วารสารสมาคมจิตแพทย์แห่งประเทศไทย
Journal of the Psychiatrist Association of Thailand
ISSN: 0125-6985
บรรณาธิการ มาโนช หล่อตระกูล
Editor: Manote Lotrakul, M.D.

วารสารสมาคมจิตแพทย์แห่งประเทศไทย    Journal of the Psychiatric association of Thailand

Neuroleptic Malignant Syndrome : การศึกษาย้อนหลัง 5 ปี

เกษม ตันติผลาชีวะ พ.บ.*

Neuroleptic Malignant Syndrome : A Five-Year Review

Kasem Tantiphlachiva M.D.*

* โรงพยาบาลสมเด็จเจ้าพระยา คลองสาน กรุงเทพฯ 10600 * Somdet Chaopraya Hospital, Bangkok 10600.

 บทคัดย่อ

Neuroleptic malignant syndrome (NMS) เป็นภาวะแทรกซ้อนที่ร้ายแรงที่สุดของยารักษาโรคจิต ซึ่งอาจทำให้ผู้ป่วยเสียชีวิตได้ ผู้รายงานได้ศึกษาย้อนหลัง ผู้ป่วยในของโรงพยาบาลสมเด็จเจ้าพระยาเป็นเวลา 5 ปี ตั้งแต่ พ.ศ. 2537 ถึง พ.ศ. 2541 พบว่าในช่วงเวลาดังกล่าว มีผู้ป่วย NMS 12 ราย คิดเป็นอุบัติการร้อยละ 0.04 ซึ่งคาดว่ายังต่ำกว่าตัวเลขจริง ครึ่งหนึ่งของผู้ป่วยได้รับการวินิจฉัยเป็นโรคจิตเภท ผู้ป่วยทุกรายมีไข้, เหงื่อออกมาก, กล้ามเนื้อเกร็ง, เม็ดเลือดขาวสูง และเอนไซม์ครีเอทีน ฟอสโฟไคเนสในเลือดสูง ปัจจัยชักนำให้เกิด NMS คือ อาการกระวนกระวาย, ภาวะขาดน้ำ, การหมดแรง, การฉีดยารักษาโรคจิตชนิดออกฤทธิ์นาน และการฉีดยาเข้ากล้ามเนื้อบ่อย อัตราตายพบร้อยละ 16.67 ผู้รายงานได้เสนอแนะแนวทาง เพื่อให้แพทย์ตระหนักถึงความสำคัญในการวินิจฉัยกลุ่มอาการนี้ได้แต่เนิ่น ๆ และให้การรักษาอย่างทันท่วงที เป็นการช่วยลดอัตราป่วยและอัตราตายลง

วารสารสมาคมจิตแพทย์แห่งประเทศไทย 2542;44(3): 189-200.

คำสำคัญ neuroleptic malignant syndrome, incidence, predisposing factors

 Abstract

Neuroleptic malignant syndrome (NMS) is the most serious and potentially fatal complication of neuroleptic pharmacotherapy. This is a retrospective study of cases at Somdet Chaopraya Hospital from 1994 to 1998. Twelve cases were diagnosed as developing NMS during the five-year period, revealing the incidence of 0.04%, which would have been higher if cases without laboratory investigations were included. Half of the patients were diagnosed as schizophrenia. Fever, sweating, muscle rigidity, leucocytosis, and increased creatine phosphokinase were found in every case. Predisposing factors were agitation, dehydration, exhaustion, use of depot neuroleptics and frequent intramuscular injections. The mortality rate was 16.67%. Suggestions are made for clinicians, emphasizing more awareness leading to early recognition of the condition and to ensure prompt treatment, thereby reducing mortality and morbidity.

J Psychiatr Assoc Thailand 1999;44(3): 189-200.

Key words : neuroleptic malignant syndrome, incidence, predisposing factors

 The neuroleptic malignant syndrome (NMS) was first described by Delay et al in 1960 during early clinical trials of haloperidol. It was originally referred to as the most serious but also the rarest and least known of complications of neuroleptic pharmacotherapy¹.

In ICD-10, it was classified under the category of Secondary parkinsonism G 21.0 Malignant neuroleptic syndrome. In DSM-IV, it was classified under the category of Medication-Induced Movement Disorders 333.92 Neuroleptic Malignant Syndrome. DSM-IV described NMS as “Severe muscle rigidity, elevated temperature, and other related findings e.g. diaphoresis, dysphagia, incontinence, changes in level of consciousness ranging from confusion to coma, mutism, elevated or labile blood pressure, elevated creatine phosphokinase (CPK) developing in association with the use of neuroleptic medication.”

The incidence of NMS was formerly estimated between 0.02% and 3.23% of patients treated with neuroleptics. More recently, by using defined diagnostic criteria, the incidence rate was around 0.2%².

The mortality of NMS in earliest studies was as high as 30%³. In more recent studies, the mortality rate has been decreasing considerably due to greater awareness and recognition of the condition.

Neuroleptics are the main drugs related to NMS causation. With the more widespread use of atypical antipsychotics, cases were reported related to their use^4-5. NMS was also reported in association with abuse of concaine⁶ and Ecstasy⁷.

Risk factors for NMS include psychomotor agitation, large dose neuroleptics at high rate of dosage increase, intramuscular injection, dehydration^8-12, exhaustion, mood disorder, previous episode of NMS^2,3, previous treatment with ECT⁹, and preexisting brain damage¹³. Hyponatremia has also been reported to be a risk factor for NMS^14,15. Withdrawal of antiparkinsonian drugs may precipitate NMS in Parkinson’s disease¹⁵. Abrupt withdrawal of both anticholinergics and neuroleptics has been reported as a probable risk factor for NMS¹⁶.

Most studies indicated no genetic factor in NMS. So far, there were only two reports of the familial occurrence of NMS². Recent studies confirmed that there was no association between NMS and mutation in the RYR1 gene similar to that found in malignant hyperthermia (MH)¹⁷, nor was there any association between NMS and cytochrome P-450 2D6 gene polymorphism or gene mutation^18,19. Similarly, no association was found between NMS and polymorphisms in 5-HT1A and 5-HT2A receptor genes²⁰.

The most widely believed pathogenesis of NMS is that central D₂ dopaminergic blockade produces muscle rigidity and persistent muscle contracture and causes hyperthermia with hypermetabolism and rhabdomyolysis similar to malignant hyperthermia. Muscle rigidity in NMS is not caused by a defect of muscle sarcoplasmic reticulum calcium release as in MH²¹. The thermoregulatory dysfunction in NMS is caused by central blocking of the anterior hypothalamus (inappropriate “set point”) or by direct myotoxicity (excessive peripheral heat production), or both²².

An alternative hypothesis is that the latent capacity of sympathetic nervous system for autonomous activity is expressed when tonic inhibitory inputs from higher central nervous system centres are disrupted. Dysregulated sympathetic nervous system hyperactivity is responsible for most features of NMS²³. Some authors postulated that NMS and toxic serotonin syndrome are examples of a non-specific generalized neurotoxic syndrome and not specific syndromes²⁴, and that these are subtypes of catatonia^24-26.

NMS must be differentiated from a wide range of disorders presenting with fever and rigidity^27-29. Thorough medical and neurological evaluations are necessary to ensure an accurate diagnosis.

The basis of management of NMS ^{2, 21, 29} is the reduction of risk factors, early recognition, withdrawal of neuroleptics, intensive medical care focusing on proper hydration, and control of temperature elevation. Psychosis and agitation can be controlled with benzodiazepines. Central dopaminergic drugs (e.g. bromocriptine, amantadine) are widely advocated effective agents. Dantrolene is a hydantoin derivative used as a muscle relaxant in treating spasticity. Carbamazepine has also been reported to be effective in NMS. ECT is recommended when other treatments are not effective^{24, 31}. Plasmapheresis is reportedly a treatment of choice when conventional therapy fails³². In Thailand, NMS came into attention only recently. To date, there have been very few reports of NMS in Thai literature.

Materials and methods

Retrospective study was carried out by reviewing medical records of patients treated at the intensive care unit of Somdet Chaopraya Hospital from January 1, 1994 to December 31, 1998. Cases treated with symptoms of fever, muscle rigidity, alteration of consciousness, or autonomic nervous system imbalance, were inspected to sort out cases of NMS and studied in detail.

Results

Among 70 cases included by using the symptom criteria mentioned above, 12 cases (17.14%) meet the criteria for diagnosis of NMS according to DSM-IV.

The incidence of NMS in this study was about 0.04% of total psychiatric admissions. The numbers of NMS and psychiatric admissions during the 5-year period are shown in Table 1.

The sex ratio of male : female patients was 5:7. The age of patients ranged from 17 to 67 years (mean age 36.25, SD 13.48). Half of the patients were diagnosed as schizophrenia. Catatonic schizophrenia and undifferentiated schizophrenia predominated the group (3 cases each). Two cases of schizoaffective disorder, 2 cases of acute psychotic disorder, 1 case of delusional disorder, and 1 case of mental retardation were found, as shown in Table 2.

Fever, diaphoresis and muscle rigidity were found in every case of NMS in this study. The temperatures range from 38.5^oc to 40.5^oc (mean 39.56^oc, SD 0.8). Nine cases (75%) developed urinary incontinence. Level of consciousness varied from drowsiness to coma. Confusion was found in 6 cases (50%). Other forms of parkinsonism, e.g. tremor and cogwheel rigidity, were also found besides muscle rigidity. The clinical findings in NMS patients are shown in Table 3.

Leucocytosis was found in every case of NMS in this study. Serum white blood cell counts ranged from 9,100 to 19,100 cells per cubic millimetre (mean 14,358.3 cells/mm.³, SD 2,762.6). Differential white cell counts revealed “shift-to-the-left” pattern, neutrophil percentages range from 70 to 92% (mean 84.67%, SD 8.12). Serum creatine phosphokinase (CPK) was elevated in 10 cases studied. Data was not available in the other 2 cases. CPK levels range from 2,383 to 17,890 units per litre (mean 6,505.2 u/l, SD 5,147.7). Laboratory findings are shown in Table 4.

The two most commonly used oral neuroleptics were haloperidol (5 cases) and perphenazine (4 cases).

Long-acting neuroleptics were used in5 cases (41.67%). Haloperidol decanoate was the most commonly used depot neuroleptic in this group (3 cases). Fluphenazine decanoate was administered in 2 cases.

Short-acting neuroleptic injections were given in 5 cases , Haloperidol was the most frequent injection (4 cases) and chlorpromazine hydrochloride was used in one case (8.33%). Zuclopenthixol acetate was injected in 2 cases.

Electroconvulsive therapy was performed in 4 cases (33.33%) before the onset of NMS. The number of ECT ranged from 2 to 6 times. The details of neuroleptic use and ECT in each case are shown in Table 5.

Predisposing factors in this series of NMS cases were : dehydration (11 cases), psychomotor agitation (9 cases), exhaustion (5 cases), frequent intramuscular injection (4 cases), and use of long-acting neuroleptics (5 cases) (Table 6).

Most cases of NMS in this study were treated by symptomatic and supportive treatments using hypothermia, intravenous fluids, correction of electrolyte imbalance, etc.

Pharmacological treatments for NMS in this study were bromocriptine (8 cases), clonazepam (5 cases), carbamazepine (2 cases), diphenylhydantoin (2 cases), sodium valproate (2 cases), methyldopa (1 case), trihexyphenidyl (1 case), and phenobarbital (1 case).

The most common complication in these 12 cases of NMS was pneumonia (3 cases), one of them was aspirated pneumonia. Urinary tract infection was found in 2 cases. Acute renal failure was the most serious complication which resulted in death in one case. The other case died of pre-existing pulmonary tuberculosis with pneumonia on top. The overall death rate was 16.67%. The duration of NMS in cases with recovery ranged from 7 to 73 days (mean 33.2, SD 20.78) (Table 7).

Discussion

The incidence of NMS in this study is 0.04% of psychiatric admissions, which is rather low. The limitation of this retrospective study from medical records may be one factor that explains the non-coverage of certain cases which might be left unnoticed. Another possible factor might be the low index of suspicion for NMS among clinicians which make some cases undiagnosed. Cases of less severity were not recognized, subsequently underreported. There were also recent reports of NMS cases without fever^{33, 34} or without muscle rigidity³⁵.

The findings in this study support previous studies^{2, 3} that age and sex are not risk factors for NMS.The predominance of schizophrenia in this study reflects the distribution of diagnosis in this psychiatric hospital whichschizophrenia comprises about half of thediagnosis on discharge.Clinical profile of catatonic schizophrenia may resemble extrapyramidal side effects caused by neuroleptics. This may be a major factor which prompts the patient to come for hospitalization before the occurrence of NMS. It may as well support the hypothesis that NMS is a variant of lethal catatonia which has been described long before the use of neuroleptics^{25, 26, 36}.

Clinical findings are compatible with NMS in all cases. Pyrexia, sweating, muscle rigidity and alteration of consciousness were more constantly found than incontinence which is more difficult to be detected and may often be unrecorded.

Laboratory investigations showed leucocytosis with left shift in all cases. Serum CPK increased obviously in every case, though it is advised not to be regarded as a specific finding. Two cases were not investigated for CPK due to lack of awareness for NMS, even though they could be diagnosed later.

No correlation could be seen between the type and dose of oral neuroleptics and the occurrence of NMS. The use of intramuscular depot neuroleptics is more likely to be associated with the occurrence of NMS, as they were used in 41.67% of cases.

Frequent intramuscular injections were found in one third of cases. In some cases, combinations of short-acting, intermediate-acting and long-acting neuroleptics are used,which may increase the risk of NMS.Agitation, dehydration and exhaustion are found to be predisposing factors in most cases of NMS. It is difficult to ensure the accuracy of data in these findings since they are interpreted from medical records only.

Combination of these factors may lead to a hypothesis that agitated patients are more likely to be dehydrated, given more neuroleptics at high dosage, getting frequent intramuscular injections and prone to be exhausted. These factors are associated with higher risk of extrapyramidal symptoms and NMS.

In some cases, it is possible that dystonia and other parkinsonian side effects may be misinterpreted as catatonia, which may lead to increased use of neuroleptics and ECT. Pharmacological treatments of NMS in this study consist of bromocriptine and anticonvulsant drugs. The essential part of treatment could be general supportive care, hydration, and electrolytes.

The average duration of NMS in this study is 33.2 days, which is longer than the previous study in Thailand³⁷. We also find a mortality rate of 16.67% while the other study reported no mortality in all 12 cases.

Comparison of cases in both psychiatric settings shows that the cases in this study were more severely psychotic, receiving higher dosage of neuroleptics with more unfavorable general physical conditions.

Another possible explanation is that the low index of suspicion for this disorder may lead to delayed treatment and increased mortality³⁸, particularly when there are preexisting physical illnesses such as tuberculosis.

Combined respiratory disturbance and renal failure is the most severe type of complications in NMS³⁹. Acute renal failure was the cause of death as demonstrated in one case of this study.

Conclusion

Neuroleptic malignant syndrome is the most serious and potentially fatal complication of drugs acting on central dopaminergic receptors. Clinicians should always be aware of its possible occurrence especially when patients are agitated, dehydrated, exhausted or have any preexisting physical illnesses. Whenever the patient develops fever, muscle rigidity, and alteration of consciousness, appropriate clinical and laboratory investigations should be done to facilitate early detection and prompt treatment. In cases of unexplained death that NMS is highly suspected, immunocytochemistry can be used to identify myoglobin in the kidney⁴⁰.

 References

1. Delay J, Deniker P. Drug-induced extrapyramidal syndromes. In : Vinken PJ, Bruyn GW, eds. Handbook of Clinical Neurology : Diseases of the Basal Ganglia. Amsterdam : North Holland Publishing Co., 1968:248-66.

2. Caroff SN, Mann SC. Neuroleptic Malignant Syndrome. Med Clin North Am 1993;77:185-202.

3. Bristow MF, Kohen D. Neuroleptic Malignant syndrome. Brit J Hosp Medicine 1996;55:517-20.

4. Hasan S, Buckley P. Novel antipsychotics and the neuroleptic malignant syndrome : a review and critique. Am J Psychiatry 1998;155:1113-6.

5. Gleason PP, Conigliaro RL. Neuroleptic malignant syndrome with risperidone. Pharmacotherapy 1997;17:617-21.

6. Wetli CV, Mash D, Karch SB. Cocaine-associated agitated delirium and the neuroleptic malignant syndrome. Am J Emerg Med 1996;14:425-8.

7. Demirkiran M, Jankovic J, Dean JM. Ecstasy intoxication : an overlap between serotonin syndrome and neuroleptic malignant syndrome. Clin Neuropharmacol 1996;19:157-64.

8. Keck PE, Pope HG, Cohen BM, McElroy SL, Nierenberg AA. Risk Factors for Neuroleptic Malignant Syndrome : A Case- Control Study. Arch Gen Psychiatry 1989; 46:914-8.

9. Sachdev P, Mason C, Hadzi-Pavlovic D. Case-control study of neuroleptic malignant syndrome. Am J Psychiatry 1997;154:1156-8.

10. Gurrera RJ. Diaphoresis and dehydration during neuroleptic malignant syndrome : preliminary findings. Psychiatry Res 1996;64:137-45.

11. Fitzgerald B, Middleton JK, Cooper SA. Adverse effects of summer amongst people with learning disabilities : neuroleptic malignant syndrome. J Intellect Disabil Res 1997;41:273-7.

12. Kuno S, Mizuta E, Yamasaki S. Neuroleptic malignant syndrome in parkinsonian patients : risk factors. Eur Neurol 1997;38:56-9.

13. Lazarus A. Neuroleptic Malignant Syndrome and Preexisting Brain Damage. J Neuropsychiatry Clin Neurosci 1992;4:185-7.

14. Elizalde-Sciavolino C, Racco A, Proscia-Lieto T, Kleiner M. Severe hyponatremia, neuroleptic malignant syndrome, rhabdomyolysis and acute renal failure : a case report. Mt Sinai J Med 1998;65:284-8.

15. Sechi G, Manca S, Deiana GA, Corda DG, Pisu A, Rosati G. Acute hyponatremia and neuroleptic malignant syndrome in Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry 1996;20:533-42.

16. Spivak B, Gonen N, Mester R, Averbuch E, Adlersberg S, Weizman A. Neuroleptic malignant syndrome associated with abrupt withdrawal of anticholinergic agents. Int Clin Psychopharmacol 1996;11:207-9.

17. Miyatake R, Iwahashi K, Matsushita M, Nakamura K, Suwaki H. No association between the neuroleptic malignant syndrome and mutations in the RYR1 gene associated malignant hyperthermia. J Neurol Sci 1996; 143:161-5.

18. Ueno S, Otani K, Kaneko S, Koshiro K, Kondoh K, Kotani Y et al. Cytochrome p-450 2D6 gene polymorphism is not associated with neuroleptic malignant syndrome. Biol Psychiatry 1996;40:72-4.

19. Kawanishi C, Hanihara T, Maruyama Y, Matsumura T, Onishi H, Inoue K et al. Neuroleptic malignant syndrome and hydroxylase gene mutations : no association with CYP 2D6A or CYP 2D6B. Psychiatr Genet 1997;7:127-9.

20. Kawanishi C, Hanihara T, Shimoda Y, Suzuki K, Sugiyama N, Onishi H et al. Lack of association between neuroleptic malignant syndrome and polymorphisms in the 5-HT1A and 5-HT2A receptor genes. Am J Psychiatry 1998;155:1275-7.

21. Bertorini TE. Myoglobinuria, malignant hyperthermia, neuroleptic malignant syndrome and serotonin syndrome. Neurol Clin 1997;15:649-71.

22. Gurrera RJ, Chang SS. Thermoregulatory dysfunction in neuroleptic malignant syndrome. Biol Psychiatry 1996;39: 207-12.

23. Gurrera RJ. Sympathoadrenal Hyperactivity and the Etiology of Neuroleptic Malignant Syndrome. Am J Psychiatry 1999; 156:169-80.

24. Fink M. Toxic serotonin syndrome or neuroleptic malignant syndrome? Pharmacopsychiatry 1996;29:159-61.

25. Lee JW, Robertson S. Clozapine withdrawal catatonia and neuroleptic malignant syndrome : a case report. Ann Clin Psychiatry 1997;9:165-9.

26. Fink M. Neuroleptic malignant syndrome and catatonia : one entity or two? Biol Psychiatry 1996;39:1-4.

27. Sewell DD, Jeste DV. Distinguishing Neuroleptic Malignant Syndrome (NMS) From NMS-Like Acute Medical Illnesses : A Study of 34 Cases. J Neuropsychiatry Clin Neurosci 1992;4:265-9.

28. Balzan MV. The neuroleptic malignant syndrome : a logical approach to the patient with temperature and rigidity. Postgrad Med J 1998;74:72-6.

29. Velamoor VR. Neuroleptic malignant syndrome. Recognition, prevention and management. Drug Saf 1998;4:265-9.

30. Thomas P, Maron M, Rascle C, Cottencin O, Vaiva G, Goudemand M. Carbamazepine in the treatment of neuroleptic malignant syndrome. Biol Psychiatry 1998;43: 303-5.

31. McKinney P, Kellner C. Multiple ECT late in the course of neuroleptic malignant syndrome. Convuls Ther 1997;13: 269-73.

32. Gaitini L, Fradis M, Vaida S, Krimerman S, Beny A. Plasmapheresis in neuroleptic malignant syndrome. Anaesthesia 1997;52:165-8.

33. Noto T, Hashimoto H, Sugae S, Okamoto K, Nakao J, Kamimura H, et el. Hypothermia Caused by Antipsychotic Drugs in a Schizophrenic Patient. J Clin Psychiatry 1987;48:77-78.

34. Hynes AF, Vickar EL. Case Study : neuroleptic malignant syndrome without pyrexia. J Am Acad Child Adolese Psychiatry 1996;35:959-62.

35. Wong MM. Neuroleptic malignant syndrome : two cases without muscle rigidity. Aust N Z J Psychiatry 1996;30:415-8.

36. Mann SC, Caroff SN, Bleier HR, Welz WKR, Kling MA, Hayashida M. Lethal Catatonia. Am J Psychiatry 1986;143:1374-81.

37. Wae-Alee D, Tanchaiswad W. Neuroleptic malignant syndrome : A review of 12 cases. Journal of The Psychiatric Association of Thailand 1996; 41:99-109.

38. Dykstra TJ, Menolasino MJ 3^rd. Neuroleptic malignant syndrome : case report and review. J Am Osteopath Assoc 1997;97: 355-7.

39. Taniguchi N, Tanii H, Nishikawa T, Miyamae Y, Shinozaki K, Inoue Y, et al. Classificaiton system of complications in neuroleptic malignant syndrome. Methods Find Exp Clin Pharmacol 1997;19:193-9.

40. Lowe JW. The obscure autopsy and neuroleptic malignant syndrome. Medicine, Science & the Law 1997;37:79-81.

 Table 1 Number of NMS patients during 5 years

 Table 2 Age, sex and psychiatric diagnoses of NMS patients

 Table 3 Clinical findings in NMS patients

+ = present, - = absent

 Table 4 Laboratory findings in NMS patients

Table 5 Psychiatric treatments before the onset of NMS

 Table 6 Predisposing factors for NMS

+ = present, - = absent

 Table 7 Treatment and clinical course of NMS