Treatment of FragileX–Associated

Tremor/Ataxia Syndromewith Unilateral DeepBrain Stimulation

Fragile X–associated tremor/ataxia syndrome (FXTAS) isa hereditary neurodegenerative disease with postural andaction tremors and cerebellar ataxia, frequently associatedwith cognitive deficits, parkinsonism, dysautonomia, and neu-ropathy. Neuroimaging often reveals T2 hyperintensity in themiddle cerebellar peduncles (MCPs). FXTAS is caused byexpansion of 55–200 repeats (premutation) of CGG trinucleo-tide in the fragile mental retardation gene 1 (FMR1). Themutation causes fragile X syndrome when the repeats exceed200.1,2 Pharmacological treatment for the tremor has a mild tomoderate effect.3 Deep brain stimulation (DBS) has been rarelyreported in FXTAS, with bilateral ventrointermediate (VIM)nucleus DBS improving tremors but worsening gait andspeech.4,5 Here we report a patient with FXTAS who under-went successful unilateral VIM DBS to improve tremors.The patient was a 65-year-old right-handed man with pro-

gressively disabling tremor in his hands for 10 years, dys-arthria and gait imbalance for 5 years, and memory declinefor 3 years. Despite being treated with primidone and topir-amate, his tremors remained disabling. He could not writeor feed himself using the right hand. His daughters (ages 33and 34) carried the FMR1 premutation but were reportedlyasymptomatic. His brother developed tremor in his fifties.On exam, he demonstrated severe postural, kinetic and

intention tremors of the upper extremities (worse on theright), mild resting tremor of the hands, jaw, tongue, and

neck, and moderate vocal tremor. He had normal tone, mildbradykinesia, and broad gait with difficulty in tandem(Video Segment 1). He had difficulty with serial 7s andshort-term recall. Brain MRI showed moderate cerebral atro-phy with symmetric hyperintense T2 signals in MCPs. ADNA test found 75 CGG repeats in the FMR1 gene.

A left VIM electrode (3387 lead, Medtronic, Minneapolis,MN) was placed and produced excellent stimulation effects atthe target midway between the middle commissure point andposterior commissure at the level of anterior/posterior com-missure plane and 11 mm lateral to the third ventricle wall.The stimulation settings (Soletra, Medtronic, Minneapolis,MN) were caseþ/contact1�; amplitude, 2.6 V; pulse width,60 ls; frequency, 185 Hz, which significantly improved alltremors (Video Segment 2). He was able to draw a smoothspiral (Fig. 1B) and hold a bottle of water steady in his righthand. The amplitude/pulse width was increased to 3.4/120 at1 year and 4.4/150 at the 18-month visit to optimize tremorcontrol. There was no decline in his gait and speech (VideoSegment 3) or memory change or depression. He reportedimprovements in daily living function. The higher-than-aver-age energy consumption over time could reflect tolerance tostimulation and/or disease progression, which led to batteryreplacement 2 years after implantation. He was instructed toturn off stimulation overnight, but he did not follow.

This case demonstrates the typical clinical, neuroimaging, andgenetic features of FXTAS. He successfully underwent unilateralVIM DBS, which improved the tremors in the dominant handwithout associated decline in speech and gait. Because FXTAS isoften poorly controlled by medications whereas bilateral VIMDBS can be associated with impaired speech and balance,4,5 uni-lateral VIM DBS to improve dominant hand function representsan effective and safe option in selected individuals.

Legend to the VideoVideo Segment 1. Preoperative exam demonstrating vocal

tremor with dysarthria, severe wing-beating postural tremorand intention tremor of the right upper extremity, unsteadygait, and poor tandem.

Video Segment 2. Postoperative exam 5 months after leftVIM DBS placement demonstrating significant improvement inwing-beating postural tremor and intention tremor of the rightupper extremity compared with those before DBS placement.

Video Segment 3. Postoperative exam 1 year after leftVIM DBS placement demonstrating stable speech and gaitcompared with those before DBS placement.

Tao Xie, MD, PhD,1* Robert Goodman, MD, PhD,2

Nina Browner, MD,3 Elizabeth Haberfeld, MD,4

Linda Winfield, RN, MPH,4

Jill Goldman, MS, MPhil, CGC,4 Blair Ford, MD4

1Department of Neurology, University of ChicagoMedical Center, Chicago, Illinois, USA

2Departments of Neurosurgery, Beth IsraelMedical Center and, St. Luke’s and Roosevelt

Hospitals, New York, New York, USA

FIG. 1. Spiral drawn by right hand before (A) and about 5 months af-ter (B) DBS surgery, demonstrating significant improvement in tremor.

------------------------------------------------------------Additional Supporting Information may be found in the online version ofthis article.* Correspondence to: Tao Xie, Department of Neurology, University ofChicago Medical Center, Chicago, Illinois, USA; txie@bsd.uchicago.eduRelevant conflicts of interest/financial disclosures: Nothing to report.Full financial disclosures and author roles may be found in the onlineversion of this article.Published online in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.24958

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Movement Disorders, Vol. 000, No. 000, 0000 1

3Department of Neurology, University of NorthCarolina at Chapel Hill, Chapel Hill,

North Carolina, USA4Department of Neurology, Columbia UniversityMedical Center, New York, New York, USA

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