THE

AMERICAN

JOURNAL

OF

PSYCHIATRY

Neuroleptic

Malignant

Syndrome

James

L. Levenson,

M.D.

CASE

REPORTS

Neuroleptic malignant syndrome is a rare but serious adverse effect of antipsychotic medication. The author describes three new cases and reviews 50 others published in the past 5 years. Demographic and clinical features, diagnosis, treatment, outcome, and pathophysiology are critically reviewed, and a new set of diagnostic criteria, incorporating physical signs and routine laboratory tests, is proposed. (Am J Psychiatry 142:1137-1145, 1985)

euroleptic malignant but potentially fatal characterized dysfunction, laboratory serum malignant psychiatrists review than of 60 the cases results creatine syndrome in

syndrome idiosyncratic by and muscular altered

is an

uncommon reaction fever,

to

neuroleptics, autonomic Pertinent an elevated roleptic French Caroffs (2), more literature. has since reported in the recent syndrome

rigidity, consciousness. leukocytosis level. first At reported the time

include phosphokinase was 1960 (1).

and Neuby of

syndrome, had been

published in 1980 reported in the world malignant SO cases syndrome have been

Interest flourished

in neuroleptic (3-7), and

in the English and past S years (8-41). reports with of treatment dantrolene

French
There of of of (8-16)

language
have or been

literature
several malignant

neuroleptic

bromocriptine of I

Our understanding neuroleptic malignant syndrome report here three more cases syndrome ment in review. Received
Division
atry,

(16-19).

the pathogenesis remains speculative. neuroleptic malignant the course and since Caroffs treat1980

and these

critically and the

analyze SO cases

Aug.

22,

1984;

of Consultation/Liaison

quests

Medical College of to Dr. Levenson,

1985

accepted Nov. 28, 1984. From the Psychiatry, Department of PsychiVirginia, Richmond. Address reprint reBox 268-MCV Station, Richmond, VA
Psychiatric Association.

23298. Copyright

American

Case I . Mr. A, a 22-year-old man with one past psychiatric hospitalization for psychotic depression treated with haloperidol, was admitted to a Richmond hospital for agitation and violent outbursts. He received haloperidol, S mg every 2 hours, and benztropine mesylate, 2 mg i.m. twice a day. Three days later he was committed to a state hospital, where he remained agitated and confused. Haloperidol was stopped and thiothixene, S 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, with fever (101-103#{176}F) 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 the Medical College of Virginia Hospital, where he was noted to have extreme rigidity, fluctuating consciousness, profuse diaphoresis, generalized tremors, tachycardia (1 10-136 beats/minute) and tachypnea (up to 40 respirations/minute). His blood pressure varied between 120 and 160 mm Hg, systolic, and 80 and 100 mm Hg, diastolic. His temperature on admission was 99#{176}F and increased to 103#{176} during his stay in the intensive care unit; he was without documented infection. He had difficulty swallowing and required tracheal intubation. His WBC count and differentials were normal on admission but became elevated to 18,100/mm3. The results of a head CAT scan, EEG, and lumbar puncture were normal. A respite in symptoms occurred after 70 mg of intravenous dantrolene was administered, but less than 1 hour after the infusion was completed Mr. A had total body rigidity and diaphoresis again. He was treated with intravenous hydration, dantrolene, SO mg every 6 hours by nasogastric tube, and bromocriptine, 5-7 mg every 8 hours by nasogastric tube, with significant improvement. Up to 160 mg/day of propranolol was given to control tachycardia. Both dantrolene and bromocriptine were discontinued after 48 hours, when results of liver function tests suggested a druginduced hepatitis. Simultaneously, Mr. A had received intravenous amobarbital sodium, 35-100 mg/hour for S days, after a trial dose had produced marked decrease in rigidity. The patients neuroleptic malignant syndrome resolved with supportive care. His serum creatine phosphokinase level

Am

Psychiatry

142:10,

October

1985

1137

NEUROLEPTIC

MALIGNANT

SYNDROME

reached a maximum of 8825 U/liter (all MM fraction) and normalized in about 1 month. After resolution of the neuroleptic malignant syndrome, Mr. A remained depressed, delusional, and intermittently mute. Nortriptyline, 75 mg h.s., was started, and there was some improvement in his depressive symptoms. Twenty-six days after the neuroleptic malignant syndrome had begun, he was given perphenazine; an increase in dose over 14 days to 50 mg/day resolved his psychosis. His pulse, blood pressure, and temperature were closely monitored and remained normal. Six weeks after starting perphenazine, Mr. A was discharged, neither depressed nor delusional. At 6-month follow-up, he was still taking SO mg/day of perphenazine and 75 mg/day of nortriptyline and was functioning well, without any adverse effects of the medication.

of a cardiorespiratory arrest from which resuscitated. The presumed cause of death embolus, but no autopsy was performed. This muscular case was unusual The because patients of response

he could not was a pulmonary

be

the

absence to dantrolene

of

rigidity.

and and
(24,

bromocriptine renal insufficiency

with This patients 29).

was

equivocal. occurred;
death reminds

Rhabdomyolysis these are common

malignant us of syndrome the lethal

complications

neuroleptic

risk

of neuroleptic

malignant

syndrome.

This

patient

has

been

described

at length

elsewhere

(42). He appeared bromocriptine, but

maturely icity period. improvement demonstrates (43, withdrawn 44).

to benefit from these medications

because of therapy suspected

dantrolene had to
with

be

and pre-

hepatotoxintravenous

Nonspecific

amobarbital

seemed
It is difficult to

beneficial to decide
to

over a more extended how much of the clinical

each drug. His of case neuroleptic also

attribute without (42).

that

neuroleptics

can
recurrence

sometimes

be

safely reintroduced malignant syndrome

Case 2. Mr. B, a 32-year-old mentally retarded man with chronic schizophrenia, had received trifluoperazine intermittently for many years. In March 1984 he was restarted on a regimen of trifluoperazine, S mg b.i.d. Two days later he was admitted to the Medical College of Virginia Hospital, mute and stuporous, with fever (104#{176}F), tachycardia (160 beats/minute), tachypnea (24 respirations/minute), and depressed tendon reflexes. His blood pressure fluctuated between I 10/40 mm Hg and 140/100 mm Hg. He had no rigidity or tremor. Laboratory results included a WBC count of 15,000/mm3 and creatine phosphokinase level of 4500 U/liter (100% MM fraction). Mild renal failure was present, with BUN at 41 mg/100 ml, a creatinine level of 3.4 mg/100 ml, and a hyperosmolar state (osmolality, 357 mosmol/kg of water; serum sodium level, 152 meq/liter). Myoglobin was detected as 3 + in the urine. Results of a cranial CAT scan, lumbar puncture, and EEG all were normal. Dantrolene, 100 mg i.v. every 6 hours, was given for 24

hours

without

effect

and then

discontinued.

The

day after

he

was admitted to the hospital, he began taking bromocriptine, 2.5 mg t.i.d. by nasogastric tube; the dose was increased to four times a day the next day. Improvement was gradual, and the dose of bromocriptine was decreased to 2.5 mg b.i.d. on hospital day 5, when the patient began to communicate and his temperature fell to 100.8#{176}F.By hospital day 7, Mr. B was afebrile, with normal heart rate, blood pressure, and respirations. His renal function had returned to normal, but his creatine phosphokinase level had abruptly risen from 4000 U/liter on day S to more than 24,000 U/liter on day 7. There was still no rigidity or tremor and no seizures had occurred, nor had he received any intramuscular injections. Bromocriptine, 2.S mg b.i.d., was continued, and dantrolene, 100 mg p.o. four times a day, was added on day 7. Mr. Bs serum creatine phosphokinase level gradually fell to 700 U/liter by day 13. His vital signs were normal, but he remained withdrawn and bedridden. He died later that day

Case 3. Ms. C, a 42-year-old woman with a 20-year history of intermittent catatonia and paranoid psychotic symptoms, had been given a diagnosis of schizoaffective disorder. She had had multiple psychiatric hospitalizations, several courses of ECT, and years of oral and parenteral antipsychotic medications. When she was transferred from a state psychiatric hospital to the Medical College of Virginia Hospital, she was mute and catatonic, with flexure contractions. At the state hospital, her chronic rigidity had become acutely worse during treatment with chlorpromazine. A neurologist had diagnosed modified neuroleptic malignant syndrome and advised against further use of neuroleptics. At our hospital, trials of loxapine, lithium, ECT (32 treatments), oral and parenteral tricyclic antidepressants, carbamazepine, and diazepam failed to produce improvement. Four months after admission, Ms. C received two doses of trifluoperazine, S mg, with benztropine mesylate, 1 mg. By the next day, she had developed much increased rigidity, fever (101#{176}F),tachycardia (104 beats/minute), tachypnea (28 respirations/minute), hypertension ( 1 56/1 1 2 mm Hg), diaphoresis, waxing and waning consciousness, and leukocytosis (WBC count of 14,000/mm3). Her serum creatine phosphokinase level was normal (56 U/liter) and never became elevated. Urinary myoglobin was not detected, and liver function tests and lumbar puncture showed no abnormal results. Neuroleptic and anticholinergic medications were immediately discontinued. All signs disappeared gradually during the next 2 days, except for the hypertension and rigidity, which declined gradually over another 48 hours. Intravenous dantrolene (two doses of 60 mg each) and lorazepam (two doses of 2 mg each) during the first 48 hours had no discernible effect on the gradually declining signs. Ms. Cs psychosis, with both manic and schizophrenic characteristics, continued, but no neuroleptics were given. She was transferred back to the state hospital 1 month later, on a regimen of lorazepam, nortriptyline, and lithium. Six months after the episode of neuroleptic malignant syndrome, she remained in the state hospital, taking 10 mg/day of lorazepam, 300 mg b.i.d. of lithium carbonate, and SO mg b.i.d. of chlorpromazine. She had tolerated chlorpromazine for 4 months, and the only adverse effect she had experienced was slight rigidity.

Like
roleptic neuroleptics

many

other

patients

who
before

have
Ms.

developed

malignant for

syndrome, many years syndrome not appear

C had developing

neureceived
neurodose. of her

leptic malignant Dantrolene did

after a relatively to affect the

small course

gradual kinase
neuroleptics rence of

improvement. level is atypical.

were neuroleptic

Her As

normal creatine in the case

restarted syndrome.

of

phosphoMr. A,
recur-

cautiously malignant

without

1138

Am

Psychiatry

142:10,

October

1985

JAMES

L. LEVENSON

CASE

ANALYSIS

AND

REVIEW

TABLE 1. Primary and Secondary Diagnoses of 53 Patients Who Developed Neuroleptic Malignant Syndrome
Diagnosis Primary disorder Schizoaffective disorder Parkinsons disease Amphetamine psychosis Heroin withdrawal Huntingtons chorea Poorly described Unspecified Secondary
Mental retardation Schizophrenia Major affective

Analysis

published
information

of cases of neuroleptic malignant syndrome since Caroffs review in 1980 (2) can provide about the demographics, previous psychi-

Number

of Patients

atric

diagnosis,

previous

medications,

symptoms

and

18
11 2 2 1 1 1 7 10 4 4 2 2 1 1

signs of neuroleptic malignant syndrome, laboratory data, treatment response, morbidity, mortality, and implications for further psychiatric treatment. Unfortunately, some authors provide incomplete descriptions of their cases, and this hampers our analysis. For example, the absence of any mention of tachycardia or leukocytosis in a case report may indicate that the patients heart rate or WBC count was normal, or it may indicate that the author failed to describe some abnormal signs. In the following discussion, patients history, physical findings, and laboratory data are included in the summary only if they were explicitly described. This explains the inconsistent number of patients listed with respect to clinical variables. The treatment and outcome of neuroleptic malignant syndrome are sometimes similarly obscured by incomplete reporting and the general lack of follow-up information.

Alcoholism Trauma Seizure disorder Cerebral palsy Narcolepsy

TABLE 2. Medications Taken by 53 Patients Who Developed Neuroleptic Malignant Syndrome

Number Patients
20a

of

Medication Neuroleptic(s) Neuroleptics alone plus anticholinergic/ Neuroleptic plus lithium Neuroleptics plus lithium plus anticholinergic Neuroleptics, other drugs not specified (13) Lithium plus benzodiazepine Tetrabenazine plus ce-methyltyrosine Withdrawal from L-dopalcarbidopa and amantadine
aTwo patients were also receiving bincludes tricyclic antidepressants One dOne tOne patient patient patient had also also anticonvulsants. andlor antiparkinsonian for and 10 years. amantadine. drugs.

Men
(N=

comprised

68%

(N32)

and

women

32%

15) of the patients whose sex was reported-the same male to female ratio as in the three new cases I have described. Patients ranged in age from 12 to 78 years, with a mean of 38 years. Their preexisting
primary neuropsychiatric diagnoses and secondary as-

sociated

diagnoses are shown in table 1. Of the patients for whom there is sufficient diagnostic information, 50% were schizophrenic and most of the remainder had affective disorders. Neuroleptic malignant syndrome is not limited to psychiatric patients, however; uncommon cases are reported with Huntingtons chorea and Parkinsons disease. Medications

1SC 3 6C 6 1 I I

been abusing amphetamines received deanol. received L-dopa/carbidopa

cyclic

antidepressant),

and (46).

alcohol

in

another

patient

also
lignant

produced
syndrome

a syndrome

resembling out

neuroleptic

ma-

At the
syndrome, medications neuroleptics, neuroleptics geslive of
Nearly

time

they

developed

neuroleptic

malignant

the patients were taking a wide variety of (table 2). Fifty of the 53 were receiving and many had been treated with for a long time without any history sugprevious neuroleptic malignant syndrome.
of the patients (excluding those whose

Many neuroleptic patients

authors have pointed malignant syndrome received halopenidol

that most cases of have appeared after on depot fluphenazine.

Of the

SO patients

in our

series

who

received

neuroalthough the other

Another On

leptics (table 3), 56% received for only 16% was it the sole
40% 30% were of the taking multiple were SO patients

halopenidol, neuroleptic;
drugs. fluphenazine. taking

half

neuroleptic

medications were unspecified) received anticholinergic drugs (antiparkinsonian and/or antidepressant agents), and about 20% were taking lithium. Neuroleptic malignant syndrome occurred in three patients without any described exposure to neuroleptics. Two cases were precipitated by withdrawal of dopaminergic agonists (L-dopa/carbidopa and amantadine) (27, 37). One patient had been taking amphetamines for more than 10 years (22). One case of neuroleptic malignant syndrome was reported, but not detailed, that was attributed to the patients having taken metaclopramide combined with cimetidine (45). An overdose of multiple benzodiazepines, phenelzine, dothiepin (a tn-

the basis of this experience, some authors have concluded that halopenidol and fluphenazine carry a higher risk of causing neunoleptic malignant syndrome (13), but this conclusion is premature and not the only plausible explanation. First, one must take into account the frequency with which a drug is prescribed. If all neuroleptics caused neuroleptic malignant syndrome with equal frequency, one would expect a higher incidence of neuroleptic malignant syndrome with the most commonly used medications. At my own institution during 1983, 66% of the prescriptions for parenteral neuroleptics were for halopenidol. On the

Am

Psychiatry

142:10,

October

1985

1139

NEUROLEPTIC

MALIGNANT

SYNDROME

TABLE 3. Neuroleptics Taken by 50 of 53 Patients Who Developed Neuroleptic Malignant Syndrome

Medication Number of Patientsa

TABLE 4. Clinical and Laboratory Neuroleptic Malignant Syndrome

Signs in 53

Patients

With

Haloperidol
Fluphenazine Chlorpromazine Trifluoperazine Thioridazine Thiothixene or derivatives

28
iS 8 6 S 2 Clinical Fever Elevated Sign serum creatine
level

Number of Patients for Whom Sign Was Mentioned 53

32 33 4S 45 24

Patients With Si N 52
31 30 40 38 19

% 98
97 91 89 84 79

Other
The

7
number of patients because many patients

phosphokinase Tachycardia

Rigidity
Altered consciousness Leukocytosis

sum is greater than the total received more than one drug.

Abnormal Tachypnea

blood

pressure

39
33 42 38

29
24 28 17

74
73 67 45

average, it was prescribed 3 #{189}imes t as often as parenteral chlorpromazine and an average of 18V2 times as often as any other individual neuroleptic. Oral haloperidol was prescribed twice as often as oral chlorpromazine and 5/2 times as often as other mdividual neuroleptics. In a recent study of neuroleptic prescriptions in a private Boston hospital (47), haloperidot was more frequently prescribed than any other drug. In addition, haloperidol and fluphenazine hydrochloride were prescribed at much higher chlorpromazine-equivalent doses than popular low-potency agents were. This was true both in the private sector and in a large Veterans Administration sample. If neuroleptic malignant syndrome is sometimes dose related, we would therefore expect an association with haloperidol.
Furthermore, sicker patients may be at higher risk

Profuse
Tremor

diaphoresis

Incontinence

38

21

creased ivation, curred

or diminished deep and opisthotonos. in four patients.

tendon Grand

reflexes, hypersalmat seizures oc-

Laboratory

data

included

elevated

serum

creatine

for neuroleptic malignant syndrome because of dehydration, exhaustion (48), malnutrition, or the use of restraints. It may also be that sicker patients are more likely to receive haloperidol than other neuroleptics. Haloperidol is often chosen for the medically ill because of the lower risk of hypotension and anticholinergic side effects. It is also the drug most often used for rapid, high-dose neuroleptization (49). Concern about depot fluphenazine rests on a different issue. The first and perhaps most important step in the treatment of neuroleptic malignant syndrome is early recognition of the syndrome and discontinuation of neuroleptics. Because of the greatly extended halflife of depot neuroleptics, significant blood levels of these drugs will remain for weeks. Clinical Signs

phosphokinase levels in all but one of the patients for whom they were reported; most patients had levels in the range of 2,000-15,000 U/liter, but six had values below 600 U/liter, and two had levels that exceeded 100,000 U/liter. WBC counts ranged from slight elevations to as high as 29,000/mm3. Hepatic enzymes were occasionally mildly elevated. Only one of the eight patients for whom such information was given had a positive test for urinary myoglobin. Results of cerebral CAT scans were normal in 15 patients, as were radionuclide brain scans in four more. Lumbar puncture was performed in 28 of the patients, and the only positive finding was a slightly elevated CSF protein level in three. Sixteen patients had EEGs and seven showed nonspecific abnormalities (with no consistent pattern among them). Muscle biopsy was performed in eight patients. One showed neurogenic atophy (36), one myogenic degeneration (32), and one mixed myoneuropathic changes (24). The results of one patients biopsy were interpreted as normal (21), and four patients showed nonspecific changes (9, 29, 33). Only one autopsy has been reported (31), in which there were no significant findings. Treatments Patients received a variety of treatments (table S). Dantrolene has been the most frequently tried, suggested by its successful use in treating a phenomenologically similar syndrome, malignant hyperthermia (SO, Si). Bromocriptine, a dopamine agonist, has been used on the basis of the theory that neuroleptic malignant syndrome is a consequence of CNS dopamine blockade (16, 18). The rationale for the other treatments appears mainly empirical. It is difficult to compare the response to dantrolene
and/or bromocriptine with that resulting from other

Clinical signs of neuroleptic malignant syndrome in the series of 53 patients are summarized in table 4. Most patients temperatures were in the range of 101-104#{176}F; the highest temperature was 107.6#{176}F, and there was only one afebrile patient. Fever, tachycardia,

rigidity,

altered

consciousness,

abnormal

blood

pres-

sure, tachypnea, and diaphoresis each occurred in more than two-thirds of the patients. Blood pressure was usually elevated, but hypotension and labile blood pressure were also noted. Many other clinical signs of lesser frequency were reported, including dysarthria, dysphagia, mutism, positive Babinskis reflexes, in-

treatments.

Comparison

is complicated

by

the

intro-

1140

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Psychiatry

142:10,

October

1985

JAMES

L. LEVENSON

TABLE 5. Treatments Malignant Syndrome

Treatment

Used for 53

Patients

With Neuroleptic

Number

of Patientsa

Dantrolene
Bromocriptine Benzodiazepines Propranolol
Anticholinergic Amantadine L-Dopa/carbidopa

or barbiturates
drugs

14 6 9 3
7 4 2

Curare
ECT Supportive aMany patients or unspecified more than one kind of treatment.

1
2 20

received

duction of treatment at varying or unspecified times after the onset of neuroleptic malignant syndrome, variation in the signs that were said to respond to treatment, and incomplete documentation of response. If all patients who received dantrolene and/or bromocriptine are compared to those who did not, the course of neuroleptic malignant syndrome does not appear dramatically different between groups; it usually lasted from a few days to a couple of weeks. In individual cases in which dantrolene appeared more helpful, it is not clear whether there was actual benefit from the drug. An alternative explanation would be that those physicians who knew of the possible benefits were more educated about neuroleptic malignant syndrome and were therefore likely to diagnose and treat it sooner (i.e., stop the neuroleptic sooner). Complications of neuro(24, 29), reported in 14 (26%) of the 53 patients in this report (the actual prevalence was probably higher). Rhabdomyolysis is an acute, diffuse breakdown of muscle tissue that may have many causes, including crush injury, severe muscle strain, infarction, alcohol consumption, heat stroke, prolonged immobilization, malignant hyperthermia, neuroleptic malignant syndrome, and metabolic disorders. Rhabdomyolysis produces extremely high serum creatine phosphokinase levels, hyperkalemia, myoglobinuria, and acute renal insufficiency. The etiology of renal failure in patients with neuroleptic malignant syndrome appears to be predominantly rhabdomyolysis. Ten of the 53 patients had acute renal failure, and most of them required temporary dialysis. The cause of acute respiratory failure is less clear but may involve aspiration, infection, shock, and pulmonary emboli. Ventilator support was necessary for the 10 patients who had this complication. Other complications included one instance each of myocardial infarction, pulmonary embolus, hepatic failure, diffuse intravascular coagulation, sepsis, and F. co/i fasciitis. Eight of the 53 patients died; this 15% mortality rate is slightly less than the 20% rate cited by earlier authors (2, 48). The leptic most common serious malignant syndrome complication is rhabdomyolysis

Unfortunately, little information has been provided about the course of these patients after resolution of the acute episode of neuroleptic malignant syndrome. The patients in cases 1 and 3 described in this paper are the only ones in the series with follow-up as long as 6 months. In both, neuroleptics were cautiously but safely reintroduced for chronic severe psychotic symptoms (42). Most patients with neuroleptic malignant syndrome have psychiatric disorders that raise the question of retreatment. Mueller et at. (18) described a patient with signs and symptoms of neuroleptic malignant syndrome that were thought to be secondary to her treatment with haloperidol. After resolution of the syndrome, she was started on thioridazine and later took thiothixene without recurrence of neuroleptic malignant syndrome. In another case (33), a woman who had recovered from neuroleptic malignant syndrome attributed to haloperidol was restarted on haloperidol less than 2 weeks after her first episode; neuroleptic malignant syndrome recurred, supportive measures were reinstituted, and haloperidol was stopped. After her recovery from the second episode of neuroleptic malignant syndrome, the patient was treated with thioridazine without recurrence of fever, rigidity, or elevation of her creatine phosphokinase level. She was observed for S weeks, discharged, and seen 1 month later, still without symptoms of neuroleptic malignant syndrome. Kleinknecht et at. (29) reported a schizophrenic patient who developed neuroleptic malignant syndrome after receiving a combination of drugs including diazepam, levopromethazine, and sulpiride. Three months later the patient was given fluphenazine and within 24 hours had a temperature of 40#{176}C, iffuse d hypertonia, diaphoresis, and a creatine phosphokinase level of more than 4800 U/liter. Bernstein (20) discussed a manic woman who developed symptoms of neuroleptic malignant syndrome after taking trifluoperazine, haloperidol, and chlorpromazine. Lithium was started, and then molindone was added without any difficulty. Rechallenge with haloperidol precipitated symptoms of neuroleptic malignant syndrome. Haloperidol was discontinued and molindone restarted with no subsequent problems. Burke et al.s patient with Huntingtons chorea (21) was given haloperidol 6 weeks after an episode of neuroleptic malignant syndrome without adverse effects.

DIFFERENTIAL

DIAGNOSIS is of prime importance in the neuroleptic malignant synthat can be easily mistaken for syndrome include rhabdomyolmalignant hyperthermia, severe

Differential diagnosis patient with suspected drome. Other disorders neuroleptic malignant
ysis mass from other causes, heat stroke

dystonic
lesions,

reactions,

catatonia,

CNS

infection,

CNS
allergic

(neuroleptic-related),

drug reaction, toxic encephalopathy (e.g., lithium or strychnine, or anticholinergic

reactions delirium),

to

Am

Psychiatry

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October

1985

1141

NEUROLEPTIC

MALIGNANT

SYNDROME

hyperthyroidism, tetany (low levels of calcium or magnesium electrolytes), and Parkinsons disease. The presence of fever and rigidity in a psychotic patient does not always signify neuroleptic malignant syndrome; in fact, most such patients have more common febrile conditions superimposed on a neurolepticinduced dystonic reaction. Even other signs suggestive of neuroleptic malignant syndrome do not unequivocally lead to that diagnosis, as illustrated in the following case.
Case 4.

tic test involves hyperthermia

muscle patients

biopsy; shows

muscle

from

malignant

a hypercontractile
halothane (51) The possibility
malignant

recompared of similar
syndrome

sponse
with

to that

caffeine of normal
in appear to

and/or muscle.
neuroleptic

pathophysiology

and
catty,

malignant
they

hyperthermia
be separate

will

be

discussed.
(30, 33,

Clini36)

entities

and can be distinguished by the temporal to administration of general anesthesia tive family history found in malignant patients.
Many other diagnoses must be

relationship and the posihyperthermia

in the

tient,
After

had
being

Mr. been

D, a 34-year-old chronic schizophrenic patreated with various neuroleptics for years.

he spent 2 weeks lying on a cold jail

considered

arrested,

differential progress
malignant

diagnosis. to a catatonic
syndrome

A severe state
in some

dystonic resembling
respects

reaction may neuroleptic

(54), but fever

floor, intermittently During this period benztropine mesylate.

handcuffed, eating and drinking he received chlorpromazine He became progressively more

little. and lethar-

and leukocytosis would complication developed

embolus). Catatonia, of

be absent unless a secondary (e.g., infection or pulmonary

course, may also be the presynsuch

gic and was transferred to a hospital, where he was found to be dehydrated, hypertensive (180/140 mm Hg), and in renal failure (BUN, 136 mg/100 ml; creatinine, 9.7 mg/i00 ml). His WBC count was 16,000/mm3. He did not have fever, rigidity, tachycardia, tremor, or diaphoresis but had a sacral decubitis. A small amount of dark brown urine, positive for

sentation
but drome most

in major
other would

affective
signs of be

disorders
neuroleptic absent.

or schizophrenia,
malignant Furthermore,

usually

myoglobin,
creatine

was
phosphokinase

obtained
level

via

catheterization.
at 100,000

His
U/liter.

serum
He

peaked

was treated with complete medical

admission was 18-month

hydration recovery.
normal. He

and hemodialysis Muscle biopsy

was subsequently

and made a 1 month after

treated with

functional catatonia can be distinguished from organic causes of catatonia (including neuroleptic malignant syndrome) through a diagnostic Amytal interview (55). Acute lethal catatonia is a rare variant in which mutism and waxy flexibility are accompanied
by severe autonomic death. As disturbances, Caroff (2) pointed often out, ending in the patients neuroleptic

haloperidol
culty (at

for chronic

psychotic

symptoms

without

diffi-

follow-up).

This patient appears to have had an episode of rhabdomyolysis not associated with neuroleptic malignant syndrome. Instead, it seems to have been caused by immobilization, dehydration, and malnutrition and should not be considered a case of neuroleptic malignant syndrome because of the absence of most typical signs of this disorder. A similar case has been described
by Deboscker et al.

malignant syndrome and lethal catatonia are clinically indistinguishable, but both are descriptive syndromes without pathognomonic diagnostic criteria. Since neuroleptic malignant syndrome clearly seems to be precipitated by neuroleptics in many cases and has occurred in patients without major psychiatric disorder, neuroleptic malignant syndrome and lethal catatonia do not appear to be the same syndrome. Better definition ther of their relationship study through careful and differences requires clinical observation. fur-

(52)

in which

a depressed,

immo-

bilized woman with a neuroleptic-induced dystonic reaction developed rhabdomyolysis, hypertension, and renal failure but had no other signs of neuroleptic malignant syndrome. Rhabdomyolysis may also occur
as a complication of rapid intramuscular neuroleptiza-

Central nervous system infection, including meningoencephalitis and postencephalitic states, may produce any or all of the signs of neuroleptic malignant
syndrome. distinction Lumbar to be puncture made. and Except EEG for a should few allow cases a of

without neuroleptic malignant syndrome (53). observers have noted the similarities between neuroleptic malignant syndrome and malignant hyperthermia. Malignant hyperthermia is a hypermetabolic state of skeletal muscle, most frequently associated with the administration of halogenated inhalational anesthetic agents and succinylcholine (50, 51). Originally thought to be an autosomal dominant trait, malignant hyperthermia is now viewed as having a multifactorial inheritance pattern. Symptoms and signs include tachycardia, tachypnea, high fever, rigidity, and an elevated creatine phosphokinase level. Rhabdomyolysis and death are common outcomes. Intravenous dantrolene sodium is specifically therapeutic in malignant hyperthermia, and oral dantrolene is effective as preoperative prophylaxis (50). The only reliable diagnostion
Many

slightly malignant changes expected

ruling

elevated CSF protein, the CSF in neuroleptic syndrome patients has been without the in glucose, white cells, and/or protein that are in CNS infections. CAT scan is useful in
out brain abscesses and other structural lesions.

I have seen a patient, tics, with a syndrome

tic malignant mycotic syndrome ganglia endocarditis.

who had never indistinguishable

that was secondary aneurysm

taken from
caused to

neurolepneurolepby a basal bacterial

Patients taking neuroleptics are at increased risk for heat stroke, which may usually be distinguished from neuroteptic malignant syndrome by the absence of rigidity and sweating. Their skin is hot and dry. Severe
allergic nomic drug reactions instability but may not produce rigidity. fever Signs and autoof allergy

should

be

looked

for,

including

rash,

wheezing,

1142

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JAMES

L. LEVENSON

TABLE 6. Criteria for Guidance Malignant Syndromea

Major Manifestations

in the Diagnosis of Neuroleptic

Minor

Manifestations

Fever
Rigidity Elevated creatine phosphokinase level

Tachycardia
Abnormal blood pressure Tachypnea Altered consciousness Diaphoresis

Leukocytosis
aThe

presence

of all three

major,

or two

major

and four minor,

manifestations malignant synof malignant

indicates drome,

a high probability of the presence of neuroleptic if supported by clinical history (e.g., not indicative

hyperthermia).

urticaria, and eosinophilia. Various toxic encephalopathies may produce a clinical picture similar to that of neuroleptic malignant syndrome, including lithium toxicity (56), strychnine poisoning, and anticholinergic delirium. Hyperthyroidism and hypocalcemic or hypomagnesemic tetany must also be considered. Parkinsons disease often includes rigidity, tremor, and autonomic neuropathy but not leukocytosis or fever. Two patients in the reports covered by this review had underlying Parkinsons disease (27, 37). In order to make a correct diagnosis, the physician who is evaluating a patient with suspected neuroleptic malignant syndrome should include the following procedures in addition to a careful history and physical examination: a CBC with differential, determination of creatine phosphokinase levels, tests of renal function (BUN, creatinine), assessment of electrolytes including calcium and magnesium, liver function tests, thyroid function tests, lumbar puncture, EEG, CAT scan, toxicology screen, and determination of serum lithium level, if appropriate. In describing cases of neuroleptic malignant syndrome in the future, clinicians are urged to specifically and explicitly note the presence or absence of signs and symptoms, a process often neglected in the case reports reviewed here. Considering the subjective sensitivity and specificity of signs, I suggest the diagnostic criteria for neuroleptic malignant syndrome that are shown in table 6, which is similar to the format guiding diagnosis of rheumatic fever (revised Jones criteria) (57). If a patient does not satisfy these criteria (as in case 4), he or she should not be given a diagnosis of neuroleptic malignant syndrome.

vent venous thrombosis and pulmonary emboli (see case 2). Other dopamine antagonists, e.g., metaclopramide (45), should be avoided. The efficacy of specific treatments remains unclear. As I have noted, treatment with dantrolene and/or bromocriptine has not been consistently or clearly superior to other interventions. Dantrolene has been used in a dose range of 0.8-2.5 mg/kg every 6 hours (e.g., beginning with 60 mg i.v. every 6 hours for the average patient until the patient has recovered sufficiently to tolerate oral intake). Hepatic toxicity is the most significant potential adverse effect of dantrolene (43). Bromocriptine doses have ranged from 7.5 to 60 mg/day, in divided doses every 8 hours, intravenously at the beginning. Hypotension is the most limiting side effect, but bromocriptine, as a dopamine agonist, may exacerbate psychosis in schizophrenic patients (58). In the cases I have reviewed, anticholinergic agents were not helpful, in concurrence with earlier reports (2). Other advocated treatments (e.g., amantadine, ECT) did not appear uniquely or convincingly superior to supportive measures alone. More experience and careful assessment of treatment response in future cases will ultimately provide better guidelines. At present, there is no clear evidence of the value of any single specific treatment. Prevention of neuroleptic malignant syndrome awaits better understanding of the underlying pathophysiology. However, avoidance of marked dehydration in neuroleptic-treated patients may reduce the prevalence and morbidity of the disorder (48),
since dehydration seems to precede it in many cases.

An insufficient volume of liquids contributes to autonomic instability, shock, acidosis, and renal insufficiency. Because neuroleptic malignant syndrome is a rare and potentially lethal complication, unanswered questions about its treatment are not likely to be resolved through a controlled, blind trial. More detailed analysis of individual cases will be necessary. Observers should note what preexisting movement disorders the patient may have had. Statements about improvement in the patients condition should specify and quantitate which symptoms improved. Longer follow-up and outcome information should be provided, including how the patients psychosis is subsequently treated and whether there is any recurrence of neuroleptic malignant syndrome.

TREATMENT PATHOPHYSIOLOGY Treatment of neuroleptic malignant syndrome involves, first of all, supportive measures. All neuroleptic drugs should be immediately discontinued. Neuroleptics are not dialyzable, and blood levels will decline slowly. Attention to hydration, nutrition, and reduction of fever is essential. Secondary complications such as hypoxia, renal failure, and acidosis must be treated vigorously. Since the patient is usually immobile and bedridden, low-dose heparin seems indicated to preThe major competing theories to explain neuroleptic malignant syndrome are central dopaminergic blockade versus a direct toxic (hypermetabolic) effect on skeletal muscle. Burke et al. (21) described a patient with Huntingtons chorea who developed neuroleptic malignant syndrome while taking a-methyltyrosine and tetrabenazine. The former inhibits catecholamine synthesis and the latter depletes CNS catecholamines

Am

Psychiatry

142:10,

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1985

1143

NEUROLEPTIC

MALIGNANT

SYNDROME

by interfering with their storage. Burke et al. argued that this suggests that neuroleptic malignant syndrome is caused by dopamine depletion or blockade, resulting in derangement of central thermoregulation. Henderson and Wooten (27) supported the same hypothesis, citing a patient with Parkinsons disease and chronic psychosis who developed neuroleptic malignant syndrome when dopaminergic agonists, Ldopa/carbidopa and amantadine, were withdrawn; however, the patient was also taking haloperidol and lithium. A similar case was discussed by Toru et at. (37), in which neuroleptic malignant syndrome developed in a patient with Parkinsons disease when Ldopa/carbidopa and amantadine were abruptly discontinued; this patient had never taken neuroleptics. The dopamine blockade theory is also supported by the report of a case of neuroleptic malignant syndrome caused by metaclopramide (45), which is a selective dopamine receptor antagonist (59). May et at. (14) documented elevated oxygen consumption in skeletal muscle that decreased with treatment and improvement of neuroleptic malignant syndrome in one patient. They concluded that a hypermetabolic state in muscle was the fundamental cause of neuroleptic malignant syndrome, although they did not address whether this state was centrally mediated or a direct effect of neuroleptics on muscle. The latter explanation would put neuroleptic malignant syndrome and malignant hyperthermia in the same category. Caroff et at. (60) have provided further evidence of similarity between neuroleptic malignant syndrome and malignant hyperthermia. Muscle biopsy tissue obtained from a patient who had recovered from neuroleptic malignant syndrome showed a hypercontractile response to fluphenazine but also a similar abnormal response to halothane. The latter is found in patients who are known to be susceptible to malignant hyperthermia, although they do not demonstrate the same sensitivity to fluphenazine. This line of evidence suggests that the pathophysiology occurs directly at muscle tissue. However, other investigators (33, 36) have performed such in vitro testing for susceptibility to malignant hyperthermia and found tissue from neuroleptic malignant syndrome patients not responding abnormally to halothane, caffeine, or other agents. After having an episode of neuroleptic malignant syndrome, patients have tolerated general anesthesia without difficulty (30). The beneficial effects of dantrolene are not as clear in neuroleptic malignant syndrome as in malignant hyperthermia. At present, most of the evidence supports separate pathophysiological mechanisms for neuroleptic malignant syndrome and malignant hyperthermia. Feibel and Schiffer (25) found excessive catecholamine excretion in one patient who had neuroteptic malignant syndrome and suggested that sympathoadrenomedullary hyperactivity might be the physiological basis for the syndrome. Others, however, have not found elevated catecholamine excretion (33). The mechanism underlying neuroleptic malignant syn-

drome some

remains combination

unclear; it may welt of those proposed.

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