Relationship Between Balance Deficits and Gait Variability in Adults With Friedreich’s Ataxia

Hypothesis: Friedreich’s ataxia (FA) is an inherited disease characterized by progressive motor weakness, sensory loss, balance deficits, and an ataxic gait pattern. Increased gait variability is a common feature of ataxia and is related to balance deficits and falls risk in people with cerebellar disorders. Earlier age at FA onset has been shown to be predictive of wheelchair use and loss of ambulation. The relationship between disease duration, balance deficits and gait variability has not been investigated in adults with FA. We hypothesize that longer disease duration and increased balance deficits are related to increased gait variability in adults with FA. Subjects: Eight adults with genetically confirmed FA (29.4 ± 9.0 years) and average disease duration 9.9 ± 3.8 years Materials/Methods: This research represents a component of a longitudinal study which examined balance, gait and neurological status in adults with FA. Gait variability, specifically step and stride length variability, was measured at comfortable and fast walking speeds using the GAITRite Walkway System. Balance was assessed using the Berg Balance Scale (BBS) and the Biodex Balance System SD. Pearson’s product correlation coefficient was employed to assess the relationship between disease duration, quantitative balance parameters and gait variability; while Spearman’s rank correlation coefficient was used to assess the relationship between BBS scores, disease duration and gait variability. Results: BBS scores were not associated with gait variability (p\u3e0.05). Disease duration was positively correlated with step length variability during fast walking (p=0.047). The Biodex Postural Stability test overall stability indices with eyes closed were positively correlated with stride length variability during comfortable walking (p=0.006) and with step and stride length variability during fast walking (p=0.014 and p=0.004, respectively). The Biodex Limits of Stability test overall directional control scores were negatively associated with step length variability during fast walking (p=0.038). There were no other significant correlations between disease duration, balance variables and gait variability. Conclusions: Greater gait variability was exhibited by adults with FA who had longer disease duration. Results demonstrated a strong association between postural stability indices, limits of stability scores and step and stride length variability, particularly during fast walking. This study is the first to demonstrate a relationship between disease duration, balance deficits and gait variability in adults with FA. Clinical Relevance: Worsening balance deficits in adults with FA may contribute to increased gait variability, particularly in those with longer disease duration. Knowledge of the relationship among these variables may assist physical therapists to predict when adults with FA would benefit most from interventions to ameliorate impairments of balance and gait variability and predict future activity limitations in walking

Assessment of Balance in Adults with Friedreich’s Ataxia

Purpose/Hypothesis: Balance deficits are common sequelae of Friedreich’s Ataxia (FA), yet, there are no standardized assessments to specifically assess balance in the FA population. Clinical rating scales for ataxia include balance items, but do not focus on balance assessment. Balance deficits are related to gait ataxia, and worsening balance and gait impairment may contribute to falls and loss of ambulation over time. The purpose of this study was to investigate changes in balance over time in adults with FA, utilizing balance specific assessments, including the Berg Balance Scale (BBS). Number of Subjects: 16 Materials/Methods: A longitudinal research design was applied to investigate changes in balance in 8 subjects with genetically confirmed FA (29.4 ± 9.0 yrs.) utilizing the BBS and the Biodex Balance System’s Limits of Stability (LOS) test at baseline, 6 months, 12 months and 24 months; 8 healthy, matched control subjects (29.6 ± 9.1 yrs.) underwent the same tests at baseline and 12 months. A linear mixed effect (LME) model was applied to determine whether FA subjects’ BBS or LOS scores demonstrated a significant linear change from baseline to 24 months. Paired t-tests were conducted to assess whether control subjects’ balance measures changed over 12 months. Results: Average disease duration of FA subjects was 10 years (range 6-16 yrs.). Control subjects attained the maximum BBS score at baseline and this did not change at 12 months. Subjects with FA exhibited a decline in mean BBS scores of 7% at 12 months and 18% at 24 months, at which time the mean BBS score was 36. Six of 8 FA subjects self-reported at least one fall per month. In the FA group, the LME model revealed a significant linear change in BBS scores (0.27 average unit decrease per month, β=-0.266, p=0.001) and in LOS backward directional control scores (0.71 average unit decrease per month, β=-0.713, p=0.024) over 24 months. No significant change in either time to complete the LOS test or overall directional control scores were observed. In the control group, no significant changes in LOS scores were apparent, with the exception of an increase in the LOS forward directional control score (t=-3.706, p=0.018). Conclusions: Adults with FA demonstrated a significant decline in BBS scores, with 5 of 7 subjects falling below the BBS cut-off score for high falls risk (40/56) by 24 months. Although subjects with FA did not show a significant decline in LOS overall directional control scores, they did demonstrate declining backward directional control scores indicative of a decreased ability to control center of pressure movement in a backward direction. Clinical Relevance: Adults with FA demonstrate worsening balance and increased falls risk over time. In this study, the BBS proved to be a sensitive assessment to detect changes in balance in adults with FA. This information may benefit clinicians who examine balance in people with FA, prior to implementing interventions to prevent falls and activity limitations of balance

EPI-743 for Friedreichs Ataxia Patients with Point Mutations

Objective: To assess the effects of EPI-743 in patients with Friedreich’s Ataxia (FA) point mutations on neurologic function as measured by the Friedreich’s Ataxia Rating Scale (FARS). Background: FA is an autosomal recessive degenerative disorder characterized by ataxia, dysarthria, sensory loss, diabetes, and cardiomyopathy. FA patients with a point mutation (FA-PM) carry an expanded GAA repeat on one allele and a point mutation/deletion on the other allele; this is a rare variant. The natural history of FA includes progressively deteriorating neurologic function with FARS worsening 3.55 points in 12 months and 6.16 points in 24 months. EPI-743 is a therapeutic being developed for treatment of patients with mitochondrial diseases and disorders of oxidative stress. Methods: Three patients with genetically confirmed FA-PM (G130V) were administered EPI-743 400mg PO TID for 18 months in an open-label study. Assessments were completed quarterly. Relative mean changes in FARS total and subscale scores from baseline to 6 and 18 months of treatment were calculated as change([percnt]) = ((meanX - mean0) / mean0 × 100) where X represents the time point. Results: After 6 months of treatment, total FARS score improved an average of 9[percnt] (baseline mean total FARS=64, 6m mean total FARS=58). While all subscales improved, bulbar and upper limb coordination sub-scales were most improved (bulbar mean improvement of 80[percnt] [from 0.83 to 0.17] and upper limb coordination 53[percnt] [from 3.17 to 1.5]). Mean improvements persisted at 18 months from baseline (FARS total: 6[percnt], bulbar subscale: 20[percnt], upper limb coordination: 37[percnt]), although they attenuated. No serious adverse events, including hematologic or cardiac, were observed. Conclusions: EPI-743 was associated with clinically significant improvement in neurological function in patients with FA-PM over 18 months. These findings support further study of EPI-743 in patients with FA due to point mutations

Ischemic stroke after use of the synthetic marijuana “spice”

Objectives: To report and associate acute cerebral infarctions in 2 young, previously healthy siblings with use of the street drug known as “spice” (a synthetic marijuana product, also known as “K2”), which they independently smoked before experiencing acute embolic-appearing ischemic strokes. Methods: We present history, physical examination, laboratory data, cerebrovascular imaging, echocardiogram, ECG, and hospital course of these patients. Results: We found that in both siblings spice was obtained from the same source. The drug was found to contain the schedule I synthetic cannabinoid JWH-018. Full stroke workup was unrevealing of a stroke etiology; urine drug screen was positive for marijuana. Conclusions: We found that our 2 patients who smoked the street drug spice had a temporal association with symptoms of acute cerebral infarction. This association may be confounded by contaminants in the product consumed (i.e., marijuana or an unidentified toxin) or by an unknown genetic mechanism. The imaging of both patients suggests an embolic etiology, which is consistent with reports of serious adverse cardiac events with spice use, including tachyarrhythmias and myocardial infarctions

Correlation of GAITRite Walkway System and Biodex Balance System Measures to the FARS Score in Friedreich\u27s Ataxia Patients: A Validation Study

Objective: To test the validity of the GAITRite Walkway System and Biodex Balance System for measuring parameters of neurological dysfunction in Friedreich’s Ataxia (FA) patients against the standard of the Friedreich’s Ataxia Rating Scale (FARS). Background: FA is a neurodegenerative disease causing ataxia and cardiomyopathy. Precise measures are needed to test disease progression in FA in clinical trials. The GAITRite Walkway System and the Biodex Balance System are quantitative measures that evaluate gait and balance dysfunction using computerized technology. Design/Methods: In this prospective, longitudinal study, ambulatory FA patients were examined at baseline, and at 6, 12, and 24 months using the GAITRite and Biodex Systems and the FARS. Healthy, matched controls were tested at baseline and 12 months. All analyses were carried out using SAS 9.4. Results:Eight FA patients and 8 controls were included in this analysis. The following GAITRite parameters correlated significantly with the total FARS score in FA patients; comfortable walking velocity (r=-0.536; p Conclusions: In this study, multiple GAITRite and Biodex measures correlated significantly with the FARS scores, suggesting a high degree of clinical significance and providing evidence for validation of these measures in FA patients

Longitudinal Study of Gait Dysfunction in Friedreich\u27s Ataxia Using the GAITRite Walkway System

Objective: To quantify longitudinal changes in gait in Friedreich’s Ataxia (FA) patients compared to controls during a 24-month period using the GAITRite Walkway System. Background: FA is a devastating neurodegenerative disease. Measures to accurately quantify small changes in neurological function in FA patients are needed to facilitate therapeutic clinical trials. Design/Methods: This was a prospective, longitudinal study that assessed ambulatory FA patients compared to age- and gender-matched controls. FA patients were examined at baseline and at 6, 12, and 24 months, using the GAITRite Walkway system, a portable instrument used to assess gait parameters, and the Friedreich’s Ataxia Rating Scale (FARS). Controls were evaluated at baseline and 12 months. Changes in various gait parameters over time were estimated and compared using descriptive statistics and multilevel modeling. Results: Eight FA patients (aged 29.4 ± 9.0) and 8 controls (aged 29.6 ± 9.1) were included in this analysis. In FA patients, the mean FARS score increased 21.0[percnt] over two years (baseline: 40.6; 12 months: 45.4; 24 months: 49.1). Using longitudinal multilevel modeling, the FARS score was estimated to increase 0.13 points per month in FA patients, reflecting an increase in neurological dysfunction. Comfortable gait velocity declined 15[percnt] after 12 months and 30.5[percnt] after 24 months in the FA group, and showed high validity for measuring neurological dysfunction. Comfortable gait velocity correlated strongly with the FARS total score (r=-0.536;p Conclusions: Comfortable gait velocity as measured by the GAITRite system showed better sensitivity to changing gait that did the FARS, and had excellent reproducibility in controls whose gait was not expected to change. Comfortable gait velocity is easily performed, and may be an important and clinically relevant endpoint for future clinical trials