Clinical Commentary

Treatment of imbalance with varenicline(Chantix�): report of a patient with fragile Xtremor ⁄ataxia syndrome

Introduction

The fragile X-associated tremor ⁄ataxia syndrome(FXTAS) is a neurodegenerative disorder thatoccurs in adult males over the age 50 years whoare carriers of the fragile X mental retardation 1(FMR-1) premutation. FXTAS symptoms includeintention and postural tremor, ataxia, cognitivedecline, parkinsonism and autonomic dysfunction(1). Currently, there is no effective treatment forataxia. We report the case of a man with FXTASwhose ataxia and imbalance were greatly improvedafter starting varenicline in an effort to stopsmoking. Discontinuation of varenicline resultedin a worsening of the gait ataxia. Open-labelresumption of varenicline has led to a sustainedresponse of 5 months.

Case report

The patient was a 64-year-old man with a 9-yearhistory of postural and intention tremor of his

arms and a 4-year history of gait ataxia. Hissymptoms became disabling in the past year withfrequent falls despite the intermittent use of awalker. His tremor along with progressive dysar-thria and memory loss had significantly impairedactivities of daily living for 1 year.The patient was identified at the Emory Univer-

sity Fragile X program through a known pedigreein which the patient�s granddaughter and grandson(born to his daughter) have fragile X syndrome(>200 CGG repeats in the FMR1 gene). He wassubsequently diagnosed with FXTAS, on the basisof the FMR1 premutation (90 CGG trinucleotiderepeats) and published clinical criteria (1). Hismaternal aunt and his mother were premutationcarriers, and two of his four brothers had posturaland intention tremor and gait ataxia. His pastmedical history revealed that he was treated fordepression 35 years ago but was otherwise non-contributory. He denied current depression. Hesmoked up to two packs of cigarettes per day for50 years, drank one to two alcoholic beverages per

Zesiewicz TA, Sullivan KL, Freeman A, Juncos JL. Treatment ofimbalance with varenicline (Chantix�): report of a patient with fragile Xtremor ⁄ataxia syndrome.Acta Neurol Scand 2009: 119: 135–138.� 2008 The Authors Journal compilation � 2008 Blackwell Munksgaard.

We describe the case of a man with Fragile X tremor ⁄ ataxia syndrome,whose ataxia and imbalance improved with the use of varenicline(Chantix�) and reverted to baseline 10 days after varenicline wasdiscontinued. Varenicline was started as part of a smoking cessationprogram.

T. A. Zesiewicz1, K. L. Sullivan1,A. Freeman2, J. L. Juncos2

1Parkinson Research Foundation Center of Excellence atUniversity of South Florida, University of South Florida,Tampa, FL, USA; 2Department of Neurology, Division ofMovement Disorders, Emory University School ofMedicine, Atlanta, GA, USA

Key words: ataxia; imbalance; varenicline; Chantix;fragile X-associated tremor ⁄ ataxia syndrome;movement disorders

Theresa A. Zesiewicz, Parkinson Research FoundationCenter of Excellence at University of South Florida,University of South Florida, Tampa, 34677 FL, USATel.: +1 813 974 5909Fax: +1 813 974 8032e-mail: tzesiewi@health.usf.edu

Part of this work was supported by NIH-NICHD R01HD29909 and P30 HD24064.

Accepted for publication May 23, 2008

Acta Neurol Scand 2009: 119: 135–138 DOI: 10.1111/j.1600-0404.2008.01070.x Copyright � 2008 The AuthorsJournal compilation � 2008 Blackwell Munksgaard

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week but was never intoxicated. He was taking nomedications.A timeline of the patient�s clinical course is

depicted in Fig. 1. The patient started varenicline1 mg twice daily which helped him quit smoking ina few days. One week after taking varenicline, henoted that his walking improved and he no longerneeded assistance from a walker to ambulate.There was also marked improvement in his bal-ance. The only side effect from varenicline wasvivid dreaming, which occurred two days afterstarting it.The patient was evaluated by the University of

South Florida (USF) movement disorders center7 weeks after starting varenicline. Vital signs andphysical examination were normal. His neurolog-ical examination included a Mini Mental StateExam (MMSE) of 26 ⁄30, mild dysarthria, mildvoice tremor, severe postural and intention tremorof his arms, mild rigidity and moderate dysmetriain all extremities. He was able to get out of a chairwithout assistance, and continued to walk 6 m fivetimes (30 m total) without rest or the assistance ofa walker. He was able to tandem walk for two tothree steps (Video clip 1 in the supportinginformation). The rest of his neurological exam,including cranial nerves, reflexes, motor and sen-sory examination, was within normal limits. Thepatient received a score of 5 (maximum possiblescore 63) on a Beck�s Depression Scale (BDI) (2). Amagnetic resonance image (MRI) of the brainshowed hyperintensities of the middle cerebellarpeduncles typical of FXTAS along with corticaland cerebellar volume loss (Fig. 2).The patient stopped varenicline 7 weeks after

starting it. Within 10 days, he reported a slightworsening of the residual ataxia and imbalance.Within 3 weeks, he again needed a walker forambulation and began to fall daily. The patientreturned to clinic off varenicline. His vital signs andphysical examination were normal, and his neuro-logical examination returned to the pre-vareniclinestate. He once again needed assistance to walk andwas unable to tandem walk even with assistance(Video clip 2 in the supporting information). Therest of the neurological examination remained

unchanged, including the postural and intentiontremor. The BDI score had not changed.At week 11, the patient re-started varenicline

1 mg twice daily, and again noted improvement inataxia within 1 week. Due to vivid dreams, thevarenicline dose was decreased to 1 mg daily atweek 12. The patient has taken varenicline for22 weeks, with a sustained ataxia improvement.A videotape of the patient was scored by a

blinded movement disorders expert (AF) usingthe Scale for Assessment and Rating of Ataxia(SARA) (3). The SARA scores on varenicline1 mg b.i.d. were �two� for functional staging forataxia (ataxic symptoms were present and wererecognized by patient, but were still mild), �one�for tandem walking (the patient was able totandem walk in less than perfect manner or thepatient could tandem walk greater than foursequential steps but less than eight steps) and�zero� for gait (normal) (Video clip 1). The SARAscores after the patient had discontinued varen-icline for 3 weeks included a �three� for functionalstaging for ataxia (ataxic symptoms consideredovert and significant), �three� for tandem walking(the patient was considered too poorly coordi-nated to attempt the task) and �two� for gait (thepatient walked with definite ataxia; may haveneeded intermittent support for walking or the

Start Week 1 Week 7 Week 8, day 3 Week 10 Week 11

Patient started varenicline.

Patient noted improved walking and balance.

Video clip #1 (first clinic evaluation).Varenicline stopped after this visit.

Patient noted worsening of ataxia and imbalance off varenicline.

Patient returned to clinic off varenicline (video clip #2).

Patient resumedvarenicline.

Figure 1. Timeline of patient�s clinical course.

Figure 2. T2-weighted images of the brain using a 3.0-T unit.Note the white matter hyperintensities in the middle cerebellarpeduncle (MCP) typical of FXTAS.

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examiner needed to walk with patient for safetysake) (Video clip 2).

Discussion

Varenicline is a highly selective partial agonist atthe a4b2 nicotinic acetylcholine receptor that isapproved by the FDA for smoking cessation. Inthis case report, a patient with FXTAS experiencedmarked improvement in gait ataxia and imbalancewhile taking varenicline. The clinical observationsin this case are supported by a blinded rating ofvideotapes taken during and after varenicline use,and a re-emergence of ataxia and imbalanceshortly after varenicline was discontinued.Effective treatment of ataxia and imbalance is

currently lacking. Case series and small controlledtrials of several medications including buspirone,fluoxetine, zolpidem and lamotrigine have demon-strated either conflicting results or limited efficacy(4).Nicotinic and muscarinic acetylcholine receptors

are found in the pons, medulla oblongata andcerebellum (5). Several animal and human studiessuggest that exogenous nicotine exposure may beharmful to the developing cerebellum (6, 7). In onestudy, the expression of these receptors was alteredin 5- to 12-week gestation abortus of smoking,compared with non-smoking pregnant women (5).Another study found that smokers have greaterpostural imbalance and body sway than non-smokers (8), while a case report documentedgreater balance dysfunction in a patient withspinocerebellar ataxia after smoking (9).Unlike nicotine, recent reports suggest that

selective activation of the a4b2 nicotinic acetyl-choline receptor subtype may improve alcohol (10)and tetrahydrocannabinoid [D9THC]-inducedataxia in experimental animals (11). It is knownthat selective activation of a4b2 nicotinic acetyl-choline receptors results in post-synaptic up-regu-lation (i.e. desensitization) of dopamine receptorsin the mesolimbic system (12, 13). This may berelevant to tolerance and dependence, but it isunlikely to explain the anti-ataxic effect of varen-icline. Early evidence suggests instead that otherneurotransmitters like glutamate can modulatenicotine-mediated attenuation of ethanol-inducedataxia (10). In addition, increased nitric oxide(NO) production following intracerebellar injec-tion of the a4b2 nicotinic acetylcholine receptorsagonist RJR-2403 may improve D9THC-inducedataxia via mechanisms of cross tolerance mediatedthrough the powerful NO intracellular signalingsystem (11). These and other non-dopaminergicactions of varenicline await further investigation.

It is possible but unlikely that smoking cessationled to gait improvement because there was a clearre-exacerbation of ataxia when varenicline wasstopped, even though the patient had quit smokingseveral weeks before. The patient also drinksalcohol occasionally without becoming intoxi-cated. As the literature suggests that vareniclinecan reduce alcohol-induced ataxia, we cannot ruleout the possibility that alcohol may aggravateataxia attributable to FXTAS.Controlled studies on the effect of varenicline to

improve conditions associated with ataxia andimbalance are warranted. Caution is needed givenrecent reports of suicidal behaviors, depressedmood and agitation in subjects attempting smok-ing cessation with this drug.

Supporting information

Additional Supporting Information may be found in the onlineversion of this article.

Video Clip Segment 1 shows the 64-year old patient onvarenicline showing little ataxia compared with the nextsegment ataxia. Segment 2 shows the patient after discon-tinuing varenicline for 3 weeks.

Please note: Blackwell Publishing are not responsible for thecontent or functionality of any supporting materials suppliedby the authors. Any queries (other than missing material)should be directed to the corresponding author for the article.

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