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© 2009 American Academy of Neurology Practice Parameter update: The care of the patient with amyotrophic lateral sclerosis (an evidence-based review) Report.

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Presentation on theme: "© 2009 American Academy of Neurology Practice Parameter update: The care of the patient with amyotrophic lateral sclerosis (an evidence-based review) Report."— Presentation transcript:

1 © 2009 American Academy of Neurology 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; M. J. Strong, MD; S. C. Woolley, PhD

2 © 2009 American Academy of Neurology If you have questions, comments, or feedback regarding this slide presentation, or would like to modify the contents for presentation in a lecture, please contact

3 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology Overview Background Gaps in care AAN guideline process Analysis of evidence, conclusions, recommendations Recommendations for future research

5 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology AAN Guideline Process Clinical Question Evidence Conclusions Recommendations

8 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology Literature Search/Review Relevant Complete Search Review abstracts Review full text Select articles Rigorous, Comprehensive, Transparent

10 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology Applying This Process to the Issue We will now turn our attention to the guidelines.

15 © 2009 American Academy of Neurology 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? 3.What is the effect of enteral nutrition administered via percutaneous endoscopic gastrostomy (PEG) on weight stability? 4.When is PEG indicated in ALS? 5.What is the efficacy of nutritional support via PEG in prolonging survival? 6.What is the effect of enteral nutrition delivered via PEG on quality of life (QOL)?

16 © 2009 American Academy of Neurology Clinical Questions, cont. 7.What is the efficacy of vitamin and nutritional supplements on prolonging survival or QOL? 8.What are the optimal pulmonary tests to detect respiratory insufficiency? 9.Does NIV improve respiratory function or increase survival? 10.How do invasive ventilation and NIV affect QOL? 11.What factors influence acceptance of invasive ventilation and NIV? 12.What is the efficacy of targeted respiratory interventions for clearing secretions?

17 © 2009 American Academy of Neurology Clinical Questions, cont. 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?

18 © 2009 American Academy of Neurology Clinical Questions, cont. 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 communication in ALS?

19 © 2009 American Academy of Neurology Clinical Questions, cont. 28.What treatments reduce pain and dyspnea in the terminal phase of ALS? 29.Do hospice care, spiritual interventions, or advance directives improve quality of life in the terminal phase of ALS? 30.What is the optimal method of withdrawing both NIV and invasive ventilation in ALS?

20 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology AAN Classification of Evidence for 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 © 2009 American Academy of Neurology AAN Classification of Evidence for 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 © 2009 American Academy of Neurology AAN Classification of Evidence for 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 © 2009 American Academy of Neurology AAN 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 disease status. Study results allow calculation of measures of diagnostic accuracy.

29 © 2009 American Academy of Neurology AAN Classification of Evidence for 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 © 2009 American Academy of Neurology Analysis of Evidence Question 1: Does riluzole prolong survival or slow disease progression in ALS?

31 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology Analysis of Evidence Question 2: Does lithium carbonate prolong survival or slow disease progression in ALS?

33 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology Analysis of Evidence Question 3: What is the effect of enteral nutrition administered via PEG on weight stability?

35 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology Analysis of Evidence Question 4: When is PEG indicated in ALS?

37 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology Analysis of Evidence Question 5: What is the efficacy of nutritional support via PEG in prolonging survival?

39 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology Analysis of Evidence Question 6: What is the effect of enteral nutrition delivered via PEG on QOL?

41 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology Analysis of Evidence Question 7: What is the efficacy of vitamin and nutritional supplements on prolonging survival or QOL?

43 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology Analysis of Evidence Question 8: What are the optimal pulmonary tests to detect respiratory insufficiency?

46 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology 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 © 2009 American Academy of Neurology Analysis of Evidence Question 9: Does NIV improve respiratory function or increase survival?

50 © 2009 American Academy of Neurology 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).

51 © 2009 American Academy of Neurology Analysis of Evidence Question 10: How do invasive ventilation and NIV affect QOL?

52 © 2009 American Academy of Neurology Conclusions 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).

53 © 2009 American Academy of Neurology Recommendations 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).

54 © 2009 American Academy of Neurology Analysis of Evidence Question 11: What factors influence acceptance of invasive ventilation and NIV?

55 © 2009 American Academy of Neurology Conclusions/Recommendation Conclusions: –Nocturnal oximetry is possibly effective in detecting early respiratory insufficiency and the early use of NIV possibly increases compliance (two Class III studies). –Bulbar involvement and executive dysfunction possibly lower compliance with NIV (two 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).

56 © 2009 American Academy of Neurology Analysis of Evidence Question 12: What is the efficacy of targeted respiratory interventions for clearing secretions?

57 © 2009 American Academy of Neurology Conclusions 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).

58 © 2009 American Academy of Neurology Recommendations 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).

59 © 2009 American Academy of Neurology Clinical Context –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.

60 © 2009 American Academy of Neurology Analysis of Evidence Question 13: How should a physician tell patients that they have ALS?

61 © 2009 American Academy of Neurology Conclusion/Recommendation 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).

62 © 2009 American Academy of Neurology Clinical Context –Useful strategies have been developed for disclosing a diagnosis of cancer (see appendix e-1 of the published guideline). 4

63 © 2009 American Academy of Neurology Analysis of Evidence Question 14: Does multidisciplinary management improve outcomes?

64 © 2009 American Academy of Neurology Conclusions/Recommendations 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).

65 © 2009 American Academy of Neurology Analysis of Evidence Question 15: What are the most effective treatments for sialorrhea?

66 © 2009 American Academy of Neurology Conclusions/Recommendations 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).

67 © 2009 American Academy of Neurology Clinical Context –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

68 © 2009 American Academy of Neurology Analysis of Evidence Question 16: What pharmacologic measures reduce pseudobulbar affect?

69 © 2009 American Academy of Neurology Conclusion/Recommendation Conclusion: –The combination of dextromethorphan/quinidine (DM/Q) is probably effective for pseudobulbar affect in ALS (one Class I study), although side effects may limit its usefulness. Recommendation: –If approved by the FDA, and if side effects are acceptable, DM/Q should be considered for symptoms of pseudobulbar affect in patients with ALS (Level B).

70 © 2009 American Academy of Neurology Analysis of Evidence Question 17: What pharmacologic interventions reduce fatigue?

71 © 2009 American Academy of Neurology Conclusion/Recommendation Conclusion: –There are no controlled studies of pharmacologic agents relieving fatigue in ALS. Riluzole may cause fatigue in some patients (two Class III studies). Recommendation: –In patients developing fatigue while taking riluzole, once risks of fatigue vs modest survival benefits have been discussed, withholding the drug may be considered (Level C).

72 © 2009 American Academy of Neurology Analysis of Evidence Question 18: What interventions reduce cramps ?

73 © 2009 American Academy of Neurology Conclusion/Recommendation Conclusion: –Studies of gabapentin, vitamin E, and riluzole for treating cramps were all negative (Class III). There are safety concerns about quinine. Recommendation: –There are insufficient data to support or refute any specific intervention for the treatment of cramps in ALS (Level U).

74 © 2009 American Academy of Neurology Analysis of Evidence Question 19: What interventions reduce spasticity?

75 © 2009 American Academy of Neurology Conclusion/Recommendation 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).

76 © 2009 American Academy of Neurology Clinical Context –In multiple sclerosis and cerebral palsy, benzodiazepam, baclofen, dantrolene, and tizanidine are effective in reducing spasticity- related symptoms. 6

77 © 2009 American Academy of Neurology Analysis of Evidence Question 20: What pharmacologic interventions reduce depression?

78 © 2009 American Academy of Neurology Conclusion/Recommendation 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).

79 © 2009 American Academy of Neurology Clinical Context –There is consensus amongst experts that depression should be treated in patients with ALS 7 ; however, there are no controlled studies of benefit or harm.

80 © 2009 American Academy of Neurology Analysis of Evidence Question 21: What pharmacologic interventions reduce anxiety?

81 © 2009 American Academy of Neurology Conclusion/Recommendation 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).

82 © 2009 American Academy of Neurology Analysis of Evidence Question 22: What pharmacologic interventions reduce insomnia?

83 © 2009 American Academy of Neurology Conclusion/Recommendation 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).

84 © 2009 American Academy of Neurology Analysis of Evidence Question 23: What is the prevalence and natural history of cognitive and behavioral impairment in ALS?

85 © 2009 American Academy of Neurology Conclusion/Recommendation 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).

86 © 2009 American Academy of Neurology Analysis of Evidence Question 24: How is cognitive or behavioral impairment in ALS diagnosed?

87 © 2009 American Academy of Neurology Conclusion/Recommendation Conclusion: –Neuropsychological assessment is possibly effective for identifying cognitive impairment in ALS (one Class II, one 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).

88 © 2009 American Academy of Neurology Analysis of Evidence Question 25: What is the effect of cognitive or behavioral impairment on management of patients with ALS?

89 © 2009 American Academy of Neurology Conclusion/Recommendation 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).

90 © 2009 American Academy of Neurology Analysis of Evidence Question 26: What treatments are effective for cognitive or behavioral impairment in ALS?

91 © 2009 American Academy of Neurology Conclusion/Recommendation Conclusion: –Data are inadequate regarding the effect of NIV on cognition. Recommendation: –There are insufficient data to support or refute treatment of cognitive or behavioral impairment in ALS (Level U).

92 © 2009 American Academy of Neurology Analysis of Evidence Question 27: What treatments for dysarthria optimize communication in ALS?

93 © 2009 American Academy of Neurology Conclusion/Recommendation 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).

94 © 2009 American Academy of Neurology Analysis of Evidence Question 28: What treatments reduce pain and dyspnea in the terminal phase of ALS?

95 © 2009 American Academy of Neurology Conclusion/Recommendation 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 terminal ALS (Level U).

96 © 2009 American Academy of Neurology Analysis of Evidence Question 29: Do hospice care, spiritual interventions, or advance directives improve quality of life in the terminal phase of ALS?

97 © 2009 American Academy of Neurology Conclusion/Recommendation 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).

98 © 2009 American Academy of Neurology Analysis of Evidence Question 30: What is the optimal method of withdrawing both NIV and invasive ventilation in ALS?

99 © 2009 American Academy of Neurology Conclusion/Recommendation 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).

100 © 2009 American Academy of Neurology Clinical Context –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.

101 © 2009 American Academy of Neurology Clinical Context –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.

102 © 2009 American Academy of Neurology Clinical Context –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.

103 © 2009 American Academy of Neurology Clinical Context, cont. –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.

104 © 2009 American Academy of Neurology Clinical Context, cont. –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.

105 © 2009 American Academy of Neurology Future Research 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 multidisciplinary clinics and symptomatic therapy for pseudobulbar effect and sialorrhea. However, future research in the following areas is still greatly needed.

106 © 2009 American Academy of Neurology Future Research, cont. Lithium carbonate –Study whether lithium slows disease progression or prolongs survival in ALS in larger clinical trials. Nutrition –Develop ALS-specific indications for nutritional adequacy in ALS and for PEG and radiologically inserted gastrostomy (RIG). –Study the optimal timing of nutritional therapy administered via PEG or RIG. –Conduct clinical studies of novel antioxidants and supplements.

107 © 2009 American Academy of Neurology Future Research, cont. 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 in patients with bulbar dysfunction.

108 © 2009 American Academy of Neurology Future Research, cont. Breaking the News –Validate measures that can be applied to studies of diagnostic disclosure. –Evaluate attitudes of neurologists and patients to strategies for breaking the news. –Conduct controlled studies of the effects of different disclosure strategies on patient satisfaction, preserving hope, and outcomes. Multidisciplinary Clinic –Examine referral bias to clinics. –Examine factors essential to benefits in clinics, optimal visit frequency, cost effectiveness of staff, and economic factors in care.

109 © 2009 American Academy of Neurology Future Research, cont. Symptomatic Management –Conduct controlled trials of pharmacologic therapy for spasticity, cramps, constipation, sialorrhea, pseudobulbar affect, pain, depression, anxiety, fatigue, and therapeutic exercise. –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.

110 © 2009 American Academy of Neurology Future Research, cont. Communication –Validate criteria to examine communication strategies. –Design clinical trials to compare different strategies for communication in ALS. Palliative Care –Design controlled trials of terminal symptom management, advanced directives, hospice, and spiritual care.

111 © 2009 American Academy of Neurology Acknowledgments 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.

112 © 2009 American Academy of Neurology References 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: 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: 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: 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 Molloy L. Treatment of sialorrhea in patients with Parkinson's disease: best current evidence. Curr Opin Neurol 2007;20: Abbruzzese G. The medical management of spasticity. Eur J Neurol 2002;9 Suppl 1:30-34; discussion

113 © 2009 American Academy of Neurology References 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: 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: 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: 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: For a complete list of references, please access the full guidelines at

114 © 2009 American Academy of Neurology Questions/Comments

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