The natural history of amyotrophic lateral sclerosis and the use of natural history controls in therapeutic trials

Abstract

We analyzed the natural history of amyotrophic lateral sclerosis in 277 patients. Our goal was to develop a better understanding of the clinical disease and thus improve the design of therapeutic trials. The Tufts Quantitative Neuromuscular Exam (TQNE) was used as the primary assessment instrument. Our analysis suggested that although more observations are desirable, six monthly TQNEs were adequate to establish the rate of disease progression. We observed a spectrum of deterioration rates without definable subgroups. The striking linearity of deterioration was confirmed. We found a high correlation between deterioration rates in arm and leg strength for individual patients, but a wide range between different patients. Sex and the age at clinical onset did not affect the deterioration rate. As compared with patients without a positive family history, those with other affected family members had a slower loss in arm but not leg strength. We propose that natural history controls can be used effectively in the design of ALS therapeutic trials.

Predictability of disease progression in amyotrophic lateral sclerosis

“…Moreover, given the well-known correlation between disease progression and survival, [12][13][14]34 we expected to find that age at onset, time between first symptom and first examination, and site of symptom onset, well established predictors of survival in ALS, also act as significant and independent covariates of disease progression, although such findings remain at odds with some previous reports. 22,23,28,30 We also found that initial FVC was significantly associated with disease progression, even after adjustment for age, gender, and site of onset. Moreover, in our previous study, this association between FVC and disease progression remained significant even after additional correction for FS-FE time and riluzole use.…”

“…Based on our present data, as well as on our previous reports, 10 we suggest that patients be assigned to treatment groups by stage of disease (AALS total score at the time of first examination) and initial rate of clinical decline. However, we 13,35,36 and others 19,28 have previously suggested that the correlation between predicted and actual rate of clinical decline is stronger if more data points are available for every patient. By contrast, both the preslope-based and FE-based predictions of the subsequent rate of disease progression require only one measurement be performed at the initial examination.…”

“…22 Other previous studies also failed to demonstrate a correlation between different measures of disease progression (e.g., the Tufts Quantitative Neuromuscular Examination, TQNE) and age at onset or gender. 28,30 In addition, the deterioration of FVC was not related to the site of onset in a group of 49 ALS patients analyzed by Marti-Fabregas et al 23 In the present study we used the time to 20-point increase in AALS total score from baseline examination as an index of disease progression. Using the Cox proportional hazards model, five parameters were determined to be significant and independent covariates of disease progression: age, site of symptom onset, FS-FE time, total initial AALS score at first examination, and AALS score preslope.…”

Progression in ALS is not linear but is curvilinear

“…Although data are conflicting [2,3], many authorities consider that ALS follows a linear course [4][5][6] and research indicates that functional status might predict survival [7], but the true shape of the progression curve as well as the best means to identify patients with similar survival rates are not known; some of the most severely disabled patients are among the longest survivors. Defining the shape of the progression curve and phenotypes with distinct survival patterns has implications for clinical care and study design.…”

The Neuroinflammation in the Physiopathology of Amyotrophic Lateral Sclerosis

“…The pattern of neurodegeneration in ALS has been described as overall linear, albeit with some variations [228,229]. One of the biggest discrepancies between individuals is the evolution of the disease, which ranges from death in less than 6 months to a limited handicap after more than 10 years following the initial diagnosis.…”