Poststroke Choreodystonia Responsive to Zopiclone: Further Evidence of a Role for the “Z‐Drugs” in Hyperkinetic Movement Disorders

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Hemichorea is the most frequent poststroke hyperkinetic movement disorder, followed by dystonia.1, 2 Abnormal movements typically emerge weeks or months into the recovery phase while the motor deficits are improving,1, 2, 3 with chorea typically developing earlier than dystonia, which tends to exhibit a relatively long delay to onset.4

Pharmacological therapies—for example, with tetrabenazine and benzodiazapines, botulinum toxin, and deep‐brain stimulation of the globus pallidus interna—have all been reported as therapeutic options. These options will frequently provide partial relief but can often be unsuccessful, particularly for large‐amplitude and complex movements that involve multiple muscle groups. There are increasing reports suggesting that 1 of the “Z‐drugs,”5 zolpidem, a short‐acting, nonbenzodiazepine hypnotic, may be beneficial in the treatment of some forms of dystonia.6

Case Report

We report the case of a 42‐year‐old, right‐handed woman with no prior medical history other than a cryptogenic stroke at age 38 years involving the head of caudate, putamen, globus pallidus, and internal capsule on the left side (Fig. 1). She presented initially with a dense right hemiparesis. Over the next 3 to 6 months, she became aware of involuntary internal rotatory movements of her right arm. Approximately 9 months after the initial stroke, when right upper limb power was almost fully recovered, she developed increasing involuntary movements in the same limb that were becoming distressing given their magnitude and impact on function in her dominant limb. Any attempt to use the right arm, for writing in particular, exacerbated the movements with associated forearm discomfort, which was improved by placing the right arm in flexion across her chest with her hand on her left shoulder. She was unable to brush her teeth, comb her hair, or use cutlery with her right upper limb.

Figure 1.

Magnetic resonance images of the brain demonstrate an area of infarction involving the caudate head, posterior putamen, and internal capsule on the left on (A) an axial T2‐weighted view and (B) a diffusion‐weighted image.

On examination after initial referral for an opinion on these movements, there was evidence of choreodystonic movements of the right upper limb, with a relatively consistent pattern of dystonic hand jerking toward the midline with arms outstretched and more persistent dystonic posturing of the right upper limb with wrist flexion and radial more than ulnar deviation. She also had more irregular distal choreoathetotic finger movements in the same limb (Video 1, Segment 1). She had mild pyramidal right upper limb weakness with shoulder abduction and elbow and finger extension graded as 4/5 according to the Medical Research Council scale. Neurological examination was otherwise normal.

Tetrabenazine was the first treatment prescribed, with early discontinuation due to a widespread, blistering rash. Clonazepam was excessively sedating and ineffective. Amantadine was also introduced in an effort to address the choreiform component of the movements, but it was poorly tolerated and was stopped. Treatment with botulinum toxin to biceps, flexor carpi radialis, and flexor carpi ulnaris muscles under electromyogram guidance on 2 occasions led to a very mild reduction in the distal involuntary movements and was discontinued due to lack of benefit.

Zopiclone was subsequently introduced, predominantly because of reported significant difficulties with sleeping due to the continuous right upper limb movement. In addition to improved sleep quality, there was an immediate and striking improvement in the hyperkinetic movements that appeared to demonstrate a dose‐response relationship. A dose of 7.5 mg once daily was not subjectively useful, but it did provide some reduction in her right upper limb choreoathetosis on examination. A higher dose of zopiclone (15 mg once daily) resulted in a more significant subjective and objective improvement of her involuntary movements, both dystonic and choreoathetotic, without troublesome sedation (Video 1, Segment 2). This dose provided a clear improvement in function, and she now has no trouble to use cutlery, brushing her teeth or hair, and can write few words. She has been treated with the higher 15‐mg dose of zopiclone for over 1 year and has had a sustained response to date.

Discussion

Zopiclone is a nonbenzodiazepine hypnotic agent with a longer duration of action than the other so‐called “Z‐drugs,” zolpidem and zaleplon; therefore, it is similar to the short‐acting benzodiazepines,5 which, in cases of troublesome dystonia, might be a desirable feature.

Zolpidem, an imidazopyridine agonist with a high specific affinity on the type A γ‐aminobutyric acid (GABA_A) benzodiazepine subtype receptors containing the α1 subunit,6 has been effective in various types of dystonia.7 An open‐label study in 34 patients with dystonia who were treated with zolpidem6 reported a higher rate of improvement in generalized and hand dystonia, whereas no improvement was observed in cervical dystonia. In another study, 2 patients with generalized dystonia,7 1 of whom carried the DYT6 mutation, responded to zolpidem, which also improved cervical dystonia in 1 of these patients. In contrast to zolpidem, zopiclone has not been previously reported in the literature as an effective treatment option for dystonia. Zopiclone is a cyclopyrrolone drug with pharmacodynamic and pharmacokinetic properties similar to those of zolpidem, binding with high affinity to the benzodiazepine‐ionophore, a chloride channel complex, and demonstrating nonselective activation of all GABA_A receptor subtypes.8 The agonist effect of zopiclone at the benzodiazepine‐sensitive inhibitory GABA_A receptors is the most likely source of its positive therapeutic effect.

When symptomatic poststroke dystonia is disabling or distressing and is refractory to other therapeutic measures, this family of agents should be considered and may have a role for use before resorting to botulinum toxin therapy, particularly where more mobile dystonia is concerned, as in this patient. Short‐term tolerance to the sedating properties in this patient was not an issue, possibly because of her young age, although, along with dependence, this remains a significant potential adverse effect. Long‐term use of zopiclone at a higher dose, although beneficial for dystonic movements, can lead to zopiclone dependence.9 Potential side effects of long‐term zopiclone use might be addressed by eszopiclone, the active (S)‐enantiomer of zopiclone, which may have a more advantageous side‐effect profile, especially regarding tolerance and liability to dependence.10 Randomized studies in all forms of primary and secondary dystonia and chorea are warranted to determine which dose is optimal and the degree to which side effects may be limiting in a larger patient group.

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

P.B.M.: 1A, 1C, 3A, 3B

R.A.W.: 3B

Disclosures

Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflict of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for the previous 12 months: Petya Bogdanova‐Mihaylova, is supported by funding from Ataxia Ireland and The Meath Foundation. Richard A. Walsh has received unrestricted grant support from AbbVie and Novartis, publishing Royalties from Oxford University Press, and an unrestricted educational grant from The Meath Foundation.

Supporting information

A video accompanying this article is available in the supporting information here.

Video 1. Segment 1: Right upper limb choreodystonic movements before treatment are observed. Segment 2: The right upper limb 2 hours after oral zopiclone 15 mg administration demonstrates dose‐dependent improvement in the choreodystonic movements.