behavioral function (classic ALS).
METHODS: Survival analysis from ALS symptom onset to death included 81 of 100 consecutive patients who could be classified definitely as ALS with abnormal executive or behavioral function or as classic ALS. Criteria were defined for compliance with noninvasive positive-pressure ventilation (NPPV) and percutaneous endoscopic gastrostomy (PEG).
RESULTS: Median survival was 2 years 4 months for the 28 patients with FTLD and 3 years 3 months for the 53 patients with classic ALS (relative hazard for death 1.93, CI 1.09 to 3.43; p = 0.024). However, the relative hazard associated with FTLD (1.49) in the multivariate model was diminished by the association of FTLD with bulbar onset and older age and was not significant in this sample size. With bulbar onset, median survival was 2 years 0 months for the 14 with ALS-FTLD and 2 years 10 months for the 10 with classic ALS (relative hazard for death 2.78, CI 1.02 to 7.55; p = 0.045), and older age was not a significant risk. Noncompliance with NPPV and PEG were 75% and 72% in ALS-FTLD, respectively, vs 38% and 31% in classic ALS (relative risks 2.00 and 2.34; p = 0.013 and 0.022).
CONCLUSIONS: Survival is significantly shorter among patients with ALS-FTLD than with classic ALS. Furthermore, patients with ALS-FTLD are twice as likely to be noncompliant.
Ryoichi Nakamura, Naoki Atsuta, Hazuki Watanabe, Akihiro Hirakawa, Hirohisa Watanabe, Mizuki Ito, Jo Senda, Masahisa Katsuno, Fumiaki Tanaka, Yuishin Izumi, Mitsuya Morita, Kotaro Ogaki, Akira Taniguchi, Ikuko Aiba, Koichi Mizoguchi, Koichi Okamoto, Kazuko Hasegawa, Masashi Aoki, Akihiro Kawata, Koji Abe, Masaya Oda, Masaaki Konagaya, Takashi Imai, Masanori Nakagawa, Shoji Tsuji, Ryuji Kaji, Imaharu Nakano, Gen Sobue
Neck weakness is a potent prognostic factor in sporadic amyotrophic lateral sclerosis patients.
J Neurol Neurosurg Psychiatry. 2013 Dec;84(12):1365-71. doi: 10.1136/jnnp-2013-306020. Epub 2013 Aug 9.
Abstract/Text
OBJECTIVE: To clarify the emergence of muscle weakness in regions of the body that affect survival, and deterioration in activities of daily living (ADL) in amyotrophic lateral sclerosis (ALS) patients.
METHODS: We conducted a multicentre-based prospective cohort study of patients with ALS. We enrolled 401 sporadic patients with ALS. Death or the introduction of invasive ventilation was defined as the primary endpoint, and the time to five clinical markers of ADL deterioration associated with bulbar paralysis or limb weakness were defined as ADL milestones. Muscle weakness was assessed in the neck flexor muscles; the bilateral abductors of the shoulders; the bilateral wrist extensor muscles; the bilateral flexor muscles of the hips; and the bilateral ankle dorsiflexion muscles. We performed Cox proportional hazards regression analyses for the primary endpoint and the five ADL milestones, adjusting for known covariate prognostic factors for ALS.
RESULTS: The Medical Research Council (MRC) score for the neck flexors was the most significant prognostic factor for the primary endpoint (HR 0.74, p<0.001), loss of speech (HR 0.66, p<0.001), and loss of swallowing function (HR 0.73, p<0.001), and was one of the significant prognostic factors for loss of upper limb function, difficulty turning in bed, and loss of walking ability (p=0.001, 0.002, and 0.008, respectively). The MRC score for the neck flexors was also a significant prognostic factor for covariates of the previously reported prognostic factors.
CONCLUSIONS: Neck weakness is an independent prognostic factor for survival and deterioration in ADL in Patients with ALS.
G Bensimon, L Lacomblez, V Meininger
A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group.
N Engl J Med. 1994 Mar 3;330(9):585-91. doi: 10.1056/NEJM199403033300901.
Abstract/Text
BACKGROUND: Amyotrophic lateral sclerosis is a progressive motor neuron disease for which there is no adequate treatment. Some research suggests that the excitatory amino acid neurotransmitter glutamate may be involved in the pathogenesis.
METHODS: To evaluate the efficacy and safety of the antiglutamate agent riluzole, we conducted a prospective, double-blind, placebo-controlled trial in 155 outpatients with amyotrophic lateral sclerosis. The dose of riluzole was 100 mg per day. Randomization was stratified according to the site of disease onset (the bulbar region or the limbs). The primary end points were survival and rates of change in functional status. The main secondary end point was change in muscle strength. Analyses were undertaken after 12 months of treatment and at the end of the placebo-controlled period (median follow-up, 573 days).
RESULTS: After 12 months, 45 of 78 patients (58 percent) in the placebo group were still alive, as compared with 57 of 77 patients (74 percent) in the riluzole group (P = 0.014). For patients with bulbar-onset disease, one-year survival rates were 35 percent (6 of 17) with placebo and 73 percent (11 of 15) with riluzole (P = 0.014), whereas for those with limb-onset disease one-year survival was 64 percent and 74 percent, respectively (P = 0.17). The survival advantage with riluzole was smaller (37 percent [29 of 78] with placebo vs. 49 percent [38 of 77] with riluzole) at the end of the placebo-controlled period, but it remained significant in the overall population (P = 0.046) as well as in the patients with bulbar-onset disease (18 percent [3 of 17] vs. 53 percent [8 of 15], P = 0.013). The deterioration of muscle strength was significantly slower in the riluzole group than in the placebo group (P = 0.028). Adverse reactions to riluzole included asthenia, spasticity, and mild elevations in aminotransferase levels. Twenty-seven patients in the riluzole group withdrew from the study, as compared with 17 in the placebo group.
CONCLUSIONS: The antiglutamate agent riluzole appears to slow the progression of amyotrophic lateral sclerosis, and it may improve survival in patients with disease of bulbar onset.
L Lacomblez, G Bensimon, P N Leigh, P Guillet, V Meininger
Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II.
Lancet. 1996 May 25;347(9013):1425-31.
Abstract/Text
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive disease with no effective treatment. In an initial study, riluzole decreased mortality and slowed muscle-strength deterioration in ALS patients. We have carried out a double-blind, placebo-controlled, multicentre study to confirm those findings and to assess drug efficacy at different doses.
METHODS: 959 patients with clinically probable or definite ALS of less than 5 years' duration were randomly assigned treatment with placebo or 50 mg, 100 mg, or 200 mg riluzole daily; randomisation was stratified by centre and site of disease onset (bulbar or limb). The primary outcome was survival without a tracheostomy. Secondary outcomes were rates of change in functional measures (muscle strength, functional status, respiratory function, patient's assessments of fasciculation, cramps, stiffness, and tiredness). The primary analysis was the comparison of the 100 mg dose with placebo by intention-to-treat. Drug-effect on survival was assessed before (log-rank test) and after adjustment for known prognostic factors (Cox's model).
FINDINGS: At the end of the study, after median follow-up of 18 months, 122 (50.4%) placebo-treated patients and 134 (56.8%) of those who received 100 mg/day riluzole were alive without tracheostomy (unadjusted risk 0.79, p = 0.076; adjusted risk 0.65, p = 0.002). In the groups receiving 50 mg and 200 mg riluzole daily, 131 (55.3%) and 141 (57.8%) patients were alive without tracheostomy (relative to placebo 50 mg adjusted risk 0.76, p = 0.04; 200 mg 0.61, p = 0.0004). There was a significant inverse dose response in risk of death. No functional scale discriminated between the treatment groups. The most common adverse reactions were asthenia, dizziness, gastrointestinal disorders, and rises in liver enzyme activities; they were commonest with the 200 mg dose.
INTERPRETATION: Overall, efficacy and safety results suggest that the 100 mg dose of riluzole has the best benefit-to-risk ratio. This study confirms that riluzole is well tolerated and lengthens survival of patients with ALS.
G Bensimon, L Lacomblez, J C Delumeau, R Bejuit, P Truffinet, V Meininger, Riluzole/ALS Study Group II
A study of riluzole in the treatment of advanced stage or elderly patients with amyotrophic lateral sclerosis.
J Neurol. 2002 May;249(5):609-15. doi: 10.1007/s004150200071.
Abstract/Text
Treatment with the neuroprotective drug riluzole has previously been shown to increase the probability of survival in patients with amyotrophic lateral sclerosis. This report describes a placebo-controlled, double-blind randomised clinical trial of riluzole carried out in ALS patients with advanced stage disease or aged over 75 years. The primary objective was to enable access to treatment to patients excluded from the pivotal trial which was run in parallel. Another goal was to assess the safety of riluzole in patients with advanced-stage disease. One hundred and sixty-eight patients were included, randomised to either riluzole 50 mg b. i. d. or to placebo, and treated for eighteen months. Riluzole was well-tolerated in this patient population, and the adverse events observed were similar in nature and frequency to those observed in previously published clinical trials in patients included in pivotal trials. The study could not include enough patients to reach adequate power to detect differences in survival between the two treatment groups, and no such difference was in fact observed. In conclusion, riluzole is well-tolerated in ALS patients with advanced stage disease.
柳澤信夫，田代邦雄，東儀英夫，他:日本における筋萎縮性側索硬化症に対するRiluzoleの二重盲検比較試験．医学のあゆみ. 1997; 182(11): 851-866.
Robert G Miller, J D Mitchell, Dan H Moore
Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).
Cochrane Database Syst Rev. 2012 Mar 14;3:CD001447. doi: 10.1002/14651858.CD001447.pub3. Epub 2012 Mar 14.
Abstract/Text
BACKGROUND: Riluzole is approved for the treatment of amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest efficacy.
OBJECTIVES: To examine the efficacy of riluzole in prolonging survival and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival, and to assess the effect of riluzole upon functional health.
SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (20 April 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2), MEDLINE (1966 to April 2011), EMBASE (1980 to May 2011) and made enquiries of authors of trials, Aventis (manufacturer of riluzole) and other experts in the field.
SELECTION CRITERIA: Types of studies: randomized controlled trials
TYPES OF PARTICIPANTS: adults with a diagnosis of amyotrophic lateral sclerosis Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality with riluzole 50 mg, 100 mg and 200 mg; neurologic function, muscle strength and adverse events.
DATA COLLECTION AND ANALYSIS: One author performed data extraction and two other authors checked them. One author checked the data and entered them into the computer. The other authors verified the data entry. We obtained missing data from the trial authors whenever possible.
MAIN RESULTS: The four trials examining tracheostomy-free survival included a total of 974 riluzole-treated patients and 503 placebo-treated patients. No new randomized controlled trials were found when we updated the searches for this update in 2011. The methodological quality was acceptable and three trials were easily comparable, although one trial (169 participants) included older patients in more advanced stages of amyotrophic lateral sclerosis and one (195 participants) had multiple primary endpoints. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (hazard ratio (HR) 0.80, 95% confidence internal (CI) 0.64 to 0.99, P= 0.042) and there was no evidence of heterogeneity (P = 0.33). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P < 0.0001) and the overall treatment effect was reduced but still significant (HR 0.84, 95% CI 0.698 to 0.997, P= 0.046). This represented a 9% gain in the probability of surviving one year (49% in the placebo and 58% in the riluzole group), and increased median survival from 11.8 to 14.8 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A three-fold increase in serum alanine transferase was more frequent in riluzole-treated patients than controls (mean difference 2.62, 95% CI 1.59 to 4.31).
AUTHORS' CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.
Writing Group, Edaravone (MCI-186) ALS 19 Study Group
Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial.
Lancet Neurol. 2017 Jul;16(7):505-512. doi: 10.1016/S1474-4422(17)30115-1. Epub 2017 May 15.
Abstract/Text
BACKGROUND: In a previous phase 3 study in patients with amyotrophic lateral sclerosis (ALS), edaravone did not show a significant difference in the Revised ALS Functional Rating Scale (ALSFRS-R) score compared with placebo. Post-hoc analysis of these data revealed that patients in an early stage with definite or probable diagnosis of ALS, defined by the revised El Escorial criteria, who met a select set of inclusion criteria showed a greater magnitude of effect than did the full study population. We aimed to substantiate this post-hoc result and assess safety and efficacy of edaravone in a phase 3 trial that focused on patients with early stage ALS who met the post-hoc analysis inclusion criteria.
METHODS: In this phase 3, randomised, double-blind, parallel-group study, patients aged 20-75 years with ALS of grade 1 or 2 in the Japan ALS Severity Classification, scores of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of 80% or more, definite or probable ALS according to the revised El Escorial criteria, and disease duration of 2 years or less were recruited from 31 hospitals in Japan. Eligible patients also had a decrease of 1-4 points in the ALSFRS-R score during a 12-week observation period before randomisation. Patients meeting all criteria were then randomly assigned 1:1 to receive 60 mg intravenous edaravone or intravenous saline placebo for 6 cycles (4 weeks per cycle with 2 weeks on, 2 weeks off) for a total treatment duration of 24 weeks. In cycle 1, the study drug or placebo was administered once per day for 14 days within a 14 day period, followed by the drug-free period. In cycle 2 and thereafter, the study drug or placebo was administered for 10 days within a 14 day period, followed by a 2 week drug-free period. Participants and investigators, including those assessing outcomes, were masked to treatment allocation. The primary efficacy outcome was the change in ALSFRS-R score from the baseline to 24 weeks (or at discontinuation if this was after the third cycle) after randomisation. The primary outcome was assessed in all patients who had received at least one treatment infusion, had at least one assessment post-baseline, and reached the end of cycle 3. For patients with missing values at the end of cycle 6, data were imputed by the last observation carried forward (LOCF) method, provided the patients had completed at least cycle 3. Safety was assessed in all patients who had received at least one treatment infusion and had at least one assessment post-baseline. This trial is registered with ClinicalTrials.gov, NCT01492686.
FINDINGS: Between Nov 28, 2011, and Sept 3, 2014, we screened 213 patients, and enrolled 192 as potential participants. Of these, 137 patients completed the observation period: 69 were randomly assigned to receive edaravone, and 68 were randomly assigned to receive placebo. 68 patients taking edaravone and 66 taking placebo were included in the primary efficacy analysis. For the primary outcome, the change in ALSFRS-R score was -5·01 (SE 0·64) in the edavarone group and -7·50 (0·66) in the placebo group. The least-squares mean difference between groups was 2·49 (SE 0·76, 95% CI 0·99-3·98; p=0·0013) in favour of edaravone. Treatment-emergent adverse events were reported in 58 (84%) patients receiving edaravone and 57 (84%) patients receiving placebo. 11 (16%) patients taking edaravone and 16 (24%) taking placebo had serious adverse events, and one (1%) patient receiving edaravone and four (6%) patients receiving placebo had adverse events (one dysphagia in edaravone group and one dyspnoea, two respiratory disorder, and one rash in the placebo group) that led to withdrawal.
INTERPRETATION: Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo. There is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria.
FUNDING: Mitsubishi Tanabe Pharma Corporation.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Johannes Brettschneider, Jerome Kurent, Albert Ludolph, J Douglas Mitchell
Drug therapy for pain in amyotrophic lateral sclerosis or motor neuron disease.
Cochrane Database Syst Rev. 2008 Jul 16;(3):CD005226. doi: 10.1002/14651858.CD005226.pub2. Epub 2008 Jul 16.
Abstract/Text
BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is the most common neurodegenerative disorder of the motor system in adults. Pain in ALS is a frequent symptom especially in the later stages of disease and can have a pronounced influence on quality of life and suffering. Treatment of pain therefore should be recognised as an important aspect of palliative care in ALS.
OBJECTIVES: To systematically review the evidence for the efficacy of drug therapy in relieving pain in ALS. We also aimed to evaluate possible adverse effects associated with the different drugs and their influence on survival and quality of life.
SEARCH STRATEGY: The authors searched the following databases: the Cochrane Neuromuscular Disease Group Trials Register (October 2007), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 1), MEDLINE (January 1966 to October 2007), EMBASE (January 1980 to October 2007), CINAHL (January 1982 to October 2007), AMED (January 1985 to October 2007) and LILACS (January 1982 to October 2007). We checked the bibliographies of trials identified and contacted other disease experts to identify further published and unpublished trials.
SELECTION CRITERIA: We searched for randomised or quasi-randomised controlled trials on drug therapy for pain in amyotrophic lateral sclerosis.
DATA COLLECTION AND ANALYSIS: Data were collected using a specially designed form and analysed using the Cochrane Review Manager software.
MAIN RESULTS: No randomised or quasi-randomised controlled trials on drug therapy for pain in ALS or MND were found.
AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials about the management of pain in ALS. Further research on this important aspect of palliative care in ALS is needed. Randomised controlled trials should be initiated to determine the effectiveness of different analgesics for treatment of pain in ALS.
Shearwood McClelland, Francois A Bethoux, Nicholas M Boulis, Matthew H Sutliff, Darlene K Stough, Kathleen M Schwetz, Danuta M Gogol, Michelle Harrison, Erik P Pioro
Intrathecal baclofen for spasticity-related pain in amyotrophic lateral sclerosis: efficacy and factors associated with pain relief.
Muscle Nerve. 2008 Mar;37(3):396-8. doi: 10.1002/mus.20900.
Abstract/Text
Clinical signs and symptoms of spasticity include hypertonia, involuntary movements (spasms, clonus), decreased range of motion, contractures, and often spasm-related pain. When spasticity is refractory to medical management, patients may be referred for intrathecal baclofen (ITB) pump placement. We reviewed a cohort of amyotrophic lateral sclerosis (ALS) patients with intractable spasticity requiring ITB to further define the impact of ITB on pain relief in this patient population. From 2003 to 2005, eight patients (mean age 43.8 years; 5 men, 3 women) with ALS received ITB for pain associated with intractable spasticity at our institution. Mean disease duration preoperatively was 47.4 months, mean follow-up was 9.8 months, and pain was evaluated using a 0-10 scoring system. All patients experienced spasticity relief in response to a preoperative bolus test injection of ITB (25-50 microg) via lumbar puncture. Following ITB pump placement, the average reduction of pain was 54% (P = 0.0082). Six patients (75%) experienced pain score reduction, three of whom had complete pain relief. Postoperative pain reduction was predicted by the degree of pain reduction following preoperative ITB test injection. These results support ITB as a treatment modality for pain associated with spasticity in ALS.
Arianna Guidubaldi, Alfonso Fasano, Tamara Ialongo, Carla Piano, Maurizio Pompili, Roberta Mascianà, Luisa Siciliani, Mario Sabatelli, Anna Rita Bentivoglio
Botulinum toxin A versus B in sialorrhea: a prospective, randomized, double-blind, crossover pilot study in patients with amyotrophic lateral sclerosis or Parkinson's disease.
Mov Disord. 2011 Feb 1;26(2):313-9. doi: 10.1002/mds.23473. Epub 2011 Jan 21.
Abstract/Text
BACKGROUND: Either botulinum toxins (BoNTs) A and B have been used for improving drooling in different neurological conditions.
METHODS: Consecutive patients affected by Amyotrophic Lateral Sclerosis (ALS) or Parkinson's Disease (PD) accompanied by severe drooling were randomized to receive botulinum neurotoxin type A (BoNT-A) or B (BoNT-B) injections into the salivary glands. Following the first treatment, when sialorrhea returned to baseline (at least three months after the first injection), subjects were re-treated with the other serotype. Ultrasound-guided injections into parotid and submandibular glands were bilaterally performed: total doses were 250 U BoNT-A (Dysport) and 2500 U BoNT-B (Neurobloc). Objective (cotton roll weight) and subjective (ad hoc clinical scales) evaluations were performed at baseline, after 1 and 4 weeks, and every 4 weeks until drooling returned to baseline.
RESULTS: Twenty-seven patients (15 ALS and 12 PD) were enrolled, fourteen completed the study. BoNT-A and BoNT-B treatments gave both subjective and objective improvements in all patients. The latency was significantly shorter after BoNT-B treatments (3.2 ± 3.7 days) compared to BoNT-A (6.6 ± 4.1 days; P = 0.002). The mean benefit duration was similar at 75 and 90 days for BoNT-A and BoNT-B, respectively (P = NS). The only toxin-related side effect was a change to saliva thickness.
CONCLUSIONS: Either 250 U Dysport or 2500 U Neurobloc have similar effectiveness and safety in controlling sialorrhea. BoNT-B has a shorter latency and comparable duration. Cost analysis, considering the doses used in this study protocol favored BoNT-B treatment.
Copyright © 2010 Movement Disorder Society.
Daniele Lo Coco, Paola Mattaliano, Rossella Spataro, Alfredo Mattaliano, Vincenzo La Bella
Sleep-wake disturbances in patients with amyotrophic lateral sclerosis.
J Neurol Neurosurg Psychiatry. 2011 Aug;82(8):839-42. doi: 10.1136/jnnp.2010.228007. Epub 2011 Jan 8.
Abstract/Text
OBJECTIVE: To evaluate the frequency, severity and determinants of sleep disturbances in patients with amyotrophic lateral sclerosis (ALS).
METHODS: Information about night-time complaints was collected using a standardised questionnaire, the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale (ESS) in a group of 100 patients with ALS and in 100 control subjects matched for age and sex. Functional disability was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R). Sleep was studied by overnight polysomnography in 12 patients.
RESULTS: Fifty-nine patients with ALS and 36 controls reported sleep disturbances. The mean global PSQI score of patients with ALS was significantly higher than the control participants (6.82 ± 4.0 vs. 4.86 ± 3.2), and three of the seven components of PSQI in patients with ALS were significantly different from controls: 'sleep latency,' 'habitual sleep efficiency' and 'sleep disturbances.' The most commonly reported night-time complaints by patients with ALS were nocturia (54%), sleep fragmentation (48%) and nocturnal cramps (45%). Poor sleep was associated with decreased ALSFRS-R score, highest depression and ESS score. After a multivariate analysis, patients' disability and daytime somnolence remained significantly associated with sleep quality. Polysomnographic studies showed decreased sleep efficiency and fragmented sleep architecture.
CONCLUSION: This study demonstrated that patients with ALS have a significant poor quality of sleep, and this correlated with the severity of ALS and daytime somnolence. Increased awareness for sleep-wake problems in patients with ALS is important, as effective intervention could lead to a better management of these patients.
Benjamin Rix Brooks
Involuntary emotional expression disorder: treating the untreated.
CNS Spectr. 2007 Apr;12(4 Suppl 5):23-7.
Abstract/Text
Patients with involuntary emotional expression disorder (IEED) have impaired social and occupational functioning and there is currently no Food an Drug Administration-approved treatment. Treatment options include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), dopaminergic agents, and a combination of dextromethorphan and quinidine. Studies of monaminergic agents have typically been small and executed in single-center settings. Assessment measures generally show significant symptomatic improvements, including a reduction in the number of laughing or crying episodes and improvements in patients' clinical condition. The tolerability profiles of these agents are well defined, and include dizziness, tachycardia and QTc prolongation (TCAs), and sleep and sexual disturbances (SSRIs). The combination of dextromethorphan and quinidine has also been assessed in two large multicenter studies in patients with amyotrophic lateral sclerosis and multiple sclerosis. Compared with placebo and either agent alone, there were significant improvements in symptoms, quality of life, and relationships. The most common side effects were dizziness and nausea, and potential drug interactions with quinidine should also be considered. Choice of treatment should be evidence-based, taking into account both efficacy and tolerability.
Richard S Bedlack
Amyotrophic lateral sclerosis: current practice and future treatments.
Curr Opin Neurol. 2010 Oct;23(5):524-9. doi: 10.1097/WCO.0b013e32833c7ac2.
Abstract/Text
PURPOSE OF REVIEW: Knowledge of amyotrophic lateral sclerosis, and in particular the care of patients with it, is evolving exponentially. More than 1700 articles with the phrase 'amyotrophic lateral sclerosis' have been published in the past 2 years; these form the basis for this timely review.
RECENT FINDINGS: In part 1, I give an update on the care of patients with amyotrophic lateral sclerosis, including ways to speed diagnosis, optimal use of riluzole, multidisciplinary teams, mechanical ventilation, gastrostomy tubes, lipid-lowering agents and symptom management. Although care has become more evidence-based, there remain a number of quandaries; for these, I will provide suggestions based upon my own experience. In part 2, I identify some exciting new treatment options that are under study. These include agents designed for novel targets within motor neurons and nonneuronal cells, agents designed for specific amyotrophic lateral sclerosis subtypes and interesting new technologies. Finally, in part 3, I define current barriers to developing even better therapeutics and offer ways around them.
SUMMARY: The care of patients with amyotrophic lateral sclerosis has evolved and is now more evidence-based than ever before. Exciting new therapies are currently being tested, which may revolutionize care even further. Barriers exist, but they are surmountable.
Aleksandar Radunović, Hiroshi Mitsumoto, P Nigel Leigh
Clinical care of patients with amyotrophic lateral sclerosis.
Lancet Neurol. 2007 Oct;6(10):913-25. doi: 10.1016/S1474-4422(07)70244-2.
Abstract/Text
Although amyotrophic lateral sclerosis and its variants are readily recognised by neurologists, about 10% of patients are misdiagnosed, and delays in diagnosis are common. Prompt diagnosis, sensitive communication of the diagnosis, the involvement of the patient and their family, and a positive care plan are prerequisites for good clinical management. A multidisciplinary, palliative approach can prolong survival and maintain quality of life. Treatment with riluzole improves survival but has a marginal effect on the rate of functional deterioration, whereas non-invasive ventilation prolongs survival and improves or maintains quality of life. In this Review, we discuss the diagnosis, management, and how to cope with impaired function and end of life on the basis of our experience, the opinions of experts, existing guidelines, and clinical trials. We highlight the need for research on the effectiveness of gastrostomy, access to non-invasive ventilation and palliative care, communication between the care team, the patient and his or her family, and recognition of the clinical and social effects of cognitive impairment. We recommend that the plethora of evidence-based guidelines should be compiled into an internationally agreed guideline of best practice.
Jesús Sancho, Emilio Servera, Eusebi Chiner, Pilar Bañuls, Elia Gómez-Merino, José N Sancho-Chust, Julio Marín
Noninvasive respiratory muscle aids during PEG placement in ALS patients with severe ventilatory impairment.
J Neurol Sci. 2010 Oct 15;297(1-2):55-9. doi: 10.1016/j.jns.2010.06.022. Epub 2010 Jul 24.
Abstract/Text
UNLABELLED: Although no clear recommendations are given about when percutaneous endoscopic gastrostomy (PEG) should be placed in amyotrophic lateral sclerosis (ALS) patients, some experts underline the risk of respiratory complications when patients had severe ventilatory muscle impairment (SVMI).
AIM: To evaluate the efficacy of noninvasive ventilation (NIV) and mechanically assisted cough (MAC) to avoid respiratory complications related to PEG placement in ALS patients with SVMI.
MATERIAL AND METHODS: Prospective study including ALS patients who had chosen to have PEG placement timed by swallowing dysfunction with the aid of NIV and MAC if needed. PEG was carried out under volume-cycled NIV through a nasal mask. MAC was applied prior to and at the end of the procedure.
RESULTS: Thirty ALS patients (60.43±12.03years) were included. Prior to PEG placement: BMI 25.0±4.6kg/m(2), ALSRFS-R 19.5±5.0, Norris bulbar sub-score 15.1±6.6, %FVC 35.9±18.1%, PCF 2.3±1.2L/s, PImax -35.6±24.6cmH(2)O, and PEmax 40.5±23.9cmH(2)O. Three patients had PEG placement under tracheotomy ventilation because NIV SpO(2) was below 88%. No patient died during the procedure nor did any have respiratory complications. Survival at 1month was 100%.
CONCLUSION: Respiratory support provided by volume-cycled NIV and MAC permits successful PEG placement in most ALS patients with SVMI.
Copyright 2010 Elsevier B.V. All rights reserved.
Hans Dieter Katzberg, Michael Benatar
Enteral tube feeding for amyotrophic lateral sclerosis/motor neuron disease.
Cochrane Database Syst Rev. 2011 Jan 19;(1):CD004030. doi: 10.1002/14651858.CD004030.pub3. Epub 2011 Jan 19.
Abstract/Text
BACKGROUND: Enteral feeding (tube feeding) is offered to many people with amyotrophic lateral sclerosis/motor neuron disease experiencing difficulty swallowing (dysphagia) and maintaining adequate nutritional intake leading to weight loss.
OBJECTIVES: To examine the efficacy of percutaneous endoscopic gastrostomy placement or other tube feeding placement on: (1) survival;(2) nutritional status; (3) quality of life;(4) minor and major complications of percutaneous endoscopic gastrostomy.
SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (24 November 2009), MEDLINE (from January 1966 to September 2009), and EMBASE (from January 1980 to September 2009) for all papers on enteral tube feeding in amyotrophic lateral sclerosis/motor neuron disease. The results were screened to identify randomised controlled trials and to identify non-randomized studies that might be worthy of review and discussion. We checked references in published articles and enlisted personal communications to identify any additional references.
SELECTION CRITERIA: A priori selection criteria included randomised and quasi-randomized controlled trials evaluating the efficacy of percutaneous endoscopic gastrostomy or other feeding tube placement. Since no such trials were discovered, all prospective and retrospective controlled studies were reviewed in the 'Background' or 'Discussion' sections of the review.
DATA COLLECTION AND ANALYSIS: We independently assessed study design and extracted data. We considered the following outcomes: (1) survival rate in months (of primary interest), (2) nutritional status measured by weight change, change in body mass index, or other quantitative index of nutritional status, (3) self-perceived quality of life and (4) safety of the procedure as indicated by minor and major complications of surgical or radiological guided PEG tube insertion.
MAIN RESULTS: We found no randomised controlled trials comparing the efficacy of enteral tube feeding with those people who continued to eat orally, without enteral feeding. We summarized the results of retrospective and prospective studies in the 'Discussion' section.
AUTHORS' CONCLUSIONS: There are no randomised controlled trials to indicate whether enteral tube feeding is beneficial compared to continuation of oral feeding for any of the outcome measures. The 'best' evidence to date suggests a survival advantage for some people with amyotrophic lateral sclerosis/motor neuron disease, but these conclusions are tentative. Evidence for improved nutrition is also incomplete but tentatively favorable. Quality of life has been addressed in studies and needs more attention. Based on a number of recent non-randomized studies comparing surgical and radiographic approaches to feeding tube insertion these two procedures for PEG tube insertion appear to be equivalent.
筋萎縮性側索硬化症の包括的呼吸ケア指診－呼吸理学療法と非侵襲陽圧換気療法（NPPV）第一部; 平成19（2007）年度 研究報告書分冊. 58.
中島 孝編： ALSマニュアル決定版. 難病と在宅ケア.日本プラニングセンター,2009.
Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD, and nocturnal hypoventilation--a consensus conference report.
Chest. 1999 Aug;116(2):521-34.
Abstract/Text
Noah Lechtzin, Yanille Scott, Anne M Busse, Lora L Clawson, Richard Kimball, Charles M Wiener
Early use of non-invasive ventilation prolongs survival in subjects with ALS.
Amyotroph Lateral Scler. 2007 Jun;8(3):185-8. doi: 10.1080/17482960701262392.
Abstract/Text
Non-invasive positive pressure ventilation (NPPV) can improve survival in ALS patients with advanced respiratory impairment, but it is not known if it is beneficial earlier in the disease course. A retrospective cohort study of patients with ALS was performed comparing survival from time of diagnosis in subjects who started NPPV use when their FVC was >or=65% predicted (Early NPPV) with subjects who started NPPV when their FVC was below 65% predicted (Standard NPPV). The Early group (n = 25) and the Standard group (n = 67) were similar except for pulmonary function (mean FVC in Early NPPV group = 74.3+/-10.1% predicted and 48.3+/-11.3 in Standard group, p<0.001). The median time from ALS diagnosis to death was significantly longer in the Early NPPV group (2.7 years vs. 1.8 years, p = 0.045). This remained significant after adjustment for potential confounding factors (H.R. = 0.55, 95% CI 0.31-0.98). Survival from time of diagnosis was nearly one year longer in the Early group. Until more definitive data are available from randomized trials, our findings suggest that clinicians either encourage earlier use of NPPV or use more sensitive tests for respiratory muscle impairment than upright FVC.
Lauren B Elman, Andrew D Siderowf, Leo F McCluskey
Nocturnal oximetry: utility in the respiratory management of amyotrophic lateral sclerosis.
Am J Phys Med Rehabil. 2003 Nov;82(11):866-70. doi: 10.1097/01.PHM.0000091985.22659.30.
Abstract/Text
OBJECTIVE: Current recommendations are to institute nocturnal nasal ventilation for amyotrophic lateral sclerosis patients with a forced vital capacity (FVC) of <50% of predicted normal. The purpose of this study was to determine whether this is appropriate.
DESIGN: A total of 87 nocturnal oximetry evaluations were performed on 78 consecutive amyotrophic lateral sclerosis patients symptomatic for sleep-disordered breathing. Nocturnal oximetry measurements were compared for those with FVC >50% vs. those with FVC of <50% of normal. FVC was measured sitting and supine.
RESULTS: A considerable number of these symptomatic patients manifested evidence of nocturnal hypoxemia as measured by oximetry. However, there was no significant difference between patients with sitting percentage-predicted FVC above and below 50% predicted in minimum oxygen saturation, mean oxygen saturation, percentage of time spent with oxygen saturation of <88%, and number of events per hour. There was no significant difference between patients with supine percentage-predicted FVC above and below 50% predicted in minimum oxygen saturation, mean oxygen saturation, percentage of time spent with oxygen saturation of <88%, and number of events per hour.
CONCLUSION: The recommendation that FVC be <50% of normal is inappropriate for justifying introduction of nocturnal nasal ventilation. Many patients are symptomatic at higher FVC and manifest evidence of nocturnal hypoxemia. Nocturnal oximetry adds additional practical information for justifying earlier respiratory intervention for symptomatic patients.
Michelle Mendoza, Deborah F Gelinas, Dan H Moore, Robert G Miller
A comparison of maximal inspiratory pressure and forced vital capacity as potential criteria for initiating non-invasive ventilation in amyotrophic lateral sclerosis.
Amyotroph Lateral Scler. 2007 Apr;8(2):106-11. doi: 10.1080/17482960601030188.
Abstract/Text
Using a retrospective analysis of 161 patients with amyotrophic lateral sclerosis (ALS) from the Western ALS study group (WALS) database, the sensitivity of maximal inspiratory pressure (MIP)< -60 cm H(2)O and forced vital capacity (FVC)< 50% as US Medicare thresholds for initiating non-invasive ventilation (NIV) were compared. Sixty-five per cent of patients at enrollment met the MIP criterion, compared with only 8% of patients who met the FVC criterion. There were no cases in which FVC< 50% antedated MIP< -60 cm H(2)O. The longitudinal data showed that patients reached the MIP criterion 4 to 6.5 months earlier than the FVC criterion. For patients with clinical signs and symptoms needing treatment with NIV, a MIP< -60 cm H(2)O allows US clinicians to obtain non-invasive ventilatory support for patients earlier than if using the FVC criterion alone.
Michele Lewis, Scott Rushanan
The role of physical therapy and occupational therapy in the treatment of amyotrophic lateral sclerosis.
NeuroRehabilitation. 2007;22(6):451-61.
Abstract/Text
Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disease for which there is no cure. There is a general misunderstanding among healthcare professionals of the proper use and potential benefits of physical and occupational therapy to treat the symptoms and resulting loss of independence. These services can help maximize mobility and comfort through equipment prescription, activity adaptation, patient and family education, and the use of appropriate exercise and range of motion techniques. The literature is controversial on the prescription of exercise in this population. Individual muscle strength, fatigue and spasticity must all be taken into account when discussing exercise with persons with ALS. It can be concluded that physical and occupational therapy intervention is beneficial to persons with ALS. However, more research is needed to decisively determine the effects of exercise on the person with ALS.
大寺亜由美,中西浩司ら：ALS患者に対して作業療法士が導入した福祉用具の実態調査（第2報）作業療法士学会抄録集.2012.
Krivickas LS, Dal Bello-Haas V, Danforth SE, Carter GT:Rehabilitation. In: Mitsumoto H, Przedborski S, Gordon PH, eds. Amyotrophic Lateral Sclerosis. New York: Taylor & Francis. 2006;691-720.
J P Van den Berg, S Kalmijn, E Lindeman, J H Veldink, M de Visser, M M Van der Graaff, J H J Wokke, L H Van den Berg
Multidisciplinary ALS care improves quality of life in patients with ALS.
Neurology. 2005 Oct 25;65(8):1264-7. doi: 10.1212/01.wnl.0000180717.29273.12.
Abstract/Text
OBJECTIVE: To examine the effect of multidisciplinary ALS care on the quality-of-life (QoL) in patients with ALS and their caregivers.
METHODS: In a cross-sectional study, 208 patients with ALS and their caregivers were interviewed. QoL was assessed using the 36-item Short Form Health Survey (SF-36) and two visual analogue scales (VAS). Criteria for multidisciplinary ALS care were: an ALS team headed by a consultant in rehabilitation medicine and consisting of at least a physical therapist, occupational therapist, speech pathologist, dietician and a social worker; use of the Dutch ALS consensus guidelines for ALS care; and at least six incident ALS patients per year.
RESULTS: Clinical characteristics and functional loss of the 133 patients receiving multidisciplinary ALS care and the 75 patients receiving general ALS care were similar. The percentage of patients with adequate aids and appliances was higher in those with multidisciplinary ALS care (93.1 vs 81.3%, p = 0.008), whereas the number of visits to professional caregivers was similar in both groups. Patients in the multidisciplinary ALS care group had a better mental QoL on the SF-36 Mental Summary Score than those in the general care group (p = 0.01). The difference in QoL was most pronounced in the domains of Social Functioning and Mental Health, and was independent of the presence of aids and appliances. No significant differences were found in the SF-36 Physical Summary Score, VAS, or in QoL of caregivers of patients with ALS.
CONCLUSION: High standard of care improves mental quality-of-life in patients with ALS.
V Dal Bello-Haas, J M Florence, A D Kloos, J Scheirbecker, G Lopate, S M Hayes, E P Pioro, H Mitsumoto
A randomized controlled trial of resistance exercise in individuals with ALS.
Neurology. 2007 Jun 5;68(23):2003-7. doi: 10.1212/01.wnl.0000264418.92308.a4.
Abstract/Text
OBJECTIVE: To determine the effects of resistance exercise on function, fatigue, and quality of life in individuals with ALS.
METHODS: Subjects with a diagnosis of clinically definite, probable, or laboratory-supported ALS, forced vital capacity (FVC) of 90% predicted or greater, and an ALS Functional Rating Scale (ALSFRS) score of 30 or greater were randomly assigned to a resistance exercise group that received a home exercise program consisting of daily stretching and resistance exercises three times weekly or to a usual care group, who performed only the daily stretching exercises. ALSFRS, the Fatigue Severity Scale (FSS), and Short Form-36 (SF-36) were completed at baseline and monthly for 6 months. FVC and maximum voluntary isometric contraction (MVIC) were monitored monthly throughout the study.
RESULTS: Of 33 subjects screened, 27 were randomly assigned (resistance = 13; usual care = 14). Eight resistance exercise subjects and 10 usual care subjects completed the trial. At 6 months, the resistance exercise group had significantly higher ALSFRS and SF-36 physical function subscale scores. No adverse events related to the intervention occurred, MVIC and FVC indicated no negative effects, and less decline in leg strength measured by MVIC was found in the resistance exercise group.
CONCLUSION: Our study, although small, showed that the resistance exercise group had significantly better function, as measured by total ALS Functional Rating Scale and upper and lower extremity subscale scores, and quality of life without adverse effects as compared with subjects receiving usual care.
Barbara Tomik, Roberto J Guiloff
Dysarthria in amyotrophic lateral sclerosis: A review.
Amyotroph Lateral Scler. 2010;11(1-2):4-15. doi: 10.3109/17482960802379004.
Abstract/Text
Dysarthria is a motor disorder of speech characterized by abnormalities of the articulation and intelligibility of speech. Phonation and the rate of facial movements may also be affected. Understanding the nature and course of dysarthria in amyotrophic lateral sclerosis (ALS) is important because loss of communication prevents patients from participating in many activities, may lead to social isolation, and reduces the quality of life. The goal of management of dysarthria in ALS patients is to optimize communication effectiveness for as long as possible. The information about dysarthria in ALS is dispersed in physiological, pathological, speech therapy, otorhinolaringological and neurological publications. This review summarizes the current state of knowledge on the clinical features, differential diagnosis, pathophysiology, investigations and management of dysarthria in ALS patients. There is a need to compare the different methods used to assess dysarthria and for controlled clinical trials to assess therapeutic strategies.
田中勇次郎: ロックドインに挑むコミュニケーション. [第4部]段階的コミュニケーション用具の提案-神経難病のための- 難病と在宅ケア 2004 ;10(3): 23-28.
Sykes N:End of life care. In:Oliver D, Borasio G, Walsh D. eds. Palliative care in amyotrophic lateral sclerosis:from diagnosis to bereavement. 2nd ed. Oxford: OUP, 2006:287-300.
荻野裕、荻野美恵子、飯ヶ谷美峰、他：ALSにおけるモルヒネの有用性について（第2報）．臨床神経学 2007;47:1160.
荻野美恵子：日本におけるALS終末期．臨床神経 2008；48：973-975.
土井静樹、南尚哉、藤木直人、他: 医療 2006；60：644-647.
R G Miller, J A Rosenberg, D F Gelinas, H Mitsumoto, D Newman, R Sufit, G D Borasio, W G Bradley, M B Bromberg, B R Brooks, E J Kasarskis, T L Munsat, E A Oppenheimer
Practice parameter: the care of the patient with amyotrophic lateral sclerosis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology: ALS Practice Parameters Task Force.
Neurology. 1999 Apr 22;52(7):1311-23.
Abstract/Text
P M Andersen, G D Borasio, R Dengler, O Hardiman, K Kollewe, P N Leigh, P-F Pradat, V Silani, B Tomik, EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis
EFNS task force on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relatives.
Eur J Neurol. 2005 Dec;12(12):921-38. doi: 10.1111/j.1468-1331.2005.01351.x.
Abstract/Text
Despite being one of the most devastating diseases known, there is little evidence for diagnosing and managing patients with amyotrophic lateral sclerosis (ALS). Although specific therapy is lacking, correct early diagnosis and introduction of symptomatic and specific therapy can have a profound influence on the care and quality of life of the patient and may increase survival time. This document addresses the optimal clinical approach to ALS. The final literature search was performed in the spring of 2005. Consensus recommendations are given graded according to the EFNS guidance regulations. Where there was lack of evidence but consensus was clear we have stated our opinion as good practice points. People affected with possible ALS should be examined as soon as possible by an experienced neurologist. Early diagnosis should be pursued and a number of investigations should be performed with high priority. The patient should be informed of the diagnosis by a consultant with a good knowledge of the patient and the disease. Following diagnosis, the patient and relatives should receive regular support from a multidisciplinary care team. Medication with riluzole should be initiated as early as possible. PEG is associated with improved nutrition and should be inserted early. The operation is hazardous in patients with vital capacity < 50%. Non-invasive positive pressure ventilation improves survival and quality of life but is underused. Maintaining the patients ability to communicate is essential. During the entire course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end of life care are important and should be fully discussed early with the patient and relatives respecting the patients social and cultural background.
T O'Brien, M Kelly, C Saunders
Motor neurone disease: a hospice perspective.
BMJ. 1992 Feb 22;304(6825):471-3.
Abstract/Text
OBJECTIVE: To describe and evaluate the management of patients with motor neurone disease from the perspective of a hospice.
DESIGN: Retrospective analysis of hospice medical and nursing notes.
SETTING: Established 62 bed teaching and research hospice.
SUBJECTS: 124 patients with motor neurone disease cared for by the hospice between January 1980 and November 1990.
MAIN OUTCOME MEASURES: Patient profile; functional status; symptom control and use of opioids; insight; mode and management of death.
RESULTS: 124 patients (67 women, 57 men) had a mean age 63.9 years. The median length of admission was 61.5 days (range 1 to 2147). 84 patients (68%) were aware of their diagnosis and its implications when first seen by a hospice doctor. Functionally, the patients were very dependent. Symptoms such as pain, dyspnoea, and insomnia were major problems that responded well to opioids. Many patients were noted to deteriorate "suddenly," and in 58% of cases death occurred within 24 hours of this deterioration. When dying, 106 patients (94%) were peaceful and settled. 101 patients (89%) received opioids during this dying period. No patient chocked to death.
CONCLUSIONS: Although motor neurone disease is an uncommon disorder, many of its symptoms occur commonly in medical practice and must be actively treated. Opioids are both safe and effective for such treatment. The term chocking is both inaccurate and inappropriate in describing the cause of death in motor neurone disease and its use should be abandoned.
D Oliver
Ethical issues in palliative care--an overview.
Palliat Med. 1993;7(4 Suppl):15-20.
Abstract/Text
There are many ethical decisions to be made during palliative care of a patient with motor neurone disease. These may concern the physical and psychosocial care of the patient and will become highlighted when death approaches. By close involvement of the patient and his/her family with the interdisciplinary team the most appropriate decisions on the patient's care can be made.
Saunders C, Walsh TE, Smith M:Hospice care in motor neuron disease. In: Saunders C, Summers DH, Teller N, eds. Hospice: the living idea. London: Edward Arnold, 1981:126-147.
R Voltz, G D Borasio
Palliative therapy in the terminal stage of neurological disease.
J Neurol. 1997 Oct;244 Suppl 4:S2-10.
Abstract/Text
As recently pointed out by the American Academy of Neurology, providing adequate palliative care to dying patients is the duty of every neurologist. Because of a lack of relevant articles in the neurological literature, we have compiled current treatment recommendations for the most important symptoms arising in the endstage of neurological diseases. These recommendations include treatment of dyspnea, death rattle, restlessness, pain, thirst, depression, and others. A discussion of difficult decisions is included, e.g., the appropriate extent of fluid substitution or the ethical implications of sedation in the terminal phase. It is hoped that this compilation may provide a basis for future research in palliative therapy in neurology.
荻野美恵子：神経内科領域における終末期の倫理的問題について ALS終末期ケアに関するアンケート調査結果. 臨床神経，2010;50：1026-1028.
