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Jefferson Journal of Psychiatry Jefferson Journal of Psychiatry
Volume 4 Issue 1 Article 10
January 1986
Diagnosis in the Neuroleptic Malignant Syndrome Diagnosis in the Neuroleptic Malignant Syndrome
James H. Dallman, MD, CPT, MC Letterman Army Medical Center, San Francisco California
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Recommended Citation Recommended Citation Dallman, MD, CPT, MC, James H. (1986) "Diagnosis in the Neuroleptic Malignant Syndrome," Jefferson Journal of Psychiatry: Vol. 4 : Iss. 1 , Article 10. DOI: https://doi.org/10.29046/JJP.004.1.011 Available at: https://jdc.jefferson.edu/jeffjpsychiatry/vol4/iss1/10
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Brief Clinical Reports
Diagnosis in the NeurolepticMalignant Syndrome
James H. Dallman, M.D. , C.P.T., M.C.
INTRODUCTION
Neuroleptic ma lignant syndrome (NMS) is an uncommon, potentiall y le thalcomplication of treatment with antipsychotic medication. First described inAmerica n journals by De lay and Deniker in 1968 (1), this syndrome has beenreported for many years in th e European and Japanese literature.
Neuroleptic malignant syndrome is characterized by fever, altered men talstatus, autonomic dysfunction, and generalized skeletal muscle ri gidity. Itsappearance usually fo llows use of high potency neuroleptics in th erapeu ticdoses . In the American literature, most reported cases have re sulted fr om use ofhaloperidol, fluphenazine, thiothixene or piperazine deri vatives (2,3). Longacting depot fluphenazine has been particularly implicated (4,5). One reportedcase has been attributed to thioridazine therapy (6), and another to tetrab enazine and alphamethyltyrosine therapy (3).
Features of NMS are also described following use o f neuroleptics inconj unct ion with lithium salts and tricyclic antidepressants, and in sedat ivewithdrawal syndromes (7,8). While persons of all ages may be affect ed , nearly75 % are under age 40 , male-to-female ratio being 2: 1 (5).
CASE REPORT
A 22-year-old housewife in her eighth month of pregnancy developedemotional labi lity which continued until the uneventful delivery of a healthybaby boy at te rm. Following discharge from the hospital , th e patient did wellunti l three wee ks post-partum, when her husband noted that she was exhibiti ngstrange behavior. She wou ld cry unexplainably and 'speak repeatedly o nreligious themes. O n several occasions, she made telephone calls to her friendsstating that their parents had died. Her speech became increasingly incoherentand fragmented, with perseveration of ideas. She began to neglect he r housework and personal hygiene, appearing self-absorbed. The patient was referredfor psychiatric evaluation and admitted to a local hospital.
Dr. Dallman wrote this paper while a fourth-year resident at Letterman Army Medical Center,San Francisco, California.
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54 JEFFERSON JOUR N A L OF PSYCHIATRY
Shortly after admiss io n, th e pati ent demonst rated restlessness and psych omotor agitation warrant ing an intramuscul ar injection of ha loperidol, 2.5 mg.Foll owing ad ministr atio n of the medication , she exh ib ited robot-like movements , muscular rigidity, and oculogyri c cr isis. Also noted were hypo kinesia ,psychomotor retardation , drowsin ess, and tongue protrusion . T reatment withhaloperidol, 2 mg daily, was continued. On th e eigh th hosp ita l day, th e patientbecame unresponsive and incont inent of urine and feces. By hosp ital da y ten , sherequired co ntinuous nursing ca re. Intravenous fluids were administered andhaloperidol was discontinued. Within two days, the pat ien t became moreresponsive and was able to reco gnize her spouse .
Twel ve days after ad m issio n to her loca l hosp ital , the patient was transfe rred to our faci lity. Ph ysical exami na tion noted an indwelling urinary catheter, large bli sters o n both heels, a protruding tongue with hypersali vat io n , andathetoid movements of the upper ex tremit ies . T he fo llowi ng day, the patientshowed increasing agitation, and thiothixen e , 40 mg ora lly, was given . Within24 hours, she was noted to be diaphoreti c and tach ycard ic. A ll neurolepticmedications were di scontinu ed , and in th e ensu ing fo ur days she improved . O nth e ninth hospital day, because of her inc reasing para noia and accompanyingagita tio n, the pati ent was given a dose of haloperidol , 10 mg in tramuscularly.Within 24 hours, she developed extreme muscular rigidi ty, di aphoresis, tach ycard ia, and hypersali vation. Her mental sta tus became increasingly stuporousand the foll owing day she developed hyperthe rmia (38 .6°C, 10 1.5°F), wh ichlasted for approx ima tely two days. A slow recove ry fo llowed with the di scont inuation of a ll neuroleptic medication . She was di sch arged after 16 days in thehospital with no persistent sid e-effects.
CLIN IC AL CHARACTERISTICS
Classica lly, N MS is ch aract erized by th e tr iad of muscul ar r igidity, hyperth ermia , and altered co nsciousness (9). Recent descriptions a lso include autonomic dysfuncti on (2 ,10) . Symptoms usuall y begin soon afte r starting or increasing the dosage of ne uroleptics . O nset of the syndrome may occur within hours,or ma y be de layed fo r severa l months fo llowi ng in itial drug exposure. So meNMS patien ts have reported p revious asymptomatic ex posure to neuroleptics: inother cases neuroleptics ha ve been resta rted without recurren ce of NMS afterth e ac ute syndrome is resol ved (2).
It is not clear why suc h var iations ex ist. Perhaps neuroleptics may benecessary but are no t in th emsel ves suffic ient to induce the syndrome. Itoh (10)noted th at physical ex ha ust ion associate d with dehydration was an underlyingco nd it ion of NMS in all 14 pati ents studied, suggesting th at dehydrat ed anddebilitated sta tes may at least predispose or contr ibute to onset of NMS. In ourpatient , th e post-partum sta te was present.
Among th e earliest sig ns of MS are extrapyramidal rigidity and in voluntary movements, some times accompanied by dysa r th r ia and d ysphagia . H yper-
BRIEF CLINICAL REPORTS 55
thermia, appearing after the extrapyramidal signs, may reach 41 0 C (10 5 0 F), ormay be only moderately elevated (2). Consciousness is altered and can appear asa dazed mutism (similar to catatonia) with subsequent progression to stupor,coma, and death (2).
Autonomic dysfunction includes pallor, diaphoresis, sialorrhea , blood pressure instability, tachycardia, pulmonary congestion, and tachypnea . In somecases, tachypneic hypoventilation from decreased chest wall compliance necessitates respiratory support. Dehydration is common and ma y progress to acuterenal failure in the absence of myoglobinuria. Less frequent signs are ocul ogyriccrisis , opisthotonus, seizures, chorea, Babinski signs, and trismus.
Symptoms usually resolve within five to ten days after stoppi ng oralneuroleptics but last for several weeks after long-acting depot inj ection s. In 16%to 30 % of cases fatalities have occurred from acute renal failure , respi rat o ryfailure, or cardiovascular collapse (2). Death has been more common amongthose who receive depot fluphenazine, probably because of its prolongedhalf-life. Postmortem examinations of the central nervous system have revea ledno consistent abnormalities.
Laboratory findings frequently are normal. Transient elevati on of serumaldolase or creatinine phosphokinase (CPK) has been repeatedly observed .Laboratory concomitants of dehydration can be seen , and liver paren ch ymalenzyme elevations have been noted. Leukocytosis with a polymorphonuclear cellpredominance is com mon without other evidence of infecti on . T he sedimentation rate ma y be e levated . Cerebrospinal fluid is normal , as is th e co mputerizedtomography scan . The electroencephalogram ma y be normal or nonspecifica llyslow, suggesting diffuse metabolic encephalopathy.
DIFFERENTIAL DIAGNOSIS
Hyperthermia and altered mental status are card ina l signs of C NS infections, therefore, NMS is most often mistaken for an infection. Bact erial, fungaland parasitic infections, viral or syphilitic encephalitis, and even tetanus must beruled out in the differential diagnosis . Occasionally, trauma or neoplasms canproduce akinetic mutism and hyperthermia of a central o r igin which a lsoresembles NMS.
Drug allergy should be considered. One must look for eos inoph ilia andcutaneous abnormalities suc h as erythema or rash. H ypertonicity in NMS issimilar to extrapyramidal rigidity and must be differentiated from basal gangliadiseases such as severe Parkinson 's di sease. Other disorders of muscle hypertonicity such as decerebrate and decorticate rigidity, tetany, and spasticit y must beruled out.
Catatonia ma y resemble NMS. The classic signs of ca ta to n ia, inclu d ingca ta lepsy and wax y flexibility, negativism, mutism , muscular r igidity, andbizarre mannerisms can be present in MS (11). Catatonia is a no nspecificdescriptive syndrome which can result from metabolic, infectious, psychi at r ic,
56 JEFFERSO JOURN AL O F PSYCHIATRY
or structural brain disorders. In " le tha l catatonia," sus ta ined agi tation progresses to withdrawal, stupor (12,13), hypotension , hyperthermia , and death indays to weeks.
If the patient has been exposed to a hot environment, heat st roke should beconsidered, especially if anticholinergic drugs have been give n as they caninhibit sweat ing . In heat stroke, as in NMS, hyperpyrexia and a depressed levelof consciousness occur, but extrapyramidal signs prior to temperature e levationare lacking.
Finally, malignant hyperthermia (MH) must be co nsidered in that hyperthermia, rigidity, and CPK elevation occur in both syndromes, and they mayhave a co mmo n pathophysiology (2 , 12, 14) . In about one-third of the cases ofMH, predisposition is transmitted as an autosomal dominant trait; familial MShas not been reported. Serum CPK, which is markedly elevat ed duri ng MH, mayalso be increased in patients between attacks or among asymptomatic familymembers. Most patients with NMS have normal serum CPK before and aftereach episode. Mortality from MH approaches 70 %, whereas among cases ofNMS it is less than 30 %.
PATHOGENESIS
T he exact pathogenesis of NMS remains unclear. A popular hypothesissuggests a peripheral mechanism, mainly because of th e clinical similaritiesbetween NMS and anesthetic-induced malignant hyperthermia (15). Studieshave indicated that MH may result from excessive release of ca lcium intoske le tal muscle cytoplasm due to altered membrane transport of ca lcium in thepresence of cer ta in drugs (15) . Excess intracellular ca lcium co uld cause therigidity and the subsequent hyperpyr exia seen in both MH and N MS.
Some autho rs (2, 12 ,16) ha ve postulated th at th e disturbance of N MS is primarily ce ntra l, suggesting that dopamine receptor blockade o r dopamine depletion in th e ba sal ganglia , hypothalamus, o r brain stem is th e mai n pathophysiologi c mechanism. Impaired th ermoregulation by neuroleptic d r ugs which blockdopamine receptors, is seen both clinicall y and ex per imenta lly. Dopamine andrelated neurotransmitters are fo u nd in th e hypothalamus, and dopam ine receptors of th e 0-1 class, whi ch mediate th ermoregulation , a re locat ed in thepreoptic anterior hypothalamus. The mesolimbic dopaminergic path ways mayalso playa role in th ermoregulation .
H yperpyrexia can result from elevat ion of the hypothalamic "set-point,"impaired heat di ssipation mechanisms, or excess heat product ion . Becausepatients with NMS swea t profusely, some peripheral routes of heat dissipationare intact. However, vasoconstr ictio n is seen in neuroleptic-treated animalsmade hyperthermic, and pallor in N MS patients sug ges ts that th ere is peripheralvasocons tr ictio n which prevents heat transfer fr om th e body core to theenvironment. A considerable amount o f heat is generated by th e profoundrigidity and tremors seen in NMS. These extrapyramidal signs precede , andprobably co ntr ib ute to, the hyperpyrexia.
BRIEF CLINICAL REPORTS
TREATMENT
57
To achieve results in treating NMS, symptoms must be recognized early andall psychotropic medications must be promptly withdrawn. Until recently,medical treatment of NMS was limited to symp toma tic th erapy with intensivesupportive medica l care, with particular attention to maintenance of res p iratory, renal , and cardiovascular systems. Vigorous treatment of hyperthe r mia aswe ll as maintaining fluid and electrolyte balance has also been important.
Recent reports describe successful pharmacologic treatment of NMS usin gdantrolene sodium (17,18,19) . Dantrolene, a direct-acting skeleta l m uscle relaxant with unclear central effects , has been shown to be efficac io us in trea tin gma lignant hyperthermia in animals and humans. In muscles, it di ssociatesexcitation-contraction coupling by inhibiting the release of ca lcium ions fr omthe sarcoplasmic reticulum (SR) through actions on th e tran sverse tubularmembrane-S R coupling, on SR directly, or both (20). Dosages of 50 mg orallytaken two to four times daily have resulted in rapid clinical improvement andshortened the duration of NMS from the usual five to ten days to less th an threedays. Further use of this agent in NMS patients is warranted to dete rmine itsefficacy, optimal dosage, and route of administration. Other pharmacologictherapies have been aimed at directl y altering the CNS dopaminergic/ ch oline rgic ratio through administration of anti-Parkinsonian age nts. McCarron et a l.(21) and Amdurski et al. (22) recently reported success fu lly treating NMS withamantadine. Bromocrip tine has also been tried (23).
SUMMARY
Neuroleptic ma lignant syndrome is a rare but underreco gnized co mplicat ion of neuroleptic therapy characterized by generalized ske leta l muscle r igidi ty,hyperthermia, autonomic dysfunction , and a ltered consciousness. Recogn itionof NMS and immediate withdrawal of neuroleptics usually leads to co mpleterecovery. Fail ure to recognize this synd rome can increase th e risk of morbidityand ma y lead to death in a significant percentage of patients. T he pathogenesisof NMS remains unknown, but both peripheral and central mech anisms ha vebeen proposed. Based on these hypotheses, there have been reports of successfultreatment using dantrolene sodium, a peripheral muscle relaxant and ce ntra llyact ing agents such as amantad ine. Further stud ies are needed to elucidate thecause and optimal treatment of this syndrome.
REFERENCES
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2. Caroff SN: The neurolepti c malignant syndrome.] Clin Psych 41 :79- 83, 19803. Burke R. Fahn S. Mayeux R, et al: Neuroleptic malignant syndrome caused by
58 JEFFERSON JOURNAL OF PSYCHI AT RY
dopamine-depleting drugs in a patient with Huntingdon disease . Neu rology 3 1:10221026, 1981
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