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Hyperventilation alternating with apnea in neuroleptic malignant syndrome associated with metoclopramide and cisapride
JOURNAL
OF THE
NEUROLOGICAL SCIENCES
ELSEVTER
Journal of the Neurological Sciences 128 (1995) 232-233
Letter to the Editor
Hyperventilation alternating with apnea in neuroleptic malignant syndrome associated with metoclopramide and cisapride Shuzo Shintani a,* , Tatsuo Shiigai b, Kuniaki Tsuchiya ‘, Masanori Kikuchi d a Department of Neurology, Toride Kyodo General Hospital, 5901-l Terada, Toride City, Ibaraki 302, Japan b Department of internal Medicine, Toride Kyodo General Hospital, Ibaraki, Japan ’ Department of Neurology, Musashino Red Cross Hospitai, Tokyo, Japan d Department of Pathology, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan
Received 27 June 1994; revised 6 October 1994; accepted 17 October 1994 Keywords:
Neuroleptic
malignant syndrome; Hyperventilation;
Apnea; Metoclopramide;
Dear Sir, Neuroleptic malignant syndrome (NMS), a side effect of neuroleptic therapy, was first described in 1968 by Delay and Deniker (1968). Hyperpyrexia, muscle rigidity, altered consciousness, and autonomic instability are the hallmarks of this syndrome. Hyperpyrexia and tachycardia are very common symptoms in NMS. However, abnormal respiratory rhythmicity in NMS had been rarely reported. A 77-year-old dentist had been well and working in his office until March 1991. Metoclopramide (six 5-mg tablets daily) and cisapride (three 2.5-mg tablets daily) had been administrated for gastroparesis, nausea, and poor appetite since April 2, 1991. One week later, he noticed stiffness of his legs. Over the next week, he became increasingly immobile and tremulous, and had difficulty in swallowing and speaking. He became depressive and developed hypersalivation. On May 7, he was admitted to our hospital in an emergency for treatment of fever, leukocytosis, lethargy, muscle rigidity, tachycardia, and alternate hyperventilation and apnea. On admission, he was lethargic with marked axial and limb rigidity, with a tendency to maintain a catatonic posture, and a mild resting tremor at 4 - 5 Hz. Blood pressure was 130/80 mm Hg. Pulse rate was irregular (130 beats/min), and he was febrile (38.8”C). Hyperventilation (40 - 50 cycles/min, duration 2 - 3 min) and apnea (duration 30 set) persisted alternately. Investigations showed that hemoglobin was 14.9 g/d1 and the white blood cell (WBCs) count was 19 700/mm3
* Corresponding author. Tel.: 81-297-74-5551;Fax: 81-297-74-2721. 0022-510X/95/$09.50 0 1995 Elsevier Science B.V. All rights reserved SSDI 0022-510)3(94)00255-X
Cisapride
; electrolytes, hepatic enzymes, blood sugar concentration, chest radiograph, and lumbar puncture findings were all normal. Creatine phosphokinase (CK) activity was 121 mu/ml (normal range 38-1601, peaking at 380 mu/ml. The patient was intubated on admission and blood gas pressure measured in room air was 88.2 mm Hg for p02, and 12.1 mm Hg for pC02. Base excess (BE) was - 1.7, the Ievei of HC03- was 13.4 mmol/I and pH was 7.650. Brain computed tomography (CT) showed moderate cortical atrophy and a small lacuna in the right putamen. A diagnosis of NMS was made and metoclopramide and cisapride were discontinued. At the same time, the patient was started on carbidopa/levodopa 300 mg, amantadine 200 mg, and bromocriptine 7.5 mg daily. The patient had remained febrile and intermittently comatose, with rigid extremities, refractory tachycardia, and alternate hyperventilation and apnea for 8 days. Since May 16, he became afebrile, his muscle rigidity gradually disappeared, and his level of consciousness improved. The abnormal rhythm of respiration disappeared, and he could speak the occasional word after removal of the endotracheal tube. On May 20, WBCs dropped to normal (7000/mm3) and blood gas pressure became normal (pH 7.469, p02 88.3 mmHg, pC02 39.0 mm Hg, BE +5.2, HC03- 28.2 mmol/l in room air). Unfortunately, he died of suffocation after vomiting on the 45th day of admission. Necropsy revealed almost normal findings in the central nervous system, except for tiny old lacunae in the left caudate nucleus and the right putamen. A fresh small hemorrhagic infarct (7 mm diameter) was present in the parietal cortex. The neurons of the substantia nigra and locus ceruleus were completely preserved.
S. Shintani et al. /Journal
of the Neurological
Symptoms of the present case included muscle rigidity, hyperpyrexia, altered consciousness, and autonomic instability. These symptoms were typical of NMS and were reduced by the administration of dopaminergic drugs (levodopa/carbidopa, amantadine, and bromocriptine). Necropsy showed a preservation of the neurons of substantia nigra and two tiny lacunae in the basal ganglia. The former finding indicated that the patient did not have Parkinson disease and the latter finding might somewhat enhance the extrapyramidal symptoms in this case. A variety of extrapyramidal disorders (such as acute dystonic reaction, parkinsonism, and tardive dyskinesia) have been reported with metoclopramide, a chlorbenzamide derivative. Recently several cases of metoclopramide-induced NMS have been reported (Cassidy and Bansal 1988; Friedman et al. 1987; Pate1 and Bristow 1987). Cisapride, a new gastrokinetic agent, has a cholinergic effect on the intramuscular neuroreceptors in the gastrointestine and has a rare side effect on the central nervous system. However, in Japan, cisapride-induced parkinsonism has recently been reported (Kuzuhara 1992; Uchiyama and Shimazaki 1990). Cisapride might have enhanced the symptoms of metoclopramide-induced NMS in the present case. The autonomic failure in this case consisted of the clinical manifestations of hyperpyrexia, tachycardia, and tachypnea alternating with apnea. The tachypnea continued for about 8 days. It was central type respiratory failure because the patient had been intubated until his recovery. Hyperventilation-induced hypocapnia resulted in the intermittent apnea. The necropsy did not show the microscopic findings related to abnormal respiratory rhythmicity in the hypothalamus, pons, and medulla. The brain stem respiratory neurons anatomically distribute in the caudal and rostra1 ventral respiratory group WRG) and the dorsal respiratory group
Sciences I28 (1995) 232-233
233
(DRG) in the medulla, the Botzinger complex, and the pontine respiratory group (PRG; nucleus parabrachialis medialis/Kijlliker-Fuse nucleus) in the pons (Feldman and Ellenberger 1988). It is suggested that the respiratory failure was probably due to the functional adrenergic and noradrenergic disorders in the autonomic respiratory centers. The pathogenesis of autonomic dysfunction in NMS has been discussed. Yamamoto et al. (1989) reported that the level of plasma norepinephrine was abnormally high in the stage of illness, and gradually returned to normal as the disease improved in NMS. This increased sympathetic nervous activity might result in the abnormal respiratory rhythmicity observed in our case. References Cassidy, T. and Bansal, SK. (1988) Neuroleptic malignant syndrome associated with metoclopramide. Br. Med. J., 296: 214. Delay, J. and Deniker, P. (1968) Drug-induced extrapyramidal syndromes. In: Vinken, P.J. and Bruyn, G.W. (Eds.), Handbook of Clinical Neurology, Vol. 6: Diseases of the Basal Ganglia, Elsevier, Amsterdam, pp. 248-266. Feldman, J.L. and Ellenberger, H.H. (1988) Central coordination of respiratory and cardiovascular control in mammals. Annu. Rev. Physiol., 50: 593-606. Friedman, L.S., Weinrauch, L.A. and D’Elia, J.A. (1987) Metoclopramide-induced neuroleptic malignant syndrome. Arch. Intern. Med., 147: 14951497. Kuzuhara, S. (1992) Parkinsonism and depression induced by cisapride. Neurol. Med. (Tokyo), 36: 217-218. Patel, P. and Bristow, G. (1987) Postoperative neuroleptic malignant syndrome. A case report. Can. J. Anaesthesiol., 34: 515-518. Uchiyama, S. and Shimazaki, H. (1990) Cisapride-induced aggravation of parkinsonism in the aged. Neurol. Med. (Tokyo), 33: 210-211. Yamamoto, T., Shimazu, K., Tamura, N., Watanabe, S., Onoda, A., Nakazato, Y. and Hamaguchi, K. (1989) Autonomic dysfunction in neuroleptic malignant syndrome. Auton. Nerv. Syst. (Tokyo), 26: 71-77.
OF THE
NEUROLOGICAL SCIENCES
ELSEVTER
Journal of the Neurological Sciences 128 (1995) 232-233
Letter to the Editor
Hyperventilation alternating with apnea in neuroleptic malignant syndrome associated with metoclopramide and cisapride Shuzo Shintani a,* , Tatsuo Shiigai b, Kuniaki Tsuchiya ‘, Masanori Kikuchi d a Department of Neurology, Toride Kyodo General Hospital, 5901-l Terada, Toride City, Ibaraki 302, Japan b Department of internal Medicine, Toride Kyodo General Hospital, Ibaraki, Japan ’ Department of Neurology, Musashino Red Cross Hospitai, Tokyo, Japan d Department of Pathology, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan
Received 27 June 1994; revised 6 October 1994; accepted 17 October 1994 Keywords:
Neuroleptic
malignant syndrome; Hyperventilation;
Apnea; Metoclopramide;
Dear Sir, Neuroleptic malignant syndrome (NMS), a side effect of neuroleptic therapy, was first described in 1968 by Delay and Deniker (1968). Hyperpyrexia, muscle rigidity, altered consciousness, and autonomic instability are the hallmarks of this syndrome. Hyperpyrexia and tachycardia are very common symptoms in NMS. However, abnormal respiratory rhythmicity in NMS had been rarely reported. A 77-year-old dentist had been well and working in his office until March 1991. Metoclopramide (six 5-mg tablets daily) and cisapride (three 2.5-mg tablets daily) had been administrated for gastroparesis, nausea, and poor appetite since April 2, 1991. One week later, he noticed stiffness of his legs. Over the next week, he became increasingly immobile and tremulous, and had difficulty in swallowing and speaking. He became depressive and developed hypersalivation. On May 7, he was admitted to our hospital in an emergency for treatment of fever, leukocytosis, lethargy, muscle rigidity, tachycardia, and alternate hyperventilation and apnea. On admission, he was lethargic with marked axial and limb rigidity, with a tendency to maintain a catatonic posture, and a mild resting tremor at 4 - 5 Hz. Blood pressure was 130/80 mm Hg. Pulse rate was irregular (130 beats/min), and he was febrile (38.8”C). Hyperventilation (40 - 50 cycles/min, duration 2 - 3 min) and apnea (duration 30 set) persisted alternately. Investigations showed that hemoglobin was 14.9 g/d1 and the white blood cell (WBCs) count was 19 700/mm3
* Corresponding author. Tel.: 81-297-74-5551;Fax: 81-297-74-2721. 0022-510X/95/$09.50 0 1995 Elsevier Science B.V. All rights reserved SSDI 0022-510)3(94)00255-X
Cisapride
; electrolytes, hepatic enzymes, blood sugar concentration, chest radiograph, and lumbar puncture findings were all normal. Creatine phosphokinase (CK) activity was 121 mu/ml (normal range 38-1601, peaking at 380 mu/ml. The patient was intubated on admission and blood gas pressure measured in room air was 88.2 mm Hg for p02, and 12.1 mm Hg for pC02. Base excess (BE) was - 1.7, the Ievei of HC03- was 13.4 mmol/I and pH was 7.650. Brain computed tomography (CT) showed moderate cortical atrophy and a small lacuna in the right putamen. A diagnosis of NMS was made and metoclopramide and cisapride were discontinued. At the same time, the patient was started on carbidopa/levodopa 300 mg, amantadine 200 mg, and bromocriptine 7.5 mg daily. The patient had remained febrile and intermittently comatose, with rigid extremities, refractory tachycardia, and alternate hyperventilation and apnea for 8 days. Since May 16, he became afebrile, his muscle rigidity gradually disappeared, and his level of consciousness improved. The abnormal rhythm of respiration disappeared, and he could speak the occasional word after removal of the endotracheal tube. On May 20, WBCs dropped to normal (7000/mm3) and blood gas pressure became normal (pH 7.469, p02 88.3 mmHg, pC02 39.0 mm Hg, BE +5.2, HC03- 28.2 mmol/l in room air). Unfortunately, he died of suffocation after vomiting on the 45th day of admission. Necropsy revealed almost normal findings in the central nervous system, except for tiny old lacunae in the left caudate nucleus and the right putamen. A fresh small hemorrhagic infarct (7 mm diameter) was present in the parietal cortex. The neurons of the substantia nigra and locus ceruleus were completely preserved.
S. Shintani et al. /Journal
of the Neurological
Symptoms of the present case included muscle rigidity, hyperpyrexia, altered consciousness, and autonomic instability. These symptoms were typical of NMS and were reduced by the administration of dopaminergic drugs (levodopa/carbidopa, amantadine, and bromocriptine). Necropsy showed a preservation of the neurons of substantia nigra and two tiny lacunae in the basal ganglia. The former finding indicated that the patient did not have Parkinson disease and the latter finding might somewhat enhance the extrapyramidal symptoms in this case. A variety of extrapyramidal disorders (such as acute dystonic reaction, parkinsonism, and tardive dyskinesia) have been reported with metoclopramide, a chlorbenzamide derivative. Recently several cases of metoclopramide-induced NMS have been reported (Cassidy and Bansal 1988; Friedman et al. 1987; Pate1 and Bristow 1987). Cisapride, a new gastrokinetic agent, has a cholinergic effect on the intramuscular neuroreceptors in the gastrointestine and has a rare side effect on the central nervous system. However, in Japan, cisapride-induced parkinsonism has recently been reported (Kuzuhara 1992; Uchiyama and Shimazaki 1990). Cisapride might have enhanced the symptoms of metoclopramide-induced NMS in the present case. The autonomic failure in this case consisted of the clinical manifestations of hyperpyrexia, tachycardia, and tachypnea alternating with apnea. The tachypnea continued for about 8 days. It was central type respiratory failure because the patient had been intubated until his recovery. Hyperventilation-induced hypocapnia resulted in the intermittent apnea. The necropsy did not show the microscopic findings related to abnormal respiratory rhythmicity in the hypothalamus, pons, and medulla. The brain stem respiratory neurons anatomically distribute in the caudal and rostra1 ventral respiratory group WRG) and the dorsal respiratory group
Sciences I28 (1995) 232-233
233
(DRG) in the medulla, the Botzinger complex, and the pontine respiratory group (PRG; nucleus parabrachialis medialis/Kijlliker-Fuse nucleus) in the pons (Feldman and Ellenberger 1988). It is suggested that the respiratory failure was probably due to the functional adrenergic and noradrenergic disorders in the autonomic respiratory centers. The pathogenesis of autonomic dysfunction in NMS has been discussed. Yamamoto et al. (1989) reported that the level of plasma norepinephrine was abnormally high in the stage of illness, and gradually returned to normal as the disease improved in NMS. This increased sympathetic nervous activity might result in the abnormal respiratory rhythmicity observed in our case. References Cassidy, T. and Bansal, SK. (1988) Neuroleptic malignant syndrome associated with metoclopramide. Br. Med. J., 296: 214. Delay, J. and Deniker, P. (1968) Drug-induced extrapyramidal syndromes. In: Vinken, P.J. and Bruyn, G.W. (Eds.), Handbook of Clinical Neurology, Vol. 6: Diseases of the Basal Ganglia, Elsevier, Amsterdam, pp. 248-266. Feldman, J.L. and Ellenberger, H.H. (1988) Central coordination of respiratory and cardiovascular control in mammals. Annu. Rev. Physiol., 50: 593-606. Friedman, L.S., Weinrauch, L.A. and D’Elia, J.A. (1987) Metoclopramide-induced neuroleptic malignant syndrome. Arch. Intern. Med., 147: 14951497. Kuzuhara, S. (1992) Parkinsonism and depression induced by cisapride. Neurol. Med. (Tokyo), 36: 217-218. Patel, P. and Bristow, G. (1987) Postoperative neuroleptic malignant syndrome. A case report. Can. J. Anaesthesiol., 34: 515-518. Uchiyama, S. and Shimazaki, H. (1990) Cisapride-induced aggravation of parkinsonism in the aged. Neurol. Med. (Tokyo), 33: 210-211. Yamamoto, T., Shimazu, K., Tamura, N., Watanabe, S., Onoda, A., Nakazato, Y. and Hamaguchi, K. (1989) Autonomic dysfunction in neuroleptic malignant syndrome. Auton. Nerv. Syst. (Tokyo), 26: 71-77.