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Neuroleptic malignant syndrome
BIOL PSYCHIATRY 1988;24:941-960
Correspondence
943
(HAM-A), and the Covi Anxiety ScaIe plus the Raskin Depression every 2 weeks. Also, the patients completed the Acute Panic inventory at visits 1 and 6 and the Hopkins Symptoms Checklist @CL-90) every 2 weeks. Comparison by paired t-tests of the difference between mean scores (baseline versus week 7) for 10 subjects showed a s~tistic~ly sig~fic~t reduction in the mean total scores for the CGI panic severity between pretreatment (7.2 -C 0.9) and posttreatment scores (3.6 t 1.4) (p < 0.001). Statistically significant improvements were also found in the total scores ofthe HAM-A @ < O.OOI), the Covi Anxiety Scale @ < O.OOl), and the panic factor (SCL-90) (p < 0.05). The phobic-anxiety subscales of the SCL90 (p < 0. IO) improved to a lesser extent. Among the 10 patients enrolled in the study, I woman dropped out after the third week because of a severe side effect (heartburn). A total of 16 adverse reactions were reported, the most tiequent being nausea and dizziness, drowsiness, and tremor. Tolerance developed over time for all side effects, except nausea. The present findings suggest that VA may have an antipanic effect. Six of the subjects were at least moderately improved for panic attacks and with respect to diffused anxiety. These results suggest that increased GABAergic transmission is relevant for anxiolysis and control of panic attacks. The side effects were not severe, and tolerance developed within a few weeks for all of them but nausea. Our findings do not support the view that VA causes serious side effects that teud to occur when combined with other ~tiepileptic agents (Dreifuss et al 1987). Thus, VA seemed to be a safe treatment when used alone for panic disorder in the adult population. The mechanism explaining the antipanic effect of VA is unknown. Although the enhanced GABA transmission
is the most liiely mechanism, there has been some controversy about it in recent years (Gramand Benson 1985). In conclusion, VA appeared to be an effective antipanic agent in this limited preliminary study. It presented some advantages over the benzodiazepines, as it did not cause withdrawal reactions; also, compared with the ~tidep~ss~~, overdosage seemed less dangerous. It might prove to be useful in a stepcare approach as a third-line treatment for the more resistant cases. A placebo-controlled clinical trial comparing VA and other antipanic agents would now be in order.
Neuroleptic
tion, including muscle rigidity, akinesia, fever, tachycardia, labile blood pressure, pallor, and diaphoresis, accompanied by altered consciousness (Levenson 1985; ShaIev and Munitz 1986). Many conditions may resemble NMS and should be ruled out, inclu~g catatonia, encephalitis, central nervous system neoplasia, exhaustion, heat stroke, allergic
Malignant
Syndrome
To the Editor: Neuroleptic malignant syudrome (NMS) is a rare, life-threatening adverse drug reaction to therapeutic doses of neuroleptics. NMS typically presents as a syndrome of extrapyramidal and autonomic dysfunc-
Franpis Primeau Rkjean Fontaine
Louis-H. Lafontaine Hospital 7401 Hochelaga Street Montreal (Quebec) HIN3M.5 Canada
References Beaudry P, Fontaine R, Chouinti G, Annable L (1986): Cionazepam in the tzeatment of patients with recurrent panic attacks. J C&n ~~c~~u~ 47233-85. Dreifuss FE, Sat&i& N, Langer DH, Sweeney KP, Moline KA, Manander KB (1987): Valproic acid hepatic fatalities: A retrospective review. Neurology 37:379-385. Fyer AJ, Liebowitz MR. et al (1987): Discontinuation of alprazolam treatment in panic patients. Am J Psych&y w&303-308. Gram L, Bentsen KD (1985): Vafproate: An updated review. Acta New01 Scud 72: 129- 139.
Liebowitz MR, Fyer AJ, Gmuan JM, Campeas R, Levin A, Davies SR, Goetz D, Klein DF (1986): Alprazolam in the treatment of panic disorders. J Clin Psychopharme01 6: 13-20.
944
BIOL PSYCHIATRY 1988;24:941-960
reaction, toxic encephalopathy, hyperthyroidism, and hypocalcemic or hypomagnesemic tetany (Mueller 1985). This report describes four Finnish cases of NMS presenting with some unusual features. Case 1. The patient was a 17-year-old girl with acute schizophreniformic psychosis who had received thioridazine, 200 mg t.i.d., without appropriate response. Five days after receiving an intramuscular injection of 200 mg clopenthixol, she developed marked rigidity, becoming febrile by the ninth day [temperature 38.O”C, pulse 78, blood pressure 138/96, WBC 5.1, creatine kinase (CPK) 26001. Computed tomography (CT) scan of the head was normal, electroencephalogram (EEG) showed increased slow-wave activity. Neuroleptic treatment was discontinued, and electroconvulsive therapy (ECT) was given on 6 occasions. Full recovery ensued 6 days after stopping the ECT. After 9 months without neuroleptics, perphenazine, 8 mglday, was instituted because of continuing schizophrenic symptoms, and this therapy has now lasted for 4 years without recurrence of NMS. Case 2. The patient was a 50-year-old woman with severe, neuroleptic-resistant catatonic schizophrenia who had previously received a neuroleptic combination of clozapine, 500 mglday, thioridazine, 200 mgiday, and melperone, 25 mg/day. Following treatment for 7 days with haloperidol, 4 mg/day orally, she was given a depot injection of 50 mg haloperidol. Two days later, she developed marked rigidity and was febrile by the fourth day. The patient’s vital signs were temperature 39.6”C, pulse 89, blood pressure 150/86. WBC was 5.5 and CPK 700. On the EEG, increased slow-wave activity was seen. The neuroleptics were discontinued and replaced by amantadine treatment, 100 mg twice daily. Full recovery ensued within 7 days. After a neuroleptic-free period of 2 months, clopenthixol-melperon was instituted, but because of an inadequate response, this was replaced by clozapine, 600 mgiday. In a longterm follow-up of 2 years, no recurrence of NMS has seen with clozapine therapy. Cuse 3. The patient was a 68-year-old woman from a local nursing home with primary degenerative dementia and behavioral disturbances. Haloperidol, 2 mg/day, was instituted after the patient’s response to melperone, 50 mg/day, proved to be insufficient. Three weeks later, she showed increased rigidity and fever (temperature 38.5”C, pulse 72, blood pressure 168/94, WBC 10.1; CPK was not measured during the acute stage). In the CT of the head, cortical atrophy was seen, and the EEG showed an increased of
Correspondence
slow-wave activity. Although hronchopneumonia complicated her recovery, the NMS symptoms subsided 2 weeks after stopping neuroleptic treatment. No neuroleptics were used during the follow-up period of 2 years. Case 4. The patient was a 61-year-old woman with severe depression, memory disturbance, and compromised functions of daily living. She was receiving melperone, 25 mg/day, and a depot injection of 10 mg flupentixol was given because of agitation, followed by a second injection of 20 mg after 10 days. Two days after the second injection, profound rigidity and salivation occurred, the patient becoming febrile 3 weeks after the first symptoms appeared (temperature 37.8”C, pulse 78, blood pressure 138/82, WBC 7.8, and CPK 1550). The CT showed central and cortical atrophy. The neuroleptics were stopped as soon as rigidity was noted, and in the febrile stage, bromocriptine, 2.5 mg b.i.d., was instituted, resulting in a marked relief of febrile symptoms within 4 days. Rigidity symptoms, however, persisted for a prolonged period of time, and the patient was hospitalized for 4 months. at the end of which she died of bronchopneumonia. Microscopic examination of the brain tissue showed senile plaques and neurofibrillary tangles typical of Alzheimer’s disease. Neuroleptic malignant syndrome affects all ages and both sexes; however, by chance, all four of our cases were women. NMS often occurs at the beginning of treatment, while doses of neuroleptics are progressively being increased (Gibb and Lees 1985), and this was also clearly the case in our patients. A partial syndrome may also precede the onset of a full-blown NMS, as in case 4. Recovery from NMS normally takes from 1 to 4 weeks, depending on the offending agent (Kellam 1987); in our cases, recovery ensued within 6-14 days. One patient with Alzheimer’s disease showed incomplete recovery, with prolonged rigidity and finally death from bronchopneumonia. In two cases with schizophrenic psychosis the neuroleptic treatment was reinstituted without recurrence of NMS. Hannu Koponen Eila Repa Ulla Lepolu
Vaajasalo Epilepsy and Rehabilitation Hospital SF-7 1130 Kortejoki Finland
BIOL PSYCHIATRY 1988;24:941-960
Correspondence
945
Levenson JL (1985): Neurolepticmalignant syndrome. Am
References
J f’sychiuwy 142: 1137-l 145.
Gibb WRG, Lees AJ (1985): The neuroleptic malignant syndrome-A review. Q J Med 56:421-429.
Mueller PS (1985): Neuroleptic chosomatics 26~654-662.
Kellam AMP (1987): The neuroleptic malignant syndrome, so-called. A survey of the world literature. Br J Psychiatry 150:752-759.
Sbalev A, Munitz H (1986): The neuroleptic malignant syndrome: Agent and host interaction. Acca Psychiatr Stand 731337-347.
State-Dependent
and a further improvement when manic (AIMS score 14). Her affective disorder has not responded to a variety of treatments, including lithium, tricyclics, monoamine oxidase (MAO) inhibitors, and L-hyptophan singly and in combination. There has also been no sustained improvement in her movement disorder, though she has had no neuroleptics for 7 years. There has been no response to benzodiazepines or anticholinergics. We are thus able to report the effect of both depression and mania on tardive dystonia and dyskinesia in a single patient. Our results link the finding of La1 et al. (1988) that mania reduced dystonia with the reports of Rosenbaum et al. (1977) and Cutler et al. (1981) which describe patients in whom tardive dyskinesia was maximal during unipolar depressive phases.
Movement
Disorder
To the Editor: La1 et al. (1988) have reported a case of tardive dystonia in which the dystonic symptoms alternated with mania. We report an analogous case of statedependent tardive dyskinesia and dystonia in a patient with a bipolar illness. The patient, a 41-year-old woman, was admitted to the National Hospital for Nervous Diseases for assessment of her neuropsychiatric condition. Her first psychiatric admission for mania was at age 19, followed by depression at age 25. At this time, she began neuroleptic therapy. In subsequent years, there were annual admissions to various hospitals for psychotic depression, while intervening episodes were treated with maintenance neuroleptic therapy. Eight years after starting neuroleptics, she developed a pronounced axial extensor dystonia (a PISA syndrome). Shortly after this, she also developed tardive dyskinesia with choreiform movements of the face, hands, and feet. Neuroleptics were discontinued. The frequency of bipolar episodes increased, and prior to the current admission, she had been experiencing 6 episodes a year. Five years ago, it was noted that her movement disorder was minimal when the patient was manic, compared with its symptoms in her euthymic condition. On this admission, she underwent two complete mood cycles in 6 weeks, so it was possible to use serial video recordings to monitor the changes in abnormal movement occurring between both poles of her affective disorder, which were rated with the Abnormal Involuntary Movement Scale (AIMS). Both dystonic and dyskinetic movements were most severe when depressed (AIMS score of 30), with a marked improvement when briefly euthymic (AIMS score 20),
malignant
syndrome.
Psy-
Simon Wesseiy A. Feinstein Michael R. Trimble
Department of Neuropsychiatry National Hospital for Nervous Diseases Queen Square London WCI, Great Britain
References Cutler NR, Post RM, Rey AC, Bunney WE (1981): Depression dependent dyskinesias in two cases of a manic depressive illness. N Engl J Med 304:1088-1089. La1 KP, Saxena S, Mohan D (1988): Tardive dystonia aternating with mania. Eiol Psychiatry 23:312-316. Rosenbaum AH, Niven RG, Hanson NP, Swanson DW (1977): Tardive dyskmesia: Relationship with a primary affective disorder. Dis Nerv Syst 38:423-427.
Correspondence
943
(HAM-A), and the Covi Anxiety ScaIe plus the Raskin Depression every 2 weeks. Also, the patients completed the Acute Panic inventory at visits 1 and 6 and the Hopkins Symptoms Checklist @CL-90) every 2 weeks. Comparison by paired t-tests of the difference between mean scores (baseline versus week 7) for 10 subjects showed a s~tistic~ly sig~fic~t reduction in the mean total scores for the CGI panic severity between pretreatment (7.2 -C 0.9) and posttreatment scores (3.6 t 1.4) (p < 0.001). Statistically significant improvements were also found in the total scores ofthe HAM-A @ < O.OOI), the Covi Anxiety Scale @ < O.OOl), and the panic factor (SCL-90) (p < 0.05). The phobic-anxiety subscales of the SCL90 (p < 0. IO) improved to a lesser extent. Among the 10 patients enrolled in the study, I woman dropped out after the third week because of a severe side effect (heartburn). A total of 16 adverse reactions were reported, the most tiequent being nausea and dizziness, drowsiness, and tremor. Tolerance developed over time for all side effects, except nausea. The present findings suggest that VA may have an antipanic effect. Six of the subjects were at least moderately improved for panic attacks and with respect to diffused anxiety. These results suggest that increased GABAergic transmission is relevant for anxiolysis and control of panic attacks. The side effects were not severe, and tolerance developed within a few weeks for all of them but nausea. Our findings do not support the view that VA causes serious side effects that teud to occur when combined with other ~tiepileptic agents (Dreifuss et al 1987). Thus, VA seemed to be a safe treatment when used alone for panic disorder in the adult population. The mechanism explaining the antipanic effect of VA is unknown. Although the enhanced GABA transmission
is the most liiely mechanism, there has been some controversy about it in recent years (Gramand Benson 1985). In conclusion, VA appeared to be an effective antipanic agent in this limited preliminary study. It presented some advantages over the benzodiazepines, as it did not cause withdrawal reactions; also, compared with the ~tidep~ss~~, overdosage seemed less dangerous. It might prove to be useful in a stepcare approach as a third-line treatment for the more resistant cases. A placebo-controlled clinical trial comparing VA and other antipanic agents would now be in order.
Neuroleptic
tion, including muscle rigidity, akinesia, fever, tachycardia, labile blood pressure, pallor, and diaphoresis, accompanied by altered consciousness (Levenson 1985; ShaIev and Munitz 1986). Many conditions may resemble NMS and should be ruled out, inclu~g catatonia, encephalitis, central nervous system neoplasia, exhaustion, heat stroke, allergic
Malignant
Syndrome
To the Editor: Neuroleptic malignant syudrome (NMS) is a rare, life-threatening adverse drug reaction to therapeutic doses of neuroleptics. NMS typically presents as a syndrome of extrapyramidal and autonomic dysfunc-
Franpis Primeau Rkjean Fontaine
Louis-H. Lafontaine Hospital 7401 Hochelaga Street Montreal (Quebec) HIN3M.5 Canada
References Beaudry P, Fontaine R, Chouinti G, Annable L (1986): Cionazepam in the tzeatment of patients with recurrent panic attacks. J C&n ~~c~~u~ 47233-85. Dreifuss FE, Sat&i& N, Langer DH, Sweeney KP, Moline KA, Manander KB (1987): Valproic acid hepatic fatalities: A retrospective review. Neurology 37:379-385. Fyer AJ, Liebowitz MR. et al (1987): Discontinuation of alprazolam treatment in panic patients. Am J Psych&y w&303-308. Gram L, Bentsen KD (1985): Vafproate: An updated review. Acta New01 Scud 72: 129- 139.
Liebowitz MR, Fyer AJ, Gmuan JM, Campeas R, Levin A, Davies SR, Goetz D, Klein DF (1986): Alprazolam in the treatment of panic disorders. J Clin Psychopharme01 6: 13-20.
944
BIOL PSYCHIATRY 1988;24:941-960
reaction, toxic encephalopathy, hyperthyroidism, and hypocalcemic or hypomagnesemic tetany (Mueller 1985). This report describes four Finnish cases of NMS presenting with some unusual features. Case 1. The patient was a 17-year-old girl with acute schizophreniformic psychosis who had received thioridazine, 200 mg t.i.d., without appropriate response. Five days after receiving an intramuscular injection of 200 mg clopenthixol, she developed marked rigidity, becoming febrile by the ninth day [temperature 38.O”C, pulse 78, blood pressure 138/96, WBC 5.1, creatine kinase (CPK) 26001. Computed tomography (CT) scan of the head was normal, electroencephalogram (EEG) showed increased slow-wave activity. Neuroleptic treatment was discontinued, and electroconvulsive therapy (ECT) was given on 6 occasions. Full recovery ensued 6 days after stopping the ECT. After 9 months without neuroleptics, perphenazine, 8 mglday, was instituted because of continuing schizophrenic symptoms, and this therapy has now lasted for 4 years without recurrence of NMS. Case 2. The patient was a 50-year-old woman with severe, neuroleptic-resistant catatonic schizophrenia who had previously received a neuroleptic combination of clozapine, 500 mglday, thioridazine, 200 mgiday, and melperone, 25 mg/day. Following treatment for 7 days with haloperidol, 4 mg/day orally, she was given a depot injection of 50 mg haloperidol. Two days later, she developed marked rigidity and was febrile by the fourth day. The patient’s vital signs were temperature 39.6”C, pulse 89, blood pressure 150/86. WBC was 5.5 and CPK 700. On the EEG, increased slow-wave activity was seen. The neuroleptics were discontinued and replaced by amantadine treatment, 100 mg twice daily. Full recovery ensued within 7 days. After a neuroleptic-free period of 2 months, clopenthixol-melperon was instituted, but because of an inadequate response, this was replaced by clozapine, 600 mgiday. In a longterm follow-up of 2 years, no recurrence of NMS has seen with clozapine therapy. Cuse 3. The patient was a 68-year-old woman from a local nursing home with primary degenerative dementia and behavioral disturbances. Haloperidol, 2 mg/day, was instituted after the patient’s response to melperone, 50 mg/day, proved to be insufficient. Three weeks later, she showed increased rigidity and fever (temperature 38.5”C, pulse 72, blood pressure 168/94, WBC 10.1; CPK was not measured during the acute stage). In the CT of the head, cortical atrophy was seen, and the EEG showed an increased of
Correspondence
slow-wave activity. Although hronchopneumonia complicated her recovery, the NMS symptoms subsided 2 weeks after stopping neuroleptic treatment. No neuroleptics were used during the follow-up period of 2 years. Case 4. The patient was a 61-year-old woman with severe depression, memory disturbance, and compromised functions of daily living. She was receiving melperone, 25 mg/day, and a depot injection of 10 mg flupentixol was given because of agitation, followed by a second injection of 20 mg after 10 days. Two days after the second injection, profound rigidity and salivation occurred, the patient becoming febrile 3 weeks after the first symptoms appeared (temperature 37.8”C, pulse 78, blood pressure 138/82, WBC 7.8, and CPK 1550). The CT showed central and cortical atrophy. The neuroleptics were stopped as soon as rigidity was noted, and in the febrile stage, bromocriptine, 2.5 mg b.i.d., was instituted, resulting in a marked relief of febrile symptoms within 4 days. Rigidity symptoms, however, persisted for a prolonged period of time, and the patient was hospitalized for 4 months. at the end of which she died of bronchopneumonia. Microscopic examination of the brain tissue showed senile plaques and neurofibrillary tangles typical of Alzheimer’s disease. Neuroleptic malignant syndrome affects all ages and both sexes; however, by chance, all four of our cases were women. NMS often occurs at the beginning of treatment, while doses of neuroleptics are progressively being increased (Gibb and Lees 1985), and this was also clearly the case in our patients. A partial syndrome may also precede the onset of a full-blown NMS, as in case 4. Recovery from NMS normally takes from 1 to 4 weeks, depending on the offending agent (Kellam 1987); in our cases, recovery ensued within 6-14 days. One patient with Alzheimer’s disease showed incomplete recovery, with prolonged rigidity and finally death from bronchopneumonia. In two cases with schizophrenic psychosis the neuroleptic treatment was reinstituted without recurrence of NMS. Hannu Koponen Eila Repa Ulla Lepolu
Vaajasalo Epilepsy and Rehabilitation Hospital SF-7 1130 Kortejoki Finland
BIOL PSYCHIATRY 1988;24:941-960
Correspondence
945
Levenson JL (1985): Neurolepticmalignant syndrome. Am
References
J f’sychiuwy 142: 1137-l 145.
Gibb WRG, Lees AJ (1985): The neuroleptic malignant syndrome-A review. Q J Med 56:421-429.
Mueller PS (1985): Neuroleptic chosomatics 26~654-662.
Kellam AMP (1987): The neuroleptic malignant syndrome, so-called. A survey of the world literature. Br J Psychiatry 150:752-759.
Sbalev A, Munitz H (1986): The neuroleptic malignant syndrome: Agent and host interaction. Acca Psychiatr Stand 731337-347.
State-Dependent
and a further improvement when manic (AIMS score 14). Her affective disorder has not responded to a variety of treatments, including lithium, tricyclics, monoamine oxidase (MAO) inhibitors, and L-hyptophan singly and in combination. There has also been no sustained improvement in her movement disorder, though she has had no neuroleptics for 7 years. There has been no response to benzodiazepines or anticholinergics. We are thus able to report the effect of both depression and mania on tardive dystonia and dyskinesia in a single patient. Our results link the finding of La1 et al. (1988) that mania reduced dystonia with the reports of Rosenbaum et al. (1977) and Cutler et al. (1981) which describe patients in whom tardive dyskinesia was maximal during unipolar depressive phases.
Movement
Disorder
To the Editor: La1 et al. (1988) have reported a case of tardive dystonia in which the dystonic symptoms alternated with mania. We report an analogous case of statedependent tardive dyskinesia and dystonia in a patient with a bipolar illness. The patient, a 41-year-old woman, was admitted to the National Hospital for Nervous Diseases for assessment of her neuropsychiatric condition. Her first psychiatric admission for mania was at age 19, followed by depression at age 25. At this time, she began neuroleptic therapy. In subsequent years, there were annual admissions to various hospitals for psychotic depression, while intervening episodes were treated with maintenance neuroleptic therapy. Eight years after starting neuroleptics, she developed a pronounced axial extensor dystonia (a PISA syndrome). Shortly after this, she also developed tardive dyskinesia with choreiform movements of the face, hands, and feet. Neuroleptics were discontinued. The frequency of bipolar episodes increased, and prior to the current admission, she had been experiencing 6 episodes a year. Five years ago, it was noted that her movement disorder was minimal when the patient was manic, compared with its symptoms in her euthymic condition. On this admission, she underwent two complete mood cycles in 6 weeks, so it was possible to use serial video recordings to monitor the changes in abnormal movement occurring between both poles of her affective disorder, which were rated with the Abnormal Involuntary Movement Scale (AIMS). Both dystonic and dyskinetic movements were most severe when depressed (AIMS score of 30), with a marked improvement when briefly euthymic (AIMS score 20),
malignant
syndrome.
Psy-
Simon Wesseiy A. Feinstein Michael R. Trimble
Department of Neuropsychiatry National Hospital for Nervous Diseases Queen Square London WCI, Great Britain
References Cutler NR, Post RM, Rey AC, Bunney WE (1981): Depression dependent dyskinesias in two cases of a manic depressive illness. N Engl J Med 304:1088-1089. La1 KP, Saxena S, Mohan D (1988): Tardive dystonia aternating with mania. Eiol Psychiatry 23:312-316. Rosenbaum AH, Niven RG, Hanson NP, Swanson DW (1977): Tardive dyskmesia: Relationship with a primary affective disorder. Dis Nerv Syst 38:423-427.