A Case of Refractory Tardive Syndrome with an Atypical Presentation: Diagnostic Confusion and Management Challenges

Tardive syndromes encompass a range of potentially irreversible hyperkinetic and hypokinetic movement disorders caused by dopamine receptor blocking agents (DRBAs). They often present with complex and fluctuating symptoms, creating diagnostic uncertainty and significant management challenges.1 This report describes a refractory case with an atypical presentation, complicated by iatrogenic effects and misdiagnosis. A 62-year-old man with generalized anxiety disorder had been treated with flupentixol and later amisulpride, among other psychotropics for approximately 1 year before developing abnormal involuntary movements. These included cervical dystonia with retrocollis and laterocollis, oromandibular dyskinesia, tongue protrusion, chewing movements, dysarthria, and emerging dysphagia. No significant abnormality was detected on various tests, including complete blood counts, peripheral blood smear examination for acanthocytes, liver and renal function tests, Vitamin B12, Vitamin D, thyroid function test, nerve conduction study and electromyography, and slit-lamp examination for Kayser–Fleischer rings. He was conservatively managed with multivitamin supplementation and other symptomatic treatment for complaints of pain and insomnia by the neurologists. However, there was no significant and sustained improvement in his symptoms. Re-evaluation in psychiatry revealed no psychosocial precipitants, no secondary gains, and a clear temporal relationship with DRBA exposure, supporting a diagnosis of tardive dyskinesia with dystonia (Abnormal Involuntary Movement Scale AIMS score of 28). Trials with first-line medications, including Vitamin E (up to 800 mg/day) and Gingko Biloba (up to 120 mg/day), were ineffective.2 High-dose clonazepam (4–5 mg/day) led to a dramatic resolution of dyskinetic movements within 1 week (AIMS = 0), and he was discharged on clonazepam, baclofen, and mirtazapine combination Supplementary Figure 1. Soon after discharge, he unintentionally reduced clonazepam to 2 mg/day, resulting in rapid and severe recurrence of symptoms (AIMS = 36), prompting initiation of tetrabenazine titrated to 75 mg/day. This caused severe parkinsonism, significant postural hypotension leading to falls, and worsening dysphagia.3 These iatrogenic hypokinetic features overlapped with his underlying hyperkinetic movements, creating substantial diagnostic confusion. Cardiac evaluation ruled out cardiac causes of hypotension, and salt supplementation was initiated. As uncertainty grew, possible functional neurological disorder and atypical parkinsonian syndromes were reconsidered by neurology.4 Fluorodeoxyglucose-positron emission tomography brain imaging later demonstrated frontoparietotemporal and lateral occipital hypometabolism with relative hypermetabolism in sensorimotor cortices, basal ganglia, and cerebellar folia; supportive of drug-induced tardive syndrome. Because tetrabenazine offered no benefit and caused major adverse effects, it was discontinued. Clonazepam was reinstated at 5 mg/day, and amantadine trial (200 mg/day) was given.5 Mirtazapine (30 mg/day) and lemborexant (10 mg/day) were prescribed for comorbid depressive, anxiety, and insomnia symptoms. This regimen led to partial improvement, enabling independent activities of daily living (AIMS 22). To address persistent cervical dystonia, 120 units of botulinum toxin were injected into the bilateral splenius capitis and semispinalis capitis muscles, resulting in marked and sustained benefit. The patient achieved substantial improvement with a combination of clonazepam, amantadine, baclofen, mirtazapine, and targeted botulinum toxin therapy. This multifaceted approach yielded significant and sustained improvement in his tardive dyskinesia as well as dystonia-related symptoms, and the patient was discharge on the following medications: clonazepam (5 mg/day), baclofen (40 mg/day), and mirtazapine (30 mg/day). This case illustrates the complexity of diagnosing and managing refractory tardive syndromes, the risks of iatrogenic complications, the importance of medication adherence, and the value of multidisciplinary collaboration. High-dose clonazepam and botulinum toxin served as effective salvage strategies in a patient unresponsive to standard treatment. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.Supplementary Figure 1: Change in various rating scale scores for the patient over the course of treatment. AIMS: Abnormal Involuntary Movement Scale, HAM-A: Hamilton anxiety, HAM-D: Hamilton depression