The frontotemporal syndrome of ALS is associated with poor survival

Abstract

Thirty percent of ALS patients have a frontotemporal syndrome (FS), defined as behavioral changes or cognitive impairment. Despite previous studies, there are no firm conclusions on the effect of the FS on survival and the use of non-invasive ventilation (NIV) in ALS. We examined the effect of the FS on survival and the start and duration of NIV in ALS. Behavioral changes were defined as >22 points on the ALS-Frontotemporal-Dementia-Questionnaire or ≥3 points on ≥2 items of the Neuropsychiatric Inventory. Cognitive impairment was defined as below the fifth percentile on ≥2 tests of executive function, memory or language. Classic ALS was defined as ALS without the frontotemporal syndrome. We performed survival analyses from symptom onset and time from NIV initiation, respectively, to death. The impact of the explanatory variables on survival and NIV initiation were examined using Cox proportional hazards models. We included 110 ALS patients (76 men) with a mean age of 62 years. Median survival time was 4.3 years (95 % CI 3.53-5.13). Forty-seven patients (43 %) had an FS. Factors associated with shorter survival were FS, bulbar onset, older age at onset, short time to diagnosis and a C9orf72 repeat expansion. The adjusted hazard ratio (HR) for the FS was 2.29 (95 % CI 1.44-3.65, p < 0.001) in a multivariate model. Patients with an FS had a shorter survival after NIV initiation (adjusted HR 2.70, 95 % CI 1.04-4.67, p = 0.04). In conclusion, there is an association between the frontotemporal syndrome and poor survival in ALS, which remains present after initiation of NIV.

Keywords: Amyotrophic lateral sclerosis; Behavioral changes; Cognitive impairment; Frontotemporal syndrome; Non-invasive ventilation; Survival.

Fig. 1

Venn diagram of the classification of amyotrophic lateral sclerosis patients (n = 110)

Fig. 2

a Kaplan–Meier analysis of the effect of frontotemporal syndrome on ALS survival. Log-rank test for equality of survival functions, p = 0.005. Black line ALS patients without frontotemporal syndrome (n = 63); dotted line ALS with frontotemporal syndrome (n = 47); +: censored cases (n = 23). b Kaplan–Meier analysis of the effect of cognitive impairment and/or behavioral changes on ALS survival. Black line classic ALS patients, without frontotemporal syndrome (n = 63); dotted line ALS with cognitive impairment (n = 18, p = 0.012); dashed line ALS with behavioral changes (n = 16, p = 0.02); dotted/dashed line ALS with both cognitive impairment and behavioral changes (n = 13, p = 0.10); +: censored cases (n = 23); four patients (two censored) who had a survival time of 15.6–29 years are not displayed in this figure

Fig. 3

Kaplan–Meier analysis of the effect of the frontotemporal syndrome on ALS survival following initiation of NIV. Log-rank test for equality of survival functions, p = 0.003. Black line ALS patients without frontotemporal syndrome (n = 29); dotted line ALS with frontotemporal syndrome (n = 14); +: censored cases (n = 12)