Care of the Patient with Amyotrophic Lateral Sclerosis

Practice Parameter update: The care of the patient with amyotrophic lateral sclerosis:Multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review) Report of theQuality Standards Subcommittee of the American Academy ofNeurology 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 ABSTRACT Objective: To systematically review evidence bearing on the management of patients with amyotro- phic lateral sclerosis (ALS). Methods: The authors analyzed studies from 1998 to 2007 to update the 1999 practice param- eter. Topics covered in this section include breaking the news, multidisciplinary clinics, symptom management, cognitive and behavioral impairment, communication, and palliative care for pa- tients with ALS. Results: The authors identified 2 Class I studies, 8 Class II studies, and 30 Class III studies in ALS, but many important areas have been little studied.More high-quality, controlled studies of symptomatic ther- apiesandpalliative careareneeded toguidemanagementandassessoutcomes inpatientswithALS. Recommendations: Multidisciplinary clinic referral should be considered formanaging patientswith ALS tooptimizehealthcaredeliveryandprolongsurvival (LevelB) andmaybeconsidered toenhancequalityof life (Level C). For the treatment of refractory sialorrhea, botulinum toxin B should be considered (Level B) and low-dose radiation therapy to the salivary glands may be considered (Level C). For treatment of pseudobulbar affect, dextromethorphan and quinidine should be considered if approved by the US Food and Drug Administration (Level B). For patients who develop fatigue while taking riluzole, withholding the drug may be considered (Level C). Because many patients with ALS demonstrate cognitive impairment, which insomecasesmeetscriteria fordementia,screeningforcognitiveandbehavioral impairmentshould be considered in patients with ALS (Level B). Other management strategies all lack strong evidence. Neurology® 2009;73:1227–1233 GLOSSARY ALS� amyotrophic lateral sclerosis;ALS-FTD� amyotrophic lateral sclerosis with a dementia meeting the Neary criteria for frontotemporal dementia; ALSbi � amyotrophic lateral sclerosis with behavioral impairment; ALSci � amyotrophic lateral sclerosis with cognitive impairment; BTxA � botulinum toxin type A; BTxB � botulinum toxin type B; DM � dextromethor- phan; FDA� Food and Drug Administration; FTD� frontotemporal dementia; NIV� noninvasive ventilation; PEG� percuta- neous endoscopic gastrostomy; Q� quinidine. Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive paralyzing disease. Most patients with ALS die within 2 to 5 years of onset. The mainstay of ALS management is symptomatic treatment and pal- liative care. More treatments are now available to ease the burden of the disease, and they are increas- ingly utilized by patients and clinicians, at least in part because of the expanding base of evidence show- ing effectiveness. Much more needs to be done in this regard, but there has been substantial progress in the past decade. This is part 2 of the revision of the 1999 practice parameter on the care of patients with amyotrophic lateral sclerosis (ALS).1 Consensus-based general principles of ALS management have been developed to guide clinicians in managing patients with ALS.1 Only evidence-based recommendations based on ALS studies are included in this revision. Seealso page1218 Supplemental data at www.neurology.org Address correspondence and reprint requests to American Academy of Neurology, 1080 Montreal Avenue, St. Paul, MN 55116 guidelines@aan.com From the Department of Neurology (R.G.M., D.F., J.S.K., S.C.W.), California Pacific Medical Center, San Francisco; University of Texas Health Science Center of San Antonio (C.E.J.); University of Kentucky (E.J.K.), Lexington; Louisiana State University Health Sciences Center (J.D.E.), New Orleans; Department of Neurology (W.J., S.K.), University of Alberta, Canada; Neurological Institute (NI-9) (H.M.), New York, NY; Division of Neurology (J.R.), UCSF, Fresno, CA; and London Health Sciences Center (C.S., M.J.S.), London, Ontario, Canada. Appendices e-1–e-5, tables e-1–e-5, and references e1–e15 are available on the Neurology® Web site at www.neurology.org. Approved by the Quality Standards Subcommittee on November 5, 2008; by the Practice Committee on March 8, 2009; and by the AAN Board of Directors on July 30, 2009. Disclosure: Author disclosures are provided at the end of the article. Special Article Copyright © 2009 by AAN Enterprises, Inc. 1227 DESCRIPTION OF THE ANALYTIC PROCESS We searched OVID, MEDLINE, EMBASE, CINAHL, Science Citation Index, BIOETHICSLINE, Interna- tional Pharmaceutical Abstracts, OVID Current Con- tents, Medline-Proquest, EIFL, and INVEST from 1998 through September 2007 combining the words ALS, Lou Gehrig’s disease, and motor neuron disease with the following words using AND: sialorrhea, pseudobulbar palsy, pseudobulbar affect, emotional la- bility, palliative care, diagnosis, telling the diagnosis, breaking the news, advance directives, botulinum toxin A, botulinum toxin B, parotid irradiation, anticholin- ergic drugs, amitriptyline, glycopyrrolate, benztropine, transdermal hyoscyamine, atropine, trihexyphenidyl hydrochloride, propranolol, metoprolol, dextromethor- phan, quinidine, opioids, opiates, oxygen, hospice, dys- pnea, pain, lorazepam, anxiety, sleep, depression, cramps, spasticity, insomnia, deep venous thrombosis, communication devices, multidisciplinary clinic, spe- cialty clinic, cognitive impairment, dementia, fronto- temporal dementia, executive dysfunction, fatigue, and constipation. We reviewed the abstracts of these articles and examined 142 articles in their entirety. The diag- nostic and therapeutic classification schemes used to grade the articles are summarized in appendices e-4a and e-4b on the Neurology® Web site at www. neurology.org. Recommendations were based on the levels of evidence as described in appendix e-5. ANALYSIS OF EVIDENCE Breaking the news. How should a physician tell patients that they have ALS? Telling the patient and family the diagnosis of ALS is chal- lenging for clinicians and patients. Two studies ana- lyzed patient perceptions of this experience (Class III and Class IV).2,3 Patients reported lack of empathy, insufficient explanation of the diagnosis and the course of the illness, and lack of information on where to get help. 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). Clinical context. Useful strategies have been developed for disclosing a diagnosis of cancer (appendix e-1).4 Multidisciplinary clinic. Does multidisciplinary manage- ment improve outcomes? In specialized multidisci- plinary clinics, patients with ALS receive comprehensive care from a physician, physical therapist, occupational therapist, speech patholo- gist, dietitian, social worker, respiratory therapist, and nurse case manager. Studies suggest varying degrees of adherence to the practice parameters (Class III).5 Specialized clinics coordinate care and interface with a primary care physician and community-based services. Patients who attend specialized ALS clinics are younger and have longer symptom duration than neurology clinic patients, indicating possible referral bias (Class II).6-9 Patient care and survival were examined for 97 patients attending specialized ALS clinics in Italy compared with 124 patients in neurology clinics (Class II).6 There was increased utilization of ri- luzole, percutaneous endoscopic gastrostomy (PEG), and noninvasive ventilation (NIV) in the ALS clin- ics, and fewer hospital admissions. Mean survival was longer in specialized ALS clinics (1,080 days vs 775 days, p � 0.008). Using the COX multivariate anal- ysis, attending an ALS specialized clinic indepen- dently predicted longer survival. Prolonged survival (7.5 months, p � 0.0001) was found for patients in Ireland attending multi- disciplinary ALS clinics (Class II).9 Patients at ALS clinics were younger and more likely to receive riluzole (99% vs 61%). Multidisciplinary care was an independent predictor of survival (p � 0.02) and reduced the risk of death by 47% in a 5-year study (Class II).9 Dutch patients in multidisci- plinary ALS clinics (n � 133) were compared with 75 patients receiving general care (Class III).10 Pa- tients were well-matched and data were collected by a blinded nurse. Patients in multidisciplinary clinic received more aids and appliances (93.1% vs 81.3%, p � 0.008) and had higher quality of life (SF-36® Health Survey, p � 0.01). Beneficial ef- fects derived from a single visit to a multidisci- plinary clinic, suggesting better coordination of care. By contrast, another Class II study documented no increase in survival from multidisciplinary clinic.11 Riluzole use was higher in multidisciplinary clinic (61% vs 43%, p � 0.02) but very few patients received PEG (6% vs 2%) or NIV (2% in each group). There was a nonsignificant 10% increase in survival in those attending a multidisciplinary clinic after 12 months. Low utilization of palliative care, case management, PEG, NIV, and riluzole, com- pared to the 2 positive studies above, may account for the lack of survival benefit in this study. Conclusions. Two Class II studies and 1 Class III study show that multidisciplinary clinics specializ- ing in ALS care are probably effective in several ways: increased use of adaptive equipment; in- creased utilization of riluzole, PEG, and NIV; im- proved quality of life; and lengthened survival. However, 1 Class II study with low use of treat- ments found no survival benefit. Recommendations. Specialized multidisciplinary clinic referral should be considered for patients with ALS 1228 Neurology 73 October 13, 2009 to optimize health care delivery (Level B) and pro- long survival (Level B), and may be considered to enhance quality of life (Level C). Symptomatic management. Effective management of symptoms is one of the primary goals of ALS pa- tient care. What are the most effective treatments for sialorrhea? Sialorrhea, or drooling, is embarrassing and is associ- ated with aspiration pneumonia. The prevalence is estimated at 50%, and 70% of patients receiving oral medications for treatment reported benefit (Class III).12 In a small trial, amitriptyline and botulinum toxin type A (BTxA) seemed equally effective, al- though 3 of 5 patients treated with amitriptyline ex- perienced side effects (Class III).13 In a double-blind, controlled trial of botulinum toxin type B (BTxB) in 20 patients with ALS with refractory sialorrhea (Class I),14 patients were ran- domized to 2,500 U of BTxB or placebo into bilat- eral parotid and submandibular glands. Treated patients reported a global improvement of 82% at 2 and 4 weeks compared to 38% in placebo (p � 0.05). At 12 weeks, 50% of patients receiving BTxB were improved compared to 14% receiving placebo. There were no important adverse events. Radiation therapy for medically refractory sialor- rhea reduced salivary production, but side effects in- cluded erythema, sore throat, and nausea (Class III).15 A “satisfactory response” was observed and sa- liva secretion rate diminished with a single dose of 7–7.5 Gy bilaterally (Class III).16 Conclusions. In patients with medically refractory sialorrhea, BTxB injections into the parotid and sub- mandibular glands are probably effective (1 Class I study). There are inadequate data on the effective- ness of 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 con- sidered (Level B) and low-dose radiation therapy to the salivary glands may be considered (Level C). Clinical context. In ALS and other diseases, anticho- linergic medications are generally tried first to reduce sialorrhea, although effectiveness is unproven.1 Botu- linum toxin has been effective in controlled trials in parkinsonism as well as ALS.17 What pharmacologic measures reduce pseudobulbar af- fect? Pseudobulbar affect, excessive laughing or cry- ing, or involuntary emotional expression disorder affects 20%–50% of patients with ALS, especially in pseudobulbar palsy.18 Although it is not a mood dis- order, antidepressants are frequently employed. A fixed-dose combination of dextromethorphan (DM)/quinidine (Q) (30 mg DM/30 mg Q BID) for treatment of pseudobulbar affect in ALS (Class I)19 reduced the frequency and severity of laughing and crying behaviors compared to either DM (p � 0.001) or Q alone (p � 0.001). Side effects were dizziness, nausea, and somnolence, which accounted for termination of treatment in 24% with DM/Q compared to 6% with DM and 5% with Q. DM/Q is not yet approved by the US Food and Drug Ad- ministration (FDA). Conclusions. The combination of 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 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? Fa- tigue may be a symptom of depression, poor sleep, abnormal muscle activation, immobility, or respira- tory dysfunction. Fatigue was a side effect of therapy in 26% of patients taking riluzole vs 13% taking pla- cebo (p� 0.07; number needed to harm� 8) (Class III).20 Asthenia occurred in 18% of patients taking riluzole vs 12% of patients taking placebo in a larger study (p � 0.004; number needed to harm � 17) (Class III).21 Conclusions. There are no controlled studies of pharmacologic agents relieving fatigue in ALS. Ri- luzole possibly causes fatigue in some patients (2 Class III studies). Recommendation. In patients developing fatigue while taking riluzole, once risks of fatigue vs modest sur- vival benefits have been discussed, withholding the drug may be considered (Level C). What interventions reduce cramps? Cramps have been a secondary outcome measure in ALS clinical trials of gabapentin (Class III),22 vitamin E (Class III),23 and riluzole (Class III).20 There was no benefit from these agents. By survey, quinine was widely used for cramps (Class IV),24 but there are no studies in ALS. Re- cently, the FDA warned against using quinine for cramps and removed unapproved quinine drugs from the market.25 Conclusions. 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 sup- port or refute any specific intervention for the treat- ment of cramps in ALS (Level U). What interventions reduce spasticity? Treating spastic- ity might improve gait and relieve painful spasms. Moderate exercise led to a small decline in the Ash- worth Spasticity Scale over 3 months, compared to a worsening with no exercise (p� 0.005) (Class III).26 Neurology 73 October 13, 2009 1229 Vitamin E 5,000 mg daily plus riluzole had no bene- ficial effect on spasticity as a secondary outcome measure (Class III).27 Conclusion. Evidence is insufficient to recommend exercise or medication for treating spasticity in ALS (Class III). Recommendation. There are insufficient data to sup- port or refute exercise or medication for treating spasticity in ALS (Level U). Clinical context. In multiple sclerosis and cerebral palsy, benzodiazepam, baclofen, dantrolene, and ti- zanidine are effective in reducing spasticity-related symptoms.28 What pharmacologic interventions reduce depression? The prevalence of depression in ALS ranges from 0 to 44%,29 although systematic studies suggest 10% in advanced ALS (Class III).30 Conclusion. There have been no controlled trials of treatment for depression in ALS. Recommendation. There are insufficient data to sup- port or refute specific treatments for depression in ALS (Level U). Clinical context. There is consensus among experts that depression should be treated in patients with ALS31; however, there are no controlled studies of benefit or harm. What pharmacologic interventions reduce anxiety? Rec- ognition and treatment of anxiety in ALS can be challenging since similar symptoms can be related to dyspnea. Conclusion. There have been no trials of treatment for anxiety in ALS. Recommendation. There are insufficient data to sup- port or refute specific treatment for anxiety in ALS (Level U). What pharmacologic interventions reduce insomnia? In- somnia is common in ALS and may be a symptom of early respiratory weakness, underlying anxiety, de- pression, or pain.32 There is a concern that sedative/ hypnotic agents may suppress the respiratory drive in patients with ALS. Conclusion. There have been no studies of treatment for insomnia in ALS. Recommendation. There are insufficient data to sup- port or refute specific treatment for insomnia in ALS (Level U). Cognitive and behavioral impairment. There is now considerable evidence for cognitive and behavioral manifestations in ALS. Specific ALS phenotypes include pure motor degeneration (ALS), ALS with cog- nitive impairment (ALSci), ALS with behavioral im- pairment (ALSbi), and ALS with a dementia meeting the Neary criteria for frontotemporal dementia (FTD) (ALS-FTD). FTD, as defined by Neary et al.,33 has in- sidious onset, gradual progression, altered social con- duct, emotional blunting, and loss of insight. These criteria are required for the diagnosis of FTD, which is supported by neuropsychological abnormalities, lan- guage dysfunction, and poor self care. ALSci reflects frontotemporal dysfunction with deficits in attention, cognitive flexibility, and word generation, with relative sparing of visuospatial function and memory. ALSbi re- fers to changes in social interactions unrelated to a psy- chiatric condition. The domain of cognitive and behavioral impair- ment in ALS is a rapidly evolving field and there is little consensus regarding diagnostic criteria and as- sessment methods. What is the prevalence and natural history of cogni- tive and behavioral impairment in ALS? Estimates of cognitive impairment range from 10% (Class III)34 to 75% (Class III).35 A population-based sample produced an estimate of 28% (Class II).36 The prevalence of impairment meeting criteria for dementia ranged from 15% (Class III)37 to 41% (Class II).38 Behavioral impairment (irritability and social disinhibition) was identified in 39% (Class III).39 Three studies (Class III)39,40,e1 documented mild cognitive decline over 6 months, while others (Class III)e2,e3 found no change over 12 months. It is not known whether patients can progress from ALSci or ALSbi to ALS-FTD. However, 15% of patients pre- senting with FTD later develop motor neuron de- generation (Class III).e4 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 im- pairments has been adequately studied. Recommendation. Screening for cognitive and behav- ioral impairment should be considered in patients with ALS (Level B). How is cognitive or behavioral impairment in ALS diag- nosed? Cognitive impairment in ALS is best identified through neuropsychological assessment using stan- dardized measures and normative data. The Mini- Mental State Examination is less sensitive to the cogni