Dear editors,

Recently, Strupp and co-workers [1] demonstrated that acetyl-dl-leucine (Tanganil®; Pierre Fabre Médicament, Boulogne, France) may lead to substantial symptomatic improvement in various forms of degenerative cerebellar ataxia (DCA) differing widely in symptom duration, severity and etiology. Medication was given for about 7 days, and 12 of their 13 patients benefited, while no side effects were reported [1]. However, endpoints were assessed unblinded, rendering objective evaluation of treatment response difficult.

Here, we report our observations in a series of patients suffering from DCA who were treated with acetyl-dl-leucine. Pharmacological treatment was combined with physio- and occupational therapy as both are important non-pharmaceutical components of the treatment of DCA [2, 3].

The study was conducted as a series of individual treatment efforts and confirms to the 1964 Declaration of Helsinki and its later amendments. After they had given informed consent for the off-label use of acetyl-dl-leucine, 10 patients with DCA (Table 1) were treated in-hospital with 5 g acetyl-dl-leucine once daily for a total duration of 7 days. Furthermore, each patient received altogether five sessions of physiotherapy at 45 min and five sessions of occupational therapy at 30 min, individually matched to the patient’s symptoms and including dedicated gait and balance training.

Table 1 Patients characteristics
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Video-recorded measurements at baseline (off-drug) and on day 7 of active treatment (on-drug) were based on the Scale for the Assessment and Rating of Ataxia (SARA) [5, 6]. SARA scores were assessed from the video recordings by three investigators who were blinded with regard to the time point of video recording. Additionally, patients were asked about their subjective improvement on medication, and possible side effects during treatment were evaluated.

Statistical analyses were performed with SPSS version 20.0 (IBM Corporation; New York, NY, USA). A p value <0.05 was considered as statistically significant.

There was excellent interrater agreement for assessment of SARA scores from video recordings with an intraclass correlation (absolute mode) between investigators of ≥0.97 (p < 0.001). Mean and median SARA scores were similar between baseline and at day 7 of treatment with acetyl-dl-leucine (Wilcoxon signed-rank test; p = 0.17, respectively, p = 0.38; Table 2). During in-hospital treatment, no side effects were observed.

Table 2 Assessment of endpoints: SARA scores at baseline and after 7 days of treatment with acetyl-dl-leucine (mean and median values of blinded assessment from video recordings by 3 raters), side effects during treatment and subjective improvement as reported by patients
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Although 7 of 10 patients reported subjective amelioration of cerebellar symptoms, we failed to detect any significant improvement as measured by SARA in assessments blinded to treatment status to reduce rater bias [7]. As physiotherapy was shown to be beneficial for individuals with DCA [2, 3], it is unlikely to have obscured any positive effect of acetyl-dl-leucine. Notably, (pre-)clinical trials studied acetyl-dl-leucine only in vestibular diseases [8, 9], so its potential mode of action in DCA remains speculative.

One limitation of our case series is that, in contrast to Strupp and co-workers [1], patients in our case series received the liquid formulation of acetyl-dl-leucine orally, because Tanganil® tablets were no longer available in Germany. Since both, the solid and liquid formulation contain neither stabilizers nor any active pharmaceutical ingredients other than acetyl-dl-leucine, we consider it unlikely that the lack of any beneficial clinical effect is attributable to different formulations.

Because the decision to treat was solely based clinically on the presence of DCA, our series contains cases of heterogeneous aetiologies and heterogeneous patterns of cerebellar signs. Therefore, failure of this syndrome-oriented approach to demonstrate beneficial effects does not exclude potential efficacy in a future symptom-oriented trial, or one that is based on nosology.

In summary, we failed to confirm a beneficial effect of acetyl-dl-leucine in combination with an intensive short-term physio- and occupational therapy in patients with DCA. At the present time, acetyl-dl-leucine cannot be recommended for treatment of patients with cerebellar ataxia.