Tetrabenazine Treatment for Post-Stroke Choreiform Movements

Patients are commonly admitted to skilled nursing facilities (SNFs) for post-stroke rehabilitation. It is common for multiple problems to contribute to post-stroke disability, all of which need to be targeted in the overall rehabilitation plan. Movement disorders are not common after stroke, occurring in about 1% to 4% of patients,1 but can contribute significantly to disability and complicate physical and occupational therapy efforts. Geriatric practitioners are likely to encounter such patients on occasion. Numerous movement disorders have been reported after stroke; hemichorea and hemiballismus are the most common,^1,2 and are characterized by smooth, nonrhythmic, purposeless movements limited to the side of the body contralateral to the stroke (Table 1). We report a patient admitted to an SNF for post-stroke rehabilitation and whose disabling post-stroke hemichorea responded well to tetrabenazine, facilitating a positive outcome and ultimate return home.

Case Report

A 71-year-old, right-handed man suffered a thromboembolic stroke 3 days following an aortic valve replacement. Upon admission to hospital, magnetic resonance imaging showed evolving encephalomalacia in the right posterior cerebral artery distribution, involving the parietal, occipital, and temporal cortex and the thalamus. Residua included mild to moderate left hemiparesis and proprioceptive deficits, dense left homonymous hemianopsia and left-sided hemineglect, mild cognitive impairment, and a sacral stage III pressure ulcer. He had also developed a post-stroke depression with anhedonia, hopelessness, tearfulness, anorexia with 25 kg weight loss (some of this was likely related to the valve replacement surgery as well), and poor effort in therapies, which responded well to venlafaxine. 

He was transferred to the Community Living Center (CLC; a VA skilled nursing and rehabilitation facility) about 7 weeks after the stroke for rehabilitation. Past medical history was significant for aortic stenosis; diabetes mellitus with poor historical control (hemoglobin A₁c generally in the 8 to 10% range, 6.4% on admission to the CLC); peripheral vascular disease; an old, right below-the-knee amputation; coronary artery disease; and hypertension. Medications included venlafaxine, glargine insulin, atorvastatin, lisinopril, metoprolol, clopidogrel, ranitidine, tamsulosin, and gabapentin.

About 6 weeks after the stroke, he began to develop mild left-sided choreiform movements, affecting the upper extremity more than the lower extremity. These were mild at first but after 3 more weeks became severe enough to interfere with use of his left arm and his gait; he was unable to effectively use the arm in transfers or when using a walker, had difficulties with all activities of daily living (ADLs), and had poor control of his leg when ambulating. He also suffered several skin tears on his left arm due to the uncontrolled movements. We considered the possibility of drug-induced chorea, but choreiform movements have never been reported with venlafaxine, gabapentin, or any of his other medications. Dyskinesia Impairment Scale (DIS)³ choreoathetosis subscale score at this time was 52. The DIS is a 12-item scale originally developed for assessment of cerebral palsy but useful for other forms of chorea. There are two subscales: a dystonia subscale and a choreoathetosis subscale. Maximum choreoathetosis score is 288, or 192 for hemichorea. The DIS score is not stratified into mild, moderate, and severe categories, but our patient’s hemichorea was moderately severe and interfered significantly with his rehabilitation.

Attempts at neuromuscular re-education through weight-bearing and use of cuff weights were minimally effective, and we ultimately elected to begin pharmacologic treatment with tetrabenazine, opting to avoid antipsychotics due to their potential negative effect on rehabilitation outcomes. Tetrabenazine 12.5 mg BID was started, and, after 3 weeks, DIS score had improved to 30, then to 20 at the final dose of 12.5 mg TID 2 weeks later. Functionally, he exhibited marked improvement in motor control and grasping and releasing with the hand, better balance with upper extremity support, better righting reflex when ambulating, and improvement in most ADLs, especially dressing. The Functional Independence Measure (FIM)⁴ is a commonly used tool in rehabilitation programs to assess functional capacity and rehabilitation outcome in 18 different areas. Total score ranges from 18 to 126, with higher scores indicating greater degrees of functional independence. A FIM score of 60 suggests moderate disability, requiring about 4 hours per day of personal care, and FIM scores over 100 suggest complete or near-complete functional independence. Our patient’s FIM score improved during rehabilitation from 44 to 58, with greatest gains in dressing, grooming, transfers, and wheelchair locomotion. It is not clear to what extent the improvement in hemichorea contributed to this improvement. 

He ultimately returned home with his wife after 16 weeks of rehabilitation. The tetrabenazine has remained effective over the past 4 months, and he has tolerated it well without any sedation, recurrent depression, or other adverse effects.

Discussion

Stroke does not generally respect strict neuroanatomical boundaries; multiple areas of disability, and thus multiple targets of rehabilitation, are the norm. Our patient was typical, with motor (hemiparesis, hemichorea); sensory (decreased proprioception, hemianopsia); cognitive (mild executive deficits and disinhibition, also hemineglect); and psychiatric (post-stroke depression) deficits, all contributing to his overall disability. The hemichorea was particularly disabling, and its response to pharmacologic treatment quite gratifying.

Post-stroke hemichorea often improves spontaneously over a period of several years²; thus, our patient’s improvement could conceivably have been unrelated to the tetrabenazine, although the improvement concurrent with the medication and over a matter of days to weeks seems unlikely to have been spontaneous. We elected to not dechallenge the tetrabenazine given his progress in rehabilitation. It should be noted also that patients with severe proprioceptive deficits can occasionally develop similar movements, so-called pseudochoreoathetosis,⁵ but this seems improbable in our patient as the movements were quite prominent at rest.

Hemichorea and hemiballismus are the most common post-stroke movement disorders, accounting for about one-third of all cases.^1,2 Movements may develop soon after the stroke or up to several weeks or even years later^1,2; Handley et al6 reported a mean onset of 4.3 days post-stroke. It is not uncommon for the choreiform movements to manifest as motor deficits improve.1,7 Localization is surprisingly variable, although the majority of cases are associated with either basal ganglionic (44%) or thalamic (37%) lesions.7 Chorea can markedly interfere with motor control and ADLs, thus complicating rehabilitative efforts.

Choreiform movements of a variety of etiologies, including Huntington disease and Sydenham chorea, tend to respond to antidopaminergic medications.^1,8 Classically, dopamine receptor blockers, ie, antipsychotics, have been used, but these are associated with a variety of problematic adverse effects including sedation, pseudoparkinsonism, tardive dyskinesia (TD),^1,8,9 and also poorer post-stroke rehabilitation outcome.¹⁰ Alternatively, chorea may respond to vesicular monoamine transporter (VMAT) inhibitors, which reversibly inhibit uptake of monoamines into presynaptic vesicles, thus depleting presynaptic dopamine stores.¹¹ Reserpine is an older, nonselective agent that inhibits both VMAT-1 in the peripheral and VMAT-2 in the central nervous system.⁹  There are older reports of its utility in Huntington disease¹² and TD¹³ (though not in post-stroke chorea), but it is also associated with a variety of adverse effects, including depression, hypotension, and peptic ulcer disease.⁹ Newer, selective VMAT-2 inhibitors, including tetrabenazine, deutetrabenazine, and valbenazine, are much better tolerated and are coming to be considered the treatment of choice for symptomatic management of chorea.^1,9,14 Tetrabenazine is much better tolerated than reserpine. Starting dose is usually 12.5 mg once daily, and the dosage can be increased in 12.5 mg increments weekly as necessary to suppress movements, given either 2/3 times per day. Doses over 25 mg twice daily are rarely necessary. The drug is generally well tolerated; most common adverse effects include depression (Jankovic⁹ has suggested that antidepressants may be protective, as they possibly were with our patient), parkinsonism and other extrapyramidal symptoms, sedation, orthostatic hypotension, and QTc prolongation.^9,11 In the case of our patient, we had concerns about possible recurrent depression with the tetrabenazine but felt that the venlafaxine might indeed be protective or that any recurrence could be treated by escalating antidepressant treatment. We also felt that this represented a more manageable risk than the risks of pseudoparkinsonism, falls, metabolic syndrome, and poor rehabilitation outcome associated with antipsychotics. It should also be noted that several other non-dopaminergic agents have occasionally been reported to be helpful in symptomatic management of chorea of various etiologies (again, not post-stroke chorea), including valproic acid, carbamazepine, topiramate, levetiracetam, benzodiazepines, amantadine, cannabinoids, and deep brain stimulation.^1,8

Tetrabenazine is effective in treatment of choreiform movements of numerous etiologies, including Huntington disease, Sydenham chorea, and neuroacanthocytosis.^8,9,15,16 To date, there have been only two other reports of successful treatment of post-stroke hemichorea with a VMAT-2 inhibitor. Calabro et al¹⁷ reported a patient whose movements had improved with haloperidol but ultimately worsened after 6 months, including de novo facial choreoathetosis; the authors suspected development of TD and substituted tetrabenazine, which was effective. Umeh et al¹⁸ reported a patient whose hemichorea had failed to respond to haloperidol, risperidone, baclofen, or valproic acid but ultimately responded moderately to tetrabenazine.

Conclusion

Hemichorea is an unusual but potentially quite disabling sequel of stroke and one in which the practitioner can intervene pharmacologically to ultimately improve rehabilitation outcome.  Tetrabenazine and other VMAT-2 inhibitors may be effective in such patients, as shown in our case. The adverse effect profile of the VMAT-2 inhibitors is quite different than that of the antipsychotics, and they may be better tolerated by many patients.

References

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