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Practice Parameter update: 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
R. G. Miller, MD, FAAN; C. E. Jackson, MD, FAAN; E. J. Kasarskis, MD, PhD, FAAN; J. D. England, MD, FAAN; D. Forshew, RN; W. Johnston, MD; S. Kalra, MD; J. S. Katz, MD; H. Mitsumoto, MD, FAAN; J. Rosenfeld, MD, PhD, FAAN; C. Shoesmith, MD, BSc;
• To review the evidence on care of the patient with amyotrophic lateral sclerosis (ALS)- Drug, nutritional, and respiratory therapies - Multidisciplinary care, symptom management, and
• In 1999, the American Academy of Neurology (AAN) published an evidence-based practice parameter for managing patients with amyotrophic lateral sclerosis (ALS).1
• Since that publication, there have been some important new studies, including a randomized controlled trial of noninvasive ventilation (NIV) in ALS.2
• Although only one drug, riluzole, has shown modest benefit and received US Food and Drug Administration (FDA) approval, there have been advances in symptomatic treatment for patients with this disease.
• This revision updates the riluzole practice advisory and addresses other management issues for care of patients with ALS.
• A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population.
• B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population.
• C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population.
• U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.
Note that recommendations can be positive or negative.
* 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).
13. How should a physician tell patients that they have ALS?
14. Does multidisciplinary management improve outcomes?
15. What are the most effective treatments for sialorrhea?16. What pharmacologic measures reduce pseudobulbar
affect?17. What pharmacologic interventions reduce fatigue?18. What interventions reduce cramps?19. What interventions reduce spasticity?20. What pharmacologic interventions reduce depression?
21. What pharmacologic interventions reduce anxiety? 22. What pharmacologic interventions reduce insomnia?23. What is the prevalence and natural history of cognitive
and behavioral impairment in ALS?24. How is cognitive or behavioral impairment in ALS
diagnosed?25. What is the effect of cognitive or behavioral impairment
on management of patients with ALS?26. What treatments are effective for cognitive or
behavioral impairment in ALS?27. What treatments for dysarthria optimize
AAN Classification of Evidencefor 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: a. concealed allocation, b. primary outcome(s) clearly defined, c. exclusion/inclusion criteria clearly defined, d. 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. e. For non inferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required**: 1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or non-inferiority. 2. 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).
AAN Classification of Evidencefor Therapeutic Intervention, cont.
3. 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. 4. 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.***
AAN Classification of Evidencefor Therapeutic Intervention, cont.
• 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).
AAN Classification of Evidencefor 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 disease status. Study results allow calculation of measures of diagnostic accuracy.
AAN Classification of Evidencefor Diagnostic Accuracy, cont.
• Class III: A case control study or cohort study where either persons with the condition or 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 diagnostic accuracy.
• Class IV: Studies not meeting Class I, II or III criteria including consensus, expert opinion or a case report.
Conclusion: – 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 (one Class III study).3
Recommendation:– There are insufficient data to support or refute specific
timing of PEG insertion in patients with ALS (Level U).3
Conclusion: – 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 (two Class II studies).
Recommendation:– PEG should be considered for prolonging survival in
Conclusions: – Creatine, in doses of 5-10g daily, is established as ineffective
in slowing the rate of progression or in improving survival in ALS (two Class I studies).
– Vitamin E 5,000 mg/d plus riluzole is probably ineffective in improving survival or functional outcomes (one Class I study). Vitamin E (1,000 mg/d 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 (one Class I study).
Recommendations:– Creatine, in doses of 5-10g 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).
Conclusions: – Nocturnal oximetry and maximal inspiratory pressure
(MIP) are possibly more effective in detecting early respiratory insufficiency than erect FVC (two Class III studies).
– Supine FVC is possibly more effective than erect FVC in detecting diaphragm weakness and correlates better with symptoms of nocturnal hypoventilation (two Class III studies).
Conclusions: – NIV is possibly effective in raising QOL for patients
with ALS who have respiratory insufficiency (five 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 (two Class III studies).
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 (four Class III studies).
– High frequency chest wall oscillation (HFCWO) is unproven for adjunctive airway secretion management (two Class III studies with conflicting results).
– Medications with mucolytics like guaifenesin or N-aceylcysteine, a B-receptor antagonist (such as metoprolol or propanolol), nebulized saline, or an anticholinergic bronchodilator such as ipratropium are widely used; however, no controlled studies exist in ALS.
Conclusions: – Two Class II studies and one 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, PEG, and NIV; improved quality of life; and lengthened survival. However, one 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).
Conclusions: – In patients with medically refractory sialorrhea, botulinum toxin B
(BTxB) injections into the parotid and submandibular glands are probably effective (one Class I study). There are inadequate data on the effectiveness of botulinum toxin A (BTxA) (one Class III study). Low-dose irradiation is possibly effective for sialorrhea (two 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).
– In ALS and other diseases, anticholinergic medications are generally tried first to reduce sialorrhea, although effectiveness is unproven.1 Botulinum toxin has been effective in controlled trials in Parkinsonism as well as ALS.5
– In multiple sclerosis and cerebral palsy, benzodiazepam, baclofen, dantrolene, and tizanidine are effective in reducing spasticity-related symptoms.6
– There is consensus amongst experts that depression should be treated in patients with ALS7; however, there are no controlled studies of benefit or harm.
Conclusion: – A significant proportion of patients with ALS
demonstrate cognitive impairment and some have dementia (two Class II, multiple Class III studies). Neither behavioral impairment in ALS nor the natural progression of cognitive or behavioral impairments have been adequately studied.
Recommendation:– Screening for cognitive and behavioral impairment
should be considered in patients with ALS (Level B).
– Protocols based on consensus for withdrawal of mechanical ventilation in intensive care units (Class IV)8 include counseling and symptom control with opioids, benzodiazepines, and anticholinergic medications.9 We could find no controlled studies in any disease.
– This evidence-based review indicates some progress in evaluating new therapies for patients with ALS. More high-quality studies have been reported leading to more confident recommendations regarding the value of NIV and PEG.
– It is one thing to publish an evidence-based practice parameter for the management of patients with ALS, and it is quite another to be able to track adherence in practice and to determine whether the publication of evidence-based guidelines has changed outcomes.
– The ALS patient CARE database was developed with the hope of standardizing new and effective therapies for patients with ALS and tracking outcomes to raise the standard of care.10
– Data obtained from the ALS CARE program have shown that the underutilization of many therapies (especially PEG and NIV) has persisted in the years since the original practice parameter on this topic, though there have been gains.
– These findings suggest that an evidence-based practice parameter may over time become more widely accepted and change practice. However, the persistent underutilization of therapies that improve survival and QOL poses a challenge for ALS clinicians to continue to raise the standard of care for patients with ALS.
Respiratory Management – Evaluate SNP as a criterion for NIV initiation. – Evaluate the impact of early NIV initiation on survival and quality
of life. – Assess the impact of executive dysfunction on NIV compliance.– Evaluate the effect of hypoventilation on executive dysfunction.– Compare techniques for clearing upper airway secretions at
various stages of respiratory and bulbar dysfunction.– Evaluate pulmonary tests, compliance with NIV, and outcomes
– Examine irradiation and botulinum toxin for sialorrhea in controlled trials.
Cognitive and Behavioral Impairment – Develop consensus criteria for cognitive and behavioral
impairment to ensure consistency in diagnosis and research. – Identify screening tests for cognitive and behavioral impairment.– Evaluate the natural history of, and treatments for, cognitive and
behavioral impairment, and their impact on compliance and survival.
The authors thank Gary Gronseth, MD; Thomas Getchius; Valerie Cwik, MD; Larry Brower; and Sid Valo for contributions to the practice parameters; Christina Metzler and Barbara Phillips, MS, OTR/L, for their contributions to the patient summary versions of the guidelines; and Sharon J. Matland, RN, MBA, for her contributions to both the practice parameters and the patient summary versions.
1. Miller RG, Rosenberg JA, Gelinas DF, et al. 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;52:1311-1323.
2. Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol 2006;5:140-147.
3. Kasarskis EJ, Scarlata D, Hill R, Fuller C, Stambler N, Cedarbaum JM. A retrospective study of percutaneous endoscopic gastrostomy in ALS patients during the BDNF and CNTF trials. J Neurol Sci 1999;169:118-125.
4. Numico G, Anfossi M, Bertelli G, et al. The process of truth disclosure: an assessment of the results of information during the diagnostic phase in patients with cancer. Ann Oncol 2009.
5. Molloy L. Treatment of sialorrhea in patients with Parkinson's disease: best current evidence. Curr Opin Neurol 2007;20:493-498.
6. Abbruzzese G. The medical management of spasticity. Eur J Neurol 2002;9 Suppl 1:30-34; discussion 53-61.
7. Andersen PM, Borasio GD, Dengler R, et al. EFNS task force on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relatives. Eur J Neurol 2005;12:921-938.
8. O'Mahony S, McHugh M, Zallman L, Selwyn P. Ventilator withdrawal: procedures and outcomes. Report of a collaboration between a critical care division and a palliative care service. J Pain Symptom Manage 2003;26:954-961.
9. Lanken PN, Terry PB, Delisser HM, et al. An official American Thoracic Society clinical policy statement: palliative care for patients with respiratory diseases and critical illnesses. Am J Respir Crit Care Med 2008;177:912-927.
10. Miller RG, Anderson F, Neelam G, Wei Hea. The ALS Patient CARE Program-Northern American Patient CARE Database. In: Mitsumoto H, Przedborski, S., Gordon, P.H., ed. Amyotrophic Lateral Sclerosis: Taylor & Francis Group, 2006: 633-648.
For a complete list of references, please access the full guidelines at www.aan.com/guidelines