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Amyotrophic Lateral Sclerosis (ALS)

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General Information

Description

  • amyotrophic lateral sclerosis (ALS) is a heterogeneous syndrome with survival < 4 years in most patients in which degeneration of cortical, brainstem, and spinal cord motor neurons and, in some patients, frontotemporal cortical neurons lead to progressive muscle weakness, muscle spasticity, dysarthria, dysphagia, cognitive and behavioral impairments, and other motor and extra-motor symptoms1,2

Also called

  • Lou Gehrig's disease
  • motor neuron disease (MND)
  • Charcot's disease (originally described by Charcot in 19th century)

Types

  • familial amyotrophic lateral sclerosis (ALS) - ALS in patients with family history of ALS or frontotemporal dementia (often associated with ALS), reported in about 5%-20% of patients1,2
  • sporadic ALS - ALS in patients without a family history of ALS, reported in about 80%-95% of patients1,2
  • PubMed23833266Journal of neurology, neurosurgery, and psychiatryJ Neurol Neurosurg Psychiatry20140501855478-85478no specific clinical characteristics identified to separate familial from sporadic ALS (J Neurol Neurosurg Psychiatry 2014 May;85(5):478OpenInNew)
  • classic ALS - spinal-onset or bulbar-onset ALS1,2
    • spinal-onset ALS - reported in about 46% of patients
      • initial motor neuron degeneration in spinal cord
      • presentations can include
        • lower motor neuron involvement proximally in the arms, often with mild upper motor neuron signs in the legs
        • lower motor neuron involvement restricted to the legs, usually asymmetrical
        • progressive, unilateral upper motor neuron involvement with facial sparing, sometimes with discrete lower motor neuron involvement
        • predominantly distal lower motor neuron signs in the limbs with limited upper motor neuron involvement
    • bulbar-onset ALS - reported in about 23% of patients
      • initial motor neuron degeneration in brainstem
      • dysarthria in all patients
      • dysphagia usually develops later (although can develop simultaneously)
      • patients generally present with both upper and lower motor neuron signs
        • lower motor neuron signs include tongue wasting (symmetrical) and fasciculations
        • upper motor neuron signs include exaggerated jaw jerk, pseudobulbar affect, and spasticity
  • spinal- or bulbar-onset ALS with concomitant frontotemporal dementia - reported in about 5%-15% of patients2
  • isolated bulbar ALS reported in about 5% of patients2
    • isolated pseudobulbar or bulbar palsy for years
    • most commonly in women with symptoms of dysarthria and emotional lability
  • restricted progressive spinal muscular atrophy (only lower motor involvement) or primary lateral sclerosis (only upper motor neuron involvement) reported in about 10% of patients2
    • progressive spinal muscular atrophy
      • generalized lower motor neuron involvement
      • onset may be focal but deficits spread to other regions and eventually leading to respiratory failure
      • upper motor neuron involvement can develop
    • primary lateral sclerosis
      • exclusive upper motor neuron signs for several years, but lower motor neuron signs can eventually develop
      • when upper motor neuro signs are symmetrical and limited to the legs (sporadic), consider hereditary spastic paraplegia as a possible diagnosis
  • other types reported in about 3% of patients2
    • cachexia - unexplained weight loss at onset, but classic ALS develops
    • respiratory onset - weakness of diaphragm and neck flexors

References

General references used

  1. Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, Shaw PJ, Simmons Z, van den Berg LH. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017 Oct 5;3:17071OpenInNew
  2. van Es MA, Hardiman O, Chio A, Al-Chalabi A, Pasterkamp RJ, Veldink JH, van den Berg LH. Amyotrophic lateral sclerosis. Lancet. 2017 Nov 4;390(10107):2084-2098OpenInNew
  3. National Institute for Health and Care Excellence (NICE) guideline on motor neurone disease: assessment and management can be found at NICE 2016 Feb:NG42OpenInNewPDFPictureAsPdf
  4. Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: The care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009 Oct 13;73(15):1218-26OpenInNewfull-textOpenInNew, corrections can be found in Neurology 2009 Dec 15;73(24):2134, Neurology 2010 Mar 2;74(9):781
  5. Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: The care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009 Oct 13;73(15):1227-33OpenInNewfull-textOpenInNew
  6. Andersen PM, Abrahams S, Borasio GD, et al; European Federation of Neurological Societies (EFNS) Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis. 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):360-75OpenInNew

Recommendation grading systems used

  • American Academy of Neurology (AAN) 2008 grading system for recommendations
    • levels of evidence
      • Level A - established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for given condition in specified population (requires at least 2 consistent Class I studies)
      • Level B - probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for given condition in specified population (requires at least 1 Class I study or at least 2 consistent Class II studies)
      • Level C - possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for given condition in specified population (requires at least 1 Class II study or at least 2 consistent Class III studies)
      • Level U - data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven (studies not meeting criteria for Class I-III)
    • classifications of evidence for therapeutic intervention
      • Class I
        • randomized, controlled clinical trial with masked or objective outcome assessment in a representative population
        • relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
        • requires
          • a) concealed allocation
          • b) clearly defined primary outcome(s)
          • c) clearly defined exclusion/inclusion criteria
          • d) adequate accounting for dropouts (with ≥ 80% of enrolled subjects completing study) and crossovers with numbers sufficiently low to have minimal potential for bias
          • e) for noninferiority or equivalence trials claiming to prove efficacy for 1 or both drugs, the following are also required (1-3 in Class Ie are required for Class II in equivalence trials - if any 1 of the 3 are missing, the class is automatically downgraded to Class III)
            • 1) authors explicitly state clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority
            • 2) standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of standard treatment (for example, for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective)
            • 3) inclusion and exclusion criteria for patient selection and outcomes of patients on the standard treatment are comparable to those of the previous studies establishing efficacy of the standard treatment
            • 4) interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers
      • Class II
        • a randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks 1 criterion a-e above
        • prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b-e above
        • relative baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
      • Class III - all other controlled trials (including well-defined natural history controls or patients serving as own controls) in representative population, where outcome is independently assessed, or independently derived by objective outcome measurement that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (such as blood tests, administrative outcome data)
      • Class IV - studies not meeting Class I, II, or III criteria including consensus, expert opinion
    • classification of evidence for diagnostic accuracy
      • Class I
        • a cohort study with prospective data collection of a broad spectrum of persons with the suspected condition, using an acceptable reference standard for case definition
        • diagnostic test is objective and performed and interpreted without knowledge of the patient's clinical status
        • study results allow calculation of measure of diagnostic accuracy
      • Class II
        • a case-control study of a broad spectrum of persons with the condition established by an acceptable reference standard compared to a broad spectrum of controls
        • a cohort study of a broad spectrum of persons with the suspected condition where the data was collected retrospectively
        • diagnostic test is objective or performed and interpreted without knowledge of disease status
        • study results allow calculation of measure of diagnostic accuracy
      • Class III
        • case-control study or cohort study where either persons with the condition or controls are of a narrow spectrum
        • condition established by an acceptable reference standard
        • reference standard and diagnostic test are objective or performed and interpreted by different observers
        • study results allow calculation of measure of diagnostic accuracy
    • Reference - AAN practice parameter update on care of patients with ALS (19822872Neurology 2009 Oct 13;73(15):1218OpenInNewfull-textOpenInNew), corrections can be found in Neurology 2009 Dec 15;73(24):2134, Neurology 2010 Mar 2;74(9):781
  • European Federation of Neurological Science (EFNS) evidence classification scheme
    • rating of recommendations
      • Level A - useful/predictive or not useful/predictive, based on ≥ 1 convincing class I study or ≥ 2 consistent, convincing class II studies
      • Level B - probably useful/predictive or not useful/predictive, based on ≥ 1 convincing class II study or overwhelming class III evidence
      • Level C - possibly useful/predictive or not useful/predictive, based on ≥ 2 convincing class III studies
      • GCPP - where there was lack of evidence but consensus was clear
    • classification of evidence
      • Class I - prospective study in broad spectrum of persons with suspected condition, using "gold standard" for case definition, where test applied in blinded evaluation, and enabling assessment of appropriate tests of diagnostic accuracy
      • Class II - prospective study in narrow spectrum of persons with suspected condition, or well-designed retrospective study in broad spectrum of persons with established condition compared to broad spectrum of controls, where test applied in blinded evaluation, and enabling assessment of appropriate tests of diagnostic accuracy
      • Class III - retrospective study with persons with established condition or controls of narrow spectrum, and where test applied in blinded evaluation
      • Class IV - any nonblinded study design, expert opinion, or case series without controls
    • PubMed21914052European journal of neurologyEur J Neurol20120301193360-75360Reference - 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):360OpenInNew)

Synthesized Recommendation Grading System for DynaMed

  • DynaMed systematically monitors clinical evidence to continuously provide a synthesis of the most valid relevant evidence to support clinical decision-making (see 7-Step Evidence-Based MethodologyOpenInNew).
  • Guideline recommendations summarized in the body of a DynaMed topic are provided with the recommendation grading system used in the original guideline(s), and allow DynaMed users to quickly see where guidelines agree and where guidelines differ from each other and from the current evidence.
  • In DynaMed (DM), we synthesize the current evidence, current guidelines from leading authorities, and clinical expertise to provide recommendations to support clinical decision-making in the Overview & Recommendations section.
  • We use the Grading of Recommendations Assessment, Development and Evaluation (GRADE)OpenInNew to classify synthesized recommendations as Strong or Weak.
    • Strong recommendations are used when, based on the available evidence, clinicians (without conflicts of interest) consistently have a high degree of confidence that the desirable consequences (health benefits, decreased costs and burdens) outweigh the undesirable consequences (harms, costs, burdens).
    • Weak recommendations are used when, based on the available evidence, clinicians believe that desirable and undesirable consequences are finely balanced, or appreciable uncertainty exists about the magnitude of expected consequences (benefits and harms). Weak recommendations are used when clinicians disagree in judgments of relative benefit and harm, or have limited confidence in their judgments. Weak recommendations are also used when the range of patient values and preferences suggests that informed patients are likely to make different choices.
  • DynaMed (DM) synthesized recommendations (in the Overview & Recommendations section) are determined with a systematic methodology:
    • Recommendations are initially drafted by clinical editors (including ≥ 1 with methodological expertise and ≥ 1 with content domain expertise) aware of the best current evidence for benefits and harms, and the recommendations from guidelines.
    • Recommendations are phrased to match the strength of recommendation. Strong recommendations use "should do" phrasing, or phrasing implying an expectation to perform the recommended action for most patients. Weak recommendations use "consider" or "suggested" phrasing.
    • Recommendations are explicitly labeled as Strong recommendations or Weak recommendations when a qualified group has explicitly deliberated on making such a recommendation. Group deliberation may occur during guideline development. When group deliberation occurs through DynaMed-initiated groups:
      • Clinical questions will be formulated using the PICO (Population, Intervention, Comparison, Outcome) framework for all outcomes of interest specific to the recommendation to be developed.
      • Systematic searches will be conducted for any clinical questions where systematic searches were not already completed through DynaMed content development.
      • Evidence will be summarized for recommendation panel review including for each outcome, the relative importance of the outcome, the estimated effects comparing intervention and comparison, the sample size, and the overall quality rating for the body of evidence.
      • Recommendation panel members will be selected to include at least 3 members that together have sufficient clinical expertise for the subject(s) pertinent to the recommendation, methodological expertise for the evidence being considered, and experience with guideline development.
      • All recommendation panel members must disclose any potential conflicts of interest (professional, intellectual, and financial), and will not be included for the specific panel if a significant conflict exists for the recommendation in question.
      • Panel members will make Strong recommendations if and only if there is consistent agreement in a high confidence in the likelihood that desirable consequences outweigh undesirable consequences across the majority of expected patient values and preferences. Panel members will make Weak recommendations if there is limited confidence (or inconsistent assessment or dissenting opinions) that desirable consequences outweigh undesirable consequences across the majority of expected patient values and preferences. No recommendation will be made if there is insufficient confidence to make a recommendation.
      • All steps in this process (including evidence summaries which were shared with the panel, and identification of panel members) will be transparent and accessible in support of the recommendation.
    • Recommendations are verified by ≥ 1 editor with methodological expertise, not involved in recommendation drafting or development, with explicit confirmation that Strong recommendations are adequately supported.
    • Recommendations are published only after consensus is established with agreement in phrasing and strength of recommendation by all editors.
    • If consensus cannot be reached then the recommendation can be published with a notation of "dissenting commentary" and the dissenting commentary is included in the topic details.
    • If recommendations are questioned during peer review or post publication by a qualified individual, or reevaluation is warranted based on new information detected through systematic literature surveillance, the recommendation is subject to additional internal review.

DynaMed Editorial Process

Special acknowledgements

  • DynaMed topics are written and edited through the collaborative efforts of the above individuals. Deputy Editors, Section Editors, and Topic Editors are active in clinical or academic medical practice. Recommendations Editors are actively involved in development and/or evaluation of guidelines.
  • Editorial Team role definitions
    Topic Editors define the scope and focus of each topic by formulating a set of clinical questions and suggesting important guidelines, clinical trials, and other data to be addressed within each topic. Topic Editors also serve as consultants for the internal DynaMed Editorial Team during the writing and editing process, and review the final topic drafts prior to publication.
    Section Editors have similar responsibilities to Topic Editors but have a broader role that includes the review of multiple topics, oversight of Topic Editors, and systematic surveillance of the medical literature.
    Recommendations Editors provide explicit review of DynaMed Overview and Recommendations sections to ensure that all recommendations are sound, supported, and evidence-based. This process is described in "Synthesized Recommendation Grading."
    Deputy Editors are employees of DynaMed and oversee DynaMed internal publishing groups. Each is responsible for all content published within that group, including supervising topic development at all stages of the writing and editing process, final review of all topics prior to publication, and direction of an internal team.

How to cite

National Library of Medicine, or "Vancouver style" (International Committee of Medical Journal Editors):

  • DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. T116744, Amyotrophic Lateral Sclerosis (ALS); [updated 2018 Nov 30, cited place cited date here]. Available from https://www.dynamed.com/topics/dmp~AN~T116744. Registration and login required.
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    Overview and Recommendations

    • Background

    • Evaluation

    • Management

  • Related Summaries

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    General Information

    • Description

    • Also called

    • Types

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    Epidemiology

    • Who is most affected

    • Incidence/Prevalence

    • Risk factors

    • Associated conditions

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    Etiology and Pathogenesis

    • Causes

    • Pathogenesis

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    History and Physical

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      History

      • Chief concern (CC)

      • History of present illness (HPI)

      • Family history (FH)

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      Physical

      • General physical

      • HEENT

      • Neck

      • Lungs

      • Extremities

      • Neuro

  • KeyboardArrowRight

    Diagnosis

    • Making the diagnosis

    • Communication About Diagnosis

    • Differential diagnosis

    • Testing overview

    • Blood tests

    • Urine studies

    • Imaging studies

    • Cerebrospinal fluid (CSF) analysis

    • Biopsy and pathology

    • Genetic testing

    • Pulmonary function tests

    • Electrophysiologic testing

    • Other diagnostic testing

  • Staging and Functional Rating Scales

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    Management

    • Management overview

    • KeyboardArrowRight

      Symptomatic care

      • KeyboardArrowRight

        Respiratory Impairment

        • Recommendations

        • Evidence and additional information

      • Weak Cough and Poor Secretion Clearance

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        Sialorrhea

        • Recommendations

        • Evidence and additional information

      • KeyboardArrowRight

        Dysphagia and Poor Nutrition

        • Recommendations

        • Evidence and additional information

      • Impaired Cognition

      • KeyboardArrowRight

        Pseudobulbar Affect

        • Recommendations

        • Evidence and Additional Information

      • KeyboardArrowRight

        Impaired Communication

        • Recommendations

        • Evidence and Additional Information

      • KeyboardArrowRight

        Spasticity

        • Recommendations

        • Evidence and Additional Information

      • KeyboardArrowRight

        Muscle Cramps

        • Recommendations

        • Evidence and Additional Information

      • Pain

      • Depression and Anxiety

      • Insomnia and Fatigue

      • Venous Thrombosis

    • Activity

    • Counseling

    • KeyboardArrowRight

      Disease-Targeted Medications

      • Recommendations

      • Riluzole

      • Edaravone

      • Other Medications, Vitamins, and Supplements

    • Surgery and Procedures

    • Consultation and referral

    • KeyboardArrowRight

      Other Management

      • Assistive Devices for Physical Impairment

      • Multidisciplinary Care

      • Other Therapies

    • End-of-Life Management

    • Follow-up

  • Complications

  • Prognosis

  • Prevention and Screening

  • KeyboardArrowRight

    Quality Improvement

    • Physician Quality Reporting System Quality Measures

  • KeyboardArrowRight

    Guidelines and Resources

    • KeyboardArrowRight

      Guidelines

      • International Guidelines

      • United States Guidelines

      • United Kingdom Guidelines

      • European Guidelines

    • Australian and New Zealand Guidelines

    • Review articles

    • MEDLINE search

  • Patient Information

  • KeyboardArrowRight

    ICD Codes

    • ICD-10 codes

  • KeyboardArrowRight

    References

    • General references used

    • Recommendation grading systems used

    • Synthesized Recommendation Grading System for DynaMed

    • DynaMed Editorial Process

    • Special acknowledgements

    • How to cite

Recommendations Editor
Esther Jolanda van Zuuren MD
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Affiliations

Head of Allergy, Dermatology, and Venereology, Leiden University Medical Centre; Netherlands

Conflicts of Interest

Dr. van Zuuren declares no relevant financial conflicts of interest.

Deputy Editor
Alexander Rae-Grant MD, FRCPC, FAAN
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Affiliations

Deputy Editor Neurology, DynaMed Plus; Massachusetts, United States; Neurologist, Cleveland Clinic; Ohio, United States

Conflicts of Interest

Dr. Rae-Grant declares no relevant financial conflicts of interest.

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