Amyotrophic Lateral Sclerosis
Treatment
In a tamoxifen dose-ranging study, Brooks and colleagues[1] randomized 60 patients (34 men, 26 women) with a mean age of 51 years and a mean ALS Functional Rating Scale (ALSFRS) score of 24 to receive 1 of 5 doses of tamoxifen. Participants were grouped by age, sex, amyotrophic lateral sclerosis (ALS) onset site, and disability, and randomized to the 5 doses from within these groups. When no differences in outcomes were found at 12 months, the study was extended to 24 months. The results demonstrated a survival benefit of treatment with 20-mg, 30-mg, and 40-mg daily doses compared with 10-mg weekly and 10-mg daily doses. However, although survival was prolonged, the investigators found no differences in isometric muscle strength or vital capacity measures among the groups.
This is a preliminary observation in a relatively young patient population with moderately advanced disease. It needs to be replicated in an appropriately powered clinical trial enrolling a more representative patient sample earlier in the course of the disease.
Hypoxia and ALS
Several presentations dealt with the effects of hypoxia in patients with ALS. Moreau and associates[2] showed that vascular endothelial growth factor (VEGF) levels were significantly lower in the cerebrospinal fluid (CSF) of ALS patients compared with neurologic controls. In contrast to hypoxemic neurologic controls, these scientists demonstrated a lack of upregulation of VEGF levels in the CSF of hypoxemic ALS patients. This paradoxical finding suggests the involvement of different mechanisms impairing the upregulation of VEGF during hypoxia in patients with ALS, depriving the motor neurons of the protective effects of VEGF.
By contrast, Devos and coworkers[3] reported an increase in inflammatory cytokines in hypoxemic patients with ALS comparable to that seen in hypoxemic controls. Hypoxemia, rather than ALS, was responsible for the increase. This may explain why the clinical trial of celecoxib in patients with ALS showed no efficacy: It would only have an opportunity to be effective late in the disease, provided that hypoxemia was not controlled, rather than throughout the course of the disease.
Noninvasive Positive Pressure Ventilation
Lechtzin and colleagues,[4] reporting for the ALS CARE Study Group on a small subgroup of patients who at enrollment had a forced vital capacity </= 50% of predicted, showed that the probability of 5-year survival from the date of symptom onset was 53% in 159 patients who used noninvasive positive pressure ventilation (NPPV) compared with 38% in 331 patients who did not use NPPV. This survival advantage remained significant after adjusting for potential confounding variables, including age, sex, riluzole use, forced vital capacity, ALSFRS, and percutaneous endoscopic gastrostomy tube use.
The higher-than-average percentage of survivors in both groups reflects the highly selected patient subgroup, comprising slowly progressing patients cared for in specialized centers. However, it replicates the findings of previous reports supporting the efficacy of NPPV in extending survival in other ALS patient populations, further establishing the benefits of this treatment modality.
Clinical Features: Evidence of Frontal Dysfunction
In a plenary session, Catherine Lomen-Hoerth discussed the spectrum of frontal lobe impairments found in some patients with ALS.[5] Traditionally, ALS has been thought not to affect the mind. However, there has been growing recognition of the presence of symptoms of frontal lobe dysfunction in some patients. These symptoms can be recognized, if looked for, and can be quantified with appropriate tests. When maximally present, they meet the criteria for frontotemporal dementia (FTD) and include evidence of executive cognitive dysfunction (in which sequencing and planning functions are compromised) and behavioral disturbances, such as disinhibition, emotional blunting, and loss of insight. Memory function is preserved. Some patients exhibit 2 partial representations of FTD : a pure executive dysfunction syndrome, in which there are no behavioral disturbances, and "possible FTD," in which behavioral disturbances predominate, but cognition, including executive functions, is preserved.
Flaherty-Craig and Simmons[6] reported on a profile of impairment in both nonbulbar and bulbar ALS that is consistent with acquired deficiencies in self-monitoring, abstract reasoning, and social judgment, with self-monitoring skills more deficient in the bulbar group. These investigators found an association among cognitive deficiencies in self-monitoring during a standardized word-retrieval test, abstract reasoning, and diminished interpersonal problem solving. Such difficulties can impair social judgment and thus compromise relationships not only with family and friends but also caregivers.
Ulug and associates[7] provided imaging evidence in support of these clinical observations. They used Magnetic Resonance Diffusion Tensor Imaging to study 16 consecutive ALS patients and 12 normal controls, and found regions of extensive frontal lobe involvement in patients with ALS, in addition to abnormalities in motor cortex and corticospinal tracts.
ALS patients with frontal dysfunction resulting in impaired insight and social judgment are likely to be difficult to manage by their families, noncompliant with treatment recommendations, and to have shorter life spans. Hence, this feature of ALS may need to be considered as an independent adverse prognostic factor. Ameliorating its impact through directed treatments may have as profound an impact on the course, quality of life, and survival of affected patients as any other available interventions.
Disease Mechanisms
Michael Strong,[8] recipient of the Sheila Essey award for ALS research, presented data showing extensive abnormalities of proteins involved in intracellular transport in the motor neurons of patients with ALS, leading him to term the disease a "proteinopathy." The reason these abnormalities emerge, or why cellular compensatory mechanisms cannot contain them, remains unknown.
MacGowan and colleagues[9] looked for reverse-transcriptase (RT) activity in the sera and CSF of 23 HIV-negative patients with sporadic ALS and compared it with RT activity in the sera and CSF of 21 controls -- patients with other neurologic diseases. They found RT activity in a greater percentage of sera (56% vs 19%, P = .015) and the CSF of ALS patients, although the latter did not reach statistical significance (39% vs 19%, P = .194). The unanswered question is whether this reflects a process that is causal of ALS or a consequence of the disease. Neuronal breakdown may result in the release of human endogenous retrovirus or retrotransposon fragments, which become the substrate for RT. Although further studies assessing possible retroviral infection in the pathogenesis of sporadic ALS may be warranted, the negative findings reported in a study of indinavir in HIV-negative patients with ALS temper the expectation that retroviral infection or release of human endogenous retrovirus will prove to be a cause of the disease, or a significant mechanism in its propagation.
Risk Factors and Epidemiology
Veldink and associates[10,11] reported that polyunsaturated fatty acids and vitamin E reduce the risk of developing ALS; that there is no association of physical activity with the disease; that smoking is a risk factor for ALS ; and that alcohol use is protective. Of interest, a secondary (exploratory) analysis showed an association between the highest levels of leisure physical activity and earlier age of onset. If not due to chance, reasons other than the level of activity itself need to be looked for to explain this observation, as this association was not seen with high levels of occupational activity.
Chiò and colleagues[12,13] presented their published findings of elevated risk for developing ALS among a cohort of Italian professional soccer players who played from 1970 to 2001. The study authors proposed several possible theories to explain their observations. Of these, the physical activity and trauma associated with soccer are least likely, because they are not new or unique features to this sport, and there are conflicting data in other populations. They raise the possibility of environmental toxins to which soccer players may have a prolonged exposure: This direction may be hardest to pursue and, in my opinion, is a less likely explanation than their third hypothesis -- the use of either illegal substances or therapeutic drugs, employed in doses in excess of or for a period longer than generally indicated. This hypothesis is most consistent with the circumstances that led to the special interest in this population of soccer players: A complaint by a football coach regarding the diffusion of illegal drugs among football players led an Italian prosecutor to order an inquiry into the causes of death in a cohort of players who had played in Italian professional and semiprofessional football between 1960 and 1996. That inquiry identified the apparent excess occurrence of ALS in these players. This study was not designed to investigate these hypotheses. Because of the special population in which this risk was observed, the findings cannot be generalized to other populations of athletes, including soccer players.
Junho 2005
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