Survival In Amyotrophic Lateral Sclerosis Patients Research Articles

Predictors of survival in amyotrophic lateral sclerosis

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative disorder of upper and lower motor neurons with a progressive bulbar or limbic muscular atrophy. The average survival in ALS patients lies between 3 to 5 years, but the survival in an individual ALS-patient is known to have a wide variety and is considered to be difficult to predict.

Supramaximal Inflation Improves Lung Compliance in Subjects With Amyotrophic Lateral Sclerosis

Lung compliance has been found to be low in patients with chronic diaphragmatic weakness or paralysis but has not been well-studied in patients with amyotrophic lateral sclerosis (ALS). Noninvasive positive-pressure ventilation (NPPV) prolongs survival in ALS patients but may also have additional beneficial effects. This study evaluated static expiratory lung compliance (CL) in subjects with ALS and determined the effect of lung inflation with supramaximal inflation on CL. This was a prospective trial comparing CL before and after supramaximal lung inflation via mouthpiece-delivered positive pressure. A single university medical center with an multidisciplinary ALS center. Fourteen subjects with ALS were compared to 4 healthy volunteers. Subjects underwent a battery of pulmonary function tests including for CL. Then they used positive pressure administered via a mouthpiece set to 10 cm H2O above their maximal static recoil pressure for 5 min. The CL measurement was then repeated. The mean (+/- SD) baseline CL was reduced (164.1 +/- 82.1 mL/cm H2O) in subjects with ALS and was significantly lower than that in healthy volunteers (237.5 mL/cm H2O; p = 0.04). CL increased significantly in subjects with evidence of diaphragm weakness (change in CL, 11.3 +/- 16.7 mL/cm H2O; p = 0.03). Healthy volunteers did not have an increase in CL. Patients with ALS and diaphragmatic weakness have reduced CL, and brief supramaximal inflation increases CL. These findings suggest that atelectasis or increased alveolar surface forces are present in ALS patients and that these patients will have increased work of breathing. Some of the beneficial effects demonstrated with NPPV therapy may be through its effects on CL and the work of breathing.

Survival of Patients with Amyotrophic Lateral Sclerosis in a Population-Based Registry

Objective: To evaluate the survival of patients with amyotrophic lateral sclerosis (ALS) in an Italian population and to assess the effects of selected prognostic indicators on survival. Background: Median survival of ALS patients has been reported to range between 12 and 23 months from diagnosis and between 23 and 36 months from onset of symptoms. Although several negative prognostic factors have been identified, the overall picture still needs clarification. Methods: We included patients enrolled in an Italian ALS Regional Register (population 4,529,003) during the calendar year 1998. The diagnosis was confirmed by an ad hoc committee using the original El Escorial criteria. Each case was regularly followed up until death or December 31, 2002, whichever came first. Survival was assessed with the Kaplan-Meier method in the whole sample, by level of diagnostic certainty, and by selected prognostic indicators (age, sex, bulbar or spinal onset, and disease duration). Multivariate analysis was done with the Cox proportional hazard function. Results: The sample comprised 79 patients (33 female; 46 male) aged 28–85 years (mean age 64.4 years). Onset of symptoms was bulbar in 30% of cases. Mean symptom duration at diagnosis was 13.3 months. ALS was definite in 43%, probable in 29%, possible in 6%, and suspected in 22%. By December 31, 2002, 56 cases (71%) had died. The cumulative probability of surviving after diagnosis was 78% at 12 months, 56% at 24 months, and 32% at 48 months. Median survival from onset was 39.2 months and from diagnosis 30.6 months. Multivariate analysis confirmed definite ALS at diagnosis and older age as adverse prognostic factors. Conclusions: Survival of ALS patients in the present sample was slightly longer than previously reported. Better palliative care and supportive treatment may explain the difference. Older age and the presence of definite ALS at diagnosis are poor prognostic predictors.

An outcome study of riluzole in amyotrophic lateral sclerosis--a population-based study in Ireland, 1996-2000.

Riluzole is the only therapy proven in clinical trials to prolong amyotrophic lateral sclerosis (ALS) survival (approximately three months). Questions remain concerning riluzole's effectiveness in everyday practice, the appropriate duration of treatment, which certain subtypes of ALS specifically benefit from the medication, and whether early administration prolongs survival in ALS patients. We report the results of a population-based outcome study of riluzole in the Irish ALS population over a five-year period. Using data from the Irish ALS Register, we examined the survival of patients diagnosed with ALS between 1 January 1996 and 31 December 2000 who attended a general neurology clinic (n = 264 patients, MD = 16). An intention to treat analysis is employed. 149 (61 %) patients were prescribed riluzole and the remaining 99 (39 %) were not. Riluzole therapy reduced mortality rate by 23 % and 15 % at 6 and 12 months respectively and prolonged survival by approximately four months. This beneficial effect was lost in prolonged follow-up. Suspected or possible ALS patients receiving riluzole experienced similar improvement in survival as the overall cohort. Survival benefit was more marked among patients with bulbar-onset disease. Multivariate analysis did not show riluzole to be an independent predictor of survival. We conclude that riluzole therapy improves ALS survival in everyday clinical practice by a short period of time. This beneficial effect is transient and stopping the medication in advanced ALS should be reconsidered. Bulbar-onset patients appear to particularly benefit from riluzole for unclear reasons. Our initial observations support riluzole use in early ALS.

Programmed cell death in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a relentless fatal paralytic disorder confined to the voluntary motor system (1). Its prevalence is about three to five in 100,000 individuals, making it the most frequent paralytic disease in adults. Although ALS can strike anyone at any age, generally the onset of the disease is in the fourth or fifth decade of life. Common clinical features of ALS include muscle weakness, fasciculations, brisk (or depressed) reflexes, and extensor plantar responses. Even though motor deficit usually predominates in the limbs, bulbar enervation can also be severely affected, leading to atrophy of the tongue, dysphagia, and dysarthria. Other cranial nerves (e.g., oculomotor nerves) are usually spared. The progressive decline of muscular function results in paralysis, speech and swallowing disabilities, emotional disturbance, and, ultimately, respiratory failure causing death among the vast majority of ALS patients within 2–5 years after the onset of the disease. Pathologically, ALS is characterized by a loss of upper motor neurons in the cerebral cortex and of the lower motor neurons in the spinal cord. Often, there is also a profound degeneration of the corticospinal tracts, which is most evident at the level of the spinal cord. The few remaining motor neurons are generally atrophic, and many demonstrate abnormal accumulation of neurofilament, in both their cell bodies and axons. To date, only a few approved treatments (e.g., mechanical ventilation and riluzole) prolong survival in ALS patients to some extent. However, the development of more effective neuroprotective therapies remains impeded by our limited knowledge of the actual mechanisms by which neurons die in ALS, and of how the disease progresses and propagates. ALS, like other common neurodegenerative disorders, is sporadic in the vast majority of patients, and familial in only a few (1). The clinical and pathological expressions of ALS are almost indistinguishable between the familial and sporadic forms, although often in the former the age at onset is younger, the course of the disease more rapid, and the survival after diagnosis shorter (1). The cause of sporadic ALS remains unknown, while that of at least some familial forms has been identified (see below). Although the identified gene defects responsible for ALS account for a minute fraction of cases, most experts believe that unraveling the molecular basis by which those mutant gene products cause neurodegeneration may shed light on the etiopathogenesis of the common sporadic form of ALS.

Disease progression in amyotrophic lateral sclerosis

This study reports the results of a long-term economic evaluation of riluzole in the treatment of amyotrophic lateral sclerosis (ALS) versus best supportive care in the United Kingdom. The analysis included in this contribution aims to provide an update of the determination of the phase of the disease that is prolonged by riluzole and also to assess the quality of the life extension offered by riluzole by taking into account the patients' utility score. Specifically, the analysis provides a more specific estimate of the cost-utility of riluzole dependent disease stage, thereby providing a useful insight of the cost-effectiveness of therapy. A Markov model was used to assess the cost-effectiveness of riluzole versus best supportive care. Transition possibilities and the distribution of patients by health states were taken from a cohort of 954 patients drawn from a large randomised, double blind, placebo-controlled, multicentre trial between 1992 and 1994. Costs associated with riluzole included the acquisition cost and bi-monthly monitoring for raised ALT levels. Patient assessed utilities were collected by use of the SG technique from two centres (King's, London and Preston) in the UK. Four distinct health states were used corresponding to mild, moderate, severe and terminal states. Applying the Markov model and extending the transitional probabilities using linear interpolation, the base case cost per life year gained was estimated at 15,192 pounds while applying Standard Gamble utility scores, the base case cost per quality-adjusted life-year (QALY) was assessed at 22,086 pounds. Carrying out a probabilistic sensitivity analysis, the cost per QALY was estimated at 22,236 pounds with standard deviation of 612 pounds. The results of the long-term analysis also show that riluzole on average increases survival in ALS patients by 6 months with approximately 5 months of the additional life gained in the early disease states, of which 4 months is spent in disease state 2, where quality of life is relatively high. However, the model is sensitive in the way in which the long-term transitional probabilities are estimated. Using averages of the first nine cycles, the cost per QALY would increase to 33,420 pounds with standard deviation of 972 pounds. Thus, this analysis highlights some of the difficulties associated with extending the short clinical effectiveness data; one way forward would be to obtain long-term observations data for both groups.

Disease progression in amyotrophic lateral sclerosis: predictors of survival.

Predicting the rate of disease progression has become important as trials of new medical treatments for amyotrophic lateral sclerosis (ALS) are planned. Bulbar onset, early impairment of forced vital capacity, and older age have all been associated with shorter survival. We performed a retrospective study to compare survival factors with disease progression in a German ALS population. We analyzed disease progression in 155 patients at intervals of 4 months over a period of 3 years. To evaluate disease progression, the ALS functional rating scale (ALS-FRS), forced vital capacity (FVC%), and a Medical Research Council (MRC) compound score based on a nine-step modified MRC scale were used. We compared age (< 55 years vs. > or =55 years), different sites of disease onset (bulbar vs. limb), and gender to the rate of disease progression and performed survival analyses. No overall significant difference could be detected when analyzing these subgroups with regard to disease progression. By contrast, significantly longer survival was observed in the younger age group (56 months vs. 38 months, P < 0.0001) and in patients with limb-onset disease (51 months vs. 37 months, P = 0.0002). Using Cox analyses values we found that the declines of ALS-FRS, FVC%, and MRC compound score were predictive of survival (P < 0.0001, P = 0.002, and P = 0.003, respectively). Future studies are needed to clarify whether nonspecific factors including muscle atrophy, dysphagia, and coexisting diseases influence prediction of survival in ALS patients. A more precise set of predictors may help to better stratify patient subgroups for future treatment trials.

Riluzole in Amyotrophic Lateral Sclerosis

Publisher Summary This chapter discusses the efficacy of riluzole in the treatment of amyotrophic lateral sclerosis (ALS). Riluzole has been demonstrated to increase the survival of patients suffering from ALS, a rapidly fatal neurodegenerative disease affecting motoneurons (MNs), in two double-blind placebo-controlled studies. Two independent double-blind placebo-controlled studies were conducted to demonstrate the efficacy of riluzole. In the first study, the benefit was observed in the whole population, but mainly for the patients with the bulbar onset form of the disease. Riluzole showed a dose-related neuroprotective effect on the hypobaric hypoxic quantitative electroencephalogram modifications by comparison with placebo. In the second study, the benefit was clearly not limited to these patients but was observed in both groups. Survival analyses have demonstrated that riluzole is able to delay the progression of the disease and increases the survival of ALS patients. It is found that riluzole efficacy in patients suffering from ALS supports an involvement of excitatory amino acids, as a primary or secondary event, in ALS etiology.