Haloperidol in Managing DYT-TOR1A Dystonia: Unveiling a Dramatic Therapeutic Response

Pavankumar Katragadda; Vikram V. Holla; Nitish Kamble; Ravi Yadav; Pramod Kumar Pal

doi:10.14802/jmd.24029

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Letter to the editor Haloperidol in Managing DYT-TOR1A Dystonia: Unveiling a Dramatic Therapeutic Response: Pavankumar Katragadda, Vikram V. Holla, Nitish Kamble, Ravi Yadav, Pramod Kumar Pal; Journal of Movement Disorders 2024;17(3):342-344.
DOI: https://doi.org/10.14802/jmd.24029
Published online: April 9, 2024

Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India

Corresponding author: Pramod Kumar Pal, MD, DNB, DM Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bengaluru, Karnataka 560029, India / Tel: +9180-26995147 / Fax: +91-80-26564830 / E-mail: palpramod@hotmail.com

• Received: February 3, 2024 • Revised: March 19, 2024 • Accepted: April 5, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Supplementary Materials
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REFERENCES

Dear Editor,

DYT-TOR1A is an autosomal dominant early-onset isolated dystonia that progresses over months to years to disabling generalized dystonia. Treatment options for DYT-TOR1A dystonia include oral medication, botulinum neurotoxin (BoNT) therapy, and bilateral globus pallidus interna deep brain stimulation (GPi-DBS) surgery [1]. Medical management is the first-line treatment, with trihexyphenidyl being the only oral medication proven to be effective in double-blind placebo-controlled trials, with an efficacy rate of 71% [2]. However, in most patients, trihexyphenidyl cannot be used due to intolerable side effects at higher doses [3]. Other oral medications used often in various combinations include baclofen, benzodiazepines, dopamine receptor blockers (DRBs) and dopamine depleters with varying responses [4]. The role of BoNT is limited in the management of DYT-TOR1A, which is restricted mostly to patients with focal or segmental involvement.

Strong evidence supports the use of GPi-DBS for treating DYT-TOR1A, especially in patients who have a suboptimal response to medical management, with studies showing approximately 70% improvement [5]. However, public health insurance and social security schemes for relatively expensive procedures such as DBS are still limited in India; hence, socioeconomic status has an impact on surgical decisions. According to a study by Patel et al. [6], approximately 40% of individuals with Parkinson’s disease who were eligible for DBS but chose to continue with medical management cited financial considerations as the primary reason. Hence, there is a need for cost-effective and optimal medical management of dystonia in resource-limited countries.

A 17-year-old boy presented with a 6-year duration of writing difficulty due to posturing, which gradually progressed over time to abnormal posturing of the whole body, including the trunk, owing to which he was bedbound at presentation. He was started on treatment at 12 years of age, initially with trihexyphenidyl (12 mg/day). Subsequently, baclofen (40 mg/day), tetrabenazine (75 mg/day), diazepam (20 mg/day), and clonazepam (3 mg/day) were administered in various combinations with suboptimal responses. On examination, he had generalized isolated dystonia with torsional dystonic movements interfering in activities of daily living (ADL) (Supplementary Video 1 in the online-only Data Supplement). The results of the remaining neurological and systemic examinations were unremarkable. He was the first child of two siblings, and his parents and 15-year-old younger brother had no neurological illness.

On evaluation, routine blood investigations and brain imaging were normal. Exome sequencing revealed a known pathogenic heterozygous variant in the TOR1A gene (NM_000113.3: c907_909del;p.Glu303del), confirming the clinical suspicion of DYT-TOR1A. He was treated initially with 300 mg/day levodopa for one week without benefit. He was offered bilateral GPiDBS. Moreover, in view of disabling generalized dystonia, haloperidol was initiated at an initial dose of 2.5 mg twice daily and was escalated to 5 mg thrice daily for more than 3 months while continuing other medications (baclofen: 30 mg/day; tetrabenazine: 75 mg/day; and clonazepam: 1.5 mg/day).

At the one-month follow-up, he had improved significantly to the extent that he could walk and perform all his ADLs. However, at the 3-month follow-up, neurological examination revealed mild parkinsonism and right upper-limb rest tremor (UPDRS-III: 22) with residual dystonia in the right upper limb. He had no difficulty performing ADLs except for mild difficulty performing distal right upper-limb activities (Supplementary Video 2 in the online-only Data Supplement). Despite the substantial improvement in dystonia with medical management, in view of drug-induced parkinsonism and the high risk of tardive syndrome with long-term usage of haloperidol, the option of bilateral GPi-DBS was reiterated to the patient’s family.

The use of DRBs and dopamine depleters in managing dystonia has been reported in several small case series with varying responses [7]. The few DRBs that have been used for dystonia treatment include typical antipsychotics (haloperidol, pimozide) and atypical antipsychotics (clozapine, risperidone). DRBs (haloperidol, pimozide, clozapine or risperidone) and dopamine depleters (tetrabenazine and reserpine) are used as third- or fourthline treatments for dystonia [8]. Clozapine has been found to have a moderate level of effectiveness in treating segmental, axial, and generalized dystonia [9]. Patients with truncal or generalized dystonia may require higher doses (450–900 mg/day) than patients with cervical dystonia (37–100 mg/day). Clozapine has a low risk of tardive dyskinesia and infrequent extrapyramidal side effects but requires careful monitoring for potential agranulocytosis. Risperidone demonstrated efficacy in both segmental and generalized dystonia at a dosage of 1.5–3 mg/day in a single trial [10]. However, compared with patients treated with clozapine, patients treated with risperidone have a greater risk of developing parkinsonism and tardive syndromes. Haloperidol and pimozide are among the first-generation DRBs with a high affinity for D2 receptors. These patients have a greater risk of drug-induced parkinsonism, acute dystonic reactions, and tardive syndrome. Haloperidol is rarely used in the management of dystonia except for refractory status dystonicus. There are very few reports in the literature on the management of dystonia with haloperidol and pimozide [11]. Manji et al. [12] reported improved outcomes with haloperidol in combination with other medications in a few of their patients with status dystonicus. However, the dramatic response to haloperidol observed in our patient was not described previously for DYT-TOR1A. Marsden et al. [11] observed a symptomatic benefit with a combination of trihexyphenidyl (6–30 mg/day), pimozide (6–25 mg/day) and tetrabenazine (75 mg/day) in adults with severe disabling axial dystonia or in children with life-threatening generalized dystonia who did not respond to trihexyphenidyl monotherapy [11]. Tetrabenazine is the most commonly used dopamine depleter and is the drug of choice for tardive dystonia. It is effective for treating various forms of generalized and focal dystonia, with marked improvement in 80.5% of patients with tardive dystonia and 62.9% of patients with idiopathic dystonia [13]. Tetrabenazine rarely causes dystonic reactions but can cause drowsiness, parkinsonism, postural hypotension, insomnia, and depression.

With the availability of advanced therapeutic options such as DBS, the need for high doses of medication with adverse effects and off-label medication has decreased. However, in resource-limited settings, when DBS is financially less viable or in the interim period before DBS, a neurologist is left with limited options. Considering the patient’s significant disability and inability to receive DBS at that point in time, we opted for haloperidol treatment. Haloperidol may not be the preferred choice for long-term treatment of DYT-TOR1A due to its side effect profile. However, in specific cases, it may be considered a potent short-term option for managing severe refractory dystonia to improve the patient’s quality of life while awaiting a more permanent treatment option, such as DBS.

Notes

Ethics 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. The written informed consent was obtained for video recording and publication in print and in online.

Supplementary Materials

The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.24029.

Video 1.

Baseline video of the patient. Video of the patient at presentation demonstrating severe disabling generalized dystonia with predominant left laterocollis, right torticollis, retrocollis, truncal dystonia along with appendicular involvement and dystonic spasms. Owing to the dystonia, the patient is shown to be having difficulty and requiring assistance for day-to-day activities such as writing, eating, dressing and walking. The Burke-Fahn-Marsden Dystonia Rating Scale score was 67/120 on the movement scale and 21/30 on the disability scale. The video was taken after written informed consent was obtained for publication in print and online.

Video 2.

Video of the patient at the 3-month follow-up after haloperidol treatment. Video of the patient demonstrating significant improvement in overall dystonia barring mild dystonia with dystonic tremor in the right upper limb after 3 months of haloperidol (15 mg/day). The patient also had reduced facial expression, hypophonic speech, tongue tremor, mild bradykinesia and reduced right arm swing. The video also demonstrated that the patient was able to eat, write, dress and walk independently compared to before. His Burke-Fahn-Marsden Dystonia Rating Scale score improved significantly (movement score: 11/120, 84% improvement; disability score: 6/30, 71% improvement). The video was taken after written informed consent was obtained for publication in print and online.

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Author Contributions

Conceptualization: Pavankumar Katragadda, Pramod Kumar Pal. Data curation: Pavankumar Katragadda, Vikram V. Holla. Formal analysis: Pavankumar Katragadda, Vikram V. Holla, Pramod Kumar Pal. Investigation: Pavankumar Katragadda, Vikram V. Holla, Nitish Kamble, Pramod Kumar Pal. Resources: Vikram V. Holla, Pramod Kumar Pal. Supervision: Ravi Yadav, Pramod Kumar Pal. Validation: Ravi Yadav, Pramod Kumar Pal. Visualization: Vikram V. Holla, Pramod Kumar Pal. Writing—original draft: Pavankumar Katragadda. Writing—review & editing: Vikram V. Holla, Nitish Kamble, Ravi Yadav, Pramod Kumar Pal.

Acknowledgments

None

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