Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS

A challenge in ALS research is to determine differences between patients who progress at different rates.¹ The search for clinical markers of disease progression is particularly important. Predicting survival time in ALS helps physicians and patients to make decisions regarding assisted ventilation.

Age, bulbar onset, nutrition state, and respiratory function are factors affecting prognosis in ALS.² Recently, these factors provided insight into predicting survival times for ALS, identifying the total score for the revised ALS Functional Rating Scale (ALSFRS-R) as a strong predictor of prognosis.^3,4

The ALSFRS-R is increasingly used to assess survival outcomes in clinic patients and clinical trials for ALS. However, changes over time in the ALSFRS-R have not been examined sufficiently.

In this study, we examined the significance of the progression rate by adding a time axis at diagnosis and conducting comparisons with total ALSFRS-R score alone.

Methods.

A total of 115 consecutive patients with ALS had been admitted to our hospital by the end of 2004 and were interviewed by neurologists and diagnosed based on physical findings and EMG. Subjects in the present study comprised 82 Japanese patients with sporadic ALS who underwent follow-up at our hospital or for whom exact information was available regarding primary endpoint (PEP) (death or time culminating in death without tracheostomy or ventilation assistance including noninvasive positive pressure ventilation).⁵ The remaining 33 patients were excluded due to a lack of survival status information available after diagnosis (n = 7), concomitant cancer (n = 5), complication with dementia (n = 4), family history of ALS (n = 3), undetermined time of symptom onset in patients with cervical spondylosis (n = 2), or initial diagnosis at another institute (n = 12). All patients with “possible” (n = 15), “probable” (n = 32), or “definite” (n = 35) ALS on initial diagnosis were included and later confirmed as “definite ALS.”⁶ Mean duration of follow-up (± SD) was 2.45 ± 1.03 years. Assessment of ALSFRS-R was recorded at “time of diagnosis” during hospitalization. Progression rate (ΔFS) was calculated as: ΔFS = (48 − ALSFRS-R at “time of diagnosis”)/duration from onset to diagnosis (month).

Time of initial onset was determined based on subjective complaints and information confirmed from family members. Data for ΔFS represented a fixed covariate at baseline of diagnosis.

Patients were divided into two groups according to ΔFS about the median (Group I, ΔFS <0.67 vs Group II, ΔFS ≥0.67) and into three arbitrary groups (ΔFS <0.5 vs 0.5≤ΔFS <1 vs ΔFS ≥1). Symptoms started in the upper limbs in 32 patients (39%), in the lower limbs in 27 (33%), as bulbar symptoms in 15 (18%), as combined type in seven (9%), and in respiratory muscles in one (1%). Combined-type ALS was defined as two regions presenting simultaneously at initial onset.

Patients were also divided into two groups according to ALSFRS-R score at baseline about the median for total ALSFRS-R (ALSFRS-R <38 vs ALSFRS-R ≥38).

Clinical characteristics were compared between Groups I and II using Student's t test for continuous variables or the χ² test for categorical variables. Associations between ΔFS or ALSFRS-R categories and postdiagnostic period until PEP were examined using the Kaplan–Meier curve and differences were analyzed using the log-rank test and the Cox proportional hazards model.

Results.

Clinical profiles of Groups I and II were shown in table 1. No significant differences in mean age at onset, sex, percent forced vital capacity, or body mass index at time of diagnosis were identified between Groups I and II. Mean duration from onset to diagnosis was 14.2 months. Median survival time (MST) was 31.4 months from onset and 17.2 months from diagnosis.

In Group II, with faster progression, duration until diagnosis was significantly shorter and the mean ALSFRS-R score was significantly lower than in Group I. No differences between Groups I and II were found in site of initial onset except for combined onset, for which all patients were in Group II. Mean ΔFS for combined-type ALS was relatively high (1.87) and prognosis was poor (MST, 8.3 months; log-rank test p < 0.001) compared with any other site of onset.

Significant differences in survival time from diagnosis until PEP were noted between Groups I and II and among each group from the slowest to the highest ΔFS (figure). Kaplan–Meier survival rates also differed significantly between groups with total ALSFRS-R <38 or ≥38 (table 2).

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Figure. Kaplan–Meier survival plots of patients according to progression rate in postdiagnostic period until primary endpoint (death or time culminating in death without tracheostomy or ventilation assistance) in ALS (n = 82). Risk of death or tracheostomy increased progressively from slowest to fastest progression rate (ΔFS <0.5 [n = 29]; 0.5≤ΔFS <1 [n = 28]; ΔFS ≥1 [n = 25]).

Using simple nominal variables of Cox proportional hazards model, survival was also found to differ between Groups I and II (p = 0.005) and between the three arbitrary groups (ΔFS <0.5 vs 0.5≤ΔFS <1, p = 0.019; 0.5≤ΔFS <1 vs ΔFS ≥1, p = 0.008; ΔFS <0.5 vs ΔFS ≥1, p = 0.003) of progression rate, whereas no significant difference in the Cox proportional hazards model of survival was noted between total ALSFRS-R <38 or ≥38, in contrast to log-rank test, adjusting for age and sex (table 2).

Discussion.

ALS is thought to have already undergone gradual progression by the time symptoms manifest, involving a long preclinical period.⁷ If the state of progression could be determined at the diagnostic stage, future progression might be predicted. We therefore analyzed ΔFS based on the ALSFRS-R score at the time of initial diagnosis.

Mean duration from onset to diagnosis in the present study was 14.2 months. According to international surveillance, median duration from onset until diagnosis is 14 months.⁸ The present data at our institution from Japanese patients with ALS were almost identical to data from populations in Western countries.⁹ Values at diagnosis are therefore worth investigating.

The significantly shorter duration until diagnosis in Group II supports previous data suggesting that prognosis decreases with earlier diagnosis.¹⁰ Duration of the prediagnostic period represents an important piece of information for predicting postdiagnostic duration until PEP. Therefore, data for ΔFS including both factors of ALSFRS-R score and symptom duration until diagnosis will be a better prognostic indicator compared to ALSFRS-R score alone.

Regarding site of initial onset, all patients with combined-type ALS belonged to Group II and displayed poor prognosis compared with all other sites, even bulbar. Combined type of ALS thus represents one factor suggestive of poor prognosis.

Total ALSFRS-R score on initial presentation is a significant predictor of mortality. We agree with the validity of total ALSFRS-R score as a predictor of survival time. In our data, however, Cox proportional hazards models revealed no significant difference between groups with ALSFRS-R scores <38 or ≥38. One possible interpretation regarding the lack of a strong association between ALSFRS-R score at evaluation and prognosis is that if patients with a high total ALSFRS-R score progress rapidly, statistical differences would appear to be lost only for evaluation of prognosis using ALSFRS-R score alone.

Risk of death or tracheostomy increased progressively from lowest to highest ΔFS. ΔFS using ALSFRS-R scores at baseline diagnosis with symptom duration forms an index as a predictor of survival, enabling evaluation of the disease process. As a result, ΔFS at the time of diagnosis in each patient appears more closely associated with future progression to PEP.

In conclusion, one-point evaluation for ΔFS at time of diagnosis could be used in the follow-up of individuals with ALS in therapeutic trials.