j The Cerebellum 2004; 3: pp 107 111 j 107

Pharmacological treatments of cerebellar ataxia

Masafumi Ogawa
Department of Neurology, National Center Hospital for Mental, Nervous, and Muscular Disorders, National Center of Neurology
and Psychiatry, Kodaira, Tokyo, Japan

The con®rmed pharmacological treatment of cerebellar ataxia is still lacking. In a recent preliminary trial, we showed that D-
cycloserine, a partial NMDA allosteric agonist, may relieve the symptoms. In this paper, major clinical trials to relieve ataxic
symptoms are reviewed. Previous studies showed some ef®cacy of physostigmine in ataxic patients. However, physostigmine
did not improve the ataxia in a recent double-blind crossover study. The replacement therapy of the de®cient cholinergic system
with choline or choline derivatives was tried in patients with Friedreich's ataxia and other ataxic patients, but the result was not
de®nitive. A levorotatory form of hydroxytryptophan (a serotonin precursor), a serotoninergic 5-HT1A agonist, a serotoninergic 5-
HT3 antagonist, and a serotonin reuptake inhibitor were also used for the therapy for ataxia. In a double-blind randomized study,
buspirone, a 5-HT1A agonist was active in cerebellar ataxia, but the effect is partial and not major. The effects of the studies
with the other serotoninergic drugs were not consistent. The effect of sulfamethoxazole-trimethoprim therapy in spinocerebellar
ataxia type3/Machado-Joseph disease (MJD) was reported, although the therapy improved spasticity or rigidity, rather than
ataxia. In contrast to previous studies, sulfamethoxazole-trimethoprim therapy in MJD had no effect in a 2001 double-blind
crossover study. The thyrotropin-releasing hormone, D-cycloserine, and acetazolamide for SCA6 may have some ef®cacy.
However, a well-designed double-blind crossover trial is needed to con®rm the effect.

Keywords: Ogawa M.
Pharmacological treatments of cerebellar ataxia
pharmacological treatment - cerebellar ataxia - study Cerebellum 2004; 3: 107-111
design - D-cycloserine

Introduction an open trial or a ®xed order trial. Order effect may often
occur in assessment of cerebellar ataxia.
The con®rmed pharmacological treatment of ataxia in Therefore, the investigator should consider the clinical
cerebellar ataxia is still lacking, although the under- and genetic background of the patient group. Subgroup
standing of the genetic disease background has remark- analyses may be needed to search for the responder in the
ably progressed. There are many problems in clinical group. The investigator should design the double-blind
trials to relieve ataxia. First, cerebellar ataxia is a crossover study with generally accepted ataxia assessment
heterogeneous disease group. Previous studies often and quanti®cation to con®rm the effect of the pharma-
included the heterogeneous patient groups, and the cological treatment in ataxic patients.
results were controversial. Second, there may be respon- Recently, we showed that D-cycloserine may improve
ders and nonresponders to the treatment, even if the ataxia in a preliminary open trial.2 D-cycloserine has been
patient group has a homogeneous genetic background. A used as an antibiotic for tuberculosis.3 Recent studies
global statistical approach may neglect some responders showed that D-cycloserine acts as a partial NMDA
in the patient group. Third, clinical assessment and allosteric agonist.4 Several lines of evidence also indicated
quanti®cation of ataxia is very dif®cult, although an that an impaired glutamate signaling process may be
international cooperative ataxia rating scale (ICARS) was involved in the patients of cerebellar ataxia. In this article,
published in 1997.1 The objective measurements of major clinical trials to relieve ataxia are reviewed and
ataxia were ideal, but rather limited. In ataxic patients discussed as well as the possible therapeutic ef®cacy of D-
with multisystem involvements, it is very dif®cult to cycloserine for cerebellar ataxia.
evaluate ataxia separate from other symptoms. Fourth, it
is dif®cult to deny the placebo effect and/or order effect in
Physostigmine
Received 25 November 2003; Revised 23 March 2004; Accepted Kark et al. applied a centrally active cholinesterase
23 March 2004 inhibitor physostigmine to patients with ataxia in
1977.5 Previous studies also demonstrated some effects
Correspondence:
of physostigmine in cerebellar ataxia patients.6,7 The
Masafumi Ogawa, Dr, Department of Neurology, National Center
Hospital for Mental, Nervous, and Muscular Disorders, National reduction of brain choline acetyltransferase and acetyl-
Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, cholinesterase reduction in olivopontocerebellar atrophy
Tokyo, 187-8551 Japan. (OPCA) was reported.8 A degeneration of afferent
Tel: ‡81 42 341 2711. Fax: ‡81 42 344 6745. E-mail: ogawa- cholinergic projections to the cerebellum in OPCA
ma@ncnpmusashi.gr.jp patients was also described.9 These ®ndings may support
 2004 Taylor & Francis
DOI 10.1080/147342204100032331
108 j M Ogawa

the effect of physostigmine. The problems of treatment minimal, selective and dif®cult to clearly detect.23
with physostigmine are its short half-life, cholinergic side Buspirone, a 5-HT1A agonist was also applied to
effects, and narrow therapeutic range.10 However, Wes- cerebellar ataxia and showed some ef®cacy.24 However,
sel et al. showed that physostigmine showed no effect in a in a double-blind randomized study, buspirone was
double-blind crossover trial in 1997.10 In this study, a active but the effect is partial and not major.25 The
transdermal system (patch) was used. The author con- effects of ondansetron, a 5-HT3 antagonist, were also
cluded that therapy with physostigmine could not be reported. Rice et al. reported that intravenous ondanse-
recommended, although the cholinergic system may play tron improved cerebellar tremor in patients with familial
a role in the pathophysiology of cerebellar ataxia. cerebellar degeneration, multiple sclerosis or drug toxi-
city,26 however, the intravenous form of ondansetron
requires several administrations. Unfortunately, a rando-
Choline and choline derivatives mized multi-center, double-blind trial with the oral form
of ondansetron in patients with cerebellar cortical
Barbeau et al. described some effects of lecithin on ataxia
atrophy showed no bene®cial effect in a global analysis,
and muscle strength in patients with Friedreich's atax-
although some responders were noted.27 An open trial
ia.11 Lecithin contains phosphatidylcholine and therapy
with ¯uoxetine, a serotonin reuptake inhibitor, using
with massive lecithin, pure phosphatidylcholine or cho-
patients with spinocerebellar ataxia type3/Machado-
line chloride may replace the de®cient cholinergic system
Joseph disease (MJD) showed no signi®cant improve-
in the disease. Some groups also reported improvements
ment after 6 weeks of treatment.28 The serotonin system
in patients with ataxias after open trials with lecithin or
may play a role in cerebellar dysfunction, however
pure phosphatidylcholine.12-14 Sorbi et al. showed that a
previous studies did not con®rm the positive effect of
4-year open trial with 9 grams daily of phosphatidylcho-
these drugs. Table 1 summarizes these and other studies.
line did not improve the natural course of the ataxias in
20 patients with Friedreich's ataxia and 24 patients with
OPCA.15 The results of double-blind studies with cho-
Thyrotropin releasing hormone
line chloride were controversial. A 6-week double-blind
crossover study with 6 g/day or 12 g/day of choline Sobue et al. showed that the thyrotropin releasing
chloride in 20 patients with ataxia showed mild but hormone (TRH) may improve ataxic symptoms in
signi®cant improvement in the upper limb coordination patients with spinocerebellar degeneration (SCD).29
in 10 patients.16 In a double-blind study with 4 g/day or The pharmacological basis of the therapy is not clear,
150 mg/kg/day of choline chloride in 13 patients with a but TRH also improved ataxic symptoms in the heredi-
variety of ataxic disorders, only one patient with idio- tary ataxic mice.30 A two-week, double-blind placebo-
pathic cerebellar degeneration showed improvement.17 A controlled study was performed in 254 patients with SCD
double-blind crossover study with 5 g/day of choline and the study showed that both 2 mg/day and 0.5 mg/day
chloride in 6 patients with cerebellar ataxia showed no TRH treatments were signi®cantly superior to placebo
signi®cant difference between the choline chloride and treatment in the predominant ataxic form of SCD.31
placebo treatment.18 There may be some responders to However, the study used a 14-grade visual analogue scale
the therapy with choline or choline derivatives, however, and judged the global effect based on 7 different grades
it is unclear that the therapy improved the natural course (ranging from marked improved to marked aggravated).
of the ataxias. Manto et al. evaluated the effect of TRH in ballistic wrist
movement with electromyography (EMG).32 The study
showed that TRH increased the EMG activities, but did
Serotoninergic system not improve the ataxic movements. TRH may improve
some symptoms in ataxic patients, however, a well-
A neurochemical de®cit of serotonin may also relate to
designed double-blind crossover study may be needed
degenerative cerebellar ataxia. Serotonin is one of the
to con®rm the effect.
cerebellar neurotransmitters and impairment of the
serotoninergic system may improve cerebellar ataxia. A
preliminary double-blind study with the levorotatory
Sulfamethoxazole-trimethoprim
form of hydroxytryptophan, a serotonin precursor,
showed some ef®cacy for ataxia in the patients with MJD is an autosomal dominant cerebellar ataxia with
various inherited or acquired cerebellar ataxias.19 How- other system involvements. A patient with MJD reported
ever, Wessel et al.20 found no effect, but Trouillas et al.21 improvement in gait and spasticity while taking sulfa-
found effects on the kinetic but not static function in methoxazole-trimethoprim for a noninfectious dysuria.33
double-blind studies with the levorotatory form of Previous studies reported improvement of neurologic
hydroxytryptophan. In an open-label study, hydroxytryp- symptoms with sulfamethoxazole-trimethoprim in
tophan did not improve the ataxic movements in the MJD.33,34 Sulfamethoxazole-trimethoprim was supposed
patients with cortical cerebellar atrophy.22 The effect of to ameliorate spasticity or rigidity rather than ataxia. Sakai
the levorotatory form of hydroxytryptophan may be et al. speculated that sulfamethoxazole-trimethoprim
Table 1
Major clinical trial of pharmacological treatments of cerebellar ataxia
Number of
Author, year (Ref.) Drug Design patients Diagnosis Duration Assessment of ataxia Result

Kark et al., 19775 Physostigmine Double-blind 8 F=8 3 month Clinical scale Effective
Kark et al., 19816 Physostigmine Double-blind, triple-crossover 21 F = 21 3 month Clinical scale Effective
Wessel et al., 199710 Physostigmine Double-blind, crossover 19 F:S = 11:8 4 weeks Clinical scale, No effect
posturographic
measures
Reding et al., 198112 Lecithin Double-blind, crossover 2 FA:F = 1:1 5 weeks Clinical scale No effect
Filla et al., 198213 Phosphatidylcholine Open trial 23 FA:F = 16:7 6 month Clinical scale Effective
Finocchiaro et al., 198514 Lecithin Open trial 11 OPCA = 11 3 month Clinical scale Slight improvement
Sorbi et al., 198815 Phosphatidylcholine Open trial 44 FA:OPCA = 20:24 4 years Clinical scale No effect
Livingstone et al., 198116 Choline chloride Double-blind, crossover 20 FA:F:S = 7:4:9 6 weeks Clinical scale Effective in 10 of 20 pts
Lawrence et al., 198017 Choline chloride Double-blind 13 FA:F:S = 1:1:11 6 weeks Clinical scale Effective in 1 pt
Sehested et al., 198018 Choline chloride Double-blind, crossover 6 F:S = 1:5 4 days Clinical scale No effect
Trouillas et al., 198819 L-5HTP Double-blind 30 FA:F:S:Others* = 4 month Clinical scale Effective
2:2:10:16
Wessel et al., 199520 L-5HTP Double-blind, crossover 39 FA:F:S = 19:11:9 10 month Clinical scale No effect
Trouillas et al., 199521 L-5HTP Double-blind 19 FA = 19 6 month Clinical scale Effective
Manto et al., 199722 L-5HTP Open trial 6 CCA = 6 6 month Clinical scale, EMG No effect
Lou et al., 199524 Buspirone Open trial 20 OPCA:CCA = 6:14 8 weeks Clinical scale, Effective in mild
posturographic ataxic pts
measures
Trouillas et al., 199725 Buspirone Double-blind 19 CCA = 19 4 month Clinical scale, Effective, but not major
posturographic
measures
Bier et al., 200327 Ondansetrone Double-blind 45 CCA:MSA:FA:F:Others* = 7 days ICARS No effect (some
15:7:4:6:13 responder)
Monte et al., 200328 Fluoxetine Open study 13 MJD = 13 6 weeks Clinical scale No effect
Sobue et al., 198331 TRH Double-blind 254 CCA, OPCA and Others 2 week Clinical scale Effective
Mello et al., 198833 S-T Double-blind 1 MJD 2 weeks Clinical scale Effective
Sakai et al., 199534 S-T Double-blind, crossover 8 MJD = 8 4 weeks Clinical scale Effective
Sakai et al., 199635 Tetrahydrobiopterin Double-blind, crossover 5 MJD = 5 10 days Clinical scale No effect
Schulte et al., 200136 S-T Double-blind, crossover 22 MJD = 22 6 month Clinical scale No effect
posturographic
measures
Jen et al, 198840 Acetazolamide Case reports 2 SCA6 = 2 n.m. Clinical observation No effect in
chronic ataxia
Yabe et al, 200141 Acetazolamide Open study 6 SCA6 = 6 88 weeks ICARS Effective
Ogawa et al, 20032 D-cycloserine Single-blind 15 MSA:CCA:F = 10:2:3 2 weeks ICARS Effective
Pharmacological treatments of cerebellar ataxia

L-5HTP = L-5 hydroxytryptophan, TRH = thyrotropin releasing hormone, S-T = sulfamethoxazole-trimethoprim F = familial cerebellar ataxia, S = sporadic (idiopathic) cerebellar ataxia,
FA = Friedreich's ataxia, OPCA = olivopontocerebellar atrophy, CCA = cortical cerebellar atrophy, Others*: include other etiologic ataxias (e.g. MS, infarction, tumor) n.m. = not mentioned
j

ICARS = international cooperative ataxia rating scale

109
110 j M Ogawa

may exhibit an effect in MJD due to increasing the the postmortem cerebella obtained from the patients with
turnover rate of tetrahydrobiopterin in the brain.34 cerebellar ataxia. Antagonists for the N-methyl-D-aspar-
However, the same authors showed that tetrahydrobiop- tate (NMDA)-type glutamate receptor, such as phency-
terin did not signi®cantly improve symptoms in a double- clidine and dizocilpine, cause cerebellar ataxia in humans
blind crossover trial in MJD.35 In contrast to previous and experimental animals.44 Phencyclidine-induced
studies, Schlute et al. reported that sulfamethoxazole- ataxia was improved by D-serine and D-alanine that act
trimethoprim had no effect in a 6-month double-blind as allosteric agonists for the NMDA receptor by stimulat-
crossover trial in 22 patients with MJD and concluded ing its glycine site in the rats.45 Glutamate is known to the
that the therapy could not be recommended.36 The neurotransmitter of the mossy and climbing ®bers in the
authors postulated that the discrepancy is due to a small cerebellum, and these observations extrapolate that
group of patients and short periods in the previous facilitation of the NMDA receptor function could
studies. A trial of sulfamethoxazole-trimethoprim versus improve ataxia in cerebellar ataxia.
antispastic medication or dopaminergic agents has not Previously, Saigoh et al. showed that the systemic
yet been reported. administration of the D-serine ethylester or D-cycloser-
ine, a partial NMDA allosteric agonist, diminishes ataxia
in mice carrying inherited or chemically-induced cerebel-
Acetazolamide lar degeneration.46 Therefore, we have evaluated the
Griggs et al. reported that acetazolamide may prevent the effects of D-cycloserine on ataxic movements in 15
episodic symptoms of episodic ataxia type2 (EA2).37 EA2 patients with cerebellar ataxia.2 This open trial demon-
is an autosomal dominant disorder, characterized by strated that a two-week D-cycloserine treatment (daily
episodes of ataxia, vertigo, nausea, nystagmus, and oral dose of 50 mg) leads to lower levels of ataxia in
fatigue. The disease is caused by mutations in the P/Q- patients with cerebellar ataxia than the preceding two-
type calcium channel Ca(v)2.1 subunit gene, CAC- week placebo-treatment as estimated by the different
NA1A, located on chromosome 19p13.2.38 Moderate measures of ataxic movement disturbances with no
expansion of a CAG repeat sequence in the coding region adverse effect. This study also suggested that D-cyclo-
of the alpha(1A) subunit gene of CACNA1A is known to serine is more effective in truncal ataxia and dysarthria
cause SCA6.39 Jen et al. reported that acetazolamide may than limb ataxia and eye movement disturbance. These
be effective for the episodic or ¯uctuating symptoms of effects may be related to the fact that an NMDA receptor
SCA6, but did not improve chronic progressive ataxia.40 antagonist has been reported to induce dysarthria or
However, Yabe et al. reported that acetazolamide could ataxic gait.47 To evaluate the anti-ataxic effects of D-
temporarily reduce chronic ataxic symptoms in an open cycloserine, a randomized, double-blind, crossover trial is
trial.41 Acetazolamide for episodic ataxia may be the only now in progress.
worldwide accepted therapy, even if the effect may be
greater in EA-2. The effect of acetazolamide to treat
chronic ataxia of patients with SCA6 is still controversial.
Conclusion
A well-designed clinical study showing the symptomatic
effect for chronic progressive ataxia is lacking. There are
Cycloserine
some candidates, but no de®nite evidence of the effect is
Several studies indicated that impaired glutamate signal- known. The basis of the degenerative ataxia may be more
ing may be involved in the pathophysiology of cerebellar complex than one mechanism such as the cholinergic
ataxia. Glutamate dehydrogenase de®ciency42 and system, serotoninergic system, glutamate system and so
changes in glutamate contents43 have been reported in on.

References
1. Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony the N-methyl-D-aspartate coupled glycine receptor has partial
SH, Wessel K, et al. International Cooperative Ataxia Rating Scale agonist characteristics. Neuroscience Letters 1989; 98(1): 91-95.
for pharmacological assessment of the cerebellar syndrome. The 5. Kark RA, Blass JP, Spence MA. Physostigmine in familial ataxias.
Ataxia Neuropharmacology Committee of the World Federation of Neurology 1977; 27(1): 70-72.
Neurology. J Neurol Sci 1997; 145(2): 205-211. 6. Kark RA, Budelli MM, Wachsner R. Double-blind, triple-crossover
2. Ogawa M, Shigeto H, Yamamoto T, Oya Y, Wada K, Nishikawa trial of low doses of oral physostigmine in inherited ataxias.
T, et al. D-cycloserine for the treatment of ataxia in spinocerebellar Neurology 1981; 31(3): 288-292.
degeneration. J Neurol Sci 2003; 210(1-2): 53-56. 7. Rodriguez-Budelli MM, Kark RA, Blass JP, Spence MA. Action of
3. Hardman JG, Limbird LE, editors.. Goodman & Gilman's The physostigmine on inherited ataxias. Adv Neurol 1978; 21: 195-
pharmacological basis of therapeutics. 9th edn. New York, : 202.
McGraw-Hill, 1996. 8. Kish SJ, Schut L, Simmons J, Gilbert J, Chang LJ, Rebbetoy M.
4. Hood WF, Compton RP, Monahan JB. D-cycloserine: a ligand for Brain acetylcholinesterase activity is markedly reduced in dom-
 Pharmacological treatments of cerebellar ataxia j 111

inantly-inherited olivopontocerebellar atrophy. J Neurol Neurosurg of thyrotropin-releasing hormone on ataxia of spinocerebellar

Psychiatry 1988; 51(4): 544-548. degeneration. Lancet 1980; 1(8165): 418-419.
9. Kanazawa I, Kwak S, Sasaki H, Mizusawa H, Muramoto O, 30. Mano Y, Matsui K, Toyoshima E, Ando K. The pharmacological
Yoshizawa K, et al. Studies on neurotransmitter markers and effect of thyrotropin-releasing hormone on ataxic mutant mice.
neuronal cell density in the cerebellar system in olivopontocerebel- Acta Neurol Scand 1986; 73(4): 352-358.
lar atrophy and cortical cerebellar atrophy. J Neurol Sci 1985; 31. Sobue I, Takayanagi T, Nakanishi T, Tsubaki T, Uono M,
71(2-3): 193-208. Kinoshita M, et al. Controlled trial of thyrotropin releasing
10. Wessel K, Langenberger K, Nitschke MF, Kompf D. Double-blind hormone tartrate in ataxia of spinocerebellar degenerations. J
crossover study with physostigmine in patients with degenerative Neurol Sci 1983; 61(2): 235-248.
cerebellar diseases. Arch Neurol 1997; 54(4): 397-400. 32. Manto M, Godaux E, Hildebrand J, Jacquy J. Effects of TRH on
11. Barbeau A. Emerging treatments: replacement therapy with choline ballistic wrist movements in cerebellar cortical atrophy: improve-
or lecithin in neurological diseases. Can J Neurol Sci 1978; 5(1): ment of two genuine de®ciencies but not of the major one. Eur J
157-160. Neurol 1998; 5(2): 159-166.
12. Reding MJ, Blass JP, Stern PH, Diponte P. Lecithin in hereditary 33. Mello KA, Abbott BP. Effect of sulfamethoxazole and trimetho-
ataxia. Neurology 1981; 31(3): 363-364. prim on neurologic dysfunction in a patient with Joseph's disease.
13. Filla A, Campanella G. A six-month phosphatidylcholine trial in Arch Neurol 1988; 45(2): 210-213.
Friedreich's ataxia. Can J Neurol Sci 1982; 9(2): 147-150. 34. Sakai T, Matsuishi T, Yamada S, Komori H, Iwashita H.
14. Finocchiaro G, Di Donato S, Madonna M, Fusi R, Ladinsky H, Sulfamethoxazole-trimethoprim double-blind, placebo-controlled,
Consolo S. An approach using lecithin treatment for olivopontocer- crossover trial in Machado-Joseph disease: sulfamethoxazole-
ebellar atrophies. Eur Neurol 1985; 24(6): 414-421. trimethoprim increases cerebrospinal ¯uid level of biopterin. J
15. Sorbi S, Piacentini S, Marini P, De Scisciolo G, Amantini A, Neural Transm Gen Sect 1995; 102(2): 159-172.
Amaducci L. Lack of ef®cacy of phosphatidylcholine in ataxias. 35. Sakai T, Antoku Y, Matsuishi T, Iwashita H. Tetrahydrobiopterin
Neurology 1988; 38(4): 649-650. double-blind, crossover trial in Machado-Joseph disease. J Neurol
16. Livingstone IR, Mastaglia FL, Pennington RJ, Skilbeck C. Choline Sci 1996; 136(1-2): 71-72.
chloride in the treatment of cerebellar and spinocerebellar ataxia. J 36. Schulte T, Mattern R, Berger K, Szymanski S, Klotz P, Kraus PH,
Neurol Sci 1981; 50(2): 161-174. et al. Double-blind crossover trial of trimethoprim-sulfamethox-
17. Lawrence CM, Millac P, Stout GS, Ward JW. The use of choline azole in spinocerebellar ataxia type 3/Machado-Joseph disease.
chloride in ataxic disorders. J Neurol Neurosurg Psychiatry 1980; Arch Neurol 2001; 58(9): 1451-1457.
43(5): 452-454. 37. Griggs RC, Moxley RT, 3rd,, Lafrance RA, McQuillen J.
18. Sehested P, Lund HI, Kristensen O. Oral choline in cerebellar Hereditary paroxysmal ataxia: response to acetazolamide. Neurol-
ogy 1978; 28(12): 1259-1264.
ataxia. Acta Neurol Scand 1980; 62(2): 124-126.
38. Denier C, Ducros A, Vahedi K, Joutel A, Thierry P, Ritz A, et al.
19. Trouillas P, Brudon F, Adeleine P. Improvement of cerebellar
High prevalence of CACNA1A truncations and broader clinical
ataxia with levorotatory form of 5-hydroxytryptophan. A double-
spectrum in episodic ataxia type 2. Neurology 1999; 52(9): 1816-
blind study with quanti®ed data processing. Arch Neurol 1988;
1821.
45(11): 1217-1222.
39. Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW,
20. Wessel K, Hermsdorfer J, Deger K, Herzog T, Huss GP, Kompf D,
Amos C, et al. Autosomal dominant cerebellar ataxia (SCA6)
et al. Double-blind crossover study with levorotatory form of
associated with small polyglutamine expansions in the alpha 1A-
hydroxytryptophan in patients with degenerative cerebellar dis-
voltage-dependent calcium channel. Nat Genet 1997; 15(1): 62-
eases. Arch Neurol 1995; 52(5): 451-455. 69.
21. Trouillas P, Serratrice G, Laplane D, Rascol A, Augustin P, 40. Jen JC, Yue Q, Karrim J, Nelson SF, Baloh RW. Spinocerebellar
Barroche G, et al. Levorotatory form of 5-hydroxytryptophan in ataxia type 6 with positional vertigo and acetazolamide responsive
Friedreich's ataxia. Results of a double-blind drug-placebo episodic ataxia. J Neurol Neurosurg Psychiatry 1998; 65(4): 565-
cooperative study. Arch Neurol 1995; 52(5): 456-460. 568.
22. Manto M, Hildebrand J, Godaux E, Roland H, Blum S, Jacquy J. 41. Yabe I, Sasaki H, Yamashita I, Takei A, Tashiro K. Clinical trial of
Analysis of fast single-joint and multijoint movements in cerebellar acetazolamide in SCA6, with assessment using the Ataxia Rating
cortical atrophy: failure of L-hydroxytryptophan to improve Scale and body stabilometry. Acta Neurol Scand 2001; 104(1): 44-
cerebellar ataxia. Arch Neurol 1997; 54(10): 1192-1194. 47.
23. Currier RD. A treatment for ataxia. Arch Neurol 1995; 52(5): 449. 42. Plaitakis A, Nicklas WJ, Desnick RJ. Glutamate dehydrogenase
24. Lou JS, Goldfarb L, McShane L, Gatev P, Hallett M. Use of de®ciency in three patients with spinocerebellar ataxia: a new
buspirone for treatment of cerebellar ataxia. An open-label study. enzymatic defect? Trans Amer Neurolog Ass 1979; 104(54): 54-
Arch Neurol 1995; 52(10): 982-988. 57.
25. Trouillas P, Xie J, Adeleine P, Michel D, Vighetto A, Honnorat J, 43. Kish SJ, Robitaille Y, el AM, Gilbert J, Deck J, Chang LJ, et al.
et al. Buspirone, a 5-hydroxytryptamine1A agonist, is active in Brain amino acid reductions in one family with chromosome 6p-
cerebellar ataxia. Results of a double-blind drug placebo study in linked dominantly inherited olivopontocerebellar atrophy. Annals
patients with cerebellar cortical atrophy. Arch Neurol 1997; 54(6): of Neurology 1991; 30(6): 780-784.
749-752. 44. Petersen RC, Stillman RC. Phencyclidine: an overview. NIDA Res
26. Rice GP, Lesaux J, Vandervoort P, Macewan L, Ebers GC. Monogr 1978(21): 1-17.
Ondansetron, a 5-HT3 antagonist, improves cerebellar tremor. J 45. Tanii Y, Nishikawa T, Hashimoto A, Takahashi K. Stereoselective
Neurol Neurosurg Psychiatry 1997; 62(3): 282-284. antagonism by enantiomers of alanine and serine of phencyclidine-
27. Bier JC, Dethy S, Hildebrand J, Jacquy J, Manto M, Martin JJ, et induced hyperactivity, stereotypy and ataxia in the rat. J Pharmacol
al. Effects of the oral form of ondansetron on cerebellar Exp Ther 1994; 269(3): 1040-1048.
dysfunction. A multi-center double-blind study. J Neurol 2003; 46. Saigoh K, Matsui K, Takahashi K, Nishikawa T, Wada K. The
250(6): 693-697. stereo-speci®c effect of D-serine ethylester and the D-cycloserine in
28. Monte TL, Rieder CR, Tort AB, Rockenback I, Pereira ML, ataxic mutant mice. Brain Res 1998; 808(1): 42-47.
Silveira I, et al. Use of ¯uoxetine for treatment of Machado-Joseph 47. Sveinbjornsdottir S, Sander JW, Upton D, Thompson PJ, Patsalos
disease: an open-label study. Acta Neurol Scand 2003; 107(3): PN, Hirt D, et al. The excitatory amino acid antagonist D-CPP-ene
207-210. (SDZ EAA-494) in patients with epilepsy. Epilepsy Research 1993;
29. Sobue I, Yamamoto H, Konagaya M, Iida M, Takayanagi T. Effect 16(2): 165-174.