Gen. Pharmac. Vol. 21, No. 4, pp. 367-386, 1990 Printed in Great Britain.All rights reserved

0306-3623/90$3.00+ 0.00 Copyright © 1990PergamonPress pie

REVIEW PATHOGENESIS AND TREATMENT OF NEUROLEPTIC MALIGNANT SYNDROME M. EBADI,* R. F. PFEIFFER and L. C. MURRIN Departments of Pharmacology and Neurology, University of Nebraska College of Medicine,42nd St. and Dewey Ave., Omaha, NE 68105, U.S.A. [Tel. (402)559-5140; Fax (402)559-7495] (Received 29 August 1989) Abstract--I. Neuroleptic drugs (antipsychotics) produce numerous side effects which include serious extrapyramidal symptoms consisting of akathisia, dystonia, neuroleptic malignant syndrome, parkinsonian reactions such as postural abnormality, tremor, akinesia or bradykinesia, rigidity, and tardive dyskinesia. 2. Among the complications of neuroleptic chemotherapy, the most serious and potentially fatal complication is malignant syndrome, which is characterized by extreme hyperthermia, "'lead pipe" skeletal muscle rigidity causing dyspnea, dysphagia, and rhabdomyloysis, autonomic instability, fluctuating consciousness, leukocytosis, and elevated creatine phosphokinase, 3. Neuroleptic malignant syndrome should be differentiated from malignant hyperthermia, lethal catatonia, and other pathological states producing some of these same symptoms. 4. In addition to neuroleptics, malignant syndrome has been caused by thymoleptics (antidepressants), metoclopramide (antiemetic), metoclopramide combined with cimetidine, tetrabenazine, overdosage of benzodiazepine, phenelzine, dothiepin and alcohol, and amphetamine. 5. Factors leading to and/or facilitating the emergence of neuroleptic malignant syndromes are reportedly organic brain syndrome, dehydration, exhaustion, external heat load, excessive sympathetic discharge, use of long acting neuroleptics, high doses of neuroleptics, rapid dose titration with neuroleptics, abrupt discontinuation of antiparkinsonism agents, and concurrent lithium therapy. 6. Although, the pathogenesis of neuroleptic malignant syndrome is not understood completely, a blockade of dopaminergic receptors in the hypothalamus, spinal cord and striatum, an alteration of dopaminergic-serotonergic transmission in the body, an enhanced synthesis and action of prostaglandin E~ and E:, and a modification of calcium-mediated signal transduction in the body have been suggested. 7. The treatment of malignant syndrome includes immediate withdrawal of neuroleptic drugs, i.v. infusion of dantrolene, and oral administration of bromocriptine; or alternatively i.v. infusion of dantrolene and the combination of levodopa--carbidopa. 8. Other measures to enhance the therapeutic effectivenessof the aforementioned regimensare to include the use of anticholinergic drugs such as benztropine to enhance the effectiveness of bromocriptine, of lorazepam if catatonic symptoms persist, or of electroconvulsive therapy (ECT) if psychotic symptoms persist. 9. These treatments, however, must be "active" rather than "passive", in order to avert fatalities and/or unfortunate sequelae from this iatrogenic and incompletely understood disease.

A variety of neurological syndromes, involving particularly the extrapyramidal system, occur following acute or chronic administration of neuroleptic (antipsychotic) drugs. They include akathisia, dystonia, neuroleptic malignant syndrome, parkinsonism, and tardive dyskinesia. Akathisia is characterized by an inability to sit still, by shifting of legs and tapping of feet while sitting, and by rocking and shifting of weight while standing. This "motoric restlessness" is not caused by agitation or anxiety, occurs more frequently among female and elderly patients, is stopped volitionally, returns spontaneously when it is not controlled consciously, and is aggravated by physical inactivity. The reduction of total dosage of neuroleptic(s), and addition of an anticholinergic drug, a member of the benzodiazipine derivatives, or propanol have been shown to reduce *To whom correspondence should be addressed. ~p 2 1 4 - ^

367

the severity of akathisia. Restless legs syndrome (RLS), is characterized by a creeping or crawling sensation that most frequently affects the legs, and induces an irresistible urge to keep the limbs in motion. Periodic movements in sleep (PMS), also called nocturnal myoclonus, causes intense and repetitive muscle jerking during sleep. Treatment with 100--200 mg levodopa (Montplaisir et al., 1986), with levodopa plus benserazide, with bromocriptine, or with piribedil (Akpinar, 1987) have been reported to be beneficial in both movement disorders. Dystonia is characterized by an exaggerated posturing of head, neck or jaw; by spastic contraction of muscles of the lips, tongue, face or throat, making drinking, eating, swallowing and speech difficult; by torticollis, retrocollis, opisthotonos, and oculogyric crisis; and by laryngeal and pharyngeal spasm leading to respiratory distress and ultimately anoxia. Neuroleptic-induced dystonia which may occur in children

368

M. EBAD1et al.

treated acutely with phenothiazine derivatives for their antiemetic properties, disappears in sleep and is treated effectively with diphenhydramine hydrochloride (Benadryl) which possesses both anticholinergic and antihistaminic properties. Parkinsonism may be characterized by postural instability, stooped posture, shuffling and festinating gate, rigidity due to enhanced muscle tone with at times "cogwheel" or "ratchet" resistance to passive movements in any direction; tremor at rest with regular rhythmic oscillations of the extremities, especially the hands and fingers; and akinesia (poverty of movement) or bradykinesia (slowness in initiating volitional activities). These symptoms, which are due to blockade of dopaminergic receptor sites in the striatum, are lessened by reduction of dosage of neuroleptics and by administrating orally anticholinergic compounds, such as trihexyphenidyl hydrochloride (Artane) or benztropine mesylate (Cogentin). Tardit, e dyskinesia, initially called "persistent dyskinesia" or "reversible and irreversible drug-related dyskinesia", is characterized by abnormal involuntary movements frequently involving the facial, buccal, and masticatory muscles and extending often to the upper and lower extremities, including the neck, trunk, fingers, and toes. For example, the typical abnormal facial movements include opening, protrusion and retrieval of the tongue and closing of the mouth, chewing, licking, sucking, puckering, smacking, panting, and grimacing. Abnormal movements associated with the disorder, which may involve any part of the body, may be ballistic, athetotic, myoclonic, dyskinetic, or choreiform in nature. The neuroleptic-induced dyskinesias, which have been reported and studied extensively in adult patients, also occur in children (Campbell et al., 1983). It is generally believed that the pathogenesis of tardive dyskinesia relates closely to the chronic blockade of dopamine receptor sites that is pathophysiology results from a hypersensitivity of striatal dopamine receptor sites and a decreased function of GABAergic efferent pathway (e.g. Hama and Ebadi, 1986; See et al., 1989). In the therapeutic management of neuroleptic-induced tardive dyskinesia, reserpine, lithium, diazepam, baclofen, and gamma-vinylgamma-aminobutyric acid all have been used with unsatisfactory results. Therefore in the absence of an effective treatment, prevention of tardive dyskinesia by (a) prescribing the neuroleptics at their lowest possible doses, (b) by providing drug free holidays, and (c) by avoiding the simultaneous and prophylactic usage of anticholinergic agents, intended to prevent the emergence of parkinsonism should be advocated and pursued energetically. (For a review and references see Ebadi and Hama, 1988). Neuroleptic malignant syndrome. Among the complications of neuroleptic chemotherapy, the most serious and potentially fatal complication is malignant syndrome, which is characterized by extreme hyperthermia, "lead pipe" skeletal muscle rigidity causing dyspnea, dysphagia, and rhabdomyolysis, autonomic instability, fluctuating consciousness, leukocytosis, and elevated creatine phosphokinase. In this report the pathogenesis and treatment of this potentially fatal iatrogenic disease will be reviewed in a comprehensive fashion.

RECOGNITION OF NEUROLEPTIC MALIGNANT SYNDROME AS A DRUG-INDUCED SIDE EFFECT

The first description of a "neurovegetative complication" of neuroleptic was made by Delay and his colleagues (1960), who used haloperidol in the management of psychosis. Delay and Deniker (1968) renamed and described "neuroleptic malignant syndrome" as a drug-induced extrapyramidai syndrome. Meltzer (1973) showed that "rigidity, hyperpyrexia, and coma" also occurred following the use of fluphenazine enanthate. The first suggestion of the involvement of dopamine in the manifestation of symptomology of neuroleptic malignant syndrome was made by Henderson and Wooten (1981) and confirmed by Burke et al. (1981) who studied the effects of dopamine depleting agents in a patient with Huntington's chorea. Furthermore the pathogenesis of neuroleptic malignant syndrome has been analyzed and case histories have been reported throughout the world (e.g. Itoh et al., 1977; Weinberger and Kelly, 1977; Geller and Greydanus, 1979; Caroff, 1980; Caroff et al., 1983) and reviewed comprehensively (e.g. Kurlan et al., 1984; Addonizio et al., 1986, 1987; Kellam, 1987; Kaufmann and Wyatt, 1987). THE SPECTRUM OF PATHOLOGICAL REACTIONS SEEN IN NEUROLEPT1C MALIGNANT SYNDROME

Neuroleptic malignant syndrome "as the most serious but the rarest and least known of the complications of neuroleptic chemotherapy" (Delay and Deniker, 1968) is viewed as a triad of fever, movement disorder, and altered mentation (see Table I, Kurlan et al., 1984). Pulmonary abnormalities, including tachypnea, dyspnea, stridor, and pulmonary edema are probably secondary complications resulting from movement disorder, alteration in the functions of the autonomic nervous system (tachycardia, diaphoresis, and labile blood pressure), and changes in mental status (stupor, lethargy, and coma). In Kurlan's study, the cluster of aforementioned symptoms occurred in 52 patients who received neuroleptics for schizophrenia (24), for affective disorder (13), for other psychiatric disorders (13), for preinduction anesthesia (1) and for withdrawal from sedative-hypnotic drugs (1), A typical case of haloperidol-induced malignant syndrome is hereby presented (Levenson, 1985). "'A 22-year old man, who had received past treatment with haloperidol, was admitted to the hospital for agitation and violent outbursts. He received haloperidol, 5 mg every 2 hours, and benztropine mesylate, 2 mg i.m. twice a day. Three days later he remained agitated and confused. Haloperidol was stopped, and thiothixene, 5 mg every 4 hours, was begun. He continued receiving the same dose of benztropine mesylate. Approximately 24-36 hours later, the patient was verbally unresponsive, catatonic, sweating, and dehydrated and had a fever (38.3--39.4°C) and tremors. He was treated with intravenous fluids and continued intramuscular benztropine mesylate. His serum creatine phosphokinase level was 498 U/liter. He was transferred to another hospital, where he was noted to have extreme rigidity, fluctuating consciousness, profuse diaphoresis, generalized tremors, tachycardia (110--136 beats/minute), and tachypnea (up to 40 respirations/ minute). His blood pressure varied between 120 and

Neuroleptic malignant syndrome Table 1. Pathophysiological reactions in neuroleptie malignant syndrome Signs in 52 patients Autonomic dysfunction Fever Tachycardia Excessive perspiration Labile blood pressure Tachypnea Urinary incontinence Respiratory stridor Pallor Flushing Cardiac arrest Movement disorder Parkinsonism Rigidity Tremor Sialorrhea Hypomimia Bradykinesia Festinating gait Other Dystonia Chorea Trismus Buccofacial dyskinesia Opisthotonos Oculogyric crises Opsoclonus Blepharospasm Other neurologic dysfunction Dysphagia Akinetic mutism Aphonia Dysarthria Hyperreflexia Extensor plantar responses Ataxia Hyperreflexia Hypotonia Impaired upward gaze Flexor posturing Extensor posturing Nystagmus Ocular flutter Seizure Mental status alteration Coma Stupor Lethargy Confusion or agitation

% of patients 100 79 60 54 25 15 6 4 4 4

2 98 92 56 31 12 4 2 33 15 8 8 6 6 6 4 2 40 38 19 19 I0 8 6 6 4 4 4

2 2 2 2 27 27 12

8

Kurlan et al. (1984).

160ram Hg systolic and between 80 and 100mm Hg diastolic. His temperature at admission was 37.2°C and increased to 39.4°C; he was without documented infection. He had difficulty swallowing and required tracheal intubation. His WBC count and differential were normal at admission, but WBC count became elevated to 18,100/mm3. The results of a head CT scan, EEG, and lumber puncture were normal." (Levenson, 1985).

EPIDEMIOLOGIC DEMOGRAPHICS

In 115 cases of neuroleptic malignant syndrome studied by Addonizio et al., (1987) the primary psychiatric diagnosis in descending order of occurrence consisted of schizophrenia (44%), bipolar mania (26%), major depression (10%), schizoaffective disorder (6%), atypical psychosis (3%), alcohol abuse (3%), bipolar depression (2%). mental

369

retardation (2%), organic mental syndrome (1%), Alzheimer's disease (1%), and sedative abuse (1%). Among these 115 cases there were 72 men (63%) and 43 women (37%). Furthermore, greater than 50% of the cases were patients 40 yr or younger. Unlike the more familiar neuroleptic-induced movement disorders, which occur in 15-50% of patients, neuroleptic malignant syndrome is relatively rare, and the annual incidence of the syndrome has been reported to be 0.15% (Sukanova, 1985), 0.4--1.4% (Delay et al., 1962; Caroff, 1980; Pope et al., 1986; Shalev and Munitz, 1986), or 2.4% (Addonizio et al., 1986).

NEUROLEPTICS CAUSING MALIGNANT SYNDROME

Among the I 15 cases reported by Addonizio et al. (1987) and 52 cases analyzed by Kurlan et al. (1984) the incidence of neuroleptic malignant syndrome seems to be considerably higher with haloperidoi than with any other neuroleptic (Table 2). In data compiled by Addonizio et al. (1987), 29% of patients had received more than one neuroleptic, and this regimen apparently significantly increases the incidence of malignant syndrome. Furthermore, it is generally believed that the incidence of malignant syndrome is higher with high potency neuroleptics than low potency ones (Table 2). With this in mind, it is difficult to understand why the incidence of malignant syndrome with a high potency neuroleptic such as fluphenazine was lower (5%) than the relatively lower potency neuroleptics such as thiothixene (7%). It is believed that the incidence of malignant syndrome is much higher with depot neuroleptics, as verified by the fact that fluphenazine decanoate produces a higher incidence of malignant syndrome (16%) than fluphenazine (5%). If so, by the same analogy, then it is difficult to understand why the incidence of malignant syndrome with haloperidol was 57% and that with haloperidol decanoate was only 1% (Table 2). This discrepancy may suggest that other unexplained and triggering factors may play major roles in the etiology and manifestation of neuroleptic malignant syndrome. Table 2. The incidence of malignant syndrome with neuroleptics of varied potencies Neuroleptic medication Haloperidol > l Neuroleptic Intramuscular n¢urolcptic Chlorpromazine Fluphenazin¢ decanoat¢ Levopromethazine Thiothixene Trifluoperazine Fluphenazine HCI Thioridazine Intravenous neuroleptic Loxapin¢ Perphenazme Bromperidol cis-CIopenthixol

Fluphenthixol Promazine Haloperidol decanoat¢ Addonizio et al. 0987).

Percent syndrome 57 29 26 24 16 9 7 6

M. EBADI et al.

370 DIFFERENTIAL DIAGNOSIS OF NEUROLEPTIC MALIGNANT SYNDROME

Many diseases and toxic reactions mimic the cardinal features of neuroleptic malignant syndrome namely fever, muscular rigidity, changes in mental status, and autonomic dysfunction. Therefore, care must be taken to differentiate neuroleptic malignant syndrome from malignant hyperthermia, lethal catatonia, heat stroke, central anticholinergic toxicity, CNS infection, severe dystonic reaction, drug- and food-related allergic reactions, electrolyte imbalance, thyrotoxicosis, strychnine poisoning, rabies, tetanus, polymyositis, rhabdomyolysis, and stiff-man syndrome (Olmsted, 1988). Among these, the differential diagnosis of neuroleptic malignant syndrome from lethal catatonia and malignant hyperthermia will be presented. Lethal catatonia

Lethal catatonia is an acute and progressive mental excitement with fever and continuous motor activity which often results in exhaustion and death. This syndrome of unexplained fulminating hyperpyrexia, usually described in the setting of catatonia, was described initially by Calmeil (1832) in psychiatric patients almost 133 years prior to the introduction of neuroleptics, and reported periodically throughout the world's literature (e.g. Kirby, 1913; Stauder, 1934; Morrison, 1973; Gjessing, 1974; Gelenberg, 1976; Stoudemire, 1982; Magrinat et al., 1983; Mann et al., 1986; Castillo et al., 1989). Lethal catatonia, which should be differentiated from neuroleptic malignant syndrome, has had numerous names including Bell's Mania (Bell, 1849), acute essential psychosis (Ladame, 1919), Scheid's cyanotic syndrome (Palmer, 1941), acute pernicious psychosis (Tolsma, 1941), psychotic exhaustion syndrome (Shulack, 1946), acute catatonic excitement (Aronson and Thompson, 1950), and delirium acuturn (Lingjaerde, 1954). The term "lethal catatonia" coined by Stauder (1934) has received widespread acceptance. Despite the diversity of nomenclature, there is considerable consistency in the clinical description of lethal catatonia. Lethal catatonia, which has been reviewed by Mann et al. (1986), "begins with the development of intense motor excitement that continues night and day almost without interruption. The patient frequently is violent and destructive, demolishing everything in sight, and given to unprovoked assaultiveness and bizarre suicide attempts. Refusal of all nutrients is characteristic and clouding of consciousness is an almost constant feature. A number of reports mention various catatonic signs occurring in association with excitement including mutism, posturing, stereotypies, catalepsy, and varying degrees of intermittent rigidity. Thought processes become increasingly disorganized, speech becomes increasingly incoherent, and auditory and visual hallucinations accompanied by bizarre delusions are often prominent. Somatic disturbances, including tachycardia, profuse perspiration, dehydration, labile or high blood pressure, cyanosis of the extremities, and hematomas of the skin, develop and progressively became worse. Fever. the most striking somatic

change, rises rapidly during this period and body temperature may attain levels as high as I I0°F (43°C). This hyperactive stage of the disorder varies in length from several hours to several weeks but lasts an average of about 8 days. In the final phase of the disorder, excitement gives way over the course of several days to stuporous exhaustion with extreme hyperthermia followed by coma, cardiovascular collapse, and death. In many cases, the skeletal musculature is described as flaccid during this terminal stupor. In other cases, however, muscular rigidity is present.'" While lethal catatonia is more commonly recognized as an outgrowth of a functional psychiatric disorder, it may also develop in association with a wide array of medical disorders affecting the CNS directly or indirectly (Mann et al., 1986). These include cerebrovascular disorders (e.g. basilar artery thrombosis, bilateral hemorrhagic lesions of temporal lobes); tumor (e.g. glioma of the third ventricle, periventricular diffuse pinealoma); head trauma (e.g. surgical removal of lesions near the hypothalamus); infections (e.g. viral encephalitis, typhoid fever, malaria, viral hepatitis, and bacterial septicemia); seizure disorders (e.g. autonomic (diencephalic) epilepsy); metabolic disorders (e.g. hyperthyroidism, uremia, and Wernicke's encephalopathy); toxic disorders (tetraethyl lead poisoning; and sedativehypnotic withdrawal. The following case demonstrates that lethal catatonia often begins with extreme psychotic excitement, which, if persistent, may lead to hyperpyrexia, exhaustion and death (described initially by Stauder, 1934, and reported by Castillo et al,, 1989). "A 25-year-old man, whose sister had died during a period of catatonic excitement, was in good health until he began talking senselessly one day. The next day he was confused and unable to work. The third clay he was in severe psychomotor excitement, was aggressive toward his family, and wanted to jump out of the window. He was admitted to the hospital, and during the first few hours, he stated that he was afraid of being tortured and that he knew the torture instruments were already being prepared. He accused the staff of preventing him from entering a monastery and of being guilty against the mother of God. His statements were only partly coherent, and he denied that he was hallucinating. Because of severe excitement he was placed in a continuous water bath. Despite scopolamine and laudanum injections, he did not sleep at all. The following afternoon he was severely excited, attacking other patients and any one who came near. The hematomas on his body, which were noted at admission, became bigger and turned yellow. His fingers and feet were cyanotic. During his second night in the hospital, he slept for a few hours after taking medication, but he became excited again and his consciousness was clouded. His psychomotor excitement alternated between wild falling to the ground and short quieter periods during which he grimaced widely and fought when someone came near. Toward evening, he appeared calmer but weaker and spent that night and the next day in bed, but he again became excited and tense, banging his head into the pillows, tearing away his clothes, and thrashing about. During short intervals of negativistic stupor, he took some nourishment. The next morning the rigidity had changed back to a wild agitation; he was crying, biting, and falling to the ground and his

Neuroleptic malignant syndrome

371

Table 3. Clinical differences between lethal catatonia and neuroleptic malignant syndrome Stage Onset

Lethal catatonia Prodrome lasting 2 weeks to 2 months, consisting of behavioral and personality changes or frank schizophrenic symptoms. Possible acute onset with no prodrome

Neuroleptic malignant syndrome Period of neuroleptic exposure can take hours to months. Develops rapidly over a few hours to days. No prodromal phase has been described

Initial symptoms

Excitement, intense anxiety, and restlessness lasting a few days. Possible self-destructive or assaultive behavior. Hallucinatory experiences and delusional thinking usually present. Possible fever, tachycardia, and acrocyanosis. Sudden death may occur

Tremors and dyskinesias are early signs. Muscle hypertonicity described as "'lead pipe" or "'plastic" rigidity. Severe excitement and intense anxiety are not major features. Autonomic instability with tachycardia, labile hypertension, and possible diaphoresis. Fever may not be present initially. Acrocyanosis has not been described. May occur in nonpsychotic patients treated with neuroleptics. No deaths reported during early phase

Full syndrome

Continued increasing excitement with wild agitation and violent, destructive behavior, lasting 3-15 days, and possible choreiform movements. Mutism, rigidity, and/or stupor may alternate with excitement. Refusal of food and fluids. Increasing and fluctuating fever, rapid and weak pulse, profuse, clammy perspiration, hypotension

Appearance of most major symptoms (severe muscle rigidity, persistent autonomic instability, fever) usually occurs after 2-9 days. Possible agitation, confusion, and clouding of consciousness

Final stage

Cachexia, convulsions, delirium, coma, exhaustion. Death may occur

Severe complications, i.e. rhabdomyolysis with elevated creatine phosphokinase, myoglobinuria, renal failure and intravascular thrombosis with pulmonary embolism and respiratory failure. Possible 20-30% mortality rate with full syndrome

Treatment

Neuroleptic and other treatments to reduce severe psychotic symptoms

Immediate cessation of all dopamine-blocking neuroleptics. Dopamine agonist (to reduce central hypodopaminergic state), calcium channel blockers (to reduce muscle rigidity), //-adrenergic blockers (to reduce tachycardia), other supportive measures as needed

Data compiled and referenced by Castillo et al. (1989).

face was bleeding. He jumped out of the water bath and did not respond to hyoscyamine injections. On the eighth day in the hospital, the patient was so exhausted that he could be kept in bed for several hours. Toward evening, he developed a parotitis and fever, which reached 40~C the next morning but fell after surgical drainage. The psychomotor excitement continued. He attempted to throw himself out of bed and to bite anyone who came near. Heavy doses of chloral hydrate induced only a few hours of sleep. He refused all food. His body was covered with hematomas. Within a few hours he died. His blood count showed no anemia and no changes reflecting inflammation." (Reported by Castillo et al., 1989). Because lethal c a t a t o n i a o f t e n requires n e u r o l e p t i c t r e a t m e n t a n d n e u r o l e p t i c t r e a t m e n t m u s t be t e r m i n ated i m m e d i a t e l y in n e u r o l e p t i c m a l i g n a n t s y n d r o m e , early clinical d i f f e r e n t i a t i o n (Table 3) is crucial. Malignant hyperthermia M a l i g n a n t h y p e r t h e r m i a , c h a r a c t e r i z e d by tachyc a r d i a , a r r h y t h m i a , u n s t a b l e b l o o d pressure, skin m o t t l i n g , h y p e r t h e r m i a , rigidity ( n o t a l w a y s p r e s e n t ) d i a p h o r e s i s , c y a n o s i s , a n d s u d d e n d e a t h , was initially r e p o r t e d by D e n b o r o u g h et al. (1962) in a family in w h i c h it was t r a n s m i t t e d as an a u t o s o m a l d o m i n a n t (Britt et al., 1969). M a l i g n a n t h y p e r t h e r m i a o c c u r s in c h i l d r e n ( o n e in 15,000) a n d in a d u l t p a t i e n t s (one in 50,000) (Britt a n d K a l o w , 1970). A g e n t s a s s o c i a t e d with m a l i g n a n t h y p e r t h e r m i a are s u c c i n y l c h o l i n e ( 7 7 % o f cases), h a l o t h a n e ( 6 0 % o f cases), n i t r o u s o x i d e - m e p e r i d i n e , m e t h o x y f l u r a n e , ether, ethyl c h l o r ide, t r i c h l o r o e t h y l e n e , c y c l o p r o p a n e , ethylene, gallamine, d-tubocurarine, isoflurane, enflurane, lidocaine a n d c a r b o c a i n e ( R y a n , 1976). T h e f o l l o w i n g

describes the first case o f m a l i g n a n t h y p e r t h e r m i a d e s c r i b e d by Denboroughet al. (1962). "The patient, a male, age 21, was admitted to the hospital with a compound fracture of the tibia and fibula on April 8, 1960. He was less concerned about the fracture than about the fact that he was likely to need a general anaesthetic, as several of his relatives had died following the administration of ether. Because o f this serious history a local anaesthetic had been used when he had needed an appendicectomy in childhood. The parents and the patient's general practitioner were interviewed and the story was confirmed. It was believed that in each case the reaction had been due to ether. It was decided to proceed cautiously avoiding ether and to be ready to stop if there were any untoward signs. The patient was premedicated with pethidine 100 mg and atropine 0.6mg and was anaesthetized with thiopentone 250 mg followed by nitrous oxide 2 l/rain oxygen l I/min and halothane using a Boyle apparatus with closed circuit and soda lime absorption. Halothane was administered up to a maximum of 2 per cent and was then reduced to 1.5 per cent. Ten minutes later the halothane concentration was reduced because the blood pressure had fallen to 80 mm Hg, and the pulse rate had risen from I00 to 160 b.p.m Anaesthesia was stopped and the operation was concluded in the next l0 rain. However, he remained deeply unconscious for a further 30 minutes and his skin was hot and sweaty. He was rubbed down with ice-cold cloths and given a blood transfusion. He gradually recovered over the next I! hours and his subsequent course was uneventful. '~ (Denborough et al., 1962). In a d d i t i o n to a n e s t h e t i c s a n d m u s c l e relaxants, t r a u m a , exercise, e n v i r o n m e n t a l heat stress, a n d viral infections m a y trigger e p i s o d e s o f m a l i g n a n t

372

M. EBADI et al.

hyperthermia (Danzl, 1988). Furthermore, there is also a drug-induced hyperthermia (Pollock, 1973) which occurs outside of the operating room and is related to the use of monoamine oxidase inhibitors with anticholinergic agents, narcotics, or psychotropic agents. The patients usually arrive in the emergency room lethargic and febrile and die quickly. Malignant hyperthermia has been divided into a rigid type and a non-rigid type. The rigid type of malignant hyperthermia may occur following administration of succinylcholine, making laryngoscopy and intubation difficult. Both types have been reported in the same family. Features which enhance the susceptibility of patients for malignant hyperthermia are muscle bulk (e.g. a healthy person with a large muscle mass), localized muscular weakness (muscular cramp should serve as a warning sign), difficulty controlling temperature (lack of a diurnal variation in temperature and a history of unexplained fever should serve as a warning signal), joint hypermotility, ptosis and squint, kyphoscoliosis, hernias and clubfoot (Ryan, 1976). In view of the clinical similarities (hyperthermia, muscular rigidity and myoglobinuria) between neuroleptic malignant syndrome and malignant hyperthermia, it has been suggested that the two syndromes may share common pathogenetic mechanisms (e.g. Caroff, 1980; Levenson, 1985; Shalev and Munitz, 1986). By using the halothane contracture test or in vitro response of skeletal muscle to halothane (Gronert, 1980; Rosenberg and Reed, 1983; Fletcher and Rosenberg, 1985), Caroff et al. (1987) have shown that the patients who recovered from neuroleptic malignant syndrome could be diagnosed as susceptible to malignant hyperthermia. On the other hand, Hermesh et al. (1988a) have shown that the patients who have had malignant neuroleptic syndrome are not at a considerably greater risk than others for developing malignant hyperthermia during surgery or ECT, suggesting that the syndromes are not related. Other inconsistencies in the literature are the results of studies by Caroff et al. (1983) and Tollefson (1982) that skeletal muscles from patients susceptible to malignant hyperpyrexia contracted abnormally when exposed to caffeine, whereas skeletal muscles from patients with neuroleptic malignant syndrome did not. On the other hand, Araki et al. (1988) studied eight cases of neuroleptic malignant syndrome and have shown that caffeine contracture of single skinned muscle fibers and sensitivity of the sarcoplasmic reticulum to caffeine was increased abnormally in six of the eight cases. Consequently, one may conclude tentatively that either neuroleptic malignant syndrome is a group of heterogeneous disorders and/or other unidentified triggering mechanisms may be involved in enhancing susceptibility to both syndromes. Alternatively, one may conclude that neuroleptic malignant syndrome and malignant hyperthermia may be separate disorders with distinct etiologic mechanisms culminating in a similar disturbance of membrane properties, which functions as a final common pathway affecting calcium movement and energetic processes in skeletal muscle (Caroff et al., 1987).

EVENTS LEADING TO OR ENHANCING THE SEVERITY O F NEUROLEPTIC MALIGNANT SYNDROME

The contributing factors leading to and/or enhancing the incidence or severity of neuroleptic malignant syndrome are dehydration (Wedzicha and Hoffbrand, 1984), exhaustion (Bernstein, 1979), preexisting organic brain syndrome (Diamond and Hayes, 1986), external heat load (Shalev et al., 1988), large dosage and rapid dose titration of neuroleptics (Gelenberg et al., 1988), excessive sympathetic discharge (Pearlman, 1986; Fiebel and Schiffer, 1981), concurrent lithium therapy, and abrupt discontinuation of antiparkinson agents. The last two triggering factors will be described in more detail in the following sections. Levodopa withdrawal induced malignant syndrome

A drug withdrawal hyperthermic syndrome resembling neuroleptic malignant syndrome has been shown to occur following administration of dopamine depleting agents in a patient with Huntington's disease (Burke et al., 1981), and in Parkinson's disease following abrupt cessation of dopamine enhancing agents such as levodopa (Toru et al., 1981; Sechi et al., 1984; Freidman et al., 1985; Gibb and Griffith, 1986), following abrupt cessation of dopamine receptor agonists such as bromocriptine given in combination with levodopa (Figa-Talamanca et al., 1985), following withdrawal from amantadine (Simpson and Davis, 1984), or in a patient with Parkinson's disease receiving antiparkinson's agents and lithium, in whom the syndrome developed during an "off" period (Pfeiffer and Sucha, 1985, 1989, who described the following case history). "A 62-year-old man developed right arm resting tremor at age 50. With time the tremor became generalized and other signs of Parkinson's disease developed. Levodopa was introduced and later replaced by carbidopa/levodopa, which was ultimately titrated to a dose of 25-175 every 2 h around the clock. Amantadine 200 mg daily was also used. Although the response to levodopa/carbidopa was initially good, gradual deterioration began at age 61. Episodes of severe, generalized tremor accompanied by profuse sweating and tachypnea developed. The episodes would appear quite abruptly, ushered in by a sensation of feeling very "hot", and last from 15 min to 3 h several times weekly. Certain foods (meat, cheese) or stress could trigger the episodes, but they often occurred without any obvious provocation. The patient's urine would become pink-tinged after some episodes. However, no formal documentation of myoglobinuria was ever made nor was muscle biopsy performed. He found that if he wrapped himself in towels soaked in ice water the episodes would pass more quickly. His family physician (E.L.S.) noted that the patient would also go outside in winter weather to "cool-off" during the episodes of severe tremor. Oxazepam 100 mg daily and paper bag breathing provided partial relief. Bromocriptine was added to the treatment regimen at age 61, but did not help and was discontinued after approximately I year. The patient's tremor subsequently became more pronounced and the episodes of sever tremor, tachypnea, and diaphoresis became more prominent. Two months after stopping bromoeriptine, lithium carbonate 300 mg t.i.d, was instituted in an effort to ameliorate the presumed "'on-off" episodes, but no improvement resulted.

Neuroleptic malignant syndrome On the day of his death, ~2 months after starting lithium, the patient awoke feeling well. Mid-morning he began to experience one of the "off" episodes. When his wife returned home from work 2 h later, she found him to be "very hot, sweating, and stiff as a board." He became incoherent and was hospitalized. On admission, blood pressure was 80/68 mm Hg, pulse rate 170 beats per minute, and axillary temperature 107°F. Neurologic examination demonstrated extremely severe generalized tremor and rigidity. Laboratory studies disclosed the following abnormalities: WBC = 19,000, CPK = 7,400, LDH = 753, SGOT = 552, BUN = 27 mg/dl, creatinine = 3.1 mg/dl. Blood cultures were not obtained. Treatment was instituted with i.v. diazepam and dantrolene along with ice packing. An antibiotic was also instituted and dopamine given to maintain blood pressure. Nevertheless, the patient continued to deteriorate, became anuric and died 10 h after admission. General autopsy demonstrated no gross or microscopic signs of infection, revealing only moderate, acute congestion and edema of the lungs and abdominal viscera. Neuropathologic examination demonstrated neuronal loss and Lewy body formation primarily in the substantia nigra pars compacta and the locus ceruleus, consistent with the clinical diagnosis of Parkinson's disease." (Pfeiffer and Sucha. 1989).

373

In analyzing the symptoms of neuroleptic malignant syndrome in 82 consecutive inpatients, Addonizio et al. (1986) concluded that "neuroleptic malignant syndrome is a spectrum of disorder that has milder variants". Kirkpatrick and Edelsohn (1985) identified a variant of neuroleptic malignant syndrome with lower temperature. Sullivan (1987) described the case of a 20-year-old man who developed generalized ridigity and signs of autonomic instability following administration of zuclopenthixol decanoate, without developing a pyrexia of over 3 7 C .

bizarre behavior such as talking to himself and barking like a dog. At this time he was admitted to a mental handicap hospital, but showed increasing levels of disturbance, with scratching, biting, kicking, bizarre talk, and self-mutilation. Diagnoses ranging from schizophreniform psychosis and manic-depressive psychosis to personality disorder were considered, in addition to his undoubted mental impairment. Treatments at various times included promazine, droperidol, sodium valproate, benperidol sulthiame, lorazepam, carbamazepine, clopenthixol decanoate, and lithium carbonate. None made any appreciable differrence. Attacks on staff escalated, and following an attempt to strangle a nurse he was admitted to Moss Side Special Hospital in August 1984 when aged 20. His self-mutilation and violence towards others continued to cause great concern and a variety of different therapeutic measures, including several different drug regimes, was tried. By May 1986 his medication was carbamazepine (500 mg q.d.s.) (for one year), lithium carbonate (500rag t.d.s.) (for eight months), procyclidine (5 mg b.d.) and diazepam (20 mg b.d.) (both since admission). Despite the serum carbamazepine and lithium carbonate levels being within the therapeutic range, his behavior remained difficult to control and zuclopenthixol decanoate (500mg weekly) was added. A week later his serum lithium level was found to be 1.96 mmol/1 and lithium was withheld. After a further week the level was 0.36 mmol/l and lithium at a lower dose of 500 mg b.d. was reintroduced. On the following day he was noted to be oversedated and ataxic and all drugs were stopped. Two days later he had two brief periods of absence accompanied by localized twitching of his jaw. He subsequently became very disturbed, indulged in head-banging, and the next day showed decreased level of consciousness, incoordination of his upper limbs and generalized hyperreflexia. He was transferred to a district general hospital where full blood count, serum multiple analysis, skull X-ray, cerebrospinal-fluid analysis, and computerized tomography scan were all normal. An electroencephalogram showed mild, generalized polyrhythmic abnormalities. No diagnosis was made and he was returned to Moss Side. The next day he was found to be comatose, just responding to painful stimuli, with blepharospasm and generalized extrapyramidaltype rigidity. He showed involuntary facial movements, a blood pressure of 150/90, sialorrhoea and dyspnoea, and was incontinent of urine. On transfer to a neurological unit a diagnosis of NMS was made, despite the absence of hyperthermia (temperature over 37.5 C). Full blood count was normal, as was a chest X-ray. Serum multiple analysis revealed aspartate transaminase to be slightly raised at 45 i.u./I (normal below 40) and creatinine phosphokinase raised at 289 i.u./l (normal below 100). No traces of lithium or carbamazepine were detected on serum estimation. He required a nasogastric tube and oxygen: therapy with intravenous thiamine, oral dantrolene (25mg t.d.s.) and oral bromocriptine (5 mg t.d.s.) was initiated. For the next 2-3 days he showed a fluctuating level of consciousness, he was frequently incontinent of urine, and his blood pressure varied from 110/70 to 150/90. The generalized rigidity and involuntary facial movements persisted. Over the next week the rigidity gradually resolved, his conscious level improved and ten days after admission he was ready for discharge." (Sullivan, 1987).

"'At an early age the patient was diagnosed as mentally impaired and exhibited problem behavior. Intermittent aggressive outbursts appeared by the age of 10, and from the age of 13 he showed episodes of

It should be cited that Kemperman (1989) reported a case of zuclopenthixol-induced neuroleptic malignant syndrome with hyperthermia.

Lithium-mediated malignant syndrome Lithium has been used in Parkinson's disease to ameliorate fluctuations in m o t o r performance (i.e. " o n - o f f " ) (Pfeiffer and Sucha, 1985), and to treat painful off-period dystonia (Quinn et al., 1986; Koehler and Mirandolle, 1988). Unlike the members of the phenothiazine derivatives, the butyrophenone derivatives, or the thioxanthine derivatives, the incidence of extrapyramidal side effects and neuroleptic malignant syndrome is quite low with clozapine. However, the incidence increases when clozapine is given with lithium (Pope et al., 1986) or when it is given with carbamazepine (Hosie et al., 1988). The incompatibility o f lithium with neuroleptics (Spring and Frankel, 1981; Frankel and Spring, 1982; Cohen and Cohen, 1974; Bamrah, 1988) is related to the studies reporting that lithium apparently inhibits the striatial synthesis of dopamine (Friedman and Gershon, 1973) and prevents neuroleptic-induced functional supersensitivity of brain dopamine receptor (Sternberg et al., 1983), thereby impairing further dopaminergic functions, the putative mechanism leading to neuroleptic malignant syndrome (Addonizio et al., 1986).

Neuroleptic malignant syndrome without hyperthermia

374

M. EB^DIet al.

Neuroleptic malignant syndrome without neuroleptics In addition to being caused by neuroleptics (Table 2, Addonizio et al., 1987), neuroleptic malignant syndrome has occurred following nonneuroleptic drugs including trimipramine (Langlow and Alarcon, 1989), amoxapine (Taylor and Schwartz, 1988), metoclopramide (Patterson, 1988; Friedman et al., 1987), metoclopramide combined with cimetidine (Destee et al., 1981), tetrabenazine (Burke et al., 1981), overdosage of benzodiazepine, phenelzinc, dothiepin and alcohol (Ritchie, 1983), and amphetamine (Chayasirisobhan et al., 1983). Brennan et al. (1988) reported a case of neuroleptic malignant following lithium and phenelzine.

elevated creatine phosphokinase (CPK), and elevated liver enzymes including serum glutamic oxaloacetic transaminase (SGOT), lactate dehydrogenase (LDH), and alkaline phosphatase, and elevated serum amylase and lipase (Lee and Tang, 1988). Among these, leukocytosis and elevated creatine phosphokinase are often obsereved. Creatine phosphokinase (ATP: creatine phosphotransferase: EC 2.7.3.2-CPK) is an enzyme which catalyzes the transfer of a phosphoryl group from phosphocreatine (phosphagen) to ADP to form ATP according to the following reaction.

"A 42-year-old woman presented to casualty with a rapid onset of restlessness, sweating and confusion. She had a history of depression with intermittent agitation and some phobic symptoms of several years duration. Her medication comprised the following: phenelzine (15 mg three times daily), lithium carbonate (800mg daily), L-tryptophan (1 g daily), diazepam (2 mg three times daily), and triazolam (0.25 mg daily). Phenelzine had been commenced six weeks previously, replacing clomipramine which had proved ineffective over four months. Relatives believed that the patient took her medications only as prescribed. Within three hours she was comatose. Pupillary and corneal reflexes were lost. Trunk and limbs were hypertonic and held in rigid hyperextension. Tendon reflexes were brisk, but plantar responses were flexor. Temperature rose from 38.5:'C on admission to ,12.5~C four hours later, She had a tachycardia and became hypotensive. A diagnosis of NMS was made and she was treated with intravenous dantrolene (60 mg three times daily), commenced within four hours. Body temperature returned to normal within 14 h; blood pressure and heart rate were controlled with dopamine and practolol. Investigation showed mild leucocytosis and initially normal biochemical parameters of hepatic, renal, and muscle function. Serum creatine phosphokinase became elevated, reaching a peak of 41 355 U/1 (normal values 24-175) on the third day. Cerebrospinal fluid was normal. Blood and urine cultures were negative. Intravenous benzylpenicillin and gentamicin were commenced before results of these became available. Severe disseminated intravascular coagulation occurred after 12h. Acute renal failure and continuing infusion of blood products necessitated treatment by peritoneal dialysis. Mechanical ventilation was instituted. By day five, elevated transaminases and alkaline phosphatase indicated severe hepatocellular damage. Profound hypoglycemia occurred suddenly and was treated promptly. The patient succumbed to repeated asystole on the sixth day. Serum taken on admission contained: lithium, 0.38 mmol/1 (therapeutic range 0.5-1.0); diazepam, 0.33 mg/l; and nordiazepam, 0.5 mg/l. No tricyclic antidepressant was detected. Unfortunately, assay for monoamine oxidase could not be performed. Autopsy showed massive centrilobular hepatocellular necrosis and some fibrin thrombi within glomeruli. Muscle histology and histochemistry were normal." (Brennan et al., 1988).

Creatine kinase is a dimer with a molecular weight of 40,000 daltons each, and by electrophoretic analysis, it can be distinguished as being muscle specific (M type) and brain specific (B type). Injured muscle releases primarily MM type isoenzyme, whereas injured heart releases mostly MB type isoenzymes. Furthermore, in addition to releasing mostly creatine kinase, injured muscle releases to a certain extent aldolase, lactate dehydrogenase, and aspartate aminotransferase. The serum level of creatine kinase increases in many diseases and conditions including sustained exercise, use of restraint, intramuscular injection, muscle trauma, neuroleptic malignant syndrome, malignant hyperthermia, alcoholism, motor neuron disease, chronic peripheral neuropathies, and following a convulsive seizure (Meltzer, 1976). The degree of elevation of creatine kinase activity (normal value, 100 IU/I) in neuroleptic malignant syndrome varies dramatically from patient to patient, and with the stage of the syndrome. Some of the reported values are 289 IU/I (Sullivan, 1987), 380 IU/I (Cohen et al., 1987), 461 IU/I (Koehler and Mirandolle, 1988), 5131U/1 (Langlow and Alarcon, 1989), 5951U/1 (Toru et al., 1981), 600IU/I (Patterson, 1988), 9401U/1 (Friedman et al., 1987), 1144IU/1 (Clarke et al., 1988), 1650 IU/I (Bamrah, 1988), between 100 to over 10,000IU/I (Kellam, 1987), 10650 IU/! (Taylor and Schwartz, 1988), 27,000 IU/I (Anderson and Weinschenk, 1987), 41,3551U/1 (Brennan et al., 1988) to as high as 100,000 IU/I (Haggerty and Gillette, 1987; Legras et al., 1988). The reason(s) for the dramatic variation in the level of creatine kinase is not known but is not related to the degree of the clinically observed rigidity (Harsch, 1987). Furthermore, it has been recognized previously that elevation in peripheral muscle creatine kinase may result from functional psychosis (Meltzer et al., 1971), from closed head injury, stroke, or meningitis (Dubo et al., 1967). Moreover muscle abnormalities have been reported in acute psychosis (Meltzer and Moline, 1970) and in neuroleptic malignant syndrome (Martin and Swash, 1987).

Creatine phosphokinase in neuroleptic malignant syndrome A variety of laboratory abnormalities have been described in neuroleptic malignant syndrome including leukocytosis with or without a shift to the left,

In addition to respiratory failure, acute renal failure, and cardiovascular collapse which occur frequently in inadequately treated- or untreated-patients with neuroleptic malignant syndrome, other serious complications have occurred even in patients treated

Phosphocreatine + ADP

Creatme KJnase

, ATP

+ Creatine

COMPLICATIONS

OF NEUROLEPTIC SYNDROME

MALIGNANT

Neuroleptic malignant syndrome well with dantrolene and dopamine enhancing substances. The reported complications are as follows. Myocardial infarction Becker et al. (1988) reported a case of a 32-year-old man who developed malignant syndrome 48 hr following administration of levomepromazine (50mg t.i.d.). 48 hr after the medication was stopped, while the patient was still febrile and rigid, syncope occurred and the patient suffered an acute diaphragmatic myocardial infarction. Periarticular ossification

Peylan et al. (1987) reported a case of a 25-year-old man who suffered from a hebephrenic type of schizophrenia, was treated with levomepromazine (200 mg daily) and developed neuroleptic malignant syndrome 36 hr following initiation of drug treatment, followed by bilateral periarticular ossification of the knees, Periarticular bone formation has been shown to occur following disturbances of the CNS such as poliomyelitis, syringomyelia, myelitis, myelodysplasia, tabes dorsalis, tetanus, anoxic brain damage, and stroke (Bayley, 1979), following spinal cord injury (Tibone et al., 1978), following head trauma (Mendelson et al., 1975; Garland et al., 1980), and following prolonged coma (Mietlants et al., 1975; Sazbon et al., 1981), Although an increase in the level of HLA-B27- a class I antigen, has been reported in a patient with ectopic ossification following traumatic spinal cord injury (Larson et al., 1981), the reason for the development of periarticular extraosseous ossification in disturbances of the central nervous system is not known. Peripheral neuropathy Anderson and Weinschenk (1987) reported a case of a 24-year-old man who developed malignant syndrome two months after taking fluphenazine intramuscularly and orally, and a month later developed peripheral neuropathy compatible with a demyelinative polyneuropathy. Another patient, a 49-year-old man, who had been taking chlorpromazine, fluphenazine, and lithium daily for several years developed neuroleptic syndrome, which resulted in hospitalization. Three weeks later, he also developed peripheral neuropathy. Both patients experienced sensory loss and abnormalities on electromyography and nerve conduction velocity testing. Respiratory distress syndrome and disseminated intrat,aseular coagulation Johnson et al. (1988) reported a case of a 54-yearold man who took haloperidol (20 mg twice daily) for six weeks and developed a classical picture of malignant syndrome followed by respiratory distress syndrome, and disseminated intravascular coagulation, which had been shown previously to occur in malignant syndrome (Caroff, 1980; Martin et al., 1985). Postmortem examination of this patient revealed no gross abnormalities of the central nervous system. However, cerebrospinal fluid removed at autopsy, contained 3 mg/ml haioperidol, precisely four days after the last dose of haloperidol (Johnson et al., 1988).

375

Necrotizing enterocolitis Legras et al. (1988) reported a case of a 33-year-old male, who developed neuroleptic malignant syndrome following oral haioperidol (25 mg daily) for three weeks followed by intramuscular haloperidol decanoate (200 mg every three weeks).

The patient required rehospitalization "'by numerous intercurrent complications. Pulmonary embolism with partial amputation of the left lower lobe, confirmed by angiography, occurred during the first weeks of hospitalization and warranted prolonged heparinotherapy. Three episodes of digestive disturbances, characterized by diarrhea with mucus, were accompanied by an increase in hypertonicity, sweating episodes, and hyperpyrexia above 41°C. The second episode preceded a state of severe shock and was attributed to a necrotizing enterocolitis. A left hemicolectomy and resection of 80cm of small intestine were performed. Vigorous antibiotic therapy with parenteral penicillin, metronidazole, and enteral vancomycin was administered for three months. Results of blood cultures were negative, but a clostridium-type bacillus was found in the stools and in the intraoperative biopsy of the small intestinal mucosa. Repeated investigations were carried out throughout the hospitalization in an effort to explain the persistent fever, but no other infective causes could be implicated. Prolonged hypertonicity and tremor caused the formation of osteoma of the large joints (shoulders, hips, knees) and retraction of the tendons of the hands and lower limbs. These regressed slowly despite intensive physiotherapy." (Legras et al., 1988). Neuroleptics possess anticholinergic properties themselves, and when combined with tricyclic antidepressant or other anticholinergic neuroleptics may promote or precipitate events leading to necrotizing enterocolitis (Evans et al., 1979; Faurel et al., 1981). The anticholinergic drugs have a tendency to slow intestinal transit, cause fecal stasis, facilitate microbial proliferation, produce intestinal dilatation, promote the invasion of the digestive mucosa by ciostridium perfringens, and foster local necrosis. The neuroleptic-promoted enterocolitis is associated with an extremely high mortality rate (Faurel et al., 1981) or if recovery occurs, it is at the expense of extensive intestinal resection, as practiced in the case of the patient treated by Legras and his colleagues (1988). T H E P A T H O G E N E S I S OF NEUROLEPTIC MALIGNANT SYNDROME

The role o f dopamine Although the pathogenesis of neuroleptic malignant syndrome is not entirely clear, a blockade of dopaminergic receptors in the corpus striatum is thought to cause muscular contraction and rigidity generating heat; and a blockade of dopaminergic receptors in the hypothalamus is thought to lead to impaired heat dissipation. Therefore, the excess heat production along with a lack of heat dissipation produces pronounced hyperthermia which is the hallmark of the syndrome. Furthermore, a blockade of dopamine receptors in the spinal cord is thought to be responsible for dysautonomia. The involvement of dopamine in the genesis of malignant syndrome is further supported by the observation that in addition to neuroleptics which block dopamine receptors, dopamine depleting agents such as reserpine,

376

M. EBADIet al.

dopamine storage blocking agents such as tetrabenazine, and dopamine synthesis inhibitors such as ~t-methylparatyrosine may also produce neuroleptic malignant syndrome. Moreover, the rapid (4 hr) reversal of hyperthermia of neuroleptic malignant syndrome by levodopa/carbidopa also indicates that an alteration in the metabolism or function of dopamine and/or its receptors may be responsible for the hyperthermia. Furthermore, since dopamine plays a role in the central thermoregulation in mammals (Kennedy and Burks, 1974; Cox and Lee, 1977; Cox et al., 1978) and since neuroleptics block dopamine receptor sites, the hyperthermia associated with neuroleptic malignant syndrome may result from a blockade of dopamine target sites within the preoptic-anterior hypothalamus (Morris et al., 1980; Henderson and Wooten, 1981). Indeed, a stereotaxic injection of dopamine into the preoptic-anterior hypothalamus causes a reduction in core temperature and this effect is blocked by haloperidol (Cox et al., 1978). Furthermore, histidyl-proline diketopiperazine [cyclo (HisPro)], an endogenously occurring cyclic dipeptide shares certain properties with dopamine, in that it causes hypothermia and is found in preoptic-anterior hypothalamus and in striatum (e.g. Prasad, 1987). In addition to hyperthermia, the parkinsonism (98%) and alteration in mental status (8-27%) seen in patients with neuroleptic malignant syndrome may result from blockade of dopaminergic receptors in the nigrostriatal system (Fig. I) and from disruption of dopaminergic function in the mesocortical system (Henderson and Wooten, 1981). The gradual (1--5 days) disappearance of parkinsonism seen in patients with neuroleptic malignant syndrome and the resumption of normal physiological functions following treatment with levodopa/carbidopa (Sinemet) support this contention. In addition to Sinemet, other dopamine-function-enhancing drugs, such as bromocriptine (Ali, 1985; Bond, 1984; Dhib-Jalbut et aL, 1983; Duke, 1984; Figa-Talamanca et al., 1985; Granato et al., 1983; Levenson, 1985; Marsden and Jenner, 1980; Mueiler et al., 1983; Rosse and Ciolino, 1985; Zubenko and Pope, 1983) and amantadine (Chayasirisobhan et al., 1983; Gangadhar et al., 1984; Lazarus, 1985a,b; McCarron et al., 1982; Woo et al., 1986) have shown efficacy in treating neuroleptic maliganant syndrome. It should be stated that the blockade of dopaminergic receptors in the spinal cord, hypothalamus, and corpus striatum can not explain completely all manifestations of neuroleptic malignant syndrome in a comprehensive fashion. For example: How could neuroleptic malignant syndrome (a dopamine deficiency state) occur simultaneously with tardive dyskinesia (a dopamine receptor supersensitivity state)?; How could neuroleptic malignant syndrome take place, and the patient remain normothermic?; How could neuroleptic malignant syndrome occur following drugs which seemingly do not block dopamine receptors?: How could bromocriptine, which is effective in treating malignant syndrome in most patients, prove ineffective in a few cases?;

How could anticholinergic drugs, which by themselves are ineffective in treating neuroleptic malignant syndrome, potentiate dramatically the effectiveness of bromocriptine and other dopamine function enhancing substances?; and How could benzodiazepine derivatives which enhance GABAergic transmission and in turn inhibit dopaminergic function, be helpful, even to a limited extent, in treating neuroleptic malignant syndrome? These and other apparent discrepancies do not negate the importance of dopamine hypoactivity in the etiology and/or manifestations of the neuroleptic malignant syndrome. They simply indicate that the anatomical location of dopamine containing neurons, the physiological function of dopamine, the pathological states involving dopamine, and the pharmacological modification of dopaminergic functions in the brain are more complex than initially anticipated. (For reviews and references, see Moore, 1987; Roth et al., 1987; Bunney et al., 1987; Murrin and Zeng, 1989). For example, a diminution in dopaminergic function need not be caused by a blockade of dopamine receptors alone, since substances that inhibit the release of dopamine produce a dopamine deficiency state (Bunney et al., 1987; Roth et al., 1987 and Fig. 1). Furthermore, dopamine neurons in the CNS are extremely heterogenous, possessing dopamine synthesis regulating autoreceptors (e.g. corpus striatum) or lacking dopamine autoreceptors (e.g. prefrontal and cingulate cortices). Therefore, the presence of absence of dopamine releasing autoreceptors or dopamine synthesis regulating autoreceptors, is of paramount therapeutic importance in modifying the synthesis and/or release of dopamine in select areas of the brain (e.g. Murrin and Roth, 1987; Meller et al., 1987). For example, one may surmise that dopamine release inhibiting substances may be effective in treating conditions such as chorea, schizophrenia, or tardive dyskinesia, where hyperfunctioning of dopaminergic neurons have been postulated. Conversely, substances which enhance the release of dopamine, may be effective in neuroleptic malignant syndrome and drug-induced parkinsonism, where hypofunctioning of dopaminergic neurons is apparent. The heterogeneity of dopaminergic neurons in the central nervous system may also be judged by the fact that they may vary not only in terms of their projection areas, but also in terms of the type of feedback pathways that they receive (Fig. 1, Bunney et al., 1987). Moreover, dopaminergic neurons and their receptors undergo dramatic developmental alterations (e.g. Murrin and Zeng, 1989), which may foster a unique circumstance to produce dissimilar or opposite pathological states even with the same drugs. For example, in the aged and 6-hydroxydopamine-treated rats, the loss of nigrostriatal dopamine is accommodated by a compensatory increase in the activity of the remaining neurons, whereas the tuberoinfundibular dopaminergic systems are unable to compensate in a similar manner (Demarest et aL, 1980). The heterogeneity of dopaminergic neurons may also be judged by the fact that the cotransmitter

Neuroleptic malignant syndrome

377

OA AUI'OIIEC|PtOII

PALLICXJS

DA~ PATHWAYS

AUTOIIECPTO~

I

ZONA COMPACTA

ONA

RLrrlcULATA

GAlA ?

u,~,. ,.

TH

J

(+) (_)

IMPULSE ~ TYROSlNE TH.P04, , ~

~I~

/

t

~II,,~I'ANTIA NIGRA

oopA

,.~111 /

.c.

I.Lt IIIt~t

UPTAKE SIT[

¢all,MO0tlJN- 0e~NOENT DA

~.-

DA

P < ~ ~

CELL

Fig. I. A schematic representation of the mechanisms involved in the control of the activity of dopaminergic neurons in the nigrostriatal pathway is provided in the top panel (copied with permission from Bunney et al., 1957). In addition to possessing autoreceptors capable of modulating the release of dopamine, the corpus striatum also contains ~-aminobutyric acid (GABA)-producing feedback pathways, whose activation leads to the release of GABA and subsequent inhibition of dopaminergic neurons. The bottom panel provides a schematic representation of a Ca2+--dependent release of dopamine, which itself is attenuated by release-modulating autoreceptors via a coupling mechanism which may involve protein carboxymethylation (PCM), whose substrate may be calmodulin or a calmodulin-dependent enzyme. In addition, synthesis modulating autoreceptors exist, which through a Ca2+-calmodulin-dependent mechanism may lead to phosphorylation of tyrosine hydroxylase (TH), producing phosphorylatcd tyrosine hydroxylase (TH-PO4), which possess a greater affinity for tetrahydrobiopterin cofactor, and subsequently enhances the synthesis of dopa and in turn dopamine (copied with permission from Roth et al., 1987).

378

M. EB^DXet al.

systems involving dopamine and peptides are varied in the central nervous system. For example, in the corpus striatum, in addition to dopamine, acetylcholine, -,,-aminobutyric acid, serotonin, glutamate, and aspartate, one also finds peptides such as enkephalin, Substance P, somatostatin, neuropeptide Y, cholecystokinin, neurotensin, and vasoactive intestinal peptide (for references see Hokfelt et al., 1987). Although many neuroleptics block dopamine receptors, they may have selective effects on the peptide(s) cotransmitting with dopamine in the striaturn and other parts of the brain. A few examples will be cited. A high degree of coexistence of cholecystokininand tyrosine hydroxylase-like immunoreactivities has been observed in the substantia nigra pars compacta (e.g. Seroogy et al., 1989). Moreover, ventral mesencephalic cholecystokinin projections encompass the full range of the well-known dopaminergic mesolimbic, mesostriatal, and mesocortical projections (Seroogy and Fallon, 1989). Therefore, it should not be surprising that the intrastriatally-injected cholecystokinin is able to stimulate dopamine-mediated transmission (Worms et al., 1986) and to elevate the density of brain D2-dopamine receptors (Dumbrille-Ross and Seeman, 1984). The chronic injection of haloperidol (Hong et al., 1985), but not clozapine (Sayers et al., 1975) increases selectively the concentration of enkephalins in the striatum. Protracted blockade of dopamine receptors by haloperidol causes a reduction in nigral content of Substance P-like immunoreactivity (Hanson et al., 1981), and of Substance P and Substance K mRNAs (Bannon et al., 1986). Moreover, the effects of haloperidol on Substance P is nonuniform in various areas of brain (Lindefors et al., 1986). Subchronic oral administration of lithium causes a time-dependent increase in the Substance P level in the striatum, which is prevented by coadministration of haloperidol (Hong et al., 1983). In PCI2 pheochromocytoma cells, lithium dramatically increases the intracellular levels of the neuropeptide neurotensin and the m R N A encoding it (Dobner et al., 1988). An extensive overlap between specific and high affinity neurotensin binding sites and dopamine perikarya and dendrites has been shown to occur in the mesocorticolimbic and nigrostriatal projection systems (Szigethy and Beaudet, 1989). Consistent with this observation are the results of observations showing that cocaine, an indirect sympathomimetic agent which enhances the extrapyramidal dopaminergic activity, increases dramatically the striatal content of neurotensinlike immunoreactivity (Hanson et al., 1989). Neuropeptide Y and catecholamine released from separate axon terminals may jointly influence the excitability of non-neuropeptide Y-containing neurons within the dorsal and ventral striatum. Furthermore, neuropeptide Y and

catecholamines are costored in few terminals of the nucleus accumbens (Aoki and Pickel, 1988). The role o f acetylcholine

The peripheral anticholinergic effects of neuroleptics which reduce sweating most probably do not play a major role in fever associated with neuroleptic malignant syndrome for the following reasons: the patients with neuroleptic malignant syndrome are diaphoretic ( 6 0 ° ) , and some neuroleptics with strong anticholinergic effects, such as thioridazine, produce a low incidence (5%) of malignant syndrome (Kurlan et al., 1984). The role o f prostaglandins

In addition to causing an alteration in the functions of various dopaminergic neurons in the brain, Yeragani and Chaitin (1987) have advanced a hypothesis that prostaglandins may be involved in the genesis of neuroleptic malignant syndrome. The evidence in support of this hypothesis is the observation that the intraventricular administration of prostaglandin El and E2 produces hyperthermia, stupor and catalepsy. Furthermore, substances such as aspirin, which inhibit the synthesis of prostaglandins, are antipyretic in nature. It is proposed that neuroleptics block dopamine receptors, enhancing the release of prolactin, stimulating the synthesis of prostaglandins. which in turn enhances Ca '-+ mobilization. Therefore, theoretically, one may be able to reverse the hyperthermia by administration of a dopamine receptor agonist such as bromocriptine or by enhancing the synthesis of dopamine by administration of levodopa/carbidopa, An alternate therapeutic regimen may be the administration of calcium channel blocking agents such as diltiazem or nimodipine. Elevations in the serum concentration of calcium have been reported in malignant hyperthermia (Gronert, 1980) and in neuroleptic malignant syndrome (Wang et al., 1985). Moreover, nifedipine, a calcium channel antagonist, has been suggested to be effective in neuroleptic malignant syndrome (Hermesh et al., 1988b). Other causes

Although a lack of consistent findings at autopsy in muscle, basal ganglia, and hypothalamus of patients with neuroleptic malignant syndrome has been reported (e.g. Morris et al., 1980), a recent case study by Horn et al. (1988) suggests that necrosis of the hypothalamic nuclei may be responsible for the syndrome. "'Microscopic examination of multiple sections of the hypothalamus revealed conspicuous bilateral loci of pyknosis and disintegration of neurons and sponginess of the neuropil in the anterior hypothalamus. These changes were slightly asymmetrical and limited to the group of neurons in the lateral hypothalamic area and tuberal nuclei. Also, a few pyknotic neurons were present in the ventral-medial hypothalamic nucleus. All the remaining hypothalamic nuclei showed perfect morphological preservation. The cerebral cortex revealed widespread small foci of nuclear pyknosis with increased cytoplasmic acidophilia, vacuolation, and disintegration of neurons. These changes were slightly more prominent in the third cortical layers, in the Sommer's sectors of Ammon's horn and generally in the depths of sulci. The white matter displayed

Neuroleptic malignant syndrome scattered small areas of poorly demarcated paleness of myelin. Purkinje cells of the cerebellum as well as many neurons in the pons showed cytoplasmic acidophilia and shrinkage of the nuclei. The basal ganglia, thalami, medulla oblongata, and spinal cord were not remarkable." (Horn et al.. 1988).

TREATMENT OF NEUROLEPT1C MALIGNANT SYNDROME

General treatments

The most important factor in treatment is the early recognition of the incipient syndrome and prompt discontinuation of neuroleptic medication. AIIsop and Twigley (1987) described a psychotic patient who developed neuroleptic malignant syndrome following administration of fluphenthixol. Since the treatment with dantrolene sodium was instituted too late, the patient died following massive intestinal hemorrhage, intraabdominal sepsis, and disseminated intravascular coagulation. The second step is to reverse the hypodopaminergic state, to institute supportive care, to monitor carefully nutrition and fluid balance, and to prevent prolonged immobility (Lazarus, 1986). In addition to blocking dopamine receptors in the hypothalamus, basal ganglia, and spinal cord, neuroleptics cause excessive release of calcium from the sarcoplasmic reticulum in peripheral muscle fibers, resulting in exaggerated muscular contraction and in enhanced thermogencsis (Caroff, 1980). Dantrolene or other muscle relaxants are useful (Goulon et al., 1983) when used in conjunction with dopamine enhancing substances. Furthermore, every attempt should be made to reduce morbidity and to avert mortality which are related to the development of cardiac problems, pneumonia, pulmonary embolus, and renal failure, secondary to myoglobinuria (Smego and Durack, 1982). Airway intubation and other supportive care may be required in some patients. The lack of fluid intake along with diaphoresis may result in dehydration requiring fluid supplementation. Furthermore, vigorous fluid therapy is needed to combat myoglobinuria. While dialysis may improve renal failure, neuroleptic agents are protein-bound and are not removed by dialysis. In treating neuroleptic malignant syndrome, it should be recalled that a significant variation may occur among patients. For example, it is generally presumed that neuroleptic malignant syndrome lasts for 5-10 days after discontinuation of oral neuroleptic (Sternberg, 1986). However, if the syndrome is caused by a long acting neuroleptic, such as fluphenazine enanthate, a more prolonged and severe case may be anticipated (Woo et al., 1986). In addition, patients who are receiving neuroleptics and suffer from heat stroke, may present with fever, rigidity, and elevated creatine kinase. However, their skin is dry and their blood pressure is low or normal (Westlake and Rastegar, 1973; M a n n and Boger, 1978). Moreover, neuroleptic malignant syndrome may occur in milder form following the administration of weaker dopamine depleting substances such as reserpine, and later develop fully in the same patient following the administration of a potent dopamine receptor blocking agent such as haloperidol (e.g. McCarthy, 1988). Finally,

379

neuroleptic malignant syndrome may be superimposed upon tardive dyskinesia (Haggerty and Gillette, 1987) making both the diagnosis and treatment difficult. "'Mr. A, a 30-year-old white male with a history of recurrent paranoid psychosis, was referred to our inpatient service for treatment of severe TD of approximately 3 years' duration. He had taken neuroleptic medication, including thioridazine, oral and depot fluphenazine, and trifluoperazine continuously for 7 years. His abnormal movements began in his tongue, and slowly progressed to involve his head, neck, trunk, and lower extremities. His family noted episodes of severe diaphoresis and hyperpyrexia, but was unable to measure his temperature. Approximately 1 month prior to admission, neuroleptics were discontinued, and lithium and diazepam initiated; psychotic symptoms were well controlled on this regimen. On admission, the patient was observed to have severe choreoathetoid movements involving all four extremities, spasms of his neck and back muscles, twisting movements of his neck and truck, grimacing, and occasional grunting; EEG, CT scan, and ceruloplasmin were normal. Serum LDH was slightly elevated. There was no family history of movement disorder. Lithium (900 mg/day; serum level 0.6 meq/ litre) and diazepam (30 mg/day) were continued. Reserpine was begun at 0.25 mg/day and was slowly increased over a 2-week interval to 1.25 mg/day. Initially he appeared to benefit, exhibiting a relative decrease in trunkal movements and having improved sleep. However, at doses of I-I.25 mg of reserpine, his movements became more pronounced, and he developed transient blood pressure elevations to 170/110 mmHg, intermittent diaphoresis, tachycardia, and pallor. Lithium and reserpine were discontinued. The patient developed intermittent stridor, dysphagia, and auditory hallucinations 5 days after the discontinuation of reserpine, and 3 days after discontinuation of lithium. He was considered to have acutely worsening TD, and was given two 50mg doses of thioridazine and one 5 6ag dose of haloperidol over 24 h. Following each dose, he fell asleep, and became free of movements for several hours. Within 4 h after receiving haloperidol, he became extremely rigid, and his rectal temperature rose to 100°F. White blood count increased to 24,000, and marked elevations were noted in CPK, LDH, and SGOT. Bromocriptine (5mg) was administered, producing a rapid (I.5 h) return to normal temperature and a significant reduction in rigidity. Subsequent course was complicated by the development of acute renal failure secondary to rhabdomyolysis (CPK>99,999U), which required renal hemodialysis. Bromocriptine was continued at a dose of 15mg/day. Unexplained temperature fluctuation, diaphoresis, and leukocytosis persisted intermittently for 7 weeks, and seemed to worsen whenever bromocriptine doses were withheld. Dyskinetic movements continued at the same level of severity as had been seen on admission, and were unaffected by a trial of lecithin and later increases in the bromocriptine dose to 27.5 rag/day. Three months after the onset of NMS, he was successfully weaned from bromocriptine and was discharged home." (Haggerty and Gillette, 1987). Since dopamine enhancing substances advocated in the treatment of neuroleptic malignant syndrome aggravate tardive dyskinesia, a physician may feel compelled to treat the potentially fatal neuroleptic syndrome.

380

M. EBADIet al.

Specific treatments

Bromocriptine

In neuroleptic malignant syndrome, central dopaminergic receptors are blocked and elevated levels of dopamine metabolites such as 3,4 dihydroxyphenylacetic acid and homovanillic acid have been found postmortem (Tollefson and Garvey, 1984). Therefore, the treament of choice is to reverse the hypodopaminergic state by administration of levodopa/ carbidopa, bromocriptine, or amantadine.

In 1983 several investigations (Granato et al., 1983; Mueller et al., 1983; Dhib-Jalbut et al., 1983; Zubenko and Pope, 1983) explored the beneficial effects of bromocriptine in reversing the syndrome. The recommended initial dose is 5.0--7.5 mg three times daily (Goidwasser and Hooper, 1988). If the syndrome has progressed to the point that the patient is unable to swallow the orally available bromocriptine, it is necessary to cause muscular relaxation by dantrolene (3 mg/kg four times daily). However, it should be stated that the hyperthermia in malignant syndrome does not respond to muscle relaxation alone (Birkhimer and Devand, 1984). Since dantrolene produces a rare but potentially fatal idiosyncratic hepatocellular injury, bromocriptine may be administered by a nasogastric tube in patients in whom a preexisting liver disease may preclude the use of dantrolene. Dhib-Jalbut et al. (1987) reported that the amount of bromocriptine mesylate to be given to a patient, depends on the body temperature and autonomic and extrapyramidal signs and symptoms. Therefore, in treating five patients with malignant syndrome, they have used 7.5-45.0 mg/day in three divided doses for ten days. In all five patients significant improvement in vital signs and reduction in creatine kinase was noted with 24-72 hr after initiation of bromocriptine treatment. Resolution of confusion and mutism was noted with 24-48 hr, and resolution of extrapyramidal rigidity occurred within one week. In two patients, early discontinuation of bromocriptine resulted in a relapse of the neuroleptic malignant syndrome, which responded to reinstitution of the drug (Dhib-Jalbut et al., 1987).

Levodopa-carbidopa

Levodopa-carbidopa (Sinemet 25/100) is often effective in reversing the hyperthermia and making the patient afebrile in hours. Treatment, however, may need to be continued for several days (e.g. Kulan et al., 1984). "A 24-year-old man shot himself in the abdomen in an apparent suicide attempt. Surgical correction of extensive intraabdominal injuries was required. The patient was postoperatively afebrile. On the fifth hospital day, 5 mg haloperidol was administered intramuscularly every 6h to combat agitation. Fever, resting tremor, and confusion appeared within 2 days, but haloperidol was continued for an additional 9 days. On the 16th hospital day, examination revealed the following; rectal temperature, 39~C; pulse, 120 beats/min; blood pressure, 140/80ram Hg; and respiratory rate, 32/min. The patient was diaphoretic, disoriented, and agitated. Hypokinetic dysarthria, blepharospasm, orofacial dystonia, cogwheel rigidity of both upper extremities, diffuse resting tremor, and opisthotonic posturing were prominent. White blood cell count was 31,000/mm ~, and creatine kinase was 440 IU/l. Cerebrospinal fluid (CSF) evaluation was normal, and no evidence of infection was found. Sodium dantrolene (2.5 mg/kg i.v) and benztropine (2 mg i.m.) were administered without benefit. On the 20th hospital day, carbidopa/levodopa (Sinemet 25/100) was administered t.i.d, by nasogastric tube, and the patient became afebrile within 4 hr of the initial dose. Sinemet 25/100 was gradually increased to 2 tablets q.i.d, and within 2 days the patient was alert and talkative. Neurological examination and vital signs completely returned to normal by the 25th hospital day. Sinemet dosage was tapered and discontinued over a 6-day period without recurrence of symptoms." (Kurlan, et al., 1984). Harris et al. (1987) reported a patient in whom malignant syndrome developed following haioperidol (15mg/day), and the therapy was initiated with dantrolene (10mg/kg/24hr). In this case, severe muscle rigidity resolved and temperature was reduced from 107 to 102°F following the administration of dantrolene. After 24hr when carbidopa/levodopa (25/100) treatment was started, the temperature dropped to 100°F. When subsequent carbidopa! levodopa was inadvertently not given, the temperature increased, despite continuous treatment with dantrolene (Harris et al., 1987). Hirschorn and Greenberg (1988) reported a case of levodopa-induced myoclonus combined with levodopa-withdrawal-induced neuroleptic malignant syndrome who was successfully treated with levodopa/carbidopa along with 2 mg/day of methysergide (a serotonin receptor antagonist). It has been suggested that prolonged levodopa therapy may result in deregulation of serotonergic transmission producing myoclonus (Klawans et al., 1975).

Dantrolene sodium (dantrium)

Dantrolene, a nitrophenylamino hydantoin derivative is a unique skeletal muscle relaxant, in that unlike competitive neuromuscular blocking agents (e.g. d-tubocurarine), depolarizing blocking agents (e.g. succinylcholine and decamethonium), and agents enhancing or mimicking GABAergic transmission (e.g.Diazepam and Baclofen), dantrolene exerts its effects by direct action on excitation-contraction coupling, and by reducing the amount of calcium released from sarcoplasmic reticulum (Van Winkle, 1976). Dantrolene, which depresses the CNS, does not affect neuromuscular transmission, nor does it change the electric properties of skeletal muscle membranes (Davidoff, 1978). Although the hepatotoxicity of dantrolene precluded its wide spread and chronic usage, it has proven beneficial in treating patients with spasticity associated with stroke, cerebral palsy, spinal cord injury, and multiple sclerosis. Furthermore, it is effective in reducing the muscular rigidity associated with malignant hyperthermia (e.g. Flewellen et al., 1983; Britt, 1984) and in neuroleptic malignant syndrome (e.g. Goulon et al., 1983; Bismuth et al., 1984). In malignant hyperthermia, a dose of 2.4 mg/kg is given by intravenous infusion for prophylaxis or initial treatment of hyperthermia (Flewellen et al., 1983). Britt (1984) recommended that dantrolene should be administered at a rate of I mg/kg/min while

Neuroleptic malignant syndrome monitoring EEG and until the heart rate and the temperature begin to fall and the muscle stiffness starts to subside. If necessary, the treatment may be repeated every minute, or otherwise a maintenance infusion of I-2 mg/kg per 3-4 hr be initiated, until all evidence of malignant hyperthermia has disappeared. In addition to levodopa or bromocriptine, dantrolene sodium produces rapid reversal of neuroleptic malignant syndrome (e.g. Delacour et al., 1981; Coons et aL, 1982: May et al., 1983; Granto et al., 1983; Greenberg and Gujavarty, 1985; Pope et al., 1986; Olmsted, 1988; Goldwasser and Hooper, 1988). The initial usual recommended dose of dantrolene, which may vary depending upon perceived need of the patient by the attending physician, (e.g. see Sullivan, 1987), is between 0.8 to 2.5mg/kg given intravenously every 6 hr (Goekoop and Cabaat, 1982) or between 0.25 and 3.0 mg given intraveneously every 6 hr (Granato et al., 1983; Coons et al., 1982). When symptoms abate and the patient is able to swallow, oral doses in the range of 100 to 200 rag/day may be substituted (May et al., 1983). Rapid resolution of symptoms (within 24 hr) is possible if treatment is begun early (Khan et al., 1985), though the usual course of treatment is 5-10days (Olmsted, 1988). Amantadine Although universal agreement on its efficacy does not exist, amantadine has been tried in the management of neuroleptic malignant syndrome (e.g. McCarron et al., 1982; Granato et al., 1983; Chayasirisobhan et al., 1983; Gangadhar et al., 1984; Lazarus, 1985a,b). Woo et al. (1986) reported a case of a 28-year-old Chinese female, who was diagnosed as "psychotic", received haloperidol 2.5mg i.m. twice, and 10 mg orally t.i.d, for 3 days. Four days before admission, after having received a total of 167.5 mg haloperidol, the patient developed neuroleptic malignant syndrome. Since no improvement was noted after discontinuing haloperidol, 3 weeks after hospitalization amantadine (100mg b.i.d.) was started. Within 24 hr, her level of consciousness became normal, the rigidity improved, the temperature fell to 37:C, and the pulse rate returned to normal. Since the patient remained asymptomatic, amantadine was stopped after 17 days. Within 24 hr, the patient became mentally withdrawn and the original symptoms returned, which necessitated the resumption of amantadine for months (Woo et al., 1986). Anticholinergic agents Anticholinergic drugs such as benztropine (Cogentin) are usually ineffective for the rigidity of neuroleptic malignant syndrome and do not affect the associated hyperthermia (De Rohan Chabot et al., 1982). However, Schrehla and Herjanic (1988) reported a schizoaffective patient who developed neuroleptic malignant syndrome, and did not respond completely with bromocriptine (5 mg p . o . t . i , d . ) but improved dramatically with 2 m g benztropine (i.m.) after initial treatment with bromocriptine. Benzodiazepine derit'ati~es Benzodiazepine derivates which enhance GABAergic function, have caused transient relief of

381

symptoms (Burke et al., 1981; Geller and Greydanus, 1979; Greenberg and Gujavarty, 1985; Lew and Tollefson, 1983; Morris et aL, 1980; Scarlett et al., 1983). Benzodiazepine derivatives have also been recommended to control "agitated" patients, while being treated for neuroleptic malignant syndrome (Goldwasser and Hooper, 1988; Olmsted, 1988). Electroconvulsive therapy ( E C T ) Addonizio and Susman (1987) presented data that ECT may be an effective treatment for persistently psychotic and agitated patient in whom there is a significant risk of recurrence of neuroleptic malignant syndrome on restarting neuroleptics. RECURRENCE OF NEUROLEPTIC MALIGNANT SYNDROME AND GUIDELINES FOR REINSTITUT1ON OF NEUROLEPTICS

McCarthy (1988) reported a fatal case of neuroleptic syndrome after a milder episode three months earlier. A 36-year-old man with a 22-year history of paranoid schizophrenia was admitted to hospital with marked generalized muscle rigidity, sweating, dysphagia, excessive salivation, drowsiness, and a pyrexia of 39"C. His anti-psychotic therapy was flupenthixol (80 mg i.m., fortnightly), trifluoperazine (20 mg b.d.) chlorpromazine (200 rag, nocte) and benztropine (2 mg, mane). His white cell count was 23.9 x 109/1, and his CPK level was mildly elevated at 249 IU/I, later rising to 299 IU/I (normal less than 190 IU/I). The results of tests on ESR 30, liver function, urea, creatinine, and electrolytes were normal. A chest x-ray and cultures of blood, urine, sputum, and a throat swab were negative. Fifteen years previously he had suffered a head injury requiring a craniotomy from which he had a residual facial palsy. On admission to hospital, he was treated with aspirin, antibiotics, fluids, and supportive care, and all neuroleptic drugs were stopped. His last dose of flupenthixol had been given 11 days before admission. He remained withdrawn with marked parkinsoniantype rigidity and profuse sweating. Vital signs showed marked fluctuation, his pulse varying from 70--150 beats per min, his blood pressure from 120/70 to 160/100mm HG and his respiration from 14-40 breaths per min. His pyrexia resolved on the third day after admission, but showed two further spikes of 38°C. On the sixth day he suffered a sudden cardiorespiratory arrest and did not respond to resuscitation. Postmortem examination showed the presence of a moderate bronchopneumonia and scars of his previous head injury, but was otherwise normal. The bronchopneumonia present was considered unlikely to have been the cause of death in this otherwise medically healthy man. The diagnosis of NMS was made. Six months previously, he had been admitted with a relapse of his illness. He was deluded, believing he was Jesus Christ, and that the doctors were agents of Satan who were unaware of his plans. He had auditory hallucinations was very agitated, and had marked formal thought disorder. Following initial treatment with chlorpromazine (200 rag, q.d.s.) and amylobarbitone sodium (200 rag, q.d.s.), his depot flupenthixol was reintroduced and increased to 80mg, fortnightly, 1 week following admission. One week later, trifluoperazine (10mg, b.d.) was started. Prescription of benztropine (2 mg, daily) and chlorpromazine (200 mg, nocte) was started I week later. Ten weeks later, he

382

M. EBADtet al. developed an acute illness. This was characterized by rigidity, a pyrexia of 38.5°C, tachycardia of 120 beats per min, hypertension of 150/100 mm Hg, drowsiness, profuse sweating, excessive salivation, and dysphagia. His white-cell count was 12.5 × 10~/litre, 87% neutrophils. A CPK level was not measured at the time, as the diagnosis of NMS was not considered. Although he had no signs of infection, his dosage of benztropine was increased (2 mg b.d.) and his fever was treated symptomatically. His neuroleptic medication was not altered. He appeared to make a full recovery over a 10-day period. A provisional diagnosis of viral illness coincident with an increase in drug-induced extrapyramidal symptoms was made at the time. The case is the first reported of a probable spontaneous remission of the symptoms of NMS without the discontinuation of neuroleptics. Although the first episode of the syndrome has been diagnosed retrospectively and CPK was not measured, we would feel that the probability is that it was a true case of NMS. There was no evidence for a viral illness causing the pyrexia and the provisional diagnosis was made in the absence of an obvious infective source and the failure to consider NMS (McCarthy, 1988).

Therefore, it is felt that the safest approach for prevention of recurrence is a regimen where low doses o f a low potency neuroleptic is prescribed, while contraindicating the concomitant usage of lithium (Susman and Addonizio, 1988).

RECAPITULATION A m o n g the complications of neuroleptic chemotherapy, the most serious and potentially fatal complication is malignant syndrome, which is characterized by extreme hyperthermia, "lead pipe" skeletal muscle rigidity causing dyspnea, dysphagia, and rhabdomyolysis, autonomic instability, fluctuating consciousness, leukocytosis, and elevated creatine phosphokinase. The incidence of neuroleptic malignant syndrome seems to be highest a m o n g neuroleptic treated schizophrenic patients 40 years or younger, following haloperidoi treatment, and in men (63%). M a n y diseases, such as malignant hyperthermia, lethal catatonia, thyrotoxicosis, tetanus, rabies, stiff-man syndrome and polymyositis; and numerous conditions such as heat stroke, anticholinergic toxicity, or strychnine poisoning mimic the cardinal features of neuroleptic malignant syndrome. The usual complications of neuroleptic malignant syndrome is respiratory failure, acute renal failure and cardiovascular collapse. Other reported but rare complications are myocardial infarction, periarticular ossification, peripheral neuropathy, respiratory distress syndrome, disseminated intravascular coagulation and necrotizing enterocolitis. The pathogenesis of neuroleptic malignant syndrome is most probably related to the blockade of dopaminergic receptors in the spinal cord, hypothalamus, and corpus striatum, reduction of dopaminergic functioning, and/or an alteration in the action of peptides such as cholecystokinin, neurotensin, substance P, or enkephalins coexisting with dopamine in various areas of brain. In addition, a modification in the prostaglandin-modulated calcium events may become an added precipitating factor. Indeed, calcium

channel blocking agents have been reported to be effective in mitigating the clinical problems in neuroleptic malignant syndrome. The treatment of neuroleptic malignant syndrome include (A) discontinuing immediately neuroleptics, (B) causing muscle relaxation by dantrolene sodium, and (C) administering dopamine function enhancing substances such as levodopa/carbidopa (Sinemet), bromocriptine, or amantadine. These treatments however, must be active, since fatalities have occurred in inappropriately treated or untreated patients. Acknowledgements--It is with great and heartfelt appreciation that the authors acknowledge the excellent secretarial skills of Mrs Lori Swigart who typed this review article in an admirable fashion. This report has been completed in part by financial supports provided from US PHS--ES03949 and NS-08932 (M.E.), from Sandoz Pharmaceutical Company (R.F.P.) and from US PHS--NS23975 (L.C.M.). REFERENCES

Addonizio G. and Susman V. L. (1987) ECT as a treatment alternative for patients with symptoms of neuroleptic malignant syndrome. J. CTin. Psychiat. 48, 102--105. Addonizio G.. Susman V. L. and Roth S. D. (1986) Symptoms of neuroleptic malignant syndrome in 82 consecutive inpatients. Am. J. Psychiat. 143, 1587--1590. Addonizio G., Susman V. L. and Roth S. D. (1987) Neuroleptic malignant syndrome: review and analysis of 115 cases. Biol. Psychiat. 22, 1004-1020. Akpinar S. (1987) Restless legs syndrome treatment with dopaminergic drugs. Clin. Neuropharmac. 10, 69-79. Ali A. H. M. (1985) The neuroleptic malignant syndrome: do we know enough? Jefferson J. Psychiat. 3, 45-49. Allsop P. and Twigley A. J. (1987) The neuroleptic malignant syndrome. Anaesthesia 42, 49- 53. Anderson S. A. and Weinschenk K. (1987) Peripheral neuropathy as a component of the neuroleptic malignant syndrome. Am. J. Med. 82, 169 170. Aoki C. and Pickel V. M. (1988) Neuropeptide Y-containing neurons in the rat striatum: ultrastructure and cellular relations with tyrosine hydroxylase-containing terminals and with astrocytes. Brain Res. 459, 205--225. Araki M., Takagi A., Higuchi I. and Sugita H. (1988) Neuroleptic malignant syndrome: caffeine contracture of single muscle fibers and muscle pathology. Neurology 30, 297-301. Aronson M. J. and Thompson S. V. (1950) Complications of acute catatonic excitement: a report of 2 cases. Am. J. Psychiat. 107, 216-220. Bamrah J. S. (1988) Neuroleptic-induced pyrexia: a benign variant. J. Nert'. Ment. Dis 176, 741-743. Bannon M. J., Lee J.-M.. Giraud P., Young A., Affolter H.-U. and Bonner T. I. (1986) Dopamine antagonist haloperidol decreases Substance P, Substance K, and preprotachykinin mRNAs in rat striatonigral neurons. J. Biol. Chem. 261, 6640-6642. Bayley S. J. (1979) Funnybones: a review of the problem of heterotopic bone formation. Orthop. Rev. 8, 113-120. Becker D., Birger M., Samuel E. and Floru S. (1988) Myocardial infarction: an unusual complication of neuroleptic malignant syndrome. J. Nert:. Ment Dis. 176, 377-378. Bell L. V. (1849) On a form of disease resembling some advanced stages of mania and fever. Am. J. Insanity 6, 97-127. Bernstein R. A. (1979) Malignant neuroleptic syndrome; an atypical case. Psychosomatics 20, 840, 845-846. Birkhimer L. J. and Devand C. L. (1984) The neuroleptic malignant syndrome: presentation and treatment. Drug Intell. Clin. Pharmac. 18, 462 465.

Neuroleptic malignant syndrome Bismuth C., De Rohan-Chabot P., Goulon M. and Raphael J. C. (1984) Dantrolene--a new therapeutic approach to the neuroleptic malignant syndrome. Acta Neurologica Scandinavica 100, 193-198. Bond W. S. (1984) Detection and management of the neuroleptic malignant syndrome. Clin. Pharmac. 3, 302-307. Brennan D., MacManus M., Howe J. and McLoughlin J. (1988) Neuroleptic malignant syndrome without neuroleptics. Br. J. Psychiat. 152, 578-579. Britt B. A. (1984) Dantrolene. Anesth. Soc. J. 31, 61-75. Britt B. A. and Kalow W. (1970) Malignant hyperthermia: a statistical review. Can. Anaesth. Soc. J. 17, 293-315. Britt B. A., Locher W. G. and Kalow W. (1969) Hereditary aspects of malignant hyperthermia. Can. Anaesth. Soc. J. 16, 89-98. Bunney B. S., Sesack S. R. and Silva N. L. (1987) Midbrain dopaminergic system: neurophysiology and electrophysiological pharmacology. In Psychopharmacology: The Third Generation of Progress (Edited by Meltzer H. Y.), pp. 81 94. Raven Press, New York. Burke R. E., Fahn S.. Mayeux R., Weinberg H., Louis K. and Willner J. H. (1981) Neuroleptic malignant syndrome caused by dopamine depleting drugs in a patient with Huntington's chorea. Neurology (New York) 31, 1022- 1026. Calmeil L. F. (1832) Dictionnaire de medecine ou repertoire general des sciences. Medicales sous le Rapport Theorique et Practique, 2nd end. Bechet, Paris. Campbell M., Grega D. M., Green W. H. and Bennett W. G. (1983) Neuroleptic-induced dyskinesia in children. Clin. Neuropharmac. 6, 207-222. Caroff S. N. (1980) The neuroleptic malignant syndrome. J. Clin. Psychiat. 41, 79--83. Caroff S. N., Rosenberg H. and Gerber J. C. (1983) Neuroleptic malignant syndrome and malignant hyperthermia. Lancet i, 244. Caroff S. N., Rosenberg H., Fletcher J. E., Heiman-Patterson T. D. and Mann S. C. (1987) Malignant hyperthermia susceptibility in neuroleptic malignant syndrome. Anesthesiology 67, 20- 25. Castillo E., Rubin R. T. and Holsboer-Trachsler E. (1989) Clinical differentiation between lethal catatonia and neuroleptic malignant syndrome. Am. J. Psychiat. 146, 324- 328. Chayasirisobhan S., Cullis P. and Veeramasuneni R. R. (1983) Occurrence of neuroleptic malignant syndrome in a narcoleptic patient. Hosp. Comm. Psychiat. 34, 548-550. Clarke C. E.. Shand D., Yuill G. M. and Green M. H. P. (1988) Clinical spectrum of neuroleptic malignant syndrome. Lancet 2, 969-970. Cohen S., Fligner C. L., Raisys V. A., Luthi R. and Dunner D. L. (1987) A case of nonneuroleptic malignant syndrome. J. Clin. Psychiat. 48, 287-288. Cohen W. J. and Cohen N. H. (1974) Lithium carbonate, haloperidol and irreversible brain damage. J. Am. Md. Assoc. 230, 1283-1287. Coons D. J., Hillman F. J. and Marshall R. W. (1982) Treatment of neuroleptic malignant syndrome with dantrolene sodium: a case report. Am. J. Psychiat. 139, 944- 945. Cox B. and Lee T. F. (1977) Do central dopamine receptors have a physiological role in thermoregulation? Br. J. Pharmac. 61, 83-86. Cox B.. Kerwin R. and Lee T. F. (1978) Dopamine receptors in the central thermoregulatory pathways of the rat. J. Ph.vsiol. (Lond.) 282, 471-483. Danzl D. F. (1988) Hyperthermic syndromes. Am. Family Physu'ian 37, 157-162. Davidoff A. R. (1978) Pharmacology of spasticity. Neurol. (Minm, apolis) 28, 46-51. Delacour J. L., Daoudal P., Chapoutot J. L. and Rocq B. (1981) Traitement du syndrome malin des neuroleptiques par le dantrolene. Nouv. Presse Med. 10, 3572-3573. GP 21.4--B

383

Delay J. and Deniker P. (1968) Drug-induced extrapyramidal syndromes. Handbook o f Clinical Neurology: Diseases o f the Basal Ganglia (Edited by Vinken P. J. and G. W. Bruyn), Vol. 6, pp. 248-266. Elsevier/North Holland, New York. Delay J., Pichot P., Lemperiere T., Elissalde B. and Peigne F. (1960) Un neuroleptique majeur non phenothiazinique et non reserpinique, l'haloperidol, dans le traitement des psychoses. Ann. Med. Psychol. I18, 145-152. Delay J., Pichot P., Lemperiere T. and Bailly R. (1962) L'emploi des butyrophenones en psychiatrie: etude statistique et psychometrique. In Symposium Internazionale Sull' Haloperidol E. Triperidol, Milano, pp. 305-.319. Demarest K. T., Riegle G. D. and Moore K. E. (1980) Characteristics of dopaminergic neurons in the aged male rat. Neuroendocrinology 31, 222-227. Denborough M. A., Forster J. F. A., Lovell R. R. H., Maplestone P. A. and Villiers J. D. (1962) Anaesthetic details in a family. J. Anaesth. 34, 395-396. De Rohan Chabot P. Elkharrat D., Conso F., Bismuth C. H. and Goulon M. (1982) Syndrome malin des neuroleptiques. Action benefique du dantrolene sur l'hyperthermie et la rigidite musculaire. La Nout, elle Presse Medicale 11, 1067-1069. Destee A., Petit H. and Warot M. (1981) Le syndrome malin des neuroleptiques. La Nouvelle Presse Medicale 19, 178. Dhib-Jalbut S., Hesselbrock R., Brott T. and Silbergeld D. (1983) Treatment of the neuroleptic malignant syndrome with bromocriptine. JAMA 250, 484-485. Dhib-Jalbut S., Hesselbrock R., Mouradian M. M. and Means E. D. (1987) Bromocriptine treatment of neuroleptic malignant syndrome. J. Clin. Psychiat 48, 69-73. Diamond J. M. and Hayes D. D. (1986) A case of neuroleptic malignant syndrome in a mentally retarded adolescent. J. Adol. Hlth Care 7, 419-422. Dobner P. R., Tischler A. S., Lee Y. C., Bloom S. R. and Donahue S. R. (1988) Lithium dramatically potentiates neurotensin/neuromedin N gene expression. J. Biol. Chem. 263, 13983-13986. Dubo H., Park D. C., Pennington R. J. T., Kalbag R. M. and Walton J. N. (1967) Serum-creatine-kinase in cases of stroke, head injury, and meningitis. Lancet 2, 743-748. Duke M. (1984) Neuroleptic malignant syndrome. Med. J. Aust. 141, 198-199. Dumbrille-Ross A. and Seeman P. (1984) Dopamine receptor elevation by cholecystokinin. Peptides 5, 1207-1212. Ebadi M. and Hama Y. (1988) Dopamine, GABA, cholecystokinin and opioids in neuroleptic-induced tardive dyskinesia. Neurosci. Behav. Rev. 12, 179-187. Evans D. L., Rogers J. F. and Peiper S. C. (1979) Intestinal dilatation associated with phenothiazine therapy: a case report and literature review. Am. J. Psychiat. 136, 970-972. Faurel J. P., Calmat A., Delas N., Courtine J. C., Adotti F., Gayet B., Neal J. F. and Gagey C. (1981) Enterocolites necrosantes apres prise prolongee de neuroleptiques. Med. Chir. Dig. 10, 9-13. Fiebel J. H. and Schiffer R. B. (1981) Sympathoadrenomedullary hyperactivity in the neuroleptic malignant syndrome: a case report. Am. J. Psychiat. 138, 1115-1116. Figa-Talamanca L., Gualandi C., DiMeo L., DiBattista G., Neri G. and LoRusso F. (1985) Hyperthermia after discontinuance of levodopa and bromocriptine therapy: impaired dopamine receptors a possible cause. Neurology 35, 258--261. Fletcher J. E. and Rosenberg H. (1985) In vitro interaction between halothane and succinylcholine in human skeletal muscle: implications for malignant hyperthermia and masseter muscle ridigity. Anesthesiology 63, 190-194.

384

M. EBADIet al.

Flewellen E. H., Nelson T. E., Jones W. P., Arens J. F. and Wagner D. L. (1983) Dantrolene dose response in awake man: implications for management of malignant hyperthermia. Anesthesiology 59, 275-280. Frankel M. H. and Spring G. K. (1982) Questions about combined lithium and haloperidol treatment. Am. J. Psychiat. 139, 537-538. Friedman E. and Gershon S. (1973) Effect of lithium on brain dopamine. Nature 243, 520-521. Friedman J. H., Feinberg S. S. and Feldman R. E. (1985) A neuroleptic malignant-like syndrome due to levodopa withdrawal. J. Am. Med. Ass. 254, 2792-2795. Friedman L. S., Weinrauch L. A. and D'Elia J. A. (1987) Metoclopramide-induced neuroleptic malignant syndrome. Arch Intern. Med. 147, 1495-1497. Gangadhar B. N., Desai N. G. and Channabasavanna S. M. (1984) Amantadine in the neuroleptic malignant syndrome. J. Clin. Psychiat. 45, 526. Garland D. E., Blum C. E. and Waters R. L. (1980) Periarticular heterotopic ossification in head-injured adults. Incidence and location. J. Bone Joint Surg. 62-A, 1143-1146.

G-elenberg A. J. (1976) The catatonic syndrome. ~Lancet 1, 1339-1341. Gelenberg A. J., Bellinghausen B., Wojcik J. D., Falk W. E. and Sachs G. S. (1988) A prospective survey of neuroleptic malignant syndrome in a short-term psychiatric hospital. Am. J. Psychiat. 145, 517-518. Geller B. and Greydanus D. E. (1979) Haloperidol-induced comatose state with hyperthermia and rigidity in adolescence: two case reports with a literature review. J. Clin. Psychiat. 40, 102-103. Gibb W. R. G. and Griffith D. N. W. (1986) Levodopa withdrawal syndrome identical to neuroleptic malignant syndrome. Postgrad. Med. J. 62, 59 60. Gjessing L. R. (1974) A review of periodic catatonia. Biol. Psychiat. 8, 23-45. Goekoop J. G. and Cabaat P. A. (1982) Treatment of NMS with dantrolene. Lancet 2, 49-50. Goldwasser H. D. and Hooper J. F. (1988) Neuroleptic malignant syndrome. Am. Family Phys. 38, 211-216. Goulon M., de Rohan Chabot P., Elkharrat D., Gadjos P., Bismuth C. and Conso F. (1983) Beneficial effects of dantrolene in the treatment of neuroleptic malignant syndrome: a report of two cases. Neurology 33, 516-518. Granato J. E., Stern B. J., Ringel A., Karim A. H., Krumholz A., Coyle J. and Adler S. (1983) Neuroleptic malignant syndrome: successful treatment with dantrolene and bromocriptine. Ann. NeuroL 14, 89-90. Greenberg L. B. and Gujavarty K. (1985) The neuroleptic malignant syndrome: review and report of three cases. Comp. Psychiat 26, 63-70. Gronert G. A. (1980) Malignant hyperthermia. Anesthesiology 53, 395-423. Haggerty J. H. Jr and Gillette G. M. (1987) Neuroleptic malignant syndrome superimposed on tardive dyskinesia. Br. J. Psychiat. 150, 104-105. Hama Y. and Ebadi M. (1986) The nullification by diazepam of haloperidol-induced increases in the level of striatal dopamine but not in the activity of glutamatic acid decarboxylase. Neuropharmacology 25, 1235-1242. Hanson G. R., AIphs L., Wolf W., Levine R. and Lovenberg W. (1981) Haloperidol-induced reduction of nigral Substance P-like immunoreactivity: a probe for the interactions between dopamine and Substance P neuronal systems. J. Pharmac. Exp. Ther. 218, 568-574. Hanson G. R., Smiley P., Johnson M.0 Letter A., Bush L. and Gibb J. W. 0989) Response by the neurotensin systems of the basal ganglia to cocaine treatment. Eur. J. Pharmac. 160, 23-30. Harris M., Nora L. and Tanner C. M. (1987) Neuroleptic malignant syndrome responsive to carbidopa/levodopa:

support for a dopaminergic pathogenesis. Clin. Neuropharm. 10, 186-189. Harsch H. H. (1987) Neuroleptic malignant syndrome: physiological and laboratory findings in a series of nine cases. J. Clin. Psychiat. 48, 328-333. Henderson V. W. and Wooten G. F. (1981) Neuroleptic malignant syndrome: a pathogenetic role for dopamine receptor blockade? Neurology 31, 132-137. Hermesh H., Aizcnberg D., Lapidot M. and Munitz H. (1988a) Risk of malignant hyperthermia among patients with neuroleptic malignant syndrome and their families. Am. J. Psychiat. 145, 1431-1434. Hermesh H., Molcho A., Aizenberg D. and Munitz H. (1988b) The calcium antagonist nifedipine in recurrent neuroleptic malignant syndrome. Clin. Neuropharm. 11, 552-555. Hirschorn K. A. and Greenberg H. S. (1988) Successful treatment of levodopa-induced myoclonus and levodopa withdrawal-induced neuroleptic malignant syndrome. A case report. Clin. Neuropharm. 11, 278-281. Hokfelt T., Johansson O., Holets V., Meister B. and Melander T. (1987) Distribution of neuropeptides with special reference to their coexistence with classical transmitters. In Psychopharmocology: The Third Generation of Progress (Edited by Meltzer H. Y.), pp. 401-416. Raven Press, New York. Hong J. S., Tilson H. A. and Yoshikawa K. (1983) Effects of lithium and haloperidol administration on the rat brain levels of Substance P. J. Pharmac. Exp. Ther. 224, 590- 593. Hong J. S., Yoshikawa K., Kanamatsu, T. and Sabol S. L. (1985) Modulation of striatal enkephalinergic neurons by antipsychotic drugs. Fedn Proc. 44, 2535-2539. Horn E., Lach B., Lapierre Y. and Hrdina P. (1988) Hypothalamic pathology in the neuroleptic malignant syndrome. Am. J. Psychiat. 145, 617-620. Hosie K. B., Dunning J. J., Bailey J. S. and Firmin R. K. (1988) Neuroleptic malignant syndrome after clozapine plus carbamazepine. Lancet 2, 1500. Itoh H., Ohtsuka N., Ogita K., Yagi G., Miura S. and Koga Y. (1977) Malignant neuroleptic syndrome--its present status in Japan and clinical problems. Folia Psychiat. Neurol. Jap. 31, 565 576. Johnson M. D., Newman J. H. and Baxter J. W. (1988) Neuroleptic malignant syndrome presenting as adult respiratory distress syndrome and disseminated intravascular coagulation. South. Med. J. 81, 543-545. Kaufmann C. A. and Wyatt R. J. (1987) Neuroleptic malignant syndrome. In Psychopharmacology: The Third Generation of Progress (Edited by Meltzer H. Y.), pp. 1421-1430. Raven Press, New York. Kellam A. M. P. (1987) The neuroleptic malignant syndrome, so-called a survey of the world literature. Br. J. Psychiat. 150, 752759. Kemperman C. J. F. (1989) Zuclopenthixol-induced neuroleptic malignant syndrome at rechallenge and its extrapyramidal effects. Br. J. Psychiat. 154, 562-563. Kennedy M. S. and Burks T. F. (1974) Dopamine receptors in the central thermoregulatory mechanisms of the cat. Neuropharmacology 13, 119-128. Khan A., Jaffe S. H., Nelson W. H. and Morrison B. (1985) Resolution of neuroleptic malignant syndrome with dantrolene sodium: case report. J. Clin. Psychiat. 46, 244-246. Kirby G. H. (1913) The catatonic syndrome and its relation to manic-depressive insanity. J. Nerv. Ment. Dis. 40, 694-704. Kirkpatrick B. and Edelsohn G. A. (1985) Risk factors for the neuroleptic malignant syndrome. Psychiat. Med. 2, 371-381. Klawans H. L. Goetz C. and Bergen D. (1975) Lcvodopainduced myoclonus. Arch Neurol. 32, 331-334.

Neuroleptic malignant syndrome Koehler P. J. and Mirandolle J. F. (1988) Neuroleptic malignant-like syndrome and lithium. Lancet 24131, 1499-1500. Kurlan R., Hamill R. and Shoulson I. (1984) Neuroleptic malignant syndrome. Clin. Neuropharmac. 7, 109-120. Ladame C. (1919) Psychose aigu~ idiopathique ou foudroyante. Schweiz Arch Neurol. Psychiat. 5, 3-28; 228. Langlow J. R. and Alarcon R. D. (1989) Trimipramineinduced neuroleptic malignant syndrome after transient psychogenic polydipsia in one patient. J. Clin. Psychiat. 50, 144-145. Larson J. M., Michalski J. P., CoUacott E. A., Eltorai D., McCombs C. C. and Madorsky J. B. (1981) Increased prevalence of HLA-B27 in patients with ectopic ossification following traumatic spinal cord injury. Rheumat. Rehab. 20, 193-197. Lazarus A. (1985a) Neuroleptic malignant syndrome: detection and management. Psychiat. Ann. 15, 706-712. Lazarus A. (1985b) Neuroleptic malignant syndrome and amantadine withdrawal. Am. J. Psychait. 142, 142. Lazarus A. (1986) Therapy of neuroleptic malignant syndrome. Psvchiat. Det,. I, 19. Lee T. H. and Tang L. M. (1988) Neuroleptic malignant syndrome. J. Neurol. 235, 324--325. Legras A., Hurel D.. Dabrowski G., Grenet D., Graveleau P. and Loirat P. (1988) Protracted neuroleptic malignant syndrome complicating long-acting neuroleptic administration. Am. J. Med. 85, 875-878. Levenson J. L. (1985) Neuroleptic malignant syndrome. Am. J. Psychiat. 142, 1137- 1145. Lew T. and Tollefson G. (1983) Chlorpromazine-induced neuroleptic malignant syndrome and its response to diazepam. Biol Psychiat. 18, 141- 146. Lindefors N., Brodin E. and Ungerstedt U. (1986) Neuroleptic treatment induces region-specific changes in levels of neurokinin A and substance P in rat brain. Neuropeptides 7, 265-280. Lingjaerde O. (1954) Delirium acutum: beitrag zum studium der pathogenese und der therapie. Arch. Psychiat. Z. Neurol. 192, 599- 612. Magrinat G., Danziger J. A.. Lorenzo J. C. and Fiemenbaum A. (1983) A reassessment of catatonia. Comp. Psychiat. 24, 218- 228. Mann S. C. and Boger W. P. (1978) Psychotropic drugs, summer heat and humidity, and hyperpyrexia: a danger restated. Am. J. Psychiat. 135, 1097-1100. Mann S. C., Caroff S. N., Bleier H. R., Welz W. K. R., Kling M. A. and Hayashida M. (1986) Lethal catatonia. Am. J. Psychiat. 143, 1374-1381. May D. C., Morris S. W., Stewart R. M., Fenton B. J. and Gaffney F. A. (1983) Neuroleptic malignant syndrome: response to dantrolene sodium. Ann. Int. Med. 98, 183-184. Marsden C. D. and Jenner P. (1980) The pathophysiology of extrapyramidal side-effects of neuroleptic drugs. Psychol. Med. 10, 55-72. Martin D. T. and Swash M. (1987) Muscle pathology in the neuroleptic malignant syndrome. J. Neurol. 235, 120-121. Martin M. L., Lucid E. J. and Walker R. W. (1985) Neuroleptic malignant syndrome. Ann. Emerg. Med. 14, 133-137. McCarron M. M., Boettger M. L. and Peck J. J. (1982) A case of neuroleptic malignant syndrome successfully treated with amantadine. J. Clin. Psychiat. 43, 381-382. McCarthy A. (1988) Fatal recurrence of neuroleptic malignant syndrome. Br. J. Psychiat. 152, 558-559. Meller E., Bohmaker K., Namba Y., Friedhoff A. and Goldstein M. (1987) Relationship between receptor occupancy and response at striatal dopamine autoreceptors. Molec. Pharmac. 31, 592-598. Meltzer H. Y. (1973) Rigidity, hyperpyrexia and coma following fluphenazine enanthate. Psychopharmacologia (Berlin) 29, 337-346.

385

Meltzer H. Y. (1976) Neuromuscular dysfunction in schizophrenia. Schizophren. Bull. 2, 106-135. Meltzer H. Y. and Moline R. (1970) Muscle abnormalities in acute psychoses. Arch Gen. Psychiat. 23, 481-491. Meltzer H. Y., Nunkin R. and Raftery J. (1971) Serum creatine phosphokinase activity in newly admitted psychiattic patients. Arch Gen. Psychiat. 24, 568-572. Mendelson L., Grosswasser Z., Najenson T., Sandbank U. and Solzi P. (1975) Petiarticular new bone formation in patients suffering from severe head injuries. Scan. J. Rehab. Med. 7, 141-145. Mietlants H., Vanhove E., de Neels J. and Veys E. (1975) Clinical survey of a pathogenic approach to petiarticular ossifications in long-term coma. Acta Orthop. Scan. 46, 190-198. Montplaisir R., Godbout R., Poirier G. and B6dard M. A. (1986) Restless legs syndrome and periodic movements in sleep: physiopathology and treatment with L-dopa. Clin. Neuropharmac. 9, 456--463. Moore K. E. (1987) Hypothalamic dopaminergic neuronal systems. Psychopharmacology: The Third Generath~n o f Progress (Edited by Meltzer H. Y.), pp. 127-139. Raven Press, New York. Morris H. H., McCormick W. F. and Reinarz J. A. (1980) Neuroleptic malignant syndrome. Arch Neurol. 37, 462-463. Morrison J. R. (1973) Catatonia: retarded and excited types. Arch Gen. Psychiat. 28, 39-41. Mueller P. S., Vester J. W. and Fermaglich J. (1983) Neuroleptic malignant syndrome-Successful treatment with bromocriptine. J. Am. Med. Ass. 249, 386-388. Murrin L. C. and Roth R. H. (1987) Nigrostriatal dopamine neurons: modulation of impulse-induced activation of tyrosine hydroxylation by dopamine autoreceptors. Neuropharmacology 26, 591-595. Murrin L. C. and Zeng W. (1989) Dopamine D~ receptor development in the rat striatum: early localization in striosomes. Brain Res. 480, 170-177. Olmsted T. R. (1988) Neuroleptic malignant syndrome: guidelines for treatment and reinstitution of neuroleptics. Southern Med. J. (U.S.A.)81, 888-891. Palmer H. A. (1941) Scheid's cyanotic syndrome J. Ment. Sci. 87, 635-638. Patterson J. F. (1988) Neuroleptic malignant syndrome associated with metoclopramide. South. Med. J. 81, 674-675. Pearlman C. A. (1986) Neuroleptic malignant syndrome. J. Clin. Psychopharmac. 6, 257-273. Peylan J., Goldberg I., Retter J. and Yosipovitch Z. (1987) Articular ossification after malignant neurolepsis. A case of schizophrenia treated with phenothiazines. Acta Orthop. Scand. 58, 284-286. Pfeiffer R. F. and Sucha E. L. (1985) On-off-induced malignant hyperthermia. Ann. Neurol. 18, 138-139. Pfeiffer R. F. and Sucha E. L. (1989) "On-off"-induced lethal hyperthermia. Movement Disorders (In press). Pollock R. (1973) Prior drug intake malignant hyperthermia. International Symposium of Malignant Hyperthermia (Edited by Gordon R. A., Britt B. A. and Kalow W.), Springfield, II1. Charles C. Thomas, New York. Pope H. G. Jr, Keck P. E., Jr and McElroy S. L. (1986) Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital. Am. J. Psychiat. 143, 1227-1233. Prasad C. (1987) Neuropeptide-dopamine interactions. I. Dopaminergic mechanisms in cyclo (His-Pro)-mediated hypothermia in rats. Brain Res. 437, 345-348. Quinn N. P., Koller W. C., Lang A. E. and Marsden C. D. (1986) Painful Parkinson's disease. Lancet 1, 1366-1369. Ritchie P. (1983) Neuroleptic malignant syndrome. Br. Med. J. 287, 560-561.

386

M. EBADIet al.

Roberts P. H. (1968) Heterotopic ossification complicating paralysis of intracranial origin. J. Bone Joint Surg. 50-B, 70-77. Rosenberg H. and Reed S. (1983) In vitro contracture tests for susceptibility to malignant hyperthermia. Anesth. Analg. 62, 415-420. Rosse R. and Ciolino C. (1985) Dopamine agonists and neuroleptic malignant syndrome. Am. J. Psychiat. 142, 270-271. Roth R. H., Wolf M. E. and Deutch A. Y. (1987) Neurochemistry of midbrain dopamine systems. Psychopharmacology: The Third Generation o f Progress (Edited by Meltzer H. Y.), pp. 81-94. Raven Press, New York. Ryan J. F. (1976) Malignant Hyperthermia. In Refresher Courses in Anesthesiology (Edited by Hershey S. G.), Vol. 4, pp. 75-86. J. P. Lippincott, Philadelphia, Penn. Sayers A. C., Burki H. R., Ruch W. and Asper H. (1975) Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine, haloperidol, loxapine and chlorpromazine. Psychopharmacologia 41, 97-104. Sazbon L., Najenson T., Tartakovsky M., Becker E. and Grosswasser Z. (1981) Widespread periarticular newbone formation in long-term comatose patients. J. Bone Joint Surg. 63-B, 120-125. Scarlett J. D., Zimmerman R., Berkovic S. F. (1983) Neuroleptic malignant syndrome. Aust. NZ J. Med. 13, 70 73. Schrehla T. J. and Herjanic M. (1988) Neuroleptic malignant syndrome, bromocriptine and anticholinergic drugs. J. Clin. Psychiat. 49, 283--284. Scchi G. P., Tanda F. and Mutani R. (1984) Fatal hyperpyrexia after withdrawal of levodopa. Neurology (New York) 34, 249-251. See R. E, Aravagiri M. and Ellison G. D. (1989) Chronic neuroleptic treatment in rats produces persisting changes in GABA^ and dopamine D-2, but not dopamine D-I receptors. Life Sci. 44, 229-236. Seroogy K. B. and Fallon J. H. (1989) Forebrain projections from cholecystokininlike-immunoreactive neurons in the rat midbrain. J. Comp. Neurol. 279, 415-435. Seroogy K. B., Dangaran K., Lim S., Haycock J. W. and Fallon J. H. (1989) Ventral mesencephalic neurons containing both cholecystokinin- and tyrosine hydroxylaselike immunoreactivities project to forebrain regions. J. Comp. Neurol. 279, 397-414. Shalev A. and Munitz H. (1986) The neuroleptic malignant syndrome: agent and host interaction. Acta Psychiat. Scand. 73, 337 347. Shalev A., Hermesh H. and Munitz H. (1988) The role of external heat load in triggering the neuroleptic malignant syndrome. Am. J. Psychiat. 145, 110-111. Shulack N. R. (1946) Exhaustion syndrome in excited psychotic patients. Am. J. Psychiat. 102, 466-475. Simpson D. M. and Davis G. C. (1984) Case report of neuroleptic malignant syndrome associated with withdrawal from amantadine. Am. J. Psychiat. 141,796-797. Smego R. A. and Durack D. T. (1982) The neuroleptic malignant syndrome. Arch Int. Med. 142, 1183-1185. Spring G. and Frankel M. (1981) New data on lithium and haloperidol incompatibility. Am. J. Psychiat. 138, 818 821. Stauder K. H., (1934) Die t6dliche Katatonie. Arch Psychiat. Ner~'enkr. 102, 614~34. Sternberg D. E. (1986) Neuroleptic malignant syndrome: the pendulum swings. Am. J. Psychiat. 143, 1273-1275.

Sternberg D. E., Bowers M. B., Heninger G. R. and Charney D. S. (1983) Lithium prevents adaptation of brain dopamine systems to haloperidol in schizophrenic patients. Psychiat. Res. 10, 79-86. Stoudemire A. (1982) The differential diagnosis of catatonic states. Psychosomatics 23, 245-252. Sukanova L. (1985) Maligni neurolepticky syndrom. (Neuroleptic malignant syndrome). Ceskoslovenska Psychiatrie 81, 91-95. Sullivan C. F. (1987) A possible variant of the neuroleptic malignant syndrome. Br. J. Psychiat. 151,689~90. Susman V. L. and Addonizio G. (1988) Recurrence of neuroleptic malignant syndrome. J. Nert'. Ment. Dis. 176, 234-24 I. Szigethy E. and Beaudet A. (1989) Correspondence between high affinity t~5l-neurotensin binding sites and dopaminergic neurons in the rat substantia nigra and ventral temental area: a combined radioautographic and immunohistochemical light microscopic study. J. Comp. NeuroL 279, 128-137. Taylor N. E. and Schwartz H. I. (1988) Neuroleptic malignant syndrome following amoxapine overdose. J. Nerr. Ment. Dis. 176, 249-251. Tibone J., Sakimura I., Nickel V. L. and Hsu J. D. (1978) Heterotopic ossification around the hip in spinal cord injured patients. A long-term follow-up study. J. Bone Joint Surg. 60-A, 769-775. Tollefson G. (1982) A case of neuroleptic malignant syndrome: In t,itro muscle comparison with malignant hyperthermia. J. Clin. Psychopharmac. 2, 266-270. Tollefson G. D. and Garvey M. J. (1984) The neuroleptic syndrome and central dopamine metabolites. J. Clin. Psychopharm. 4, 150--153. Tolsma F. J. (1941) Acute pernicious psychose. Folia Psychiatrica Neurologica Neurochirurgica Neerlandica 69, 10- 32. Toru M., Matsuda O., Makiguchi K. and Sugano K. (1981) Neuroleptic malignant syndrome-like state following a withdrawal of antiparkinsonian drugs. J. Nerr. Ment. Dis. 169, 324-327. VanWinkle W. B. (1976) Calcium release from skeletal muscle sarcoplasmic reticulum: site of action of dantrolene sodium. Science 193, 1130- 1131. Wang R. T., Aftergood D. E. and Carlson H. E. (1985) Hypercalcemia in the neuroleptic malignant syndrome. Arch Intern. Med. 145, 143-144. Wedzicha J. A. and Hoffbrand B. I. (1984) Malignant neuroleptic syndrome and hyponatraemia. Lancet i, 963. Weinberger D. R. and Kelly M. J. (1977) Catatonia and malignant syndrome: a possible complication of neuroleptic administration. J. Nero'. Merit. Dis. 165, 263 -268. Westlake R. J. and Rastegar A. (1973) Hyperpyrexia from drug combinations. J. Am. Med. Ass. 225, 1250. Woo J., Tech R. and Vallence-Owen J. (1986) Neuroleptic malignant syndrome successfully treated with amantidine. Postgrad. Med. J. 62, 809-810. Worms P., Martinez J., Brier C., Castro B. and Biziere K. (1986) Evidence for dopaminomimetic effect of intrastriatally injected cholecystokinin octapeptide in mice. Eur. J. Pharmac. 121, 395 401. Yeragani V. K. and Chaitin P. (1987) A prostaglandin theory of neuroleptic malignant syndrome. Med. Hypoth. 24, 143-149. Zubenko G. and Pope H. G. (1983) Management of a case of neuroleptic malignant syndrome with bromocriptine. Am. J. Psychiat. 140, 1619-1620.

Pathogenesis and treatment of neuroleptic malignant syndrome.

1. Neuroleptic drugs (antipsychotics) produce numerous side effects which include serious extrapyramidal symptoms consisting of akathisia, dystonia, n...
2MB Sizes 0 Downloads 0 Views