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.
MOOD AND COGNITION
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.
TRIALS AND FUTURE PROSPECTS
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(Drug information on pentoxifylline) and xaliproden, were shown to be possibly deleterious.5 As for riluzole(Drug information on 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(Drug information on ceftriaxone) (Rocephin), minocycline(Drug information on 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(Drug information on 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(Drug information on memantine) (Namenda), glatiramer acetate(Drug information on glatiramer acetate) (Copaxone), and thalidomide(Drug information on 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.
HOPE AND PURPOSE
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.
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