J Korean Acad Rehab Med 2010; 34: 777-780 Case Report after Bromocriptine Therapy in a Patient - A Case Report -

Joo Hyun Park, M.D., Ph.D.2, Geun Young Park, M.D., Ph.D.1, Sun Im, M.D.1, Soon Hei Yoo, M.D.2, Jin Jun, M.D.2, Jin Ook Kwon, M.D.1, Sung Hee Jung, M.D.2, Hee Chan Jung, M.D.2

Department of Rehabilitation , 1Bucheon St. Mary's Hospital, The Catholic University of Korea, Bucheon 420-717, 2Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul 137-040, Korea

Rare side effects of bromocriptine, such as, trigermial neuralgia, have been reported in patients with pituitary adenoma but no such case has been reported in post-stroke patients. This case reports on a stroke patient who developed trigeminal neuralgia after bromocriptine therapy. A 48-year-old man, diagnosed with left middle cerebral artery territory infarction and transcortical motor aphasia, was prescribed with 2.5 mg of bromocriptine. After two days, he complained of pain in the right trigeminal distribution. Brain MRI, facial EMG, blink reflex, revealed no abnormalities. His pain showed no relief to various pharmacological agents. However, pain disappeared with discontinuation of bromocriptine and recurred again with readministration. In addition, pain intensity correlated with increase of bromocriptine dosage. Based on these findings, we concluded that patient’s trigerminal neuralgia was related to bromocriptine administration. An antidote, which consisted of a dopamine antagonist was prescribed together with bromocriptine and the patient subsequently showed relief of pain and improvement of aphasia.

Key Words Trigeminal neuralgia, Bromocriptine, Stroke

INTRODUCTION somnolence, and there is only one report of non-func- tional pituarity tumor patient who developed a trigemi- Trigeminal neuralgia is a that appears in the nal neuralgia with an administration of bromocriptine.1 distribution along one or more divisions of the fifth However, there is no report about a stroke patient cranial nerve with repetitively extreme paroxysmal attack. who developed a trigeminal neuralgia with bromocri- The most commonly identified abnormalities are known ptine. Nevertheless we have experienced the case after to be the compression of the trigeminal nerve by the administration of bromocriptine for the post stroke vessel. Rarely, cerebello-pontine angle tumor, pontine aphasia, and therefore, would like to report about the infarction, arteriovenous malformation and multiple scle- case. rosis can lead to trigeminal neuralgia. Bromocriptine is an ergot-derived dopamine receptor agonist which is a treatment for Parkinson’s disease, CASE REPORT hyperprolactinemia and post stroke aphasia. Common adverse effects are nausea, , dizziness and A 48-year-old man was admitted at 2 months post-

Received July 1, 2010; Accepted September 10, 2010 Corresponding author: Joo Hyun Park Department of Rehabilitation Medicine, College of Medicine, The Catholic University of Korea, Banpo 4-dong, Seocho-gu, Seoul 137-701, Korea Tel: +82-2-2258-2822, Fax: +82-2-2258-2825, E-mail: [email protected] Copyright © 2010. Korean Academy of Rehabilitation Medicine Joo Hyun Park, et al.

icus of left middle cerebral artery infarction, for com- prehensive rehabilitation of aphasia and right motor weakness. Patient had no specific underlying disease like diabetes, hypertension and . Brain mag- netic resonance imaging showed acute infarction on left basal ganglia, insular lobe, frontoparietal perculum and part of parietal lobe. When admitted, he was able to perform two-step command, and mini-mental state examination was 24 points. Korean paradise western aphasia examination showed transcortical motor aphasia, with aphasia quo- tient of 51/100 and language quotient of 52/100. We started speech therapy twice a week and bromocriptine therapy after admission. At that time, the patient ad- ministered aspirin, artemisiae asiatica 95% ethanol ex- tract, donepezil and tizanidine. We added no other drug except bromocriptine while admission. Before bromo- Fig. 1. (A) Figure shows the pain distribution that patient criptine therapy, he was able to express one word, experienced with administration of bromocriptine. The pa- while after, his status improved to connecting 2-3 tient’s pain distribution corresponds to the ophthalmic and words to make a simple sentence. On the second day mandibular territory of trigeminal nerve. (B) The pain in- after initiating 2.5 mg bromocriptine, the patient com- tensity is seven by the visual analog scale. plained of a series of repetitive excruciating neuralgic pain in the right trigeminal nerve distribution. His pain from 7,000/μl to 3,000/μl. Due to the fact that the scored 3 by a visual analogue scale. Physical examina- pain attacks developed after bromocriptine admin- tion (including eye movements, visual acuity and fields, istration, pain intensity was proportional to dosage, and corneal reflex, facial sensory test and visual inspection all studies for the purpose of differential diagnosis of on face and oral cavity) showed no abnormalities. facial pain showed no abnormalities, we assumed that Prodromal symptom of migraine and abnormality of vi- this rare case of trigeminal neuralgia was induced by tal sign were not shown. We increased the amount of bromocriptine administration. To confirm our hypoth- bromocriptine to 5 mg on the 4th day. This aggravated esis, we evaluated the causal relationship between the the pain to 7. We administered tyrenol and meloxicam pain attack and bromocriptine therapy by a single- for relieving the pain, but it did not work. In order to blinded pharmacologic test. After informed consent was properly evaluate the nature, intensity and distribution obtained, we observed the change of pain intensity of pain, we examined through pictures and texts. Pain with administration of placebo. On the 11th day of neu- was dull but consistent, and got worse for a short time ralgic attack, we reduced amount of bromocriptine from periods by paroxysmal attack. Pain appeared in the dis- 7.5 mg to 2.5 mg. This alleviated the pain from 7 to 3. tribution along the ophthalmic and madibular branch of On the 14th day, as soon as we stopped bromocriptine, trigeminal nerve (Fig. 1). We assumed that the cause of neuralgic pain totally disappeared. However, language pain was trigeminal neuralgia based on the nature and fluency became worse after bromocriptine therapy distribution of pain. Therefore we administered carba- stopped. To reconfirm the relationship between the pain mazepine 300 mg for pain relief. In order to identify attack and bromocriptine, we re-initiated bromocriptine the cause of pain, we performed a series of studies therapy. On the first day of re-initiation, the patient that included brain magnetic resonance imaging, soma- complained of a neuralgic pain in the same distribution, tosensory evoked potential study, blink reflex and facial which resembled the pain nature of previous attack. nerve conduction studies with EMG, but none of these Pain intensity was also proportional to dosage. Despite tests revealed any abnormalities. We administered 300 the examination to prove the relationship between dop- mg of carbamazepine as a treatment of trigeminal neu- amine system and bromocriptine-induced trigeminal neu- ralgia, which failed to alleviate the pain. Then, we stop- ralgia, the examined blood prolactin level was within ped carbamazepine therapy because WBC level dropped the normal range. The bromocriptine therapy was need-

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ed to improve the fluency and therefore domperidone, bromocriptine turned out to increase the risk of valvu- antagonist of bromocriptine, was dosed in combination lar heart disease if highly dosed for a long period of for pain relief. The pain intensity scored 6 by VAS time.5 score with only bromocriptine 5 mg dose, but with the In the past, Ferrari et al.1 proposed the relationship combination of domperidone 50 mg, pain intensity re- between bromocriptine and trigeminal neuralgia for the duced to 2. Trigeminal neuralgia was resolved and first time through the report of non-functional pituarity speaking fluency also improved after one month with tumor patient that developed a trigeminal neuralgia combination treatment of bromocriptine 5mg and dom- with bromocriptine. Past case suggested that bromoc- peridone 50 mg. riptine induced transient increase in total pituitary vol- ume by accumulation of prolactin storage granule, pro- ducing intermittent pressure on the ophthalmic branch of DISCUSSION the fifth nerve, resulting in trigeminal neuralgia attack. But in this case, we concluded that some functional ab- Bromocriptine has been used as the treatment for normalities, not structural abnormalities like com- Parkinson’s disease, hyperprolactinemia and post stroke pression of trigeminal nerve by pituitary gland, may led aphasia since the introduction of the early 1970’s, and to trigeminal neuralgia for some reasons. First, pro- is widely used due to the rare fatal adverse effect. lactin plasma level was not associated with bromo- There has been a report about trigeminal neuralgia with criptine dose. Second, blink reflex study and MRI showed an administration of bromocriptine in pituarity tumor no structural abnormalities. We administered domperi- patient, but no such case has been reported in post- done, dopamine antagonist, on the base of previous stroke patients. case1 of relieving the neuralgic pain. Domperidone alle- Bromocriptine is known to be effective in non-fluent viated neuralgic pain. Therefore we partially assumed aphasia and this drug mechanism is explained through bromocriptine-induced trigeminal neuralgia was asso- the dopamine system.2-4 Dopamine system play an im- ciated with dopamine system, but could not perfectly portant role in motor control, cognition, language, at- reveal pathogenetic mechanism. tention. Dopamine is mostly found in midbrain neuron Pain paroxysmally attacked the distribution along and three dopamine pathway appears in this area. This ophthalmic and mandibular branch of trigeminal nerve dopamine pathway is part of the network that links which lasted for several seconds to several minutes. frontal cortex, dorsolateral prefrontal cortex and inferior Therefore, it fulfilled the criteria A, B and C of diag- parietal cortex which play key roles of arousal, atten- nostic criteria of trigeminal neuralgia defined by Inter- tion and motivation. If vascular lesion occurs in dop- national Headache Society (IHS).6 The typical amine pathway, dopamine bioavailability decreases, and that should be differentiated with trigeminal neuralgia, it leads to non-fluent aphasia and deficiency of lan- are clustered headache, migraine, glossopharyngeal neu- guage attention.3,4 As a result, it is expected that if ralgia, post herpes neuralgia TM joint syndrome and dopamine agonist is administered to the patients who dental pain.7,8 According to IHS diagnotic criteria, we injured dopamine pathway through acquired brain in- ruled out migraine by absence of nausea, vomiting, pho- jury, aphasia is improved. Many researches were pro- tophobia and prodromal symptom. Moreover, we were ceeded in this context, and bromocriptine appeared to able to rule out the possibility of be effective especially in transcortical motor aphasia.2-4 since the symptom of sympathetic system like con- The most common adverse effect of bromocriptine is junctival congestion and nasal congestion were not nausea, and such diseases as headache, general weak- shown. Lastly, we ruled out other diseases for facial ness, dizziness, constipation, fatigue, losing appetite, dys- pain since there were no symptom of abnormalities of pepsia, somnolence, vomiting, stomachache and halluci- facial pain, oral cavity, periodontal tissue and TM joint. nation can also appear. Moreover, valvular heart dis- The choice of medication is carbamazepine. It ap- ease is being issued as a serious side effect. It is re- pears that carbamazepine can reduce the pain symp- ported that the long term use of pergolide and ca- toms in about 70% of the cases with daily dose of bergoline (dopamine agonist) increased the risk of de- 400-800 mg/day. However, carbamazepine can induce velopment of valvular heart disease to a Parkinson dis- abnormalities of blood marrow like leukocytopenia, and ease patient. The same ergot derived dopamine agonist, for that reason, blood test should be done regularly. In

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this case, patient stopped administering bromocriptine we were not able to fully identify the nature and dis- since the low dose of 300 mg induced leukocytopenia. tribution of pain due to aphasia. Accordingly, we could In case of no reaction to carbamazepine, we should not totally rule out the possibility of migraine and re- consider whether it is due to secondary symptomatic ferral pain as a cause of facial pain. Next, even though trigeminal neuralgia, deficiency of drug dose or re- the pain was relieved through the administration of fractory to drug. In this case, it is difficult to rule out domperidone, we could not explain the mechanism for the fact that the patient was low dosed, but we should the pain relief. It is known that the pathophysiologic also consider the previous similar case report1 of car- mechanism of trigeminal neuralgia is caused by the bamazepine not being effective in bromocriptine in- compression of the trigeminal nerve by the vessel, but duced trigeminal neuralgia. the connection between the dopamine system has not We concluded that bromocriptine therapy induce tri- yet been defined. geminal neuralgia for several reasons. First, brain MRI However, it is the first time, since the introduction revealed left middle cerebral artery infarction and no in the 1970s, to report about side effect of bromocrip- abnormalities around brainstem where the trigeminal tine which caused trigeminal neuralgia to a patient nerve come from. Therefore there is little possibility of with post stroke aphasia. Therefore, such rare side ef- neural system associated with trigeminal nucleus struc- fect should be taken into consideration with bromo- turally damaged. Second, patient had no underlying dis- criptine prescription. In conclusion, we propose the ap- ease like headache, migraine, trigeminal neuralgia before. proach for bromocriptine-induced trigeminal neuralgia And there is no report about side effects such as trige- in the situation of continuation of bromocriptine thera- minal neuralgia from the drugs the patient dosed ex- py needed for improvement of aphasia. By combination cept bromocriptine. Third, pain was closely connected therapy of domperidone, we can manage the neuralgic to bromocriptine. For example, pain attacks developed pain. right after the bromocriptine administration and neu- ralgic pain resolved after we stopped it. One of the side effects of bromocriptine therapy are REFERENCES migraine and severe headache, which should be differ- entiated from trigeminal neuralgia. One of the main 1) Ferrari MD, Haan J, van Seters AP. Bromocriptine-induced pathophysiology believed to involve in migraine is sero- trigeminal neuralgia attacks in a patient with a pituitary tonin 5-HT receptor. However, dopaminergic systems al- tumor. 1988; 38: 1482-1484 2)Albert ML, Bachman DL, Morgan A, Helm-Estabrooks N. so appear to play a major yet less recognized role in Pharmacotherapy for aphasia. Neurology 1988; 38: 877- 9 the disorder. Indeed, Sicuteri proposed that a dopami- 879 nergic hypersensitivity exists in migraine. In dopamine 3)Bachman D, Morgan A. The role of pharmacotherapy in hypersensitive migraine, administration of very low dose the treatment of aphasia: preliminary results. Aphasiology of dopamine agonist can induce prodromal symptom, 1988; 2: 225-228 4) Albert ML. Treatment of aphasia. Arch Neurol 1998; 55: such as yawning, drowsiness, irritability, gastrokinetic 1417-1419 change and hypotension. Most of migraineur of dopa- 5)Tan LC, Ng KK, Au WL, Lee RK, Chan YH, Tan NC. mine hypersensitive migraine tend to have past history Bromocriptine use and the risk of valvular heart disease. of migraine. But in this case, patient had no prodromal Mov Disord 2009; 24: 344-349 symptom of migraine with administration of bromoc- 6)Headache Classification Subcommittee of the International riptine and no past history of migraine. Also pain dis- Headache Society. The international classification of head- ache disorders, 2nd edition. Cephalagia 2004; 24: 9-160 tribution was not restricted to ophthalmic area, extend- 7)Zakrzewska JM. Diagnosis and differential diagnosis of ing to mandibular area. For such a reason we con- trigeminal neuralgia. Clin J Pain 2002; 18: 14-21 cluded it is highly unlikely that patient pain was in- 8) Siccoli MM, Bassetti C, Sandor PS. Facial pain: clinical duced by dopamine hypersensitive migraine. differential diagnosis. Lancet Neurol 2006; 5: 257-267 In this case, we have diagnosed trigeminal neuralgia 9) Sicuteri F. Dopamine, the second putative protagonist in headache. Headache 1977; 17: 129-131 by bromocriptine, but there were few restrictions. First,

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