Skip Navigation
Skip to contents

JMD : Journal of Movement Disorders

OPEN ACCESS
SEARCH
Search

Articles

Page Path
HOME > J Mov Disord > Volume 5(1); 2012 > Article
Original Article
Preliminary Study of Intravenous Amantadine Treatment for Ataxia Management in Patients with Probable Multiple System Atrophy with Predominant Cerebellar Ataxia
Jinyoung Youna, Hyeeun Shinb, Ji Sun Kima, Jin Whan Choa
Journal of Movement Disorders 2012;5(1):1-4.
DOI: https://doi.org/10.14802/jmd.12001
Published online: April 30, 2012

aDepartment of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

bDepartment of Neurology, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea

Corresponding author: Jin Whan Cho, MD, PhD Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea, Tel +82-2-3410-1279, Fax +82-2-3410-0052, E-mail praisecho@hanmail.net
The authors have no financial conflicts of interest.
• Received: March 16, 2012   • Revised: April 30, 2012   • Accepted: April 30, 2012

Copyright © 2012 The Korean Movement Disorder Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

next
  • 11,241 Views
  • 94 Download
  • 7 Crossref
  • Background and Purpose:
    Multiple system atrophy with predominant cerebellar ataxia is a disabling neurologic disease. However, effective management has not yet been established. We conducted a short-term, open-label preliminary study to assess the benefits of intravenous amantadine treatment in patients with probable multiple system atrophy with predominant cerebellar ataxia.
  • Methods:
    Twenty patients (10 male, 10 female) with probable multiple system atrophy with predominant cerebellar ataxia received 400 mg of amantadine by intravenous per day for 5 days. Ataxia severity was evaluated by the International Cooperative Ataxia Rating Scale before and after intravenous amantadine therapy and all subjects reported subjective improvement after intravenous amantadine treatment using a patient global impression scale. We analyzed the total and subscale scores by the ataxia scale and patient global impression scale.
  • Results:
    The mean age was 57.4 years (range: 47–72) and the mean disease duration was 30.8 months (range: 11–79). The ataxia severity significantly decreased after intravenous amantadine therapy from 42.5 to 37.3 (p < 0.001). The mean patient global impression scale for improvement was 2.9 and there were no side effects of intravenous amantadine treatment observed. When we assessed responders, the duration of intravenous amantadine effect was more than 1 month in 4 subjects of 7 responders.
  • Conclusions:
    Our findings suggest that intravenous amantadine treatment can be a safe management option in cerebellar ataxia, although the mechanism is unclear. Thus, further double-blind, long-term studies with a larger sample size are needed.
Multiple system atrophy with predominant cerebellar ataxia (MSA-C) is an adult-onset, sporadic, progressive neurodegenerative disease characterized by prominent cerebellar ataxia with varying severity of autonomic failure, urogenital dysfunction, parkinsonian features and corticospinal disorders.1 MSA can reduce perceived quality of life,2 but no cure or protection is currently available. Furthermore, even though somewhat effective symptomatic therapy is available to treat parkinsonism and dysautonomia in MSA, there is no symptomatic treatment for cerebellar ataxia, the main clinical feature of MSA-C.3
Because amantadine hydrochloride has been shown to antagonize N-methyl-D-aspartate (NMDA) receptors and stimulate dopamine release, amantadine has been used to treat many diseases involving the central nervous system. Because of the effect as a NMDA receptor antagonist, amantadine was regarded as one of possible agents for symptomatic ataxia management.47 However, despite clinical trials on the effect of amantadine treatment on cerebellar ataxia, there are still controversies regarding the effect of amantadine on cerebellar ataxia.47
Orally administrated amantadine might have some limitations because of different pharmacokinetics when administrated intravenously8 and an interindividual variability of oral amantadine absorption.9 However, to the best of our knowledge, there was no study focusing on the effect of intravenous (IV) amantadine on cerebellar ataxia. We conducted a short-term, open-label preliminary study to access the benefit of IV amantadine in patients with ataxia.
Subjects
This open-labeled preliminary study was conducted at the movement clinic in Samsung Medical Center, Seoul, Korea. We enrolled patients diagnosed with probable MSA-C according to the second consensus statement on the diagnosis of multiple system atrophy.1 Information regarding age, gender and disease duration were collected as basic demographic data. Patients were excluded if they had 1) marked parkinsonism (resting tremor or rigidity of 2 or more score in one limb by unified Parkinson disease rating scale) to minimized the bias from improved parkinsonism after IV amantadine treatment; 2) history of psychiatric symptoms such as hallucination, delusion, or confusion; 3) cognitive dysfunction (Korean version mini-mental status examination ≤ 24); 4) history of epileptic seizure; 5) history of side effects associated with orally administrated amantadine; and finally; 6) renal or hepatic dysfunction as indicated by blood laboratory results on admission. All subjects were reviewed and provided informed consent before initiation of study procedures. The study received approval by an independent ethics review board, the Institutional Review Board of Samsung Medical Center.
We administrated 200 mg in 500 cm3 of IV amantadine over a 3-hour period, twice per day (400 mg/day) for 5 days (Figure 1). The dose and duration of treatment were based on previous studies of IV amantadine.10,11 For clinical rating, we evaluated cerebellar ataxia by the International Cooperative Ataxia Rating Scale (ICARS)12 before and after IV amantadine treatment for 5 days. All subjects reported subjective improvement after IV amantadine treatment using the patient global impression of improvement (PGI-I).13
We designated 2 groups based on response to IV amantadine. Responders were defined as subjects who showed score improvement of 5 or more on the ICARS.14 Non-responders were subjects showing score improvement of 2 or less on the ICARS. We compared demographic data, PGI-I and baseline ICARS score between the 2 groups. And we followed up responders 1 month after IV amantadine treatment to assess the duration of effect.
Statistical analysis
All data are presented as mean ± standard deviation. We compared the severity of cerebellar ataxia rated by ICARS before and after IV amantadine administration. Differences were evaluated using paired Student’s t-tests or Wilcoxon’s signed rank tests for continuous and ordinary variables, while Pearson’s chi-square test or Fisher’s exact test was used for categorical variables. The correlation between PGI-I score and the difference in ICARS scores after IV amantadine treatment was evaluated by Spearman’s correlation analysis. p-values < 0.05 were considered statistically significant. All statistical analyses were conducted using commercially available software (SPSS for Windows, version 16.0; SPSS Inc., Chicago, IL, USA).
Twenty subjects (10 males and 10 females) diagnosed as having probable MSA-C were enrolled from the movement disorder clinic. The mean age was 57.4 ± 8.2 years and disease duration was 30.8 ± 17.7 months. All subjects completed IV amantadine treatment for 5 days without any complications.
When the ICARS scores from baseline and post-IV amantadine treatment were compared, a significant reduction in score after IV amantadine treatment was observed. Especially, scores in subscales I (posture and gait disturbance), II (kinetic functions) and III (speech disorder) were significantly improved (Table 1). An improvement in total ICARS score of 5 or greater was observed in 8 subjects (responders), whereas 8 subjects (non-responders) had an improvement in total ICARS score of 2 or less, including one subject who demonstrated minimal worsening (from 22 to 24). When responders visit out-patients clinic 1 month after IV amantadine treatment, 4 (50%) notified that the effect of IV amantadine did not last for 1 month and their ICARS scores increased to the baseline ICARS score level (Figure 2). The mean ICARS score at 1 month after IV amantadine treatment was not significantly reduced when comparing with baseline ICARS score (47.8, and 42.8, ICARS scores of baseline and 1 month after treatment, respectively). But decrease in ICARS scores were maintained in 4 responders (44.3, 33 and 31.8, ICARS scores of baseline, after treatment and 1 month after treatment, respectively).
Mean PGI-I was 2.85 ± 1.2 and 12 subjects (60%) felt their ataxia improved after IV amantadine treatment (4 patients felt very much improved, 3 felt much improved and 5 felt little improved). No subjects reported a worsened condition by the PGI-I after the IV amantadine treatment.
When the demographic data of responders and non-responders were compared, the more severe kinetic dysfunction (subscale II in ICARS) and shorter disease duration were observed in responders (Table 2). A correlation between PGI-I score and the difference in ICARS scores was also observed (p = 0.001, ρ = −0.677).
The study presented here is the first to assess the effect of IV amantadine on cerebellar ataxia in MSA-C. Because few previous studies have explored the use of IV amantadine in other diseases,10,11 we chose a daily dose and duration of treatment that was as high and long as practical based on those previous assessments. In this study, IV amantadine treatment improved ataxia in MSA-C patients and 60% of subjects reported improvement. Additionally, there were no side effects observed of IV amantadine treatment or worsening of PGI-I, although 2 points on the total ICARS score in one subject were worse after treatment. Based on these results, we propose that IV amantadine treatment can be an effective and safe management option for ataxia in MSA-C patients in spite of short duration of the effect.
Although the exact mechanism by which amantadine works in the central nervous system is not known, the drug is considered to have two major actions: a dopaminergic effect and an NMDA receptor antagonistic effect. Due to the dopaminergic effect of amantadine, effects on the bradykinesia and rigidity can appear to improve ataxia.15 But first of all, we excluded MSA-C patients with marked parkinsonism such as resting tremor and rigidity. And in subscale analysis, there was significant improvement in not only subscale II (kinetic functions) but also subscale I (posture and gait disturbance) which is not regarded as indicative of dopaminergic dysfunction. NMDA receptors are important in neuronal signaling in the cerebellum, especially in the climbing fibers, mossy fibers and granule cells.16 Additionally, some study assessing memantine, a potent blocker of NMDA receptors was effective in mitigating ataxia.17 These points suggest that NMDA receptors play an important role in ataxia, and may indicate why amantadine was effective in improving cerebellar ataxia.
A previous study in humans assessing the effectiveness of up to 600 mg/day of orally administrated amantadine reported no improvement in ICARS scores after amantadine treatment.7 But there was limitation due to the large interindivisual variability of oral amantadine absorption.9 And in animal studies, IV amantadine treatment resulted in different pharmacokinetics than those observed after orally administrated amantadine.8 Two-compartment model best describes the deposition of amantadine after IV administration, while a one-compartment model best describes the deposition of oral amantadine. When similar dose of amantadine was administrated by IV and orally, the maximum concentration was much higher after IV treatment.8 It is possible that a similar difference exists when the drug is applied in humans and based on these features of IV amantadine treatment, it may be more effective than oral amantadine.
Although our results demonstrated an effect of IV amantadine on ataxia, there were 8 non-responders. Thus, it is very important to select patients that will likely respond to treatment with IV amantadine. Responders had more severe limb ataxia (subscale II, kinetic function) and shorter disease duration. Although there was significant improvement in both subscale I and II of ICARS, MSA-C patients with severe limb ataxia may be responders of IV amantadine treatment. And responders showed shorter disease duration although there was no difference in total ICARS score. Considering this result, responders could be regarded as having a more progressive clinical course. Therefore we suggest that MSA-C patients with more severe limb ataxia and progression would more likely benefit from IV amantadine treatment than others, and that these can be the predictors for the effect to IV amantadine medication.
When we compared PGI-I scores between responders and non-responders, responders had significantly higher PGI-I scores. There was also a correlation between PGI-I score and the difference between the pre- and post-treatment ICARS scores. These results suggest that IV amantadine treatment is an effective management option from the perspective of both patients and clinicians.
This study had some limitations. First of all, the present study was also limited in that it was open-label, short-term and of an uncontrolled design, making the results susceptible to the placebo effect. To overcome these limitations, further studies that are double-blinded with a placebo-controlled design are needed. Second, although ICARS is a useful tool for ataxia, ICARS can be contaminated by parkinsonism.15 Thus, we excluded the patients with marked parkinsonism. Moreover, the clinical improvement was seen in posture and gait disturbance scores in ICARS, which is not only dependent on dopaminergic function. Finally, although there were some studies suggesting the different effect of oral and IV amantadine, more studies are needed to confirm the usefulness of IV amantadine.9,18,19
Figure 1.
Flow chart of this study. IV: intravenous, K-MMSE: Korean version Mini-Mental Status Examination, ICARS: International Cooperative Ataxia Rating Scale, PGI-I: patient global impression of improvement.
jmd-5-1-1-1f1.gif
Figure 2.
ICARS score of all subjects. ICARS: International Cooperative Ataxia Rating Scale.
jmd-5-1-1-1f2.gif
Table 1.
Total ICARS score and each subscale score before and after amantadine treatment
Score before amantadine Score after amantadine p-value
ICARS, total 42.5 ± 13.3 37.3 ± 13.5 <0.001*
I. Posture and gait disturbance 17.1 ± 6.0 15.2 ± 6.6 0.007*
II. Kinetic functions 20.1 ± 7.0 17.5 ± 6.4 <0.001*
III. Speech disorders 3.4 ± 1.6 3.1 ± 1.6 0.034*
IV. Oculomotor disorders 1.5 ± 1.3 1.5 ± 1.4 0.564

p-value was calculated by paired t-test and Wilcoxon’s signed rank test.

* p-value < 0.05. ICARS: International Cooperative Ataxia Rating Scale.

Table 2.
Demographic data, baseline ICARS score and clinical global impression-improvement scale by group (responders and non-responders)
Responders (n = 7) Non-responders (n = 8) p-value
Age (years) 59.0 ± 7.7 58.1 ± 10.0 0.847
Sex (male/female) 5/3 3/5 0.619
Disease duration (month) 15.8 ± 11.2 34.4 ± 21.6 0.035*
PGI-I 1.8 ± 1.0 3.4 ± 0.5 0.006*
Baseline ICARS, total 47.8 ± 14.2 34.9 ± 9.6 0.061
  I. Posture and gait disturbance 18.5 ± 5.3 14.6 ± 5.8 0.187
  II. Kinetic functions 23.3 ± 8.3 15.9 ± 4.7 0.046*
  III. Speech disorders 3.4 ± 1.8 2.9 ± 1.6 0.567
  IV. Oculomotor disorders 2.0 ± 1.5 1.5 ± 1.3 0.552

PGI-I, clinical global impression-improvement scale. p-value was calculated by Mann-Whitney U test, unpaired Student t-test and Fisher’s exact test.

* p-value < 0.05. ICARS: International Cooperative Ataxia Rating Scale, PGI-I: patient global impression of improvement.

  • 1. Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71:670–676.ArticlePubMedPMC
  • 2. Winter Y, Spottke AE, Stamelou M, Cabanel N, Eggert K, Höglinger GU, et al. Health-related quality of life in multiple system atrophy and progressive supranuclear palsy. Neurodegener Dis 2011;8:438–446.ArticlePubMed
  • 3. Colosimo C, Pezzella FR. The symptomatic treatment of multiple system atrophy. Eur J Neurol 2002;9:195–199.ArticlePubMed
  • 4. Botez MI, Botez-Marquard T, Elie R, Le Marec N, Pedraza OL, Lalonde R. Amantadine hydrochloride treatment in olivopontocerebellar atrophy: a long-term follow-up study. Eur Neurol 1999;41:212–215.ArticlePubMed
  • 5. Botez MI, Botez-Marquard T, Elie R, Pedraza OL, Goyette K, Lalonde R. Amantadine hydrochloride treatment in heredodegenerative ataxias: a double blind study. J Neurol Neurosurg Psychiatry 1996;61:259–264.ArticlePubMedPMC
  • 6. Filla A, De Michele G, Orefice G, Santorelli F, Trombetta L, Banfi S, et al. A double-blind cross-over trial of amantadine hydrochloride in Friedreich’s ataxia. Can J Neurol Sci 1993;20:52–55.ArticlePubMed
  • 7. Hassin-Baer S, Korczyn AD, Giladi N. An open trial of amantadine and buspirone for cerebellar ataxia: a disappointment. J Neural Transm 2000;107:1187–1189.ArticlePubMed
  • 8. Siao KT, Pypendop BH, Stanley SD, Ilkiw JE. Pharmacokinetics of oxymorphone in cats. J Vet Pharmacol Ther 2011;34:599–604.ArticlePubMed
  • 9. Aoki FY, Sitar DS. Clinical pharmacokinetics of amantadine hydro-chloride. Clin Pharmacokinet 1988;14:35–51.ArticlePubMed
  • 10. Kim YE, Kim HJ, Yun JY, Jeon BS. Intravenous amantadine is safe and effective for the perioperative management of patients with Parkinson’s disease. J Neurol 2011;258:2274–2275.ArticlePubMed
  • 11. Magnet MK, Bonelli RM, Kapfhammer HP. Amantadine in the akinetic-rigid variant of Huntington’s disease. Ann Pharmacother 2004;38:1194–1196.ArticlePubMed
  • 12. Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony SH, Wessel K, et al. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci 1997;145:205–211.ArticlePubMed
  • 13. Guy W. ECDEU Assessment Manual for Psychopharmacology. US Department of Health and Welfare Publication (ADM). Rockville, MD: National Institutue of Mental Health; 1976.
  • 14. Lynch DR, Perlman SL, Meier T. A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia. Arch Neurol 2010;67:941–947.ArticlePubMed
  • 15. Tison F, Yekhlef F, Balestre E, Chrysostome V, Quinn N, Wenning GK, et al. Application of the International Cooperative Ataxia Scale rating in multiple system atrophy. Mov Disord 2002;17:1248–1254.ArticlePubMed
  • 16. Stell BM, Rostaing P, Triller A, Marty A. Activation of presynaptic GABA(A) receptors induces glutamate release from parallel fiber synapses. J Neurosci 2007;27:9022–9031.ArticlePubMedPMC
  • 17. Ortigas MC, Bourgeois JA, Schneider A, Olichney J, Nguyen DV, Cogswell JB, et al. Improving fragile X-associated tremor/ataxia syndrome symptoms with memantine and venlafaxine. J Clin Psychopharmacol 2010;30:642–644.ArticlePubMedPMC
  • 18. Kim YE, Yun JY, Jeon BS. Effect of intravenous amantadine on dopaminergic-drug-resistant freezing of gait. Parkinsonism Relat Disord 2011;17:491–492.ArticlePubMed
  • 19. Lucetti C, Del Dotto P, Gambaccini G, Dell’ Agnello G, Bernardini S, Rossi G, et al. IV amantadine improves chorea in Huntington’s disease: an acute randomized, controlled study. Neurology 2003;60:1995–1997.ArticlePubMed

Figure & Data

References

    Citations

    Citations to this article as recorded by  
    • Low Dose Amantadine and Escitalopram in Progressive Supranuclear Palsy and Multiple System Atrophy
      Porimita Chutia, Shailendra Mohan Tripathi
      Annals of Neurosciences.2024;[Epub]     CrossRef
    • Targeting NMDA receptors with an antagonist is a promising therapeutic strategy for treating neurological disorders
      Md. Rajdoula Rafe, Pranoy Saha, Stephen Temitayo Bello
      Behavioural Brain Research.2024; 472: 115173.     CrossRef
    • Amantadine withdrawal in a patient with spinocerebellar ataxia
      Andrew Pak, Emiley Chang
      BMJ Case Reports.2023; 16(11): e256840.     CrossRef
    • M1 and Cerebellar tDCS for MSA-C: a Double-Blind, Randomized, Sham-Controlled, Crossover Study
      Jong Hyeon Ahn, Dongyeong Lee, Minkyeong Kim, Jin Whan Cho, Won Hyuk Chang, Jinyoung Youn
      The Cerebellum.2022; 22(3): 386.     CrossRef
    • Effects of preoperative intravenous amantadine sulfate infusion on wake up test duration and postoperative opioid consumption in adolescents undergoing spine corrective surgery
      Ghada M. Aboelfadl, Saeid Elsawy, Belal O. Elnady, Rasha Hamed
      Perioperative Care and Operating Room Management.2021; 24: 100166.     CrossRef
    • Amantadine in the treatment of Parkinson’s disease. New opportunities in the context of COVID-19
      E.A. Katunina
      Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova.2021; 121(4): 101.     CrossRef
    • Efficacy of Parenteral Amantadine Therapy in the Treatment of Multiple System Atrophy With Predominant Parkinsonism
      Adit Friedberg, Ilana Erikh, Maria Nassar, Elliot Sprecher, Ilana Schlesinger
      Clinical Neuropharmacology.2018; 41(5): 160.     CrossRef

    Comments on this article

    Add a comment
    Figure
    • 0
    • 1
    Related articles
    Preliminary Study of Intravenous Amantadine Treatment for Ataxia Management in Patients with Probable Multiple System Atrophy with Predominant Cerebellar Ataxia
    Image Image
    Figure 1. Flow chart of this study. IV: intravenous, K-MMSE: Korean version Mini-Mental Status Examination, ICARS: International Cooperative Ataxia Rating Scale, PGI-I: patient global impression of improvement.
    Figure 2. ICARS score of all subjects. ICARS: International Cooperative Ataxia Rating Scale.
    Preliminary Study of Intravenous Amantadine Treatment for Ataxia Management in Patients with Probable Multiple System Atrophy with Predominant Cerebellar Ataxia
    Score before amantadine Score after amantadine p-value
    ICARS, total 42.5 ± 13.3 37.3 ± 13.5 <0.001*
    I. Posture and gait disturbance 17.1 ± 6.0 15.2 ± 6.6 0.007*
    II. Kinetic functions 20.1 ± 7.0 17.5 ± 6.4 <0.001*
    III. Speech disorders 3.4 ± 1.6 3.1 ± 1.6 0.034*
    IV. Oculomotor disorders 1.5 ± 1.3 1.5 ± 1.4 0.564
    Responders (n = 7) Non-responders (n = 8) p-value
    Age (years) 59.0 ± 7.7 58.1 ± 10.0 0.847
    Sex (male/female) 5/3 3/5 0.619
    Disease duration (month) 15.8 ± 11.2 34.4 ± 21.6 0.035*
    PGI-I 1.8 ± 1.0 3.4 ± 0.5 0.006*
    Baseline ICARS, total 47.8 ± 14.2 34.9 ± 9.6 0.061
      I. Posture and gait disturbance 18.5 ± 5.3 14.6 ± 5.8 0.187
      II. Kinetic functions 23.3 ± 8.3 15.9 ± 4.7 0.046*
      III. Speech disorders 3.4 ± 1.8 2.9 ± 1.6 0.567
      IV. Oculomotor disorders 2.0 ± 1.5 1.5 ± 1.3 0.552
    Table 1. Total ICARS score and each subscale score before and after amantadine treatment

    p-value was calculated by paired t-test and Wilcoxon’s signed rank test.

    p-value < 0.05. ICARS: International Cooperative Ataxia Rating Scale.

    Table 2. Demographic data, baseline ICARS score and clinical global impression-improvement scale by group (responders and non-responders)

    PGI-I, clinical global impression-improvement scale. p-value was calculated by Mann-Whitney U test, unpaired Student t-test and Fisher’s exact test.

    p-value < 0.05. ICARS: International Cooperative Ataxia Rating Scale, PGI-I: patient global impression of improvement.


    JMD : Journal of Movement Disorders Twitter
    Close layer
    TOP