Acute Laryngeal Dystonic Reactions to Neuroleptics

Review Article Acute Laryngeal Dystonic Reactions to Neuroleptics J.

M.D. EDMOND H. PI. M.D.

RALPH

KOEK,

Two cases ofacute laryngeal dystonia (laryngospasm), a rarely reported extrapyramidal reaction to neuroleptics, occurred in a public psychiatric hospital. A review ofthe literature revealed only seven well-documented case reports. This article discusses the clinical significance ofthis rare, alarming, and probably underreported phenomenon. Factors related to recognition, prediction, and management are also discussed. The review strongly advocates immediate intravenous administration ofanticholinergic drugs to relieve dystonia.

ince chlorpromazine was introduced into psychiatry in 1952, its extrapyramidal side effects and those of related drugs have been extensively studied. I- 3 Other authors have mentioned acute dystonias involving the laryngeal and pharyngeal musculature that have caused respiratory embarrassment.4 Some have speculated that such dystonias may be responsible for unexpected and otherwise unexplainable deaths associated with neuroleptic treatment.4-7 Laryngeal dystonia appears to be recognized well enough to be included in standard medical texts. 8•9 However, our literature review failed to produce a systematic discussion of the disorder. Many questions remain about the incidence, risk factors, and lethality of acute laryngeal dystonia. 7

S

This paper reviews seven cases of laryngo-

spasm in the literature and two cases recently seen in our hospital. Our goal is to familiarize clinicians with relevant clinical factors in this potentially life-threatening syndrome.

Two New Cases Case I. Mr. A. was a 29-year-old, 200-pound Caucasian with a 12-year history of bipolar disorder. He VOLUME 30· NUMBER 4· FALL 1989

had been treated with lithium and various neuroleptics. He also had a history of polysubstance abuse and a diagnosis of mixed personality disorder. He was agitated and delusional at admission and received 2 mg of lorazepam orally, followed by 100 mg of chlorpromazine orally two hours later. The next morning, he received 100 mg of chlorpromazine orally, followed by two 50-mg doses intramuscularly to control agitation. At noon on the second day, he was given 100 mg of chlorpromazine orally. At4 P.M. severe extrapyramidal side effects were reported. At evaluation, he was found to have both torticollis and laryngeal stridor; he was given 37.5 mg diphenhydramine i. v.• resulting in immediate resolution of the stridor and the other dystonic symptoms. At 8 P.M. on the second day, the patient was again reported to be in distress. Upon evaluation, he was observed to be clutching his throat with both

hands in obvious respiratory distress. His tongue was stiffly extended. his jaw was contorted to one

Received June 8. 1988; revised September 19. 1988; accepted November 8. 1988. From the Department of Psychiatry. Los Angeles CountylUniversity of Southern California Medical Center. Los Angeles. California. Address reprint requests to Dr. Pi. Department of Psychiatry. USC School of Medicine, 1934 Hospital Place. Los Angeles. CA 90033. Copyright © 1989 The Academy of Psychosomatic Medicine.

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Laryngeal Dystonic Reactions to Neuroleptics

side. and his neck was twisted. These symptoms resolved with diphenhydramine administered intravenously; a total of 62.5 mg was required. Benztropine mesylate (2 mg im) initially failed to relieve the symptoms. Neuroleptics were discontinued. and the patient was given diphenhydramine 50 mg po tid for

three more days. No further extrapyramidal symptoms occurred. Subsequent history revealed possible laryngospasm in response to haloperidol in the past and other evidence of heightened sensitivity to neuroleptics. including severe akathetic reactions and lithium-haloperidol combined neurotoxicity. He had

TABLE 1. Well-documented cases of acute laryngeal dystonia due to neuroleptics from 1952 to the present Neuroleptk (dose)

Treatment and Outcome

Reference (year)

Age

Sex

Diagnosis

20

M

pneumonia

prochlorperazine (70 mg im over preceding three days)

atropine I mg iv: no effect procarbezine 5 mg po: no effect phenobarbital 60 mg im: no effect amobarbital 750 mg iv: relief

2

21

F

uremia

prochlorperazine (90 mg im over preceding five days)

calcium gluconate 1000 mg iv: no effect Waugh and phenytoin 120 mg iv: no effect Metts. 1960 13 phenobarbital 120 mg iv: no effect diphenhydramine 25 mg iv: relief with recurrence

3

28

M

acute psychosis

haloperidol (10 mg/day for 3 days then 20 mg/day for 3 days over preceding six days)

diphenhydramine 50 mg iv: relief

Aahertyand Lahmeyer. 1978 10

4

39

M

schizophrenia

haloperidol diphenhydramine 50 mg iv: relief (10 mglday for six days then 20 mg/day for I day over preceding seven days)

Aahertyand Lahmeyer. 10 1978

5

21

M

alcohol abuse with aggressive outbursts

haloperidol (IOmgimtwo days then 5 mg im I day prior)

Menuck. 1981 12

6

44

F

schizophrenia

haloperidol resuscitation: death (60mgimand 60 mg po two days then 110 mg po one day prior)

7

19

M

bipolar disorder. thiothixine 4 mg (route and manic phase frequency unknown; started five days prior)

benztropine I mg im: no effect diphenhydramine 50 mg iv: relief

Ravietal.. 1982 11

29 8 (two episodes)

M

bipolar disorder. chlorpromazine manic phase (350 mg po and 50mgimover 24 hours prior)

diphenhydramine 37.5 mg iv: relief (I st episode) benztropine 2 mg im: no change diphenhydramine 62.5 mg iv: relief (2nd episode)

Mr.A. (our patient)

9 25 (two episodes)

M

schizoaffective disorder

diphenhydramine 50 mg iv: relief Mr.B. ( Ist episode) (our patient) benztropine 2 mg im: worse after 5 min. diphenhydramine 50 mg iv: relief (2nd episode)

Case

360

haloperidol (20 mg im over 7 hours prior to first episode)

benztropine 2 mg iv: relief after 6 to 7 minutes with 2 doses

Christian and Paulson. 1958 14

Modestin et aI.• 1981 S

PSYCHOSOMATICS

KoekandPi

not been taking any medications for several weeks prior to admission. Case 2. Mr. B. was a 25-year-old black male with a three-year history of multiple psychiatric hospitalizations and treatment with lithium and various neuroleptics for schizoaffective disorder. He was agitated when he was admitted with auditory hallucinations and delusions of control. He was admitted to the psychiatric emergency room, where he was given two lO-mg doses of haloperidol intramuscularly. Five hours after the second dose, he had a severe dystonic reaction with torticollis and mild breathing difficulties. The symptoms were relieved by 50 mg diphenhydramine given intravenously. He was given no further neuroleptics. Twelve hours after the first episode, he was found to be diaphoretic and in opisthotonous, retrocollis, and oculogyric crisis. He was unable to speak and evidenced laryngeal stridor. He was given 2 mg benztropine mesylate intramuscularly, which produced no relief. After a few minutes, the laryngeal stridor worsened. He was then given 50 mg diphenhydramine intravenously; this resulted in rapid reduction of muscle tone and elimination of stridor. There was no recurrence of extrapyramidal symptoms. Prior to admission, Mr. B. had been on lithium carbonate, 300 mg bid to tid, perphenazine 20 mg po bid, and benztropine mesylate I mg po bid. There was a history of polysubstance abuse. DISCUSSION In reviewing the seven well-documented cases in the English-language literatureS,Io-I4 and the two cases described here, a number of important clinical features of patients who have developed the symptoms of laryngeal or pharyngeal dystonia emerge. The cases from the literature and our additional cases are summarized in Table 1. Clinical Characteristics and Differential Diagnosis Characteristic symptoms in patients during episodes of acute laryngeal dystonia include dyspnea and indications of extreme subjective distress, such as clutching the throat. Dystonias involving muscles of the head and neck are also seen. In the cases we describe, associated dystonias included torticollis, retrocollis, tongue and VOLUME 30· NUMBER 4· FALL 1989

jaw stiffness, oculogyric crisis, and opisthotonus. Associated acute dystonic symptoms were lacking in only two cases from the literature. 10,1 I One of these patients was described as anxious and tremulous on the day preceding and just prior to the onset of the respiratory distress II; the other patient was found lying in bed making agonized gestures and pointing to his throat. 10 Because parenteral administration of anticholinergic drugs provided prompt relief of the symptoms, mechanical obstruction of the airway due to aspiration of food or intrinsic structural airway defects is unlikely to have caused stridor. Another consideration in neuroleptic-treated patients with abnormal muscle rigidity is neuroleptic malignant syndrome (NMS). However, the lack of fever, vital-sign abnormalities, or an altered level of consciousness combined with the rapid relief of symptoms seen after anticholinergic administration allow NMS to be distinguished from laryngeal dystonia relatively easily. Because of our patients' substance abuse histories, we also considered the possibility that they were malingering to obtain anticholinergic drugs lS or to avoid neuroleptic treatment. However, the characteristic nature of the presenting symptoms and their relief following administration of diphenhydramine made this explanation ofthe patients' symptoms seem less likely. Risk Factors In general, young males show an increased incidence of acute dystonias when treated with high potency agents or during the first several days following initiation of neuroleptic treatment. I ,2.8.16.17 The data from the cases in Table 1 are consistent with this observation: six of the nine cases occurred in males under 30 and one occurred in a 21-year-old female, five of the nine cases involved haloperidol, and all occurred within eight days of starting treatment. Of note in our series is that the three most commonly used classes of neuroleptics-phenothiazines, butyrophenones, and thioxanthenes-are represented. Also, in two cases from the literature review l3 •14 and in one of our patients (Mr. A.), only lOW-potency phenothiazines had been used. Haloperidol 361

Laryngeal Dystonic Reactions to Neuroleptics

was the neuroleptic used in the largest numbers of cases (five of nine patients). None of the patients were receiving more than one neuroleptic at the time they experienced laryngeal dystonia. Allergic reactions, panic attacks with hyperventilation, and tardive dyskinesia with respiratory musculature involvement must also be considered in the differential diagnosis. High doses and parenteral administration of neuroleptics have also been associated with an increased incidence of acute dystonias. 2.18 However, only the patient in Case 5 in Table I received what could be considered an extremely high dose of neuroleptic; most of the patients had been given what would be regarded as low or moderate doses by most practitioners. Thus, the possibility of idiosyncratic hypersensitivity to the extrapyramidal side effects of neuroleptics must be considered when assessing the risk of laryngeal dystonia. A history of hypersensitivity to neurolepticinduced neurologic side effects may be a risk factor for future development ofacute dystonia,2.8 and such a history should be sought. Seven patients had such a history. In two cases in the Iiterature lO and one of our patients (Mr. 8.), laryngeal dystonia occurred in the early morning hours, as blood neuroleptic levels presumably were falling. An association between falling blood neuroleptic levels and acute dystonic reactions has been noted. 8.10 Our data were insufficient for drawing conclusions about diagnostic variables as risk factors for development of laryngeal dystonic reactions. Patients with both affective disorders and schizophrenic disorders were represented in our series. Other conditions reported to predispose patients to development of such reactions include hyperthyroidism,6 hypocalcemia,8 hypoparathyroidism,9 a family history of idiopathic Parkinson's disease,2 or a family history of drug-induced dystonia or dystonia musculorum deformans. 16 None of these conditions were known to be present in the patients in our series. However, four patients had a medical problem that theoretically could have predisposed them to neurologic dysfunction: Rh-isoimmunization reaction at birth (Mr. A.); uremia l3 and pneumonia '4 in two patients 362

given prochlorperazine for relief of nausea and vomiting; and a possible alcohol-related organic mental disorder in one patient. 12 Management Our case review demonstrates that as with other acute dystonic reactions,2.8·19 parenteral administration of agents with central anticholinergic activity, such as benztropine mesylate or diphenhydramine HCI, rapidly provides relief of muscle spasm. With laryngeal dystonias, this may be life saving, as other authors have noted. 4.10.13 One case of death due to laryngeal dystonia has been documented. S That patient received no anticholinergic agent. In the case reported by Ravi et a1. 11 and in both of our patients, intramuscular benztropine mesylate was not immediately effective; in one case,I2 two injections of benztropine (2 mg, iv) were required. These findings strongly suggest that immediate, intravenous administration of diphenhydramine in doses ranging from 25 mg to 62.5 mg is an effective treatment for neuroleptic-induced acute laryngeal or pharyngeal dystonia. With a larger number of cases, it may become evident that benztropine and other antiparkinsonism drugs are as effective as intravenous diphenhydramine, but in our review, intramuscular benztropine was not effective. Relationship to Sudden Death As noted above, laryngeal dystonia tends to occur suddenly and unexpectedly and is potentially fatal. Thus, it is important to investigate the relationship between it and sudden, unexpected, otherwise unexplainable death in psychiatric patients. Since the introduction of antipsychotics, numerous investigations into their relationship to sudden death have been conducted,'9-22 and various causative mechanisms have been proposed. 20.22.23 In these reports, laryngeal dystonia is not mentioned as a possible cause of sudden death, although other writers4.10. 13 speculated that it could be. In a recent review, Davis and Zhang24 pointed out that definitive data proving that laryngeal dystonia accounts for cases of neurolepPSYCHOSOMATICS

Koek and Pi

tic-associated asphyxia and sudden death are lacking. Iflaryngeal dystonia related to neuroleptic drug use is a cause of sudden death, it must be a rare occurrence: only one well-documented case has been reported. s Furthermore, unexpected, otherwise unexplainable, autopsy-negative sudden death is probably not found with greater frequency in psychiatric patients than in the general population,24,25 nor has a definite increase in the incidence of such deaths been seen in the time since neuroleptic introduction than in the preneuroleptic era. 23.26.27 The number of deaths due to laryngeal dystonia must therefore be quite small. The incidence, however is clearly not zero, as case 6 demonstrates. S

•

•

•

CONCLUSION Acute laryngeal dystonia is a potentially lethal side effect of one of the most commonly prescribed drug classes in psychiatry. It is probably underreported and has not been thoroughly studied, and its relationship to sudden death in psychiatric patients requires further study. Our review supports including laryngeal dystonia among other acute dystonic extrapyramidal side effects ofneuroleptics and suggests some caveats with respect to neuroleptic use: • Physicians should closely monitor patients

•

during the initial days of therapy and remain alert to the possibility of laryngeal dystonia. Physicians should be familiar with the characteristic presentation of laryngeal dystonia: sudden onset of respiratory distress in a patient on neuroleptics, usually in the presence of other dystonias. Physicians should be familiar with and have materials available to treat laryngeal dystonia, notably via immediate iv administration of diphenhydramine or possibly another agent with central anticholinergic activity. Physicians should exercise caution and make judicious use of neuroleptics in nonpsychiatric patients and should consider alternatives to neuroleptic administration, such as lorazepam for sedation. Physicians should consider prophylactic administration of anticholinergic agents during the initial days of neuroleptic therapy in some patients, such as young males and those with known hypersensitivity to extrapyramidal side effects.

The authors thank Tran Cuc-Tranfor valuable assistance in preparation ofthe manuscript and Greg Gray, M.D., and Charles Patterson, M.D.,for helpful comments.

References I. Simpson OM. Pi EH, Sramek 11: Neuroleptics and antipsychotic drugs. in Dukes MNO (ed): Meyler's Side Effeets of Drugs. JJth Ed. Amsterdam. Netherlands. Excerpta Medica Teniary Publications, 1988. pp 105-119 2. Senle EC Jr. Ayd FJ Jr: Haloperidol: a quarter-century of experience. J Clin Psychiatry 44:440-448, 1983 3. Rifkin A: Extrapyramidal side effects: a historical perspective. J Clin Psychiatry 48(suppI9):3-6. 1987 4. Mann SC. Cohen MP. Boger WP: The dangeroflaryngeal dystonia. Am J Psychiatry 136: 1344-1345. 1979 5. Modestin J, KrapfR, Boker W: A fatality during haloperidol treatment: mechanism of sudden death. Am J Psychiatry 138:1616-1617.1981 6. Weiner MF: Haloperidol. hypenhyroidism. and sudden death. AmJ Psychiatry 136:717-718. 1979 7. Aaheny JA. Lahmeyer H: Reply to a lener to the editor. AmJ Psychiatry 136:1345. 1979 8. Baldessarini RJ: Chemotherapy in Psychiatry. Principles

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and Practice. Cambridge. Mass. Harvard University Press, 1985 9. Davis 1M: Antipsychotic drugs. in Kaplan HI. Sadock BJ (eds): Comprehensive Textbook of Psychiatry. 4th Ed. Baltimore. Williams & Wilkins. 1985. pp 1507-1508 10. Flaheny JA. Lahmeyer HW: Laryngeal-pharyngeal dystonia as a possible cause of asphyxia with haloperidol treatment. AmJ Psychiatry 135:1414-1415.1978 11. Ravi SO. Borge OF. Roach Fl.: Neuroleptics, laryngealpharyngeal dystonia. and acute renal failure. J Clin Psychiatry43:300.1982 12. Menuck M: Laryngeal-pharyngeal dystonia and haloperidol. Am J Psychiatry 138:394-395. 1981 13. Waugh WH. Mens JC Jr: Severe extrapyramidal motor activity induced by prochlorperazine: its relief by the intravenous injection of diphenhydramine. N Engl J Med 262:353-354.1960 14. Christian CD. Paulson 0: Severe motility disturbance

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after small doses of prochlorperazine. N Engl J Med 259:828-830.1958 15. MacVicar K: Abuse of antiparkinsonian drugs by psychiatric patienls. Am J Psychiatry 134:809-811. 1977 16. Rupniak NMJ. Jenner P. Marsden C: Acute dystonia induced by neuroleptic drugs. Psychopharmacology!BerIinJ88:403-419.1986 17. Keepers JA. Casey DE: Clinical managemenl of aCUle neuroleptic-induced extrapyramidal syndromes. Current Psychiatric Therapies 23: 139-157. 1986 18. Donlan PT: High dosage neuroleptic Iherapy: a review. Int Pharmacopsychiatry 11:235-245. 1976 19. Reinen RE. Hennan CG: Unexplained dealhs during chlorpromazine therapy. J Nerl' Ment Dis 131:435-442. 1960 20. Leestma JE. Koenig KL: Sudden death and phenOlhiazines: a currenl controversy. Arch Gen Psychiatry 18:137-148.1968 21. Leber P: Sudden death as a risk of neuroleptic treatment a cOnlinuing controversy. Psychopharmacol Bull 17:6-9.

1981 22. Moore MT. Book MH: Sudden death in phenothiazine therapy: a clinicopathologic study of 12 cases. Psychiatr Q 44:389-402. 1970 23. Richardson HL. Graupner KI. Richardson ME: Intramyocardial lesions in patienls dying suddenly and unexpectedly. JAMA 195:254-260. 1966 24. Davis JM. Zhang MY: Sudden dealh in psychiatric patienls. Psychiatric Annals 18:311-319. 1988 25. Ungrari G: Neuroleptic-related sudden death: proven or a mere hypothesis. Pharmacopsychiatry 13:29-33. 1980 26. Brill M. Patton RE: Clinical statistical analysis of population changes in New York State menial hospitals since the introduction of psychotropic drugs. Am J Psychiatry 119:20--35.1962 27. Craig TJ. Lin SP: Monality among psychiatric inpatienls. Age-adjusted comparison of populations before and after psychotropic drug era. Arch Gen Psychiatry 38:935-938. 1981

COlDingUp in the Winter 1990 Issue Competency Evaluations in a General Hospital By Michael G. Farnsworth, M. D. Consultation-Liaison in Child Psychiatry and the Evolution of Pediatric Psychiatry By Gregory K. Fritz, M. D.

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