Report of the Quality Standards Subcommittee of the American Academy of Neurology

1. 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; M. J. Strong, MD; S. C. Woolley, PhD Practice Parameter update: The care of the patient with amyotrophic lateral sclerosis (an evidence-based review)

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3. Presentation Objectives • To review the evidence on care of the patient with amyotrophic lateral sclerosis (ALS) • Drug, nutritional, and respiratory therapies • Multidisciplinary care, symptom management, and cognitive/behavioral impairment • To present evidence-based recommendations

4. Overview • Background • Gaps in care • AAN guideline process • Analysis of evidence, conclusions, recommendations • Recommendations for future research

5. Background • 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.

6. Gaps in Care • As of the publication of this guideline update, only one drug, riluzole, has received FDA approval. • The evidence for recent advances in symptomatic treatment for patients with ALS was not systematically examined before this parameter update. • Consensus-based general principles of ALS management have been developed to guide clinicians in managing patients with ALS.

7. AAN Guideline Process • Clinical Question • Evidence • Conclusions • Recommendations

8. Clinical Questions • The first step in developing guidelines is to clearly formulate questions to be answered. • Questions address areas of controversy, confusion, or variation in practice. • Questions must be answerable with data from the literature. • Answering the question must have the potential to improve care/patient outcomes.

9. Literature Search/Review Complete Search Review abstracts Review full text Select articles Relevant Rigorous, Comprehensive, Transparent

10. AAN Classification of Evidence • All studies rated Class I, II, III, or IV • Five different classification systems: • Therapeutic • Randomization, control, blinding • Diagnostic • Comparison to gold standard • Prognostic • Screening • Causation

11. AAN Level of Recommendations • 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.

12. Translating Class to Recommendations • A = Requires at least two consistent Class I studies.* • B = Requires at least one Class I study or two consistent Class II studies. • C = Requires at least one Class II study or two consistent Class III studies. • U = Studies not meeting criteria for Class I through Class III.

13. Translating Class to Recommendations, cont. * 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).

14. Applying This Processto the Issue We will now turn our attention to the guidelines.

15. Clinical Questions 1. Does riluzole prolong survival or slow disease progression in ALS? 2. Does lithium carbonate prolong survival or slow disease progression in ALS? • What is the effect of enteral nutrition administered via percutaneous endoscopic gastrostomy (PEG) on weight stability? • When is PEG indicated in ALS? • What is the efficacy of nutritional support via PEG in prolonging survival? • What is the effect of enteral nutrition delivered via PEG on quality of life (QOL)?

16. Clinical Questions, cont. • What is the efficacy of vitamin and nutritional supplements on prolonging survival or QOL? • What are the optimal pulmonary tests to detect respiratory insufficiency? • Does NIV improve respiratory function or increase survival? • How do invasive ventilation and NIV affect QOL? • What factors influence acceptance of invasive ventilation and NIV? • What is the efficacy of targeted respiratory interventions for clearing secretions?

17. Clinical Questions, cont. • How should a physician tell patients that they have ALS? • Does multidisciplinary management improve outcomes? • What are the most effective treatments for sialorrhea? • What pharmacologic measures reduce pseudobulbar affect? • What pharmacologic interventions reduce fatigue? • What interventions reduce cramps? • What interventions reduce spasticity? • What pharmacologic interventions reduce depression?

18. Clinical Questions, cont. • What pharmacologic interventions reduce anxiety? • What pharmacologic interventions reduce insomnia? • What is the prevalence and natural history of cognitive and behavioral impairment in ALS? • How is cognitive or behavioral impairment in ALS diagnosed? • What is the effect of cognitive or behavioral impairment on management of patients with ALS? • What treatments are effective for cognitive or behavioral impairment in ALS? • What treatments for dysarthria optimize communication in ALS?

19. Clinical Questions, cont. • What treatments reduce pain and dyspnea in the terminal phase of ALS? • Do hospice care, spiritual interventions, or advance directives improve quality of life in the terminal phase of ALS? • What is the optimal method of withdrawing both NIV and invasive ventilation in ALS?

20. Methods • OVID, MEDLINE EMBASE, CINAHL, Science Citation Index, BIOETHICSLINE, International Pharmaceutical Abstracts (IPAB), OVID Current contents, Medline-ProQuest, EIFL, and INVEST • 1998 through September 2007 • Relevant, fully published, peer-reviewed articles

21. Methods, cont. • Search terms • Combined the words ALS, Lou Gehrig's disease, and motor neuron disease with the following words using AND: • respiratory, respiratory failure, respiratory insufficiency • nutrition, enteral nutrition, malnutrition, weight loss, gastrostomy • clinical trials • mechanical insufflation-exsufflation, high frequency chest wall oscillation, Vest, Bipap, tracheostomy ventilation, dysphagia, mechanical ventilation, noninvasive ventilation, hypoventilation, • bronchial secretions, sleep-disordered breathing, breath stacking • sialorrhea, pseudobulbar palsy, pseudobulbar affect, emotional lability

22. Methods, cont. • Search terms, cont. • palliative care, diagnosis, telling the diagnosis, breaking the news, advance directives, hospice • botulinum toxin A, botulinum toxin B, parotid irradiation, anticholinergic drugs, amitriptyline, glycopyrrolate, benztropine, transdermal hyoscyamine, atropine, trihexyphenidyl hydrochloride, propranolol, metoprolol, dextromethorphan, quinidine, opioids, opiates, lorazepam • oxygen, dyspnea, pain, anxiety, sleep, depression, cramps, spasticity, insomnia, deep venous thrombosis, communication devices, fatigue, constipation • multidisciplinary clinic, specialty clinic • cognitive impairment, dementia, frontotemporal dementia, executive dysfunction

23. Methods, cont. • All panelists reviewed each article for inclusion. • Risk of bias was determined using the classification of evidence for each study (Classes I–IV). • Strength of practice recommendations were linked directly to levels of evidence (Levels A, B, C, and U). • Conflicts of interest were disclosed.

24. Literature Review • Inclusion criteria: • Relevant to the clinical questions • Limited to human subjects • Randomized controlled trials, cohort studies, case control studies, case series, meta-analyses, and review papers • Exclusion criteria: • Articles related to postpolio conditions, cancer, or non-ALS disease • Articles not peer-reviewed

25. 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).

26. 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.***

27. 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).

28. 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.

29. 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.

30. Analysis of Evidence Question 1: Does riluzole prolong survival or slow disease progression in ALS?

31. Conclusion/Recommendation Conclusion: • Riluzole is safe and effective for slowing disease progression to a modest degree in ALS (four Class I studies). Recommendation: • Riluzole should be offered to slow disease progression in patients with ALS (Level A).

32. Analysis of Evidence Question 2: Does lithium carbonate prolong survival or slow disease progression in ALS?

33. Conclusion/Recommendation Conclusion: • There are inadequate data on the effectiveness of lithium carbonate (one Class III study). Recommendation: • There are insufficient data at this time to support or refute treatment with lithium carbonate in patients with ALS (Level U).

34. Analysis of Evidence Question 3: What is the effect of enteral nutrition administered via PEG on weight stability?

35. Conclusion/Recommendation Conclusion: • Enteral nutrition administered via PEG is probably effective in stabilizing body weight/body mass index (two Class II, seven 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).

36. Analysis of Evidence Question 4: When is PEG indicated in ALS?

37. Conclusion/Recommendation 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

38. Analysis of Evidence Question 5: What is the efficacy of nutritional support via PEG in prolonging survival?

39. Conclusion/Recommendation 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 patients with ALS (Level B).

40. Analysis of Evidence Question 6: What is the effect of enteral nutrition delivered via PEG on QOL?

41. Conclusion/Recommendation Conclusion: • No evidence exists regarding the effect of enteral nutrition on quality of life. Recommendation: • There are insufficient data to support or refute PEG for improving quality of life in patients with ALS (Level U).

42. Analysis of Evidence Question 7: What is the efficacy of vitamin and nutritional supplements on prolonging survival or QOL?

43. Conclusions 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).

44. Recommendations 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).

45. Analysis of Evidence Question 8: What are the optimal pulmonary tests to detect respiratory insufficiency?

46. Conclusions 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).

47. Conclusions, cont. Conclusions, cont.: • Sniff transdiaphragmatic pressure (Pdi) and sniff nasal pressure (SNP) are possibly effective in detecting hypercapnia and nocturnal hypoxemia (two Class III studies).

48. Recommendations 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).

49. Analysis of Evidence Question 9: Does NIV improve respiratory function or increase survival?

50. Conclusions/Recommendation Conclusions: • NIV is probably effective in prolonging survival (one Class I, three Class III studies). • NIV is probably effective in slowing the rate of FVC decline (one Class I, one Class III study). Recommendation: • NIV should be considered to treat respiratory insufficiency in ALS, both to lengthen survival and to slow the rate of FVC decline (Level B).