Metoclopramide-induced parkinsonism due to bilateral basal ganglia and brain stem involvement in a patient with laryngeal carcinoma

J Clin Exp Invest www.jceionline.org Vol 3, No 4, December 2012 1 Department of Medical Oncology, Dicle Üniversity Faculty of Medicine, Diyarbakır, Turkey 2 Department of Neurology , Dicle Üniversity Faculty of Medicine, Diyarbakır, Turkey 3 Department of Radyology , Dicle Üniversity Faculty of Medicine, Diyarbakır, Turkey Correspondence: Ali İnal, Dicle Üniversitesi Tıp Fakültesi Tıbbi Onkoloji kliniği, Diyarbakır, Türkiye Email: dr.ainal@gmail.com Received: 19.09.2012, Accepted: 26.11.2012 Copyright © JCEI / Journal of Clinical and Experimental Investigations 2012, All rights reserved JCEI / 2012; 3 (4): 536-538 Journal of Clinical and Experimental Investigations doi: 10.5799/ahinjs.01.2012.04.0217


INTRODUCTION
The drug-induced parkinsonism accounts for approximately 2.7% of these patients. 1Metoclopramide is a dopamine receptor antagonist and may occasionally cause extrapyramidal side effects due to its dopaminergic antagonistic effect. 2,3Parkinsonism and basal ganglion involvement due to antiemetic drugs, such as metoclopramide, is rarely reported, 4 whereas bilateral basal ganglia and brain stem involvement has not yet been reported until now on the brain MRI of the patients with drug-in-duced Parkinsonism.We present the first case of metoclopramide-induced Parkinsonism together with brain stem and basal ganglion involvement in a patient with laryngeal carcinoma treated with chemotherapy.

CASE REPORT
A 52-year-old male patient with locally advanced laryngeal carcinoma.He started to receive a chemotherapy regimen consisted of docetaxel, cisplatin, and 5-fluorouracil (DCF).He was admitted to our clinic because of severe nausea and vomiting 15 days after the first course of chemotherapy.Fluid replacement and metoclopramide (oral, 20 mg daily) were commenced to control dehydration and vomiting.Tremor in the hands, dysarthria, mask face, restlessness, irritability and limited movement developed in the patient on the 6th day of metoclopramide therapy.Neurologic examination revealed akathisia, sialorrhea, hypomimia, bradykinesia, parkinsonian gait and tremor in all extremities.Drug-induced parkinsonism and akathisia (extrapyramidal side effect) were diagnosed for the patient by the consultation with the neurology department.Complete blood count, electrolytes, anti DNA, Vitamin B12, folic acid and thyroid functions were within the normal ranges.On his cerebral MRI, T1 hypointense and T2 hyperintense signal changes were de-termined in the bilateral basal ganglia, including putamen, globus pallidus and the head of the caudate nucleus, as well as in the mesencephalon area, including nucleus ruber and nucleus ruber (fig.1a,1b).Laryngeal cancer metastasis was not considered, because the contrast substance was not uptaken by the lesions on the contrast-enhanced MRI of the cerebrum.
Metoclopramide therapy was immediately discontinued and oral biperiden was started with the dose of 2 mg three times daily.Parkinsonism symptoms slightly improved on the 3 rd day of biperiden therapy.Neurologic examination performed 15 days later revealed bilateral tremor in the hands of the patient has disappeared and limited movement and dysarthria have considerably regressed.The parkinsonian findings almost completely improved on control examination after one month.The lesions in the basal ganglion were absent on the follow-up MRI of the cerebrum.However, T1 hypointense and T2 hyperintense changes were observed on the brain stem lesions, including nucleus ruber (Fig. 1c,1d).Biperiden therapy was gradually decreased and discontinued.DCF course was repeated for three times.Metoclopramide was not preferred as an antiemetic in this patient.Parkinsonism complaints did not recur, and the patient has been free of any associated symptoms.

DISCUSSION
Symptoms due to the damage of the extrapyramidal system, such as parkinsonism, acute dystonic reaction, akathisia, motor tics, myoclonus and tardive dyskinesia, may be seen.One of these symptoms may occur alone, or they may present together. 4It has been put forward that the pathogenesis of druginduced Parkinsonism results from the imbalance between acetylcholine and dopamine in the central nervous system (CNS).Extrapyramidal side effects commonly appear 24 hours after metoclopramide is started and generally disappears 24 hours after discontinuation.Extrapyramidal side effects quite rarely persist for weeks or months. 3In this case, dysarthria, irritability, desire to move continuously, slowing down in walking, and tremor were developed after 24 hours following metoclopramide given in order to prevent nausea.Metoclopramide-induced Parkinsonism and akathisia, rather than idiopathic Parkinson's disease, was considered owing to the fact that he had no history of Parkinson's disease and that his complaints have begun bilaterally and acute.No other reason was found that could lead to parkinsonism and akathisia.It has been reported that certain chemotherapeutic agents cause parkinsonism. 5Parkinsonism symptoms were not present in this case during the first course of anticancer therapy.Following the second course of anticancer therapy, parkinsonism was seen at the same time with metoclopramide.After the relief of parkinsonism, it did not recur following the third course of anticancer therapy.3][4]6 Consequently, Parkinsonism and akathisia were not attributed to the anticancer therapy.Moreover, they gradually disappeared with the cessation of metoclopramide.Metoclopramide-induced Parkinsonism and akathisia together with the involvement of basal ganglion, thalamus and brain stem in cancer patients has not yet been reported.However, in Parkinsonism caused by toxic substances, such as carbon monoxide and manganese, globus pallidus, substantia nigra, nucleus ruber and brain stem can also be involved.9][10] The cerebral MRI performed in the subacute period revealed bilateral involvement of the putamen, as well as globus pallidus, the head of the caudate nucleus, substantia nigra from the mesencephalon to pons, and nucleus rubber in this case.This shows that the effect of metoclopramide on the extrapyramidal pathways is similar with that of manganese and carbon monoxide intoxication.Parkinsonism complaints of the patient decreased within one month with chemotherapy.Caudate nucleus, globus pallidus and putamen lesions of the present case disappeared on his control MRI performed after three months.Although the Parkinsonism signs have disappeared, nucleus ruber lesions persisted at the mesencephalon level.
Metoclopramide-induced Parkinsonism and akathisia can be seen rarely.Putamen, globus pallidus, the head of caudate nucleus and nucleus ruber may also be affected in such patients.In a case of metoclopramide-induced Parkinsonism, cerebral MRI should be performed to visualize the major damage in the extrapyramidal system.

Figure 1 ,
Figure 1, a; Axial T2 MRI revealed T2 hyperintense signal changes in the caudate nucleus, globus pallidus and putamen, b; as well as in the mesencephalon region, including nucleus ruber and the periphery of nucleus rubber, c; The follow-up cerebral T2 axial revealed the increased signal to disappear in the caudate nucleus, globus pallidus and putamen, d; however, the increased signal persisted in the mesencephalon region.