Definitions of the levels of the recommendations (A, B, C, U) and classification of the evidence (Class I-IV) are provided at the end of the "Major Recommendations" field.
Breaking the News
How should a physician tell patients that they have amyotrophic lateral sclerosis (ALS)?
Conclusion
There have been no controlled trials of breaking the news in ALS.
Recommendation
There is insufficient evidence to support or refute any specific method of disclosing the diagnosis in ALS (Level U).
Multidisciplinary Clinic
Does multidisciplinary management improve outcomes?
Conclusions
Two Class II studies and 1 Class III study show that multidisciplinary clinics specializing in ALS care are probably effective in several ways: increased use of adaptive equipment; increased utilization of riluzole, percutaneous endoscopic gastrostomy (PEG), and noninvasive ventilation (NIV); improved quality of life; and lengthened survival. However, 1 Class II study with low use of treatments found no survival benefit.
Recommendations
Specialized multidisciplinary clinic referral should be considered for patients with ALS to optimize health care delivery (Level B) and prolong survival (Level B), and may be considered to enhance quality of life (Level C).
Symptomatic Management
What are the most effective treatments for sialorrhea?
Conclusions
In patients with medically refractory sialorrhea, botulinum toxin B (BTxB) injections into the parotid and submandibular glands are probably effective (1 Class I study). There are inadequate data on the effectiveness of botulinum toxin A (BTxA) and amitriptyline (1 Class III study). Low-dose irradiation is possibly effective for sialorrhea (2 Class III studies).
Recommendations
In patients with ALS who have medically refractory sialorrhea, BTxB should be considered (Level B) and low-dose radiation therapy to the salivary glands may be considered (Level C).
What pharmacologic measures reduce pseudobulbar affect?
Conclusions
The combination of dextromethorphan/quinidine (DM/Q) is probably effective for pseudobulbar affect in ALS (1 Class I study), although side effects may limit its usefulness.
Recommendation
If approved by the Food and Drug Administration (FDA), and if side effects are acceptable, DM/Q should be considered for symptoms of pseudobulbar affect in patients with ALS (Level B).
What pharmacologic interventions reduce fatigue?
Conclusions
There are no controlled studies of pharmacologic agents relieving fatigue in ALS. Riluzole possibly causes fatigue in some patients (2 Class III studies).
Recommendations
In patients developing fatigue while taking riluzole, once risks of fatigue versus modest survival benefits have been discussed, withholding the drug may be considered (Level C).
What interventions reduce cramps?
Conclusions
Studies of gabapentin, vitamin E, and riluzole for treating cramps were all negative (Class III). There are safety concerns about quinine.
Recommendations
There are insufficient data to support or refute any specific intervention for the treatment of cramps in ALS (Level U).
What interventions reduce spasticity?
Conclusion
Evidence is insufficient to recommend exercise or medication for treating spasticity in ALS (Class III).
Recommendation
There are insufficient data to support or refute exercise or medication for treating spasticity in ALS (Level U).
What pharmacologic interventions reduce depression?
Conclusion
There have been no controlled trials of treatment for depression in ALS.
Recommendation
There are insufficient data to support or refute specific treatments for depression in ALS (Level U).
What pharmacologic interventions reduce anxiety?
Conclusion
There have been no trials of treatment for anxiety in ALS.
Recommendation
There are insufficient data to support or refute specific treatment for anxiety in ALS (Level U).
What pharmacologic interventions reduce insomnia?
Conclusion
There have been no studies of treatment for insomnia in ALS.
Recommendation
There are insufficient data to support or refute specific treatment for insomnia in ALS (Level U).
Cognitive and Behavioral Impairment
What is the prevalence and natural history of cognitive and behavioral impairment in ALS?
Conclusions
A significant proportion of patients with ALS demonstrate cognitive impairment and some have dementia (2 Class II, multiple Class III studies). Neither behavioral impairment in ALS nor the natural progression of cognitive or behavioral impairments has been adequately studied.
Recommendation
Screening for cognitive and behavioral impairment should be considered in patients with ALS (Level B).
How is cognitive or behavioral impairment in ALS diagnosed?
Conclusion
Neuropsychological assessment is possibly effective for identifying cognitive impairment in ALS (1 Class II, 1 Class III).
Recommendation
Screening tests of executive function may be considered to detect cognitive impairment in patients with ALS prior to confirmation with formal neuropsychological evaluation (Level C).
What is the effect of cognitive or behavioral impairment on management of patients with ALS?
Conclusion
Insufficient data exist on the effect of cognitive or behavioral impairment on the management of patients with ALS.
Recommendation
There are insufficient data to support or refute the impact of cognitive and behavioral impairment on management in ALS (Level U).
What treatments are effective for cognitive or behavioral impairment in ALS?
Conclusions
Data are inadequate regarding the effect of pharmacologic treatment or NIV for cognitive or behavioral impairment in ALS.
Recommendation
There are insufficient data to support or refute treatment of cognitive or behavioral impairment in ALS (Level U).
Communication
What treatments for dysarthria optimize communication in ALS?
Conclusion
No controlled studies examined communication in ALS.
Recommendation
There are insufficient data to support or refute treatment to optimize communication in ALS (Level U).
Palliative Care
What treatments reduce pain and dyspnea in the terminal phase of ALS?
Conclusion
No controlled studies examined treating pain or dyspnea in late-stage ALS.
Recommendation
There are insufficient data to support or refute specific treatments for pain and dyspnea in late-stage ALS (Level U).
Do hospice care, spiritual interventions, or advance directives improve quality of life in the terminal phase of ALS?
Conclusion
No controlled studies examined hospice, spiritual care, or advance directives in ALS.
Recommendation
There are insufficient data to support or refute hospice, spiritual care, or advance directives in ALS (Level U).
What is the optimal method of withdrawing both noninvasive and invasive ventilation in ALS?
Conclusion
There are no controlled studies examining withdrawal of ventilation in ALS.
Recommendation
There are insufficient data to support or refute specific strategies for withdrawal of ventilation in ALS (Level U).
Definitions:
Classification of Evidence for Studies of Therapeutic Intervention
Class I = A randomized, controlled clinical trial of the intervention of interest 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. The following are also required:
- Concealed allocation
- Primary outcome(s) clearly defined
- Exclusion/inclusion criteria clearly defined
- Adequate accounting for drop-outs (with at least 80% of enrolled subjects completing the study) and cross-overs with numbers sufficiently low to have minimal potential for bias
- For non-inferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*:
- The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or non-inferiority.
- The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment. (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
- The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
- The 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 one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant 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 a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**
Class IV = Studies not meeting Class I, II, or III criteria including consensus or expert opinion.
*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.
**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).
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. The diagnostic test is objective or performed and interpreted without knowledge of the patient's clinical status. Study results allow calculation of measures 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 or a cohort study where a broad spectrum of persons with the suspected condition where the data was collected retrospectively. The diagnostic test is objective or performed and interpreted without knowledge of the disease status. Study results allow calculation of measures of diagnostic accuracy.
Class III = A case control study or a cohort study where either the persons with the condition or the controls are of a narrow spectrum. The condition is established by an acceptable reference standard. The reference standard and diagnostic test are objective or performed and interpreted by different observers. Study results allow calculation of measures of a diagnostic accuracy.
Class IV = Studies not meeting Class I, II, or III criteria including consensus, expert opinion or a case report.
Classification of Recommendations
Level A = Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.*)
Level B = Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)
Level C = Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)
Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.
*In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if: 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).