cerebellar ataxia is a frequent and often - disabling syndrome that is mainly characterized by limb and gait ataxia as well as speech and ocular function impairment . in the majority of cases
so far , treatment of cerebellar ataxia has remained a difficult task as no medication has yet been proven really effective .
there were attempts in the past to treat cerebellar signs , for example downbeat nystagmus ( dbn ) , episodic ataxia type 2 ( ea2 ) , or cerebellar gait ataxia   with aminopyridines .
physiotherapy is recommended and applied in clinical practice but has only moderate effects [ 57 ] .
therefore , new drugs are needed , as cerebellar ataxia often leads to a significant disability of the affected patients .
since 1957 , acetyl - dl - leucine ( tanganil ; pierre fabre , castres , france ) , an acetylated derivative of a natural amino acid , has been widely used  mainly in france  for the symptomatic treatment of acute vertigo and dizziness and to improve central vestibular compensation .
clinical experience has shown that it is a well - tolerated and safe drug without serious adverse effects [ 911 ] .
electrophysiological measurements have demonstrated that acetyl - dl - leucine modulates the activity of central vestibular neurons by normalizing the membrane potential of depolarized or hyperpolarized neurons , a mechanism that may lead to the observed improvement of central compensation .
furthermore , clinical studies with branched - chain amino acids demonstrated a symptomatic improvement of cerebellar symptoms .
as acetyl - dl - leucine is a branched - chain amino acid and in view of the phylogenetic and electrophysiological similarities and close interactions between vestibular and cerebellar neurons , we hypothesized that this agent might have a positive effect on ataxic symptoms in cerebellar disorders .
thirteen patients ( eight males ; median age 51  years , range 1368 ; median symptom duration 3  years , range 225  years ; for further details see table  1 ) were treated with acetyl - dl - leucine 5  g / day without titration ( 500  mg tablets of tanganil ) for 7  days .
all patients gave their informed consent for the compassionate use of acetyl - dl - leucine .
the measurements were based on the scale for the rating and assessment of ataxia ( sara ) [ 15 , 16 ] , an eight - item clinical rating scale ( gait , stance , sitting , speech , coordination ; range 040 ) , and the spinocerebellar ataxia functional index ( scafi ) [ 17 , 18 ] , which consists of the 8-m - walking - time ( 8mw ) , 9-hole - peg - test ( 9hpt ) for appendicular function and the number of  pata  repetitions over 10  s ( pata ) .
these tests were performed at baseline and during treatment ( on day 9    3  days).table  1patient characteristics , categorized by patient number , gender , age , etiology , age at onset , duration of disease , mri , and neuro - ophthalmological findingspatient no.sexagetypeage at onsetduration ( in years)brain mri findingsneurological findings1male60saoa582normal1 , 5 ( unilateral ) , 6 , 7 , horizontal hypermetric saccades , square wave jerks2male51saoa483normal1 , 2 , 3 , 6 , 7 hypometric saccades3male54saoa513normal1 , 2 , 7 , 84female63saoa3825atrophy of vermis1 , 2 , 3 , 4 , 6 , 75male23sca2203atrophy of cerebellum1 , 2 , 7 , slow saccades6 
 female57adca449atrophy of the vermis1 , 37 
 female68adca5414atrophy of the vermis1 , 2 , 3 , 6 , 7 , 8 , hypometric saccades , svv deviation8female47sca1443atrophy of the cerebellum1 , 2 , 5 ( bilateral ) , 6 , 7 , hypermetric saccades9female56saoa542atrophy of the vermis and anterior lobe1 , 610 
 male25aoa1213atrophy of cerebellum1 , 2 , 7pnp , muscle atrophy , dysarthrophonia , ocular apraxia11 
 male23aoa1112atrophy of cerebellum1 , 2 , 7pnp , muscle atrophy , dysarthrophonia , ocular apraxia12 
 male19aoa109atrophy of cerebellum1 , 7pnp , muscle atrophy , dysarthrophonia , ocular apraxia13 
 male13aoa112atrophy of cerebellum7dysarthrophonia 
 aoa ataxia with oculomotor apraxia ( aoa1 and aoa2 genetically excluded ) , saoa sporadic adult - onset ataxia of unknown etiology , adca autosomal dominant cerebellar ataxia , svv subjective visual vertical , pnp polyneuropathy , 1 saccadic smooth pursuit , 2 gaze - evoked nystagmus , 3 head - shaking nystagmus , 4 rebound nystagmus , 5 pathological head - thrust test ( uni- or bilateral ) , 6 impaired visual fixation suppression of the vor , 7 pathological optokinetic reflex , 8 downbeat nystagmus 
 relatives of family one ( cousins ) 
 relatives of family two ( siblings ) patient characteristics , categorized by patient number , gender , age , etiology , age at onset , duration of disease , mri , and neuro - ophthalmological findings 
 aoa ataxia with oculomotor apraxia ( aoa1 and aoa2 genetically excluded ) , saoa sporadic adult - onset ataxia of unknown etiology , adca autosomal dominant cerebellar ataxia , svv subjective visual vertical , pnp polyneuropathy , 1 saccadic smooth pursuit , 2 gaze - evoked nystagmus , 3 head - shaking nystagmus , 4 rebound nystagmus , 5 pathological head - thrust test ( uni- or bilateral ) , 6 impaired visual fixation suppression of the vor , 7 pathological optokinetic reflex , 8 downbeat nystagmus 
 relatives of family one ( cousins ) 
 relatives of family two ( siblings ) quality of life during this symptomatic treatment was evaluated by using the euro - qol-5d-3l questionnaire ( eq-5d-3l ) .
the known side effects such as skin reactions ( rash , urticaria , itching ) were also systemically evaluated .
figures were designed with graphpad prism ( v5 , graphpad software inc . , la jolla , ca , usa ) .
as data were not normally distributed , non - parametric testing was performed ( wilcoxon signed - rank test ) with a bonferroni correction .
1 did not perform the scafi , he was excluded from the statistical analysis of this test ) .
mean total sara decreased from a baseline of 16.1    7.1 to 12.8    6.8 ( p  =  0.002 , wilcoxon signed - rank test ) . during treatment
the sara subsection scores were notably lower for gait ( p  =  0.022 ) , speech disturbance ( p  =  0.007 ) , finger - chase ( p  =  0.042 ) , nose - finger - test ( p  =  0.035 ) , rapid - alternating - hand - movements ( p  =  0.002 ) and heel  shin - slide ( p  =  0.018 ) ( table  2 ; figs .  1 , 2 ) . the scafi items also improved , represented by the 8  mw ( p  =  0.003 ) , the 9hpt of the dominant hand ( p  =  0.011 ) and the pata rate ( p  =  0.005 ) .
moreover , the eq-5d-3l changed from a baseline of 10.7    1.6 to 9.5    2.0 ( p  =  0.003 ) , indicating that quality of life was higher during treatment . the visual analogue scale ( vas)as part of the eq-5d-3l  rose from 0.57    0.21 to 0.63    0.19 ( p  =  0.241 ) .
eleven out of 13 patients reported a subjective improvement on therapy ( nos . 1 , 3 , 4 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ) .
the patients did not report any side effects.table  2clinical assessment of patients by sara and scafi at baseline and on medicationpatient no.baselineon medicationsara8  mwpata9hpt - d9hpt - nsara8  mwpata9hpt - d9hpt - n113.00 
  
  
  

 
 214.005.1020.0032.0038.0012.004.8026.0021.0041.00312.004.9014.0041.2038.209.504.7022.0037.8033.80411.508.6015.0028.8030.407.008.1024.0026.8027.10513.005.2023.0041.4040.709.004.4023.0030.4029.906 
 8.006.6016.0025.9025.406.006.0024.0024.6025.407 
 17.0010.1019.0037.6040.7011.008.0022.0029.7038.70817.0014.6024.0062.0049.8012.5012.7025.0059.1051.70913.006.7014.0045.0030.7012.006.5026.0035.7027.8010 
 27.00 
 11.00 
  
 27.00 
 11.00 
  
 11 
 27.0062.2017.00 
  
 23.0044.0018.00 
  
 12 
 29.0028.6011.00 
  

22.0027.3013.00 
  

 sara scale for the assessment and rating of ataxia , scafi spinocerebellar ataxia functional index , 8  mw 8-m - walking - time , 9hptd 9-hole peg test of the dominant hand , 9hptn 9-hole peg test of the non - dominant hand 
 relatives of family one ( cousins ) 
 relatives of family two ( siblings ) 
 not performed for other reasons 
 not able to perform due to disabling reasonsfig . 
1individual changes on a scale for the rating and assessment of ataxia ( sara ) and b quality of life questionnaire euro - qol-5d-3l ( eq-5d-3l ) on medication with acetyl - dl - leucine ( 5  g / day ) for 9    3 daysfig . 
2value changes on a scale for the assessment and rating of ataxia ( sara ) and spinocerebellar ataxia functional index ( scafi ) sub - score items in terms of b 8  m walk ( 8  mw ) , c pata word count in 10  s and d 9-hole - peg - test ( 9hpt ) of the dominant and non - dominant hand before and during the therapy with acetyl - dl - leucine ( 5  g / day ) ( mean    sd ) clinical assessment of patients by sara and scafi at baseline and on medication 
 sara scale for the assessment and rating of ataxia , scafi spinocerebellar ataxia functional index , 8  mw 8-m - walking - time , 9hptd 9-hole peg test of the dominant hand , 9hptn 9-hole peg test of the non - dominant hand 
 relatives of family one ( cousins ) 
 relatives of family two ( siblings ) 
 not performed for other reasons 
 not able to perform due to disabling reasons individual changes on a scale for the rating and assessment of ataxia ( sara ) and b quality of life questionnaire euro - qol-5d-3l ( eq-5d-3l ) on medication with acetyl - dl - leucine ( 5  g / day ) for 9    3 days value changes on a scale for the assessment and rating of ataxia ( sara ) and spinocerebellar ataxia functional index ( scafi ) sub - score items in terms of b 8  m walk ( 8  mw ) , c pata word count in 10  s and d 9-hole - peg - test ( 9hpt ) of the dominant and non - dominant hand before and during the therapy with acetyl - dl - leucine ( 5  g / day )
the 13 patients in this case series had ataxia as the leading symptom of cerebellar disorders of different etiologies .
patients on medication with acetyl - dl - leucine showed a significant improvement of both the ataxic symptoms  measured by sara and scafi  as well as quality of life .
the daily administration of 5  g / day used in this case series is in the upper range of the drug s recommended dosage , but lower than in studies on its use for acute vertigo [ 8  g / day ; for reference see ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-023099-13/de ) ] . as expected from its safety profile , acetyl - dl - leucine was well tolerated ; patients did not report any side effects . currently there is no proven symptomatic pharmacotherapy for cerebellar ataxias .
drugs such as varenicline , riluzole   or erythropoietin in friedreich s ataxia   were tested in the past . in a placebo - controlled trial with varenicline
as mentioned above , aminopyridines are effective in a subset of symptoms ( dbn   or ea2 ) . because there are no effective anti - ataxia drugs
the improvement of function after 4  weeks of intensive physiotherapy was 5.2 sara points ; patients regained functional performance equivalent to that after two or more years of disease progression .
compared to this , patients on treatment with acetyl - dl - leucine had an improvement of 3.3 sara points after treatment for 9    3  days .
it has to be mentioned that the patient group in this case series was inhomogeneous 
so it is probable that the positive effects might be even be better in a more homogenous group of patients .
although acetyl - dl - leucine has been in use for more than 50  years , its exact pharmacological and electrophysiological modes of action have not been fully elucidated .
an animal model of acute unilateral labyrinthectomy in guinea pigs showed that acetyl - dl - leucine restored the membrane potential of both hyperpolarized and depolarized vestibular neurons [ 8 , 12 ] .
this effect is assumed to be mediated by its direct interactions with membrane phospholipids   such as phosphatidylinositol 4,5-bisphosphate , which influences ion channel activity . on the basis of these findings
, acetyl - dl - leucine may also stabilize the membrane potential of cerebellar neurons .
the input from cerebellar purkinje cells and mossy / climbing fiber collaterals controls the action potential of cerebellar and vestibular nuclei , which in turn project to the brainstem , thalamus and spinal cord .
thus , acetyl - dl - leucine may act through afferent and efferent projections on upstream and downstream structures , thereby influencing motor control .
cerebellar network and be involved in the balancing of information between the cerebellum and effector muscles .
however , the modes of action of acetyl - dl - leucine in cerebellar disorders are still largely hypothetical and require further research .
our clinical findings on its efficacy in cerebellar ataxia must be carefully evaluated in electrophysiological studies and animal models of cerebellar ataxia as well as placebo - controlled and pet imaging studies in humans .
second , the change in the symptoms after termination of the treatment was not systematically evaluated .
third , we can not rule out either a placebo effect or a training effect on components of the ataxia assessment ( e.g. , 9hpt ) , but neither effect can explain the significant and clinically convincing effects documented by the standard ataxia scores sara and scafi . in conclusion , its improvement of cerebellar ataxia and the absence of adverse effects indicate that acetyl - dl - leucine is a worthy candidate for further clinical trials and also basic research .
 no existing medication has yet been shown to convincingly improve cerebellar ataxia . 
 therefore , the identification of new drugs for its symptomatic treatment is desirable . 
 the objective of this case series was to evaluate the efficacy of treatment of cerebellar ataxia with the amino acid acetyl - dl - leucine ( tanganil ) . 
 thirteen patients ( eight males , median age 51  years ) with degenerative cerebellar ataxia of different etiologies ( sca1/2 , adca , aoa , saoa ) were treated with acetyl - dl - leucine ( 5  g / day ) without titration for 1  week . 
 motor function was evaluated by changes in the scale for the rating and assessment of ataxia ( sara ) and in the spinocerebellar ataxia functional index ( scafi ) during treatment compared to a baseline examination . 
 quality of life ( euroqol-5d-3l ) and side effects were also assessed . 
 mean total sara decreased remarkably ( p  =  0.002 ) from a baseline of 16.1    7.1 to 12.8    6.8 
 ( mean    sd ) on medication . 
 there were also significant improvements in sub - scores for gait ( p  =  0.022 ) , speech ( p  =  0.007 ) , finger - chase ( p  =  0.042 ) , nose - finger - test ( p  =  0.035 ) , rapid - alternating - movements ( p  =  0.002 ) and heel - to - shin ( p  =  0.018 ) . 
 furthermore , patients showed better performance in the scafi consisting of the 8-m - walking - time ( 8  mw , p  =  0.003 ) , 9-hole - peg - test of the dominant hand ( 9hptd , p  =  0.011 ) and the pata rate ( p  =  0.005 ) . 
 quality of life increased during treatment ( p  =  0.003 ) . 
 no side effects were reported . in conclusion , acetyl - dl - leucine significantly improved ataxic symptoms without side effects and therefore showed a good risk  
 benefit profile . 
 these findings need to be confirmed in placebo - controlled trials . 
Introduction
Design/methods
Results
Discussion