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Neuroleptic malignant syndrome associated with bromocriptine withdrawal in Parkinson's disease — a case report
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General Hospital Psychiatry 33 (2011) 301.e7 – 301.e8
Case Report
Neuroleptic malignant syndrome associated with bromocriptine withdrawal in Parkinson's disease — a case report Yung-Fu Wu, M.D.a , Yuk-Shing Kan, M.D.b,⁎, Chen-Hong Yang, M.D.b b
a Department of Psychiatry, Armed Forces Beitou Hospital, Taipei 112, Taiwan Department of Psychiatry, Taipei Veterans General Hospital, Taipei 112, Taiwan Received 13 October 2010; accepted 20 November 2010
Abstract A 74-year-old man had 15-year history of Parkinson's disease and received bromocriptine monotherapy for 3 years. We present the first case report of neuroleptic malignant syndrome associated with the withdrawal of bromocriptine. The symptoms were alleviated by adequate replenishment of intravenous fluid, temperature reduction and replacement of bromocriptine. Clinicians need to be aware of this potential complication and that a thorough history of current medications is crucial to its identification. © 2011 Elsevier Inc. All rights reserved. Keywords: Neuroleptic malignant syndrome; Bromocriptine; Parkinson's disease; Dopamine
1. Introduction
2. Case report
Neuroleptic malignant syndrome (NMS) is a potentially fatal process characterized by hyperthermia, autonomic instability, altered mental status and severe muscular rigidity. The pathophysiology of NMS remains unknown, although current articles mention the notion of acute phase response including the activation of leukocyte, the release of cytokines and a host of systemic effects [1,2]. Laboratory analysis often reveals leukocytosis, elevated serum creatine kinase (CK) level and minimal to moderate elevations of lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine transaminase (ALT) [3]. Neuroleptic malignant syndrome is most commonly described as an adverse reaction to dopamine receptor blocking agents as well as to withdrawal of antiparkinsonian drugs in patients with Parkinson's disease (PD) [4]. Here we describe a patient with PD who developed NMS the first week after bromocriptine withdrawal.
This patient (a 74-year-old man) had a 15-year history of PD. In August 2010, his medications included 5 mg of bromocriptine per day for PD. There had been no change in medications and dosage for 3 years. He was independent in most daily activities but still required constant supervision. In September 2010, he was transferred to our emergency department (ED) by his wife due to the progressive onset of muscle rigidity, diaphoresis and fluctuation in consciousness for 1 week. His body temperature on arrival was 38.7°C, with elevated blood pressure of 163/104 mmHg, pulse of 113 bpm and respiratory rate of 25/rpm. Laboratory investigation revealed mild leucocytosis (white blood cell count, 10.1×109/L) with shift to the left and high CK level (9569 U/L). The analysis of arterial blood gas indicated metabolic acidosis, and 12-lead electrocardiogram showed sinus tachycardia without any infarct changes. Chest radiography was unremarkable. In the ED, he became somnolent during the day, hyperthermic (39°C) and rigid, and his level of consciousness was reduced. No meningeal sign or pathological reflex was found. Brain computed tomography (CT) revealed no intracerebral hemorrhage. On admission to the medicine service, muscular rigidity and autonomic dysfunction were profound. The results of serum analysis were as follows: AST: 296 U/L, ALT: 64 U/L, LDH: 538 U/L, CK: 14,470 U/L, blood urea nitrogen: 22 mg/dl, creatinine:
⁎ Corresponding author. Tel.: +011 886 2 28711290; fax: +011 886 2 28768403. E-mail address: [email protected] (Y.-S. Kan). 0163-8343/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.genhosppsych.2010.11.013
301.e8
Y.-F. Wu et al. / General Hospital Psychiatry 33 (2011) 301.e7–301.e8
1.34 mg/dl, sodium: 137 mmol/L, potassium: 3.6 mmol/L and C-reactive protein: 2.55 mg/dl. An evaluation for sources of infection was unrevealing. Cerebrospinal fluid (CSF) examination was normal. Cultures of the blood, urine and CSF were sterile. Concomitant therapy medications were nontoxic. A psychiatrist and neurologist were consulted on day 4 of treatment and noted the intermittent episodes of visual hallucination and agitation 10 days prior to this admission. The abrupt discontinuation of bromocriptine 1 week prior to onset of symptoms was considered as a possible cause of the patient's symptoms. Neuroleptic malignant syndrome associated with bromocriptine withdrawal was diagnosed from the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. General symptomatic and supportive measures (adequate replenishment of intravenous fluid and temperature reduction using cooling blankets) were administered along with high volumes of intravenous crystalloids, bicarbonate infusion to alkalinize urine and prevent renal failure, bromocriptine 2.5 mg qid, acetaminophen 500 mg every 6 h and thiamine 100 mg bid. The bromocriptine improved muscle rigidity within 2 days, and temperature decreased along with arterial pressure. On day 11 of treatment, his CK was 36 U/L. He was clearer, was less rigid and complied with simple orders. He continues to take bromocriptine three times daily without recurrence of NMS after discharge, and his family have been advised against reducing or discontinuing this drug. 3. Discussion Bromocriptine monotherapy may be beneficial in delaying motor complications and dyskinesias of PD [5,6]. Although recent articles describe this clinical phenomenon as NMS or NMS-like syndromes [7,8], our emphasis in this report is on the risk of NMS after bromocriptine withdrawal. Neuroleptic malignant syndrome symptom onset may range from hours to months [9]. In our patient, the first symptoms developed 1 week after the last administration of bromocriptine. The differential diagnosis includes infection, neuroleptic-induced heat stroke, intracerebral hemorrhage and toxicity from other medications [10]. Central nervous system infection was excluded by CSF analysis. Neurolepticinduced heat stroke was ruled out by medication history (no other neuroleptic or anticholinergic agents) and medical history (no recent seizure attack, increase in physical activity or exposure to high ambient temperature). Brain CT revealed no hemorrhage or infarction. No other potential course of medications such as lithium was prescribed. The patient's good response to treatment with bromocriptine led us to believe the symptoms were due to bromocriptine withdrawal.
Neuroleptic malignant syndrome was first described by Delay and Deniker in 1968 [11]. Although not known, the pathogenesis of NMS is thought to be related to central dopaminergic blockade, dopamine withdrawal or dopamine deficiency [8], and may involve dopaminergic transmission block in the basal ganglia, corpus striatum, hypothalamus and spinal cord [12,13]. Dopaminergic blockade in the anterior hypothalamus reduces inhibition of serotonin stimulation and contributes to the hyperthermia [13]. Dopaminergic blockade in the corpus striatum causes muscle contraction and rigidity [13]. Dopamine receptor blockade in the nigrostriatal and mesocortical systems may affect consciousness, and at the level of the spinal cord, it may cause autonomic disturbances and functional impairment [13]. To our knowledge, it is the first case report of NMS associated with bromocriptine withdrawal. When bromocriptine is used in PD, there is an iatrogenic increase in dopaminergic transmission. In this setting, withdrawal of bromocriptine may lead to NMS. Here we emphasize that clinicians should be aware of this potential complication and that a thorough history of current medications is crucial to its identification. References [1] Anglin RE, Rosebush PI, Mazurek MF. Neuroleptic malignant syndrome: a neuroimmunologic hypothesis. CMAJ 2010;182:E834–8. [2] Rosebush PI, Anglin RE, Richards C, Mazurek MF. Neuroleptic malignant syndrome and the acute phase response. J Clin Psychopharmacol 2008;28:459–61. [3] Carbone JR. The neuroleptic malignant and serotonin syndromes. Emerg Med Clin North Am. 2000;18:317–325, x. [4] Keyser DL, Rodnitzky RL. Neuroleptic malignant syndrome in Parkinson's disease after withdrawal or alteration of dopaminergic therapy. Arch Intern Med 1991;151:794–6. [5] van Hilten JJ, Ramaker CC, Stowe R, Ives NJ. Bromocriptine versus levodopa in early Parkinson's disease. Cochrane Database Syst Rev 2007:CD002258. [6] Brooks DJ. Dopamine agonists: their role in the treatment of Parkinson's disease. J Neurol Neurosurg Psychiatry 2000;68:685–90. [7] Gillman PK. Neuroleptic malignant syndrome: mechanisms, interactions, and causality. Mov Disord 2010;25:1780–90. [8] Ananth J, Aduri K, Parameswaran S, Gunatilake S. Neuroleptic malignant syndrome: risk factors, pathophysiology, and treatment. Acta Neuropsychiatr 2004;16:219–28. [9] Strawn JR, Keck Jr PE, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry 2007;164:870–6. [10] Caroff SN, Campbell EC, Sullivan KA. Neuroleptic malignant syndrome in elderly patients. Expert Rev Neurother 2007;7:423–31. [11] Delay J, Deniker P. Drug-induced extrapyramidal syndromes: diseases of the basal ganglia. In: Vinken PJ, Bruyn GW, editors. Handbook of clinical neurology. Amsterdam: North-Holland Publishing Co; 1968. p. 248–66. [12] Bhanushali MJ, Tuite PJ. The evaluation and management of patients with neuroleptic malignant syndrome. Neurol Clin 2004;22:389–411. [13] Bottoni TN. Neuroleptic malignant syndrome: a brief review. Hosp Physician 2002;15:58–63.
General Hospital Psychiatry 33 (2011) 301.e7 – 301.e8
Case Report
Neuroleptic malignant syndrome associated with bromocriptine withdrawal in Parkinson's disease — a case report Yung-Fu Wu, M.D.a , Yuk-Shing Kan, M.D.b,⁎, Chen-Hong Yang, M.D.b b
a Department of Psychiatry, Armed Forces Beitou Hospital, Taipei 112, Taiwan Department of Psychiatry, Taipei Veterans General Hospital, Taipei 112, Taiwan Received 13 October 2010; accepted 20 November 2010
Abstract A 74-year-old man had 15-year history of Parkinson's disease and received bromocriptine monotherapy for 3 years. We present the first case report of neuroleptic malignant syndrome associated with the withdrawal of bromocriptine. The symptoms were alleviated by adequate replenishment of intravenous fluid, temperature reduction and replacement of bromocriptine. Clinicians need to be aware of this potential complication and that a thorough history of current medications is crucial to its identification. © 2011 Elsevier Inc. All rights reserved. Keywords: Neuroleptic malignant syndrome; Bromocriptine; Parkinson's disease; Dopamine
1. Introduction
2. Case report
Neuroleptic malignant syndrome (NMS) is a potentially fatal process characterized by hyperthermia, autonomic instability, altered mental status and severe muscular rigidity. The pathophysiology of NMS remains unknown, although current articles mention the notion of acute phase response including the activation of leukocyte, the release of cytokines and a host of systemic effects [1,2]. Laboratory analysis often reveals leukocytosis, elevated serum creatine kinase (CK) level and minimal to moderate elevations of lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine transaminase (ALT) [3]. Neuroleptic malignant syndrome is most commonly described as an adverse reaction to dopamine receptor blocking agents as well as to withdrawal of antiparkinsonian drugs in patients with Parkinson's disease (PD) [4]. Here we describe a patient with PD who developed NMS the first week after bromocriptine withdrawal.
This patient (a 74-year-old man) had a 15-year history of PD. In August 2010, his medications included 5 mg of bromocriptine per day for PD. There had been no change in medications and dosage for 3 years. He was independent in most daily activities but still required constant supervision. In September 2010, he was transferred to our emergency department (ED) by his wife due to the progressive onset of muscle rigidity, diaphoresis and fluctuation in consciousness for 1 week. His body temperature on arrival was 38.7°C, with elevated blood pressure of 163/104 mmHg, pulse of 113 bpm and respiratory rate of 25/rpm. Laboratory investigation revealed mild leucocytosis (white blood cell count, 10.1×109/L) with shift to the left and high CK level (9569 U/L). The analysis of arterial blood gas indicated metabolic acidosis, and 12-lead electrocardiogram showed sinus tachycardia without any infarct changes. Chest radiography was unremarkable. In the ED, he became somnolent during the day, hyperthermic (39°C) and rigid, and his level of consciousness was reduced. No meningeal sign or pathological reflex was found. Brain computed tomography (CT) revealed no intracerebral hemorrhage. On admission to the medicine service, muscular rigidity and autonomic dysfunction were profound. The results of serum analysis were as follows: AST: 296 U/L, ALT: 64 U/L, LDH: 538 U/L, CK: 14,470 U/L, blood urea nitrogen: 22 mg/dl, creatinine:
⁎ Corresponding author. Tel.: +011 886 2 28711290; fax: +011 886 2 28768403. E-mail address: [email protected] (Y.-S. Kan). 0163-8343/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.genhosppsych.2010.11.013
301.e8
Y.-F. Wu et al. / General Hospital Psychiatry 33 (2011) 301.e7–301.e8
1.34 mg/dl, sodium: 137 mmol/L, potassium: 3.6 mmol/L and C-reactive protein: 2.55 mg/dl. An evaluation for sources of infection was unrevealing. Cerebrospinal fluid (CSF) examination was normal. Cultures of the blood, urine and CSF were sterile. Concomitant therapy medications were nontoxic. A psychiatrist and neurologist were consulted on day 4 of treatment and noted the intermittent episodes of visual hallucination and agitation 10 days prior to this admission. The abrupt discontinuation of bromocriptine 1 week prior to onset of symptoms was considered as a possible cause of the patient's symptoms. Neuroleptic malignant syndrome associated with bromocriptine withdrawal was diagnosed from the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. General symptomatic and supportive measures (adequate replenishment of intravenous fluid and temperature reduction using cooling blankets) were administered along with high volumes of intravenous crystalloids, bicarbonate infusion to alkalinize urine and prevent renal failure, bromocriptine 2.5 mg qid, acetaminophen 500 mg every 6 h and thiamine 100 mg bid. The bromocriptine improved muscle rigidity within 2 days, and temperature decreased along with arterial pressure. On day 11 of treatment, his CK was 36 U/L. He was clearer, was less rigid and complied with simple orders. He continues to take bromocriptine three times daily without recurrence of NMS after discharge, and his family have been advised against reducing or discontinuing this drug. 3. Discussion Bromocriptine monotherapy may be beneficial in delaying motor complications and dyskinesias of PD [5,6]. Although recent articles describe this clinical phenomenon as NMS or NMS-like syndromes [7,8], our emphasis in this report is on the risk of NMS after bromocriptine withdrawal. Neuroleptic malignant syndrome symptom onset may range from hours to months [9]. In our patient, the first symptoms developed 1 week after the last administration of bromocriptine. The differential diagnosis includes infection, neuroleptic-induced heat stroke, intracerebral hemorrhage and toxicity from other medications [10]. Central nervous system infection was excluded by CSF analysis. Neurolepticinduced heat stroke was ruled out by medication history (no other neuroleptic or anticholinergic agents) and medical history (no recent seizure attack, increase in physical activity or exposure to high ambient temperature). Brain CT revealed no hemorrhage or infarction. No other potential course of medications such as lithium was prescribed. The patient's good response to treatment with bromocriptine led us to believe the symptoms were due to bromocriptine withdrawal.
Neuroleptic malignant syndrome was first described by Delay and Deniker in 1968 [11]. Although not known, the pathogenesis of NMS is thought to be related to central dopaminergic blockade, dopamine withdrawal or dopamine deficiency [8], and may involve dopaminergic transmission block in the basal ganglia, corpus striatum, hypothalamus and spinal cord [12,13]. Dopaminergic blockade in the anterior hypothalamus reduces inhibition of serotonin stimulation and contributes to the hyperthermia [13]. Dopaminergic blockade in the corpus striatum causes muscle contraction and rigidity [13]. Dopamine receptor blockade in the nigrostriatal and mesocortical systems may affect consciousness, and at the level of the spinal cord, it may cause autonomic disturbances and functional impairment [13]. To our knowledge, it is the first case report of NMS associated with bromocriptine withdrawal. When bromocriptine is used in PD, there is an iatrogenic increase in dopaminergic transmission. In this setting, withdrawal of bromocriptine may lead to NMS. Here we emphasize that clinicians should be aware of this potential complication and that a thorough history of current medications is crucial to its identification. References [1] Anglin RE, Rosebush PI, Mazurek MF. Neuroleptic malignant syndrome: a neuroimmunologic hypothesis. CMAJ 2010;182:E834–8. [2] Rosebush PI, Anglin RE, Richards C, Mazurek MF. Neuroleptic malignant syndrome and the acute phase response. J Clin Psychopharmacol 2008;28:459–61. [3] Carbone JR. The neuroleptic malignant and serotonin syndromes. Emerg Med Clin North Am. 2000;18:317–325, x. [4] Keyser DL, Rodnitzky RL. Neuroleptic malignant syndrome in Parkinson's disease after withdrawal or alteration of dopaminergic therapy. Arch Intern Med 1991;151:794–6. [5] van Hilten JJ, Ramaker CC, Stowe R, Ives NJ. Bromocriptine versus levodopa in early Parkinson's disease. Cochrane Database Syst Rev 2007:CD002258. [6] Brooks DJ. Dopamine agonists: their role in the treatment of Parkinson's disease. J Neurol Neurosurg Psychiatry 2000;68:685–90. [7] Gillman PK. Neuroleptic malignant syndrome: mechanisms, interactions, and causality. Mov Disord 2010;25:1780–90. [8] Ananth J, Aduri K, Parameswaran S, Gunatilake S. Neuroleptic malignant syndrome: risk factors, pathophysiology, and treatment. Acta Neuropsychiatr 2004;16:219–28. [9] Strawn JR, Keck Jr PE, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry 2007;164:870–6. [10] Caroff SN, Campbell EC, Sullivan KA. Neuroleptic malignant syndrome in elderly patients. Expert Rev Neurother 2007;7:423–31. [11] Delay J, Deniker P. Drug-induced extrapyramidal syndromes: diseases of the basal ganglia. In: Vinken PJ, Bruyn GW, editors. Handbook of clinical neurology. Amsterdam: North-Holland Publishing Co; 1968. p. 248–66. [12] Bhanushali MJ, Tuite PJ. The evaluation and management of patients with neuroleptic malignant syndrome. Neurol Clin 2004;22:389–411. [13] Bottoni TN. Neuroleptic malignant syndrome: a brief review. Hosp Physician 2002;15:58–63.