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Acetyl-DL-leucine (AL) is an acetylated derivative of the essential amino-acid leucine. It has been used for the symptomatic treatment of vertigo and dizziness in France since 1957. Clinical experience has shown that it is a well-tolerated and safe drug without serious adverse1–4. Acetyl-DL-leucine is able to cross the blood-brain barrier, explaining the reported effects and treatment responses in animal models and patients with unilateral vestibular loss (UVL) and cerebellar ataxia.
The effects of acetyl-DL-leucine on the activity of the medial vestibular nucleus (MVN) and vestibular-related networks were measured electrophysiologically in an UVL guinea pig5. The nature of response depended on the resting membrane potential. Acetyl-dl-leucine acted mainly on abnormally hyperpolarized and/or depolarized MVN neurons, by bringing back their membrane potential towards a mean value of −65 to −60 mV. Because of this stabilizing effect, acetyl-DL-leucine reduced the asymmetry within the vestibular-related networks caused by the UVL, decreasing the activity of the MVN neurons on the hyperactive intact side and increasing activity on the silent lesioned side, without affecting the neurons with a normal membrane potential. This mechanism is most likely mediated by its direct interactions with membrane phospholipids such as phosphatidylinositol-4,5-bisphosphate, which influences ion channel activity6.
Studies in humans on the action of acetyl-DL-leucine were in accordance with the animal studies7. It has been shown that the effect depended on the presence of vestibular compensation (VC) before the labyrinthectomy. In patients with almost complete vestibular lesion prior to surgery, VC had taken place before the surgery, with vestibular neurons having regained a normal resting potential. In this group of UVL patients, no effect of the therapy was observed. This study has shown that acetyl-DL-leucine can ameliorate the static component of the VC following vestibular de-afferentation, without having an effect on the dynamic component.
Furthermore, a prior [18F]-Fluoro-desoxyglucose ([18F]-FDG)-µPET study in an UVL rat model investigating the regional cerebral metabolic rate for glucose (rCGMglc) revealed that only L-isomer or DL-racemate, but not N-acetyl-D-leucine caused a significant acceleration of VC, acting in a dose-dependent manner. Moreover, only L-isomer caused a significant increase of rCGMglc in the vestibulocerebellum and a decrease in the posterolateral thalamus and subthalamic region8. This is supported by a recent study, focused on the examining of the pharmacological effects of acetyl-DL-leucine in an UVL cat model, showing that L-isomer is an active component of the DL-racemate, since it significantly accelerates the vestibular compensation process9.
Studies showed that the calcium homeostatis is dysregulated in NPC disease, similar to spinocerebellar ataxias (SCAs), as reflected in the calcium depletion in the late endosome/lysosome10. This leads to the functional disturbance of Purkinje cells. Since the input from Purkinje cells and mossy/climbing fiber collaterals controls the action potential of the vestibular and the cerebellar nuclei11, which in turn project to the brainstem, thalamus and spinal cord12, acetyl-DL-leucine may act through afferent and efferent projections on upstream and downstream structures, thus influencing movement control.
A clinical study in patients with degenerative cerebellar ataxia of different etiologies has shown a positive effect on the cerebellar symptomatology, without causing any side effects13. Patients improved significantly on 6 out of 8 sub-scores of the Scale for Assessement and Rating of Ataxia (SARA) (gait, speech, finger-chase, nose-finger-test, rapid-alternating-movements, and heel-to-shin). The evaluation of the Spinocerebellar Ataxia Functional Index (SCAFI) showed a better performance in 3 out of 4 elements (8-m-walking-time, 9-Hole-Peg-Test of the dominant hand and PATA rate). Of note, the objective improvement was additionally reflected in the increased quality of life during treatment.
Another clinical study demonstrated an improved coefficient of variation of stride time in the gait analysis in 14 out of 18 patients with cerebellar ataxia14. The improvement of variability was restricted to the condition of slow walking, where walking stability is thought to critically rely on the sensory integration function of the cerebellum15.
In contrast, in a case-series with 10 patients with degenerative cerebellar ataxia, no improvement in SARA was observed 16. However, 7 out of 10 patients described a subjective improvement on medication. Since at the time of this study, the acetyl-DL-leucine tablets were not available, a liquid formulation of 5 g once a day was administered, which may account for the failure to confirm the therapeutic benefit.
In twelve patients with Niemann-Pick typ C (NPC), acetyl-DL-leucine improved cerebellar ataxia signs and symptoms, as assessed by SARA and SCAFI17. SARA changed significantly from 10.8 points at baseline to 7 points on medication and increased again on 10.5 points, yielding an absolute change of 3.8 points between baseline and on medication and 10.5 points between on medication and after one month of washout. SCAFI 9-Hole-Peg Test of the dominant hand, modified disability rating scale and quality of life, as assessed by caregivers also changed significantly. Remarkably, patients acted more independently in daily life, had more drive to perform the activities on their own, and interacted more with caregivers and their physiotherapeuts. Since some of these subjective findings are closely related to higher cognitive functions, we hypothesized that acetyl-DL-leucine might act not just on the level of cerebellum, but also at the level of higher-order structures, such as fronto-temporal lobe or limbic system. The improvement of cognitive capabilities was already reported in a 90-old man suffering mild cognitive impairment and gait disorder. These signs remarkably improved on medication with acetyl-DL-leucine18.
In addition, a decrease of frequency of cerebellar fixation instability problem, square wave jerks, was also subjectively noted by the study doctor and the caregiver. In order to objectify this sign, patients with ataxia telangiectasia, genetic disorders with a pronounced cerebellar atrophy, ocular motor problems such as downbeat-nystagmus, gaze-holding nystagmus, direction-specific gaze-palsies, smooth pursuit deficits and slow saccades were treated with acetyl-dL-leucine for one month with a following one month titration. Preliminary data suggest a remarkable increase of fixation stability, thus improving the function of the vestibulo-cerebellum. In one patient, the slow-phase velocity of the downbeat-nystagmus changed of 3.6 °/s in the position with gaze to the left and 2.1 °/s with the gaze straight-ahead.
Postural stability and fine motor function improved in these patients despite the polyneuropathy in these patients.