Fixed drug combination (levosulpiride and rabeprazole)-induced atypical Parkinsonian’s disorders with associated anxiety and low-lying depression

Abstract

We hereby describe a rare case of levosulpiride-induced atypical parkinsonism presenting with sluggish movements, atypical kinetic tremors (tremors with voluntary movement), periorbital tremors, dystonia, difficulty in speech and coordination, postural imbalance, with additional features of difficulty in swallowing and drooling with associated recent onset psychiatric disturbances such as anxiety and low-lying depression. The dechallenge of levosulpiride and medications for associated anxiety and low-lying depression caused a complete remission of the disease within 2 ½ months.

Introduction

Levosulpiride is a prokinetic medication that is chemically related to cisapride, however, it is a substituted benzamide. This antipsychotic, which is the levorotatory enantiomer of sulpiride, most likely acts by inhibiting postsynaptic dopaminergic receptors at higher doses and presynaptic dopaminergic autoreceptors at lower doses. Thus, additionally to being an antipsychotic, it retains prokinetic properties and acts both centrally and in the gut, making it useful mainly for nausea, flatulence, gastroesophageal reflux disease (GERD), inflammatory bowel disease, and peptic ulcer disease.[1]

Extrapyramidal syndrome, which includes acute muscle dystonia, neuroleptic malignant syndrome, dyskinesia, and Parkinson’s disease (PD), is commonly linked to D2 receptor antagonists, sometimes known as antipsychotic medications.

Recently few reports of levosulpiride induced[2,3,4] have been reported in the literature. However, still, there is very less information available regarding this potentially serious adverse drug event among the physicians which can affect the quality of life adversely.

We hereby present a case of levosulpiride-induced atypical parkinsonism presenting with sluggish movements, kinetic tremors (tremors with voluntary movement), periorbital tremors, dystonia, difficulty in speech and coordination, postural imbalance, with additional features of difficulty swallowing, and drooling with associated recent onset psychiatric disturbances such as agitation, anxiety followed by low-lying depression.

Case Report

A 72-year-old obese male (110 kg), height 5’3, and body mass index is 43 kg/m². With a medical history of hypertension, type 2 diabetes mellitus, hypothyroidism, and angina presented to a private clinic with GERD of recent origin with severe constipation.

He was prescribed a fixed drug combination of rabeprazole and levosulpiride once daily for 30 days along with a tablet of chlordiazepoxide and clidinium bromide combination at bedtime. The patient did not show any improvement in the gastric ailment even after 1 week of the treatment. The dose of capsule Fixed drug combination (FDC) (rabeprazole and levosulpiride) was made twice daily by the patient himself against medical advice. The patient was also taking metoprolol 25 mg, amlodipine 5 mg, telmisartan 40 mg, atorvastatin-fenofibrate (10 mg + 120 mg), nitrocontin 2.6 mg twice daily, zolpidem 10 mg, levothyroxine 75 µg, and metformin + glimepiride (500 mg + 2 mg) for the other comorbid diseases. After 8 weeks of treatment for GERD, the patient presented to the clinic back with complaints of sluggish movements, kinetic tremors (tremors with voluntary movement), periorbital tremors, dystonia, difficulty in speech and coordination, postural imbalance, with additional features of difficulty swallowing, and drooling with associated recent onset psychiatric disturbances such as agitation, anxiety followed by low-lying depression. However, the physician failed to correlate such manifestations with any of the offending drugs. With another week of continued same treatment, the severity of the manifestation increased affecting quality of the life of the patient warranting specialized consultation.

Neurological consultation was sought and after a detailed neurological examination, the possibility of drug-induced atypical parkinsonism was suspected by the neurologist.

The patient was alert and conscious without convulsions, vomiting, blurred vision, or diplopia. Sensory and pupillary light reflexes were normal. General sensory examination was considerably normal. Both the superficial and deep tendon responses were within acceptable bounds. The finger-tapping test showed asymmetric bradykinesia (right > left) and forearm muscle stiffness. The patient’s head magnetic resonance imaging was essentially normal for age.

Further de challenge of the drug ameliorated the symptoms starting after 3rd week and achieving 50% amelioration within 6 weeks and almost complete resolving of the drug induced event within two and half months of de challenge. No antiparkinsonism drug was prescribed for the said element. The patient was put on pantaprozole 40 mg, tablet escitalopram – 10 mg once daily, and lorazepam 2 mg SOS for the associated anxiety and low-lying depression. The amelioration of anxiety and low-lying depression in the said case required prolonged treatment and slow tapering of each medication was done after another 4 weeks after full recovery of drug-induced parkinsonism.

The possibility that ongoing medication or illness is responsible for the adverse drug reaction (ADR) mentioned is almost negligible, as medications for comorbid conditions were allowed to continue and did not worsen the ADR. For ethical reasons, no repeat challenge was performed and no attempt was made to study the dose-response relationship, so the mechanism and type of ADR cannot be commented on. Furthermore, the occurrence of ADRs could not be accounted for by any concurrent disease, medicine, or chemical. ADR was likely as assessed by WHO Uppsala by monitoring the central causal scale and Naranjo score.[5]

The severity of the reaction assessed using the Hartwig ADR Severity Rating scale classified the ADR as severe level 2. The Schumock and Thornton scale was used to evaluate prevention and it fell under the definitely preventable category.

The assessment of causality, strong temporal association, and improvement of symptoms after discontinuation of levosulpiride (LSP) confirmed the diagnosis of Drug induced parkinsonism (DIP). Furthermore, the symptom could not be explained by any other concurrent medicine use or co-occurring disorders.

Discussion

Mathew et al.[3] reported that levosulpiride may cause de novo parkinsonism or may worsen the parkinsonian features in a patient already having PD and if detected early and stopped, the patients can improve completely like our case.

Choudhury et al.[4] described a number of patients who developed levosulpiride-provoked movement disorders, particularly dyskinetic motion. In contrast to our case, they reported that the patients had consumed the suspected drug for a median of 13 months (range, 1–60 months), and said that levosulpiride-induced dyskinesia is challenging to manage since, even with appropriate treatment, its recovery is frequently insufficient. However, our case had the acute presentation and resolved within 2 months completely without any residual neurological deficit.

Radhakrishnan and Goyal[2] reported seven cases of levosulpiride-induced dystonia, and unlike our case report presentation, all patients showed at least 50% improvement after stopping levosulpiride, but none had fully recovered at the mean follow-up of 5.5 months.

Levosulpiride is a prokinetic agent that is extensively used in India by general physicians as a fixed drug combination mostly with pantaprozole or rabeprazole. Levosulpiride is related to a number of movement problems, including tremors, parkinsonism, dyskinesias, and infrequently dystonia. It does this by selectively inhibiting gastrointestinal and brain D2 receptors.[2,3,4]

However, the current case report is worth for the information of the physician that levosulpiride can rarely present as atypical parkinsonism as it presented in the current case with sluggish movements, kinetic tremors (tremors with voluntary movement), periorbital tremors, dystonia, difficulty in speech and coordination, postural imbalance, with additional features of difficulty speaking, swallowing, and drooling with associated recent onset psychiatric disturbances such as agitation, anxiety followed by low lying depression as part of the clinical picture. The mechanism of its atypical presentation and associated anxiety and low-lying depression cannot be precisely explained. Anxiety and low-lying depression in the said patient, however, required treatment and resolved after the remission of the features of parkinsonism indicating a psychosomatic element rather than a part of drug-induced disease.

Conclusion

Thus, clinicians should be aware of levosulpiride-induced atypical parkinsonism with associated anxiety and low-lying depression and should therefore avoid this drug in aged individuals or patients of PD.

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.