Friedreich's ataxia medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]
Overview
• Physostigmine
Physostigmine is US FDA-approved for use in anticholinergic toxicity and has been studied as a treatment in Alzheimer's disease and cerebellar ataxia [58,59]. The rationale for evaluating physostigmine in ataxia, including FRDA, is its inhibition of acetylcholinesterase, which prolongs central and peripheral effects of acetylcholine [60]. A double blind, placebo-controlled, crossover study investigated the effects of oral physostigmine on ataxic symptoms in 21 patients with various hereditary ataxias (10 patients with FRDA) over four consecutive 3-month phases [61]. Patients were initially treated with physostigmine 3 mg daily and were then titrated up to 8 mg/daily over a 3-week period, and maintained at that dose for the remainder of the treatment phase. One 9-year old patient reported nausea, which resolved after the dosage was reduced by half. Evaluators assessed patients for nystagmus, dysmetria, conversational speech, repetitive speech, lingual movements, upper and lower limb coordination, posture, stance, and gait in a standardized ‘scale’. Overall, 13 patients saw improvement in symptom scores while on physostigmine in comparison to placebo (p < 0.025) [61]. The authors did not provide specifics on the types of ataxias that responded to physostigmine, but stated that the drug appeared to have impacts on dysmetria, dysrhythmia and speed of movement.
• Riluzole
Riluzole is currently used in the treatment of amyotrophic lateral sclerosis (ALS) and demonstrated positive effects on ataxia patients in one clinical trial [62]. It has been proposed that the mechanism of action may relate to the small conductance calcium-activated potassium channels that appear to regulate excitability in neurons found within deep cerebellar nuclei [64,65]. Abnormal, rapid firing of these neurons may contribute to ataxia, and it may be that riluzole reduces this hyperexcitability [62,66]. The efficacy of riluzole in ameliorating FRDA has not been examined in a focused trial; however, FRDA patients were included in a clinical study of various ataxias that showed mixed results [62]. In this double-blind placebo controlled trial, a sample of 40 patients with various cerebellar ataxias (eight of whom had FRDA) were randomly assigned to the riluzole 100 mg daily or placebo arm for 8 weeks [62]. The primary end point of the study was a decrease in the ICARS score of 5 points or more at 4 and 8 weeks compared with baseline. About 68% of the participants who received riluzole experienced a decrease of 5 points or greater in their ICARS score. However, only one of the three FRDA patients in the riluzole group experienced a reduction of 5 or greater points in the ICARS score at 8 weeks, while another FRDA patient had an increase of 1 point in the ICARS at 8 weeks. One of the FRDA patients treated with placebo also had 5 points decrease in ICARS scores at 8 weeks. Two patients who received riluzole were observed to have a slight increase of alanine aminotransferase levels (<1.5 times above normal limit). Liver function tests in patients taking riluzole should be monitored once per month for 3 months, once every 3 months for the following 9 months, and intermittently thereafter [62]. Further study is necessary to determine whether riluzole has any benefit in patients with FRDA.
• Varenicline
Varenicline (Chantix®, Pfizer Inc.), an alpha4 beta2 nicotinic partial agonist, has been demonstrated to have some clinical benefit in spinocerebellar type 3 (Machado Joseph) patients [67]. However, a Phase II trial to study the effect of varenicline in FRDA patients [68] was discontinued early due to concerns of safety in FRDA patients, several of whom reported worsening balance.
• Amantadine
Amantadine is an antiviral medication that is used to treat dyskinesia in Parkinson's disease and tardive dyskinesia arising from chronic neuroleptic therapy. An open-label study involving 16 FRDA patients investigated the effects of amantadine using the Functional Ataxia Scoring Scale (FASS), which evaluates ocular movements, lingual movements, upper limb coordination, lower limb coordination, posture and gait [69]. Two blinded evaluators scored unedited video recordings, cassette recordings of speech and writing samples of each patient. An average of the raters’ individual scores were used to calculate a total disability score for each patient both before and 1 h after the administration of amantadine syrup 1 mg per pound of patient body weight up to 100 mg. The 1-h postadministration TDS improved by an average of 29.5% (p < 0.0005) when compared with the preadministration TDS; however, the effects of amantadine gradually dissipated over 4 h. Patients who were less functionally disabled at baseline were found to have the best response to the treatment, and those without signs of congestive heart failure (n = 13) continued amantadine treatment beyond the single dose. The initial drug trial dosage for each patient was increased every 6 weeks to tolerance (max dose = 100 mg TID). While no cardiac side effects were encountered, hallucinations, constipation, livedo reticularis, and difficulty concentrating were reported [69].
A double-blind cross-over study investigated the effects of amantadine hydrochloride in 12 patients with FRDA and 2 patients with autosomal dominant cerebellar ataxia. Patients were randomly assigned to a placebo–amantadine or amantadine–placebo treatment sequence that included a 2-week interval between treatments. Manual dexterity and writing assessments were videotaped at baseline and 90 min after administration of 100 mg amantadine or placebo. Three blinded evaluators used the FASS to independently score the videos, finding no treatment effects [70].
Medical Therapy
- Pharmacologic medical therapy is recommended among patients with Friedreich's ataxia.
- Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].
- Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].
- Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].
Disease Name