1. Center for Neurological Restoration, Cleveland Clinic Foundation
Bilateral versus unilateral thalamic deep brain stimulation in patients with Fragile X–Associated Tremor Ataxia Syndrome.
R Mehanna and I Itin .
Center for Neurological Restoration, Cleveland Clinic Foundation
Cleveland, Ohio, USA
Family history: positive for mild tremor in his father in his 40’s, as well as questionable mild balance problems in his mother at an advanced age. His father passed at 55 years of age in an accident and his mother passed at 89 due to old age. He had one sister with questionable balance problems, one 45 year-old-son with imbalance and dizziness, and one daughter with recurrent depression requiring hospital admissions. His third child was healthy. He also had 5 grandchildren form his sons, 2 boys and 3 girls, who were healthy and doing fine in school. The patient’s daughter has no children. His paternal aunt might also have had tremors, but she was an alcoholic like many relatives on his father’s side of the family. The patient himself did not smoke or drink alcohol.
Examination (both stimulators ON): remarkable only for a Mini Mental Status Exam score of 28/30, severe dysarthria, minimal dysmetria in the arms, more significant dysmetria in the legs, dysdiadochokinesia, a wide based unsteady gait and inability to ambulate without assistance. There was no visible hand tremor or evidence of parkinsonism.
Differential diagnosis: Fragile X premutation tremor-ataxia syndrome (FXTAS), multiple systems atrophy-cerebellar type (MSA-C), heredofamilial and metabolic types of ataxia.
Work up: serum vitamin E and ceruloplasmin levels; Anti Nuclear Antibodies (ANA); Anti Gliadin antibodies (Ab); anti transglutaminase Ab; anti-glutamic acid decarboxylase Ab; Anti-Neuronal Nuclear Ab (ANNA) type 1,2 and 3; anti-glial nuclear Ab Type 1; Purkinje cell cytoplasmic Ab Type 1, 2 and Tr; anti-Amphiphysin Ab; anti- CRMP-5 Ab; P/Q and N type calcium channel binding Ab; striational Ab; acetylcholine receptor binding Ab; acetylcholine receptor ganglionic neuronal Ab and neuronal voltage gated potassium Ab was normal.
However, the FMR1 genetic testing revealed 94 CGG repeats, diagnostic for FXTAS. The outside hospital brain MRI that was obtained after the second surgery, and that was not available to us at the initial visit, was obtained and reviewed. It revealed a bilateral middle cerebellar peduncle T2 hyperintensity (“MCP sign”) which is found in the majority of FXTAS patients (11).
Diagnosis: It was concluded that the patient’s symptoms were secondary to FXTAS, and worsened after the second DBS surgery.
Discussion
Introduction
Leehey et al (6) first reported good tremor control but also development of marked ataxia and dysarthria in a FXTAS patient initially diagnosed with ET and treated with bilateral Vim DBS. Senova at al (8) and Xie et al (9) recently reported one patient each with good unilateral tremor control and no worsening of ataxia and/or dysarthria with unilateral Vim DBS, advocating the use of a unilateral rather than bilateral procedure in FXTAS patients with intractable tremor. However, Peters et al (10) reported one FXTAS patient treated with bilateral Vim DBS with good tremor control and no worsening of ataxia post operatively. In addition, Ferrara et al (7) reported another patient treated with bilateral Vim DBS in which tremor improved but gait and speech subjectively worsened after surgery. The authors thought that worsening was due to the natural history of FXTAS rather than to DBS because dysarthria and ataxia did not improve after turning the DBS off for 18 hours. However, our patient as well as the patient reported by Leehey et al (6) experienced progression of symptoms immediately after surgery and before turning the DBS on, suggesting that DBS implant, rather than activation, might be the cause of ataxia and dysarthria worsening.
Our patient underwent staged VIM DBS with markedly different outcomes after each stage and thus served as his own control in a way. This case clearly relates worsening of FXTAS symptoms to bilateral surgery despite good tremor control and clearly argues in favor of unilateral surgical approach for intractable tremor in FXTAS.
Fragile X–Associated Tremor Ataxia Syndrome (FXTAS) is a relatively recently described condition due to an intermediate trinucleotide repeat expansion (55–200 CGG repeats) within the fragile X mental retardation (FMR1) gene. This disease is characterized by progressive cerebellar ataxia, tremor, parkinsonism and mild cognitive decline (1,2). The FMR1 premutation causing FXTAS is estimated to affect 1/3000 to 1/800 men and 1/250 women (3-5), with only 40% penetrance in adult men carrier (5).
FXTAS is frequently misdiagnosed as essential tremor (2,6) and thus occasionally treated with deep brain stimulation (DBS) to the nucleus ventralis intermedialis of the thalamus (Vim). Only 5 FXTAS patients treated with Vim DBS for intractable tremor have been reported in the literature. Leehey et al (6) and Ferrara et al (7) each reported one patient in whom ataxia worsened after bilateral Vim DBS. Since then, the tendency has been to recommend a unilateral Vim DBS in FXTAS patients with intractable tremor, with good tremor control and no worsening of ataxia and/or dysarthria in 2 additional published cases (8,9). However, the number of published cases to base such a recommendation upon is small. Besides, 1 of the 3 patients treated with bilateral DBS had good tremor control without worsening of his ataxia (10). In addition, Ferrara et al attributed the worsening of ataxia in their patient to the natural history of FXTAS rather than to bilateral DBS (7). We report the case of a FXTAS patient treated with staged procedure, thus exposed successively to unilateral and bilateral Vim DBS, and describe the impact of each procedure on tremor and ataxia.
Table: DSB treated FXTAS cases in the literature.
Case
History: A right handed male patient developed a progressively worsening bilateral hand action tremor around 55 years of age. He was diagnosed with essential tremor and responded well to propranolol and then to add-on topiramate 7 years later. 13 years after the onset of his tremor, he developed imbalance, mild dysphagia to fluids and his tremor became refractory to medications, including gabapentin, pregabalin and primodone. The combination of propranolol and topiramate being insufficient in controlling his tremor, he underwent left Vim DBS implant 14 years after tremor onset with near complete resolution of the right hand tremor and successful weaning off all anti-tremor medications. Because of the persistence of his left hand tremor, he underwent a right Vim DBS 6 months later. This allowed good control of his left hand tremor but caused an immediate progression of his ataxia as well as the development of cognitive decline, dysarthria and apraxia. A stroke was ruled out after extensive work up including a brain MRI that was read as normal by the team managing the patient. The patient was then referred to our clinic.
At that time, he used a walker to ambulate most of the time, could dress with difficulty, would be able to fix a sandwich if his wife laid all the ingredients out, and his speech was difficult to understand.
His past medical history was positive for migraines, coronary artery disease with coronaro-aortic bypass graft 6 years prior to his visit, prostatectomy, cholecystectomy and appendectomy.
Figure: our patient taken as his own witness
* Ataxia worse even with DBS OFF or before DBS was ever turned ON.
Conclusion
FXTAS is a frequent cause of ataxia and tremor, albeit frequently under diagnosed or misdiagnosed as ET. Bilateral Vim DBS for intractable tremor in FXTAS patients has been reported in only 3 patients, with conflicting reports regarding its impact on ataxia. We here report a patient who underwent a staged Vim DBS procedure, with immediate worsening of his ataxia after the second one, arguing in favor of a unilateral surgical approach for intractable tremor in FXTAS.
References
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