The AAN Quality Standards Subcommittee has updated its 1999 treatment and care guidelines for patients with amyotrophic lateral sclerosis (ALS), based on a systematic review of evidence-based studies of nutritional and respiratory therapies published between 1998 and 2007. The Subcommittee also updated the 1997 AAN Drug Advisory on riluzole, as well as the AAN 1999 practice parameter on patient management, including multidisciplinary care, symptom management, and cognitive and behavioral impairment.
The recommendations were published in the Oct. 13 issue of Neurology.
Lead author Robert G. Miller, MD, director of the Forbes Norris MDA/ALS Research and Treatment Center of the California Pacific Medical Center in San Francisco, highlighted the new parameters in an interview with Neurology Today.
WHAT ARE THE MAIN CHANGES TO THE NEW GUIDELINES FOR DRUG, NUTRITIONAL, AND RESPIRATORY THERAPIES?
We found that important treatments for patients with ALS remain underutilized. Noninvasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), and riluzole are particularly important and have the best evidence supporting wider use.
Riluzole should be offered to slow disease progression, and PEG should be considered to stabilize weight and prolong survival in patients with ALS. NIV should be considered for respiratory insufficiency to lengthen survival, and may be considered to slow the decline of forced vital capacity (FVC), and may be considered to improve quality of life (QOL). Early initiation of NIV may increase compliance. Insufflation or exsufflation may be considered to help clear upper airway secretions.
WHAT ARE THE RECOMMENDATIONS REGARDING RILUZOLE?
Riluzole is approved for slowing progression, and the 1997 practice advisory recommended 50 mg twice daily to prolong survival for definite or probable ALS of under five years' duration, with FVC greater than 60 percent, and without tracheostomy. Expert opinion suggested potential benefit for those with suspected or possible ALS with symptoms longer than five years, FVC greater than 60 percent, and without tracheostomy.
Since then, four class I trials have shown riluzole has a modest beneficial effect in slowing progression (prolonging survival two to three months). Five studies of large databases spanning five to 10 years have demonstrated a survival benefit of six to 21 months. After 10 years of patient experience, the drug appears to be safe and modestly effective, but expensive.
DOES LITHIUM CARBONATE PROLONG SURVIVAL OR SLOW DISEASE PROGRESSION?
We found too little evidence on the effectiveness of lithium on which to base a recommendation. It might be considered for prolonging survival in ALS, but the recommendation is highly tentative until we have the results of a multicenter national controlled therapeutic trial. The complete study results are expected in July 2010, with preliminary findings to be released in March.
WHAT WERE THE FINDINGS REGARDING NUTRITIONAL CARE?
Dysphagia is diagnosed clinically. Videofluoroscopic evaluation of the swallowing mechanism may identify food textures that can be handled successfully; however, it is not a required test to establish the presence or absence of dysphagia. Strategies to maintain oral nutritional intake consist of altering food consistency and using nutritional supplements. Ultimately, PEG or an equivalent procedure, such as a radiologically inserted gastrostomy device (RIG), may be necessary.
Weight loss is serious and leads to a poor prognosis in ALS. Thus, it is important to emphasize to patients that PEG does not eliminate oral feeding but can help stabilize weight and offers a convenient method for administering medication and fluid. Enteral nutrition administered via PEG, which does eliminate the pleasure of taste, is probably effective in stabilizing body weight/body mass index, and should be considered for patients with impaired oral food intake or significant weight loss.
ARE VITAMINS AND SUPPLEMENTS BENEFICIAL?
Almost 80 percent of patients take high-dose vitamins, minerals, or other nutriceuticals, but no studies have proven beneficial for any of these in ALS. Only creatine and vitamin E have been examined for efficacy.
We concluded that creatine in doses of 5–10g daily should not be given because it is not effective in slowing disease progression, nor should high-dose vitamin E. We could not make any recommendation regarding lower doses.
WHAT DOES THE EVIDENCE SUGGEST FOR OPTIMAL RESPIRATORY MANAGEMENT?
Diagnosis and management of respiratory insufficiency is critical because most deaths from ALS result from respiratory failure. New approaches to monitoring respiratory problems appear promising. Nocturnal oximetry may be considered to detect hypoventilation (regardless of the FVC), while supine FVC and maximal inspiratory pressure (MIP) may be considered useful in routine respiratory monitoring, in addition to the erect FVC. Sniff nasal pressure (SNP) may detect hypercapnia and nocturnal hypoxemia.
DOES NIV OR TRACHEOSTOMY INVASIVE VENTILATION (TIV) IMPROVE RESPIRATORY FUNCTION AND SURVIVAL, OR IMPROVE PATIENTS' QOL?
There have now been three class III studies and one class I study showing increased survival from NIV. In one study, patients using NIV had a median survival benefit of 205 days. On the basis of this and other studies, we concluded that NIV is probably effective in prolonging survival and in slowing the rate of decline in FVC. Consequently we recommend NIV should be considered to treat respiratory insufficiency in ALS, both to lengthen survival and to slow the rate of FVC decline.
Also, most patients using either NIV or TIV would choose ventilation again; however, caregivers said administering TIV lowered their own quality of life.
PLEASE SHARE IMPORTANT UPDATES ON MULTI-DISCIPLINARY CARE, SYMPTOM MANAGEMENT, AND COGNITIVE/BEHAVIORAL IMPAIRMENT
Again, it was very clear that many useful interventions and therapies are not being widely utilized. One major recommendation we made was that multidisciplinary clinic referral should be considered for managing patients to optimize health care delivery and prolong survival, and may enhance their QOL.
Specialized multidisciplinary clinics for ALS patients are effective in several ways — including fostering greater use of adaptive equipment and administration of riluzole, PEG, and NIV. There are also several studies indicating improved QOL and longer survival.
WHAT WERE THE RECOMMENDATIONS REGARDING SIALORRHEA?
Almost half of all ALS patients experience sialorrhea, or drooling, and 70 percent of them taking oral medication report some benefit.
In one double-blind, controlled trial of botulinum toxin type B in 20 patients with refractory sialorrhea, treated patients reported a global improvement of 82 percent after two to four weeks compared to 38 percent in the placebo group.
Radiation therapy for medically refractory sialorrhea may also reduce sialorrhea but carries associated side effects.
WHAT DID THE COMMITTEE FIND ON PSEUDOBULBAR AFFECT?
For pseudobulbar affect, dextromethorphan and quinidine (Zenvia) should be considered if approved by the FDA. Avinir Pharmaceuticals announced positive results of its phase 3 study of dextromethorphan/quinidine in August, and plans to submit the data to FDA in the first half of 2010. For patients who develop fatigue while taking riluzole, withholding the drug also may be considered.
WHAT ABOUT THE CARE OF PATIENTS WHO HAVE A COGNITIVE OR BEHAVIORAL IMPAIRMENT?
Although a significant proportion of patients demonstrate cognitive impairment, and some have dementia, neither behavioral impairment in ALS nor the natural progression of cognitive or behavioral impairments has been adequately studied. Screening for cognitive and behavioral impairment should be considered in patients, using accepted neuropsychological assessment tools. It is a rapidly evolving field, and there is little consensus regarding diagnostic criteria and assessment methods.
HOW SHOULD CLINICIANS DEAL WITH FATIGUE IN PATIENTS?
Fatigue may be a symptom of depression, poor sleep, abnormal muscle activation, immobility, or respiratory dysfunction, and is a side effect reported by 26 percent of patients taking riluzole versus 13 percent taking placebo in one study. Once risks of fatigue versus modest survival benefits have been discussed with patients, withholding riluzole may be considered. There are no controlled studies of pharmacologic agents relieving fatigue in ALS.
WHAT INTERVENTIONS REDUCE SPASTICITY?
The evidence in ALS is insufficient to recommend exercise or medication for treating spasticity, and there are insufficient data to support or refute exercise or medication. Nonetheless, in multiple sclerosis and cerebral palsy, benzodiazepam, baclofen, dantrolene, and tizanidine are effective in reducing spasticity-related symptoms.
WERE THERE SUGGESTIONS FOR FUTURE RESEARCH?
We need better measures for evaluating the diagnosis and disclosure to patients, as well as more information on attitudes of neurologists and patients toward strategies for breaking the news.
Controlled trials are also needed regarding pharmacologic therapy for spasticity, cramps, constipation, sialorrhea, pseudobulbar affect, pain, depression, anxiety, fatigue, and therapeutic exercise, as are controlled studies of irradiation and botulinum toxin for sialorrhea.
Finally, consensus criteria for cognitive and behavioral impairment are needed to ensure consistency in diagnosis, and we need to identify optimal screening tests for cognitive and behavioral impairment in ALS patients.