Raising the Bar on ALS Care: It's Possible and Appreciated


Presenting a diagnosis of amyotrophic lateral sclerosis (ALS) is one of the most difficult tasks that a neurologist may have to undertake. Despite the tragic quality of the news, experts in ALS care are exhorting fellow neurologists not to give up on patients in whom ALS is diagnosed.

Presenting a diagnosis of amyotrophic lateral sclerosis (ALS) is one of the most difficult tasks that a neurologist may have to undertake. Despite the tragic quality of the news, experts in ALS care are exhorting fellow neurologists not to give up on patients in whom ALS is diagnosed.

The disease can be managed and patients can achieve an acceptable quality of life (QOL)-and even be made to feel purposeful-as they live with the illness. "The important thing to remember is that although ALS can't be cured, it can be managed. If we can offer patients hope and assure them that we will work closely with them to manage the complications that arise and help them through a very confusing and complicated pathway, it will be appreciated," remarked Zachary Simmons, MD, professor of neurology and director of the Neuromuscular Program and ALS Clinic at Penn State Milton S. Hershey Medical Center in Hershey, Pennsylvania.

Delivering the diagnosis is particularly difficult, but guidelines exist to help office-based physicians meet the challenge. The practice parameter of the American Academy of Neurology (AAN) on care of the patient with ALS1 encourages physicians to:

  • Schedule ample time in a comfortable, quiet atmosphere to present the diagnosis in person to the patient and the patient's caregiver or other support person in a direct but compassionate way.
  • Inform the patient, in plain language, that the disease is incurable and progressive but that the complications are treatable and that the prognosis is variable.
  • Be open to the patient's desire to seek a second opinion.
  • Reassure the patient that he or she will be cared for and that all efforts will be made to maintain function.
  • Evaluate what the patient already knows about ALS and how much he wants to know at that time, and direct the patient to information resources and support services.
  • Encourage the patient to participate in clinical trials.

"I think 'breaking the news'-and whether it has been done well or badly-is something the patient will remember for the rest of his life. Most patients will tell you that it is a relief to have a diagnosis even if it is not a good one," Simmons remarked. "The challenge is being honest without taking away all hope. The typical worst-case scenario is to be told, 'You have ALS. This is a fatal neurological disorder. There is nothing I can do. You need to go home and get your affairs in order.'"

A similar sentiment was related by Walter G. Bradley, DM, FRCP, professor and chairman of the Department of Neurology at the University of Miami Miller School of Medicine. "Having no effective medications to arrest the disease or get back lost function makes ALS a very depressing subject even for professionals," he explained, which may lead some general neurologists to appear callous in presenting the diagnosis. "I've heard this for 40 years now from patients: 'The neurologist I first saw said you've got a progressive disease; you're going to be dead in 18 months. Go home, put your affairs in order, and enjoy what little life you have left.' It is a very callous and self-protective approach for a neurologist who feels inadequate. But we all feel inadequate in the face of this disease," Bradley said.

"In presenting the diagnosis, you need to give the patient and family time to understand," Bradley, a coauthor of the AAN ALS practice parameter, continued. "You can't do this at the end of a 20-minute follow-up. You have to schedule another half to 1 hour to meet with the family a week or so after you've had to face them with the diagnosis. At this time, it is important to give the patient access to all the information that is available: the Web sites, publications, etc."

Office-based neurologists who have a dark view of how to manage patients with ALS can find inspiration in gains made by specialized ALS centers. "It is clear that 2 management mechanisms of ALS alter longevity and QOL in affected patients. These are nutritional care with feeding gastrostomy tube placement when swallowing becomes inadequate and respiratory function support with noninva-sive positive pressure ventilation [NPPV]," noted Bradley. "Both interventions improve function."

Simmons stressed this point as well. "You do improve QOL using noninvasive ventilatory support because sleep quality improves. Patients have more energy; they sleep better. They survive longer but with an improved QOL," Simmons said. He added that, although the literature is soft on whether a gastrostomy tube improves QOL, his observation-which was echoed by Bradley-is that improving nutrition and hydration is of benefit. "Patients have an overall feeling of well- being. They don't have to deal with swallowing problems and the choking and gagging that comes with bulbar dysfunction," said Simmons. Bradley added that ventilatory support and feeding tubes probably enhance function and survival simply because the patient is getting adequate nutrition and oxygen. Lack of these probably plays a role in acceleration of disease progression, he said.

A study by Traynor and colleagues2 showed that an aggressive multidisciplinary care model, which is generally provided at ALS clinics, improves outcomes. The study, which looked at comprehensive multidisciplinary ALS clinics in Ireland, found that compared with the 1-year mortality rate seen among patients receiving care from general neurology practices, the 1-year mortality rate in patients attending ALS clinics was reduced by nearly 30%.3

The study by Bradley and colleagues, which reviewed how well the AAN ALS care practice parameter had been adopted, found that the overall standard of care of patients with ALS had improved since the parameter was published in 1999.3 The study was based on evaluation of information in the ALS Clinical Assessment, Research, and Education (CARE) database, which primarily contains information on patients attending ALS clinics. Bradley and coauthors offered this up as a caveat: their study elucidates how well ALS clinics in the United States are serving patients with ALS, but the quality of care in the general community is undocumented. Bradley commented that, because most specialists in ALS care came from general neurology practices and remember a time before the advent of ALS clinics, they have a good idea of what goes on in general practice and know that it is not the multidisciplinary care that is provided by specialized clinics.

"There are 3 reasons why specialized ALS centers are able to provide better care," said Bradley. "The first is the multidisciplinary team approach. The second is that, by and large, the neurologists who run specialized centers have proved that they are empathetic to persons with ALS." Bradley reiterated that the third factor, which he stressed was significant, was the more common use of gastrostomy tubes and ventilatory support in the specialized clinic setting.

According to Bradley, ALS centers are far more proactive in providing function- and life-sustaining interventions than general neurology practices. He suggested that those working in general neurology practices should examine what they can adopt from the specialty care model because many patients do not have access-whether because of geography or other factors-to specialized clinics.

Although Bradley and his coauthors pointed out that use of gas- trostomy tubes and NPPV in- creased significantly since publica- tion of the AAN ALS care practice parameter,3 these interventions are still underused. The study by Bradley and colleagues suggested that lack of use is often patient- driven and is related to perceptions, preferences, and tolerance issues. Simmons' view about underutilization of feeding tubes and ventilatory support goes back to judgments on the part of physicians about QOL and prolongation of life in the face of a disorder that exacts severe debility before death.

"If you look at the ALS CARE database, it will show that if you compare the number of persons who get gastrostomy tubes and NPPV with the number of persons who should get them according to the AAN ALS practice parameter, it's very low. Why? The attitude, unfortunately, is that perhaps it would be better for death to come sooner," Simmons said.

"Some physicians feel that if we can't cure or stabilize an illness, then we are not contributing meaningfully to the patient," Simmons continued. "Physicians who treat ALS have come to a different conclusion."

His recommendation, like that of Bradley, is that in the absence of access to an ALS clinic, the general neurologist should make an effort to offer the patient what the system can provide: home care, hospice care, equipment, supplies, information, medication for pain, and management of symptoms.

Simmons and colleagues are currently working in collaboration with the Amyotrophic Lateral Sclerosis Association (ALSA) to improve care in underserved areas with the goal of providing support and resources to office-based neurologists. "We're looking at ways to improve access to care either through satellite clinics, telemedicine, or something along those lines," he said.

Another aspect of ALS management is monitoring patients' ability to emotionally cope. Mood-modifying agents should be prescribed if anxiety or depression become problematic, noted Simmons. Some patients may need a referral to mental health counseling, but Simmons stressed that, more important, patients need a support system, which should be defined by the patient. For some, support is derived, for example, from friends, family, and from advocacy and patient-to-patient outreach; for others from spirituality and religious affiliations; and for others from mental health interventions. "As physicians, we need to be sensitive to which support systems work for an individual patient," he said.

The patient also needs to be monitored for frontotemporal deficits, which can affect the ability to make appropriate care and endof-life decisions. Simmons and his team recently published an article demonstrating the value of a rapid screening battery to assess cognitive dysfunction in persons with ALS.4 They evaluated 110 patients with ALS (40 had bulbar involvement) and 24 controls using a 20-minute neuropsychological assessment.

Overall, 28.7% of patients with ALS showed deficiencies in verbal associative fluency. Of patients with bulbar involvement, more than a third (37.5%) had deficits in this domain. About 22% demonstrated deficits in abstract reasoning, and 35.7% of patients with nonbulbar disease and 60% of patients with bulbar disease demonstrated deficits in judgment. Patients with bulbar disease had higher deficit scores for all domains tested than did patients with nonbulbar disease.

Cognitive dysfunction is underrecognized, according to Simmons. "Much of the literature implies that there isn't much cognitive dysfunction in ALS; however, it isn't uncommon," he said. "We don't know whether everyone with ALS will develop cognitive dysfunction if they survive long enough, but we've identified a fairly large subgroup and are looking into this now." He added that he and colleagues also are investigating interventions that need to be put in place for patients in whom cognitive deficits are identified.

Drug trials for ALS treatments have been disappointing. Most agents that appeared to be promising in animal models have not produced results in humans-and some, such as pentoxifylline and xaliproden, were shown to be possibly deleterious.5 As for riluzole (Rilutek), which the FDA approved because it showed modest improvement in survival, a controversy exists about whether giving a rather expensive drug to a patient so that he can live an average 3 months longer regardless of function is of value, said Bradley. He holds the view that any drugs that enter the ALS treatment armamentarium in the near future probably will be equivalent in effect and cost to riluzole; nevertheless, the search forges onward.

Traynor and colleagues recently reviewed 113 neuroprotective agents, which they narrowed down to 20 agents for possible study in phase 3 trials.6 Of these, ceftriaxone (Rocephin), minocycline, the neurotrophic factor insulin-like growth factor 1 polypeptide, and ONO-2506 already are in phase 3 trials. Ceftriaxone is thought to protect against glutamate toxicity, minocycline may prevent motor neuron apoptosis associated with mutant SOD1 aggregation effects, and ONO-2506 prevents astrocytosis.6

The researchers named talampanel, an AMPA glutamate receptor modifier developed for use in epilepsy, and tamoxifen, a kinase C inhibitor, as agents suitable for phase 3 trials in the near future. As for the remaining agents in Traynor and colleagues' top-20 list, which include such agents as coenzyme Q10, memantine (Namenda), glatiramer acetate (Copaxone), and thalidomide, more data are required to evaluate the value of phase 3 investigation.

Hope may still lie in neuro- trophins, according to Bradley. In his view, trials of neurotrophins were unsuccessful for the treatment of ALS because of challenges in getting polypeptides into the cells that need them. "Small molecular weight compounds that could stimulate receptors and be taken by mouth could be developed," he explained. "There hasn't been a major push in industry for developing such agents, but there ought to be because they probably would be useful for a wide range of neurological diseases," Bradley contended.

He added that the pharmaceutical industry dropped research and development of neurotrophins for ALS "like a hot potato" because too much money was lost in the endeavor. "No one wants to talk about it anymore," Bradley remarked. "There are models that may be effective but they are not being developed. Most of the clinical trials have gone back to the physicians and researchers who must get funding from the NIH, ALSA, and those types of sources, because the pharmaceutical industry has dropped out."

Both Bradley and Simmons remarked that effective treatments for ALS would not enter the picture until the cause of the disease was fully elucidated. A combination of genetic and environmen- tal factors is probably at play. Bradley noted that exposure to environmental toxins-specifically Cyanobacteria, which produce the atypical amino acid b-methylamino-l-alanine-may be more significant than currently recognized and is probably tied in with predisposing genetic factors.

Simmons noted that ALS is probably associated with multiple causative factors and has multiple variations that respond to different interventions. "It is probably a combination of complex genetic predisposition with superimposed triggers that are acquired or environmental. The combination is not always the same for people," Simmons said, so it is not a surprise that clinical trial results have been disappointing.

"Ideally, I see clinical trials developing on the basis of genetic work," said Simmons. He reported that recent research conducted by the NIH and other groups have identified a number of genes specific to patients with ALS. He also explained that a project is under way that aims to collect blood from 2000 persons with ALS and 2000 controls to examine genetic differences. "If we can identify genes that are different in persons with ALS, we can stratify patients based on genetic differences and collect epidemiological data to provide insight into environmental factors. Once this is done, we can classify ALS in different ways. Then we can do trials that focus on specific ALS subtypes," said Simmons.

Although Simmons believes that discovering the genetics of ALS is close at hand, both he and Bradley concede that beyond symptom management, treatments to intercept the disease are for the future. This is additional difficult news for patients and their families. Bradley, however, made a strong point about the value to patients of entering clinical trials.

"The reason is 2-fold," he said. "First, patients participating in clinical trials are seen more frequently and are generally seen by caring multidisciplinary teams; they get a better level of care, resulting in better patient outcomes. Second, the psychological impact of taking part in research for persons who have been told that they have an untreatable disease is phenomenally important." Patients derive significant personal satisfaction and sense of purpose in the thought that even though they may not derive the benefit, their participation in a clinical trial may one day help other persons affected by ALS, said Bradley.

REFERENCES1. 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. Traynor BJ, Alexander M, Corr B, et al. Effect of a multidisciplinary amyotrophic lateral sclerosis (ALS) clinic on survival: a population based study, 1996-2000. J Neurol Neurosurg Psychiatry. 2003;74:1258-1261.
3. Bradley WG, Anderson F, Gowda N, Miller RG; ALS Care Study Group. Changes in the management of ALS since the publication of the AAN ALS Practice Parameter 1999. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004;5:240-244.
4. Flaherty-Craig C, Eslinger P, Stephens B, Simmons Z. A rapid screening battery to identify frontal dysfunction in patients with ALS. Neurology. 2006:67:2070-2072.
5. Meininger V. Clinical trials in ALS: what did we learn from recent human trials. Neurodegenerative Dis. 2005;2:208-214.
6. Traynor BJ, Bruijn L, Conwit R, et al. Neuroprotective agents for clinical trials in ALS. Neurology. 2006;67:20-27.

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