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.
Slowing the Disease Process
What is the effect of riluzole on slowing the disease process or prolonging survival in amyotrophic lateral sclerosis (ALS)?
Conclusion
Riluzole is safe and effective for slowing disease progression to a modest degree in ALS (4 Class I studies).
Recommendation
Riluzole should be offered to slow disease progression in patients with ALS (Level A).
Does lithium carbonate prolong survival or slow disease progression in ALS?
Conclusions
There are inadequate data on the effectiveness of lithium carbonate (1 Class III study).
Recommendations
There are insufficient data at this time to support or refute treatment with lithium carbonate in patients with ALS (Level U).
Nutrition
What is the effect of enteral nutrition administered via percutaneous endoscopic gastrostomy (PEG) on weight stability?
Conclusion
Enteral nutrition administered via PEG is probably effective in stabilizing body weight/body mass index (2 Class II, 7 Class III studies).
Recommendation
In patients with ALS with impaired oral food intake, enteral nutrition via PEG should be considered to stabilize body weight (Level B).
When is PEG indicated in ALS?
Conclusions
There are no studies of ALS-specific indications for the timing of PEG insertion, although patients with dysphagia will possibly be exposed to less risk if PEG is placed when forced vital capacity (FVC) is above 50% of predicted (1 Class III study).
Recommendation
There are insufficient data to support or refute specific timing of PEG insertion in patients with ALS (Level U).
What is the efficacy of nutritional support via PEG in prolonging survival?
Conclusions
Studies using appropriate controls or multivariate analysis demonstrated that PEG is probably effective in prolonging survival in ALS, although insufficient data exist to quantitate the survival advantage (2 Class II studies).
Recommendation
PEG should be considered for prolonging survival in patients with ALS (Level B).
What is the effect of enteral nutrition delivered via PEG on quality of life?
Conclusion
No evidence exists regarding the effect of enteral nutrition on quality of life.
Recommendations
There are insufficient data to support or refute PEG for improving quality of life in patients with ALS (Level U).
What is the efficacy of vitamin and nutritional supplements on prolonging survival or quality of life?
Conclusions
- Creatine, in doses of 5–10 g daily, is established as ineffective in slowing the rate of progression or in improving survival in ALS (2 Class I studies).
- Vitamin E 5,000 mg/day plus riluzole is probably ineffective in improving survival or functional outcomes (1 Class I study). Vitamin E (1,000 mg/day plus riluzole) was marginally effective in slowing the progression of ALS from milder to more severe ALS health states using a single measure but is ineffective using multiple other measures (1 Class I study).
Recommendations
Creatine, in doses of 5–10 g daily, should not be given as treatment for ALS because it is not effective in slowing disease progression (Level A). High-dose vitamin E should not be considered as treatment for ALS (Level B), while the equivocal evidence regarding low-dose vitamin E permits no recommendation (Level U).
Respiratory Management
What are the optimal pulmonary tests to detect respiratory insufficiency?
Conclusions
- Nocturnal oximetry and maximal inspiratory pressure (MIP) are possibly more effective in detecting early respiratory insufficiency than erect FVC (2 Class III studies).
- Supine FVC is possibly more effective than erect FVC in detecting diaphragm weakness and correlates better with symptoms of nocturnal hypoventilation (2 Class III studies).
- Sniff transdiaphragmatic pressure (Pdi) and sniff nasal pressure (SNP) are possibly effective in detecting hypercapnia and nocturnal hypoxemia (2 Class III studies).
Recommendations
- Nocturnal oximetry may be considered to detect hypoventilation (regardless of the FVC) (Level C).
- Supine FVC and MIP may be considered useful in routine respiratory monitoring, in addition to the erect FVC (Level C).
- SNP may be considered to detect hypercapnia and nocturnal hypoxemia (Level C).
Does noninvasive ventilation (NIV) improve respiratory function or increase survival?
Conclusion
NIV is probably effective in prolonging survival (1 Class I, 3 Class III studies) and in slowing the rate of FVC decline (1 Class I, 1 Class III study).
Recommendations
- NIV should be considered to treat respiratory insufficiency in ALS, both to lengthen survival (Level B) and to slow the decline of FVC (Level B).
- NIV may be considered to improve quality of life (Level C).
How do invasive and noninvasive ventilation affect quality of life?
Conclusions
- NIV is possibly effective in raising quality of life (QOL) for patients with ALS who have respiratory insufficiency (5 Class III studies).
- Tracheostomy invasive ventilation (TIV) is possibly effective in preserving QOL for patients with ALS, but possibly with a greater burden for their caregivers (2 Class III studies).
Recommendations
- NIV may be considered to enhance QOL in patients with ALS who have respiratory insufficiency (Level C).
- TIV may be considered to preserve QOL in patients with ALS who want long-term ventilatory support (Level C).
What factors influence acceptance of invasive and noninvasive ventilation?
Conclusions
- Nocturnal oximetry is possibly effective in detecting early respiratory insufficiency and the early use of NIV possibly increases compliance (2 Class III studies).
- Bulbar involvement and executive dysfunction possibly lower compliance with NIV (2 Class III studies).
Recommendation
NIV may be considered at the earliest sign of nocturnal hypoventilation or respiratory insufficiency in order to improve compliance with NIV in patients with ALS (Level C).
What is the efficacy of targeted respiratory interventions for clearing secretions?
Conclusions
- Mechanical insufflation/exsufflation (MIE) is possibly effective for clearing upper airway secretions in patients with ALS who have reduced peak cough flow, although the clinically meaningful difference is unknown (4 Class III studies).
- High frequency chest wall oscillation (HFCWO) is unproven for adjunctive airway secretion management (2 Class III studies with conflicting results).
Recommendations
- MIE may be considered to clear secretions in patients with ALS who have reduced peak cough flow, particularly during an acute chest infection (Level C).
- There are insufficient data to support or refute HFCWO for clearing airway secretions in patients with 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).