Episodic Ataxia Type 1: Natural History and Effect on Quality of Life

Abstract

Episodic ataxia type 1 (EA1) is a rare autosomal potassium channelopathy, due to mutations in KCNA1. Patients have childhood onset of intermittent attacks of ataxia, dizziness or imbalance. In order to quantify the natural history of EA1, its effect on quality of life and in preparation for future clinical trials, we set up an international multi-centre study of EA1. We recruited thirty-three participants with EA1: twenty-three completed 1-year follow-up and eighteen completed 2-year follow-up. There was very little accumulation of disability or impairment over the course of the 2 years of the study. The outcome measures of ataxia (SARA and functional rating of ataxia) and the activities of daily living scale were largely stable over time. Self-reported health-related quality of life (SF-36) scores were lower across all domains than controls, in keeping with a chronic condition. Physical subdomain scores appeared to deteriorate over time, which seems to be driven by the female participants in the study. This is an interesting finding and warrants further study. Attacks of EA1 reported by participants in real time via an interactive voice response system showed that symptoms were not stereotyped; however, attack duration and frequency was stable between individuals. This large prospective study is the first ever completed in subjects with EA1. We document the natural history of the disorder over 2 years. These data will enable the development of outcome measures for clinical trials of treatment.

Keywords: EA1; Episodic ataxia type 1; KCNA1; Natural history; SF-36.

Fig. 1

Measures of disability. (a) Change in Scale for the Assessment and Rating of Ataxia (SARA) score over the duration of the study. The SARA score ranges from 0 to 40, with 0 indicating no ataxia and 40 the most severe degree of ataxia. Five participants were stable at 0. SARA scores were analysed for each time point for all participants (n = 18) and compared between baseline, year 1 and year 2. This analysis was performed for the total cohort as well as both subgroups (EA with attacks alone and EA attacks with persistent cerebellar ataxia (PCA)) to see if one group was influencing the results for the entire cohort. Data shows mean ± SEM. (b) Change in functional rating of ataxia over the duration of the study. Evaluator rated classification of the severity of ataxia over three visits (n = 18). Functional rating of ataxia ranges from 1 to 6, where 1 represents minimal signs and no disability whilst 6 is total disability. These stages were (1) minimal signs detected by the physician during screening but able to run or jump without loss of balance, representing no disability. (2) Symptoms recognised by the patient but still mild. However, there is an inability to run or jump without losing balance. The patient is physically capable of living an independent life, but daily activities may be somewhat restricted, representing minimal disability. (3) Overt and significant symptoms requiring regular or periodic holding on to wall or furniture or use of a stick for stability and walking, representing moderate disability. (4) Requiring a frame, crutches or two sticks to walk, being able to perform several activities of daily living, representing moderate disability. (5) Confined but can navigate a wheelchair, performing some activities of daily living that do not require standing or walking, representing severe disability. (6) Confined to wheelchair or bed with total dependency for all activities of daily living, representing total disability. Where the evaluator felt that the status was about the middle between two stages, an increment of 0.5 could be used. Functional rating of ataxia scores were analysed for each time point for all participants (n = 18) and compared between baseline, year 1 and year 2. This analysis was performed for the total cohort as well as both subgroups (EA with attacks alone and EA attacks with persistent cerebellar ataxia (PCA)) to see if one group was influencing the results for the entire cohort. Data shows mean ± SEM. (c) Change in activities of daily living (ADL) score over the duration of the study. An activities of daily living (ADL) assessment covered the ability to wash, dress, swallow, breathe, walk, sit, toilet and whether there were any falls, with a maximum score of 36 (0 being no impairment). This was a self-reported assessment. Total activities of daily living scores were analysed for each time point for all participants (n = 18) and compared between baseline, year 1 and year 2. Most participants (n = 9) had a stable score of 0. This analysis was performed for the total cohort as well as both subgroups (EA with attacks alone and EA attacks with persistent cerebellar ataxia (PCA)) to see if one group was influencing the results for the entire cohort. Data shows mean ± SEM

Fig. 2

Quality of life. (a) Change in SF-36 health-related quality of life over the duration of the study. Self-reported health-related quality of life measure (SF-36) subdomain normalised scores from baseline to year two (n = 16). Error bars are SEM. (b) Change in the SF-36 health-related quality of life measure over the duration of the study according to gender. Comparison between self-reported health-related quality of life measure (SF-36) subdomain normalised scores of male and female participants from baseline to year two (male n = 8, female n = 8). Error bars are SEM. PF, physical functioning; RP, role physical; BP, bodily pain; GH, general health; V, vitality; SF, social functioning; RE, role emotional; MH, mental health; PC, physical component score; and MC, mental component score. The component scores are aggregates of the 8 subdomains, divided into physical (physical functioning, role physical, bodily pain, general health) and mental categories (vitality, social functioning, role emotional, mental health)

Fig. 3

Quality of life according to gender. Comparison between the sexes for the SF-36 health-related quality of life physical and mental component scores using a random effects model. Self-reported health-related quality of life measure (SF-36) physical and mental component scores were analysed according to gender from baseline to year two (male n = 8, female n = 8). The population physical and mental component normalised score means were derived using a random effects model and compared. The component scores are aggregates of the 8 subdomains, divided into physical (physical functioning, role physical, bodily pain, general health) and mental categories (vitality, social functioning, role emotional, mental health). (a) Physical component score. Comparison between means on the self-reported health-related quality of life measure (SF-36) physical component scores according to gender. (b) Mental component score. Comparison between means on the self-reported health-related quality of life measure (SF-36) mental component scores according to gender

Fig. 4

Self-reported symptoms captured by the interactive voice response (IVR) system. Data on attacks was obtained from 6 individuals and 77 attacks over the course of the study. Participants were asked a series of yes/no questions on an automated system to record the nature of their attacks. (a) Symptoms during attacks. Participants were asked what symptoms they had during the current attack (yes/no). (b) Attack severity. Participants were asked to rate the severity of the effect of the attack, where 0 is not severe and 9 is very severe (visual analogue scale). (c) Attack duration. Participants were asked to record the duration of the attack. (d) Number of additional EA1 attacks suffered on the day of reporting. In order to increase compliance, participants were not required to call with every attack on a given day but described the symptoms for one attack and then recorded the number of additional attacks suffered on that day