Distinguishing Neuroleptic Malignant Syndrome (NMS) From NMS-Like Acute Medical Illnesses: A Study of 34 Cases Daniel

D. Sewell,

Dilip

A study of 34 hospitalized patients with suspected neuroleptic malignant syndrome (NMS) found that 24 had NMS and the other 10 had acute, usually serious, medical problems. There were no demographic, psychopathologic, or treatment-related differences between the groups. NMS patients had more dehydration, cogwheeling, diaphoresis, disorientation, drooling, dysphagia, and rigidity and higher diastolic blood pressure. The groups had similar fevers, heart rates, creatine kinase levels, and white blood cell counts. Three non-NMS patients died during their acute illnesses. Results suggest that considering NMS as a diagnosis and ruling out other acute illnesses such as pneumonia are equally important when a patient on neuroleptic medication becomes medically ill. (The Journal Neurosciences

of Neuropsychiatry 1992; 4:265-269)

and

Clinical

V. Jeste,

T

he reported frequency of neuroleptic malignant syndrome (NMS) varies, but it appears to be relatively low. Our literature search revealed reported frequencies ranging from 0.02% to 1.9%.12 The mortality rate reported for NMS varies between 4% and 25%.13 Although NMS occurs infrequently, the potentially high mortality rate makes this one of the most serious side effects in psychopharmacology.

studies

Retrospective

agitation,

HIV

infection,

ment-related

possible

neuroleptic

dose,

comitant

lithium

Currently, NMS remains

proposed

and

risk high-potency

certain

putative illness,

male factors

potential

risk factors dehydration,

gender.3’9’17

include neuroleptics,

Treathigh and

daily con-

treatment.14

diagnostic

in the absence of a specific strictly a clinical diagnosis.

Levenson’5

test, and

Pope et a!.6 have published operational criteria for NMS. Pope’s criteria were recently revised.3 The diagnosis of NMS presents a challenge to the clinician because NMS-like symptoms generate an extensive differential diagnosis, including lethal catatonia, malignant hyperthermia, serotonin syndrome, lithium toxicity,

central

son16

found

Received

25, 1991. requests

Veterans CA 92161.

OF NEUROPSYCHIATRY

have

risk factors for NMS. Patient-related include advanced age, affective

extrapyramidal to a concurrent

JOURNAL

M.D. M.D.

anticholinergic

syndrome,

side effects (EPSE) medical problem. 16 published

cases

heatstroke,

with

fever

Levinson that

might

and

secondary and Simphave

been

20,1991; revised October 25, 1991; accepted October From the San Diego VA Medical Center. Address reprint to Dr. Sewell, Psychiatry Service (VII6A), Department of Affairs Medical Center, 3350 La Jolla Village Drive, San Diego, August

265

NEUROLEPTIC

MALIGNANT

misdiagnosed rent

medical

could

not

as NMS

SYNDROME

because

problems

such

were

be clearly

present

implicated

as the

significant that cause

concurof the

fever.

Accurate diagnosis of NMS, although sometimes difficult,18 is crucial because early intervention may decrease morbidity and mortality1920 and because appropriate treatments

depend

on the

correct

diagnosis.

Previous studies of NMS have been characterized by certain methodological limitations. We found only one study with more than 20 patients with NMS.21 Studies completed before 1985 were limited by an absence of published operational criteria for NMS. Lastly, we found only two studies of NMS that included a comparison group, and in both of these the comparison group consisted

of patients

who

were

not

acutely

medically

The main goal of our study was to identify features best distinguish NMS patients develop some other acute medical illness psychotropic medications. In pursuit studied the charts of acutely medically had been suspected of having NMS.

blood, urine, sputum, and cerebral spinal fluid cultures, approximately half of the patients in each group; chest X ray, 22 NMS, 9 non-NMS; electrocardiogram, 19 NMS patients, 8 non-NMS patients. The two authors jointly reviewed the data in order to divide the cases into two groups: NMS and non-NMS. In order to be in the NMS group a patient had to meet Pope’s revised criteria.3 We used the cases that did not meet criteria for NMS as a comparison group. Each patient in this non-NMS group had developed an acute medical problem while being treated with psychotropic medication; the medication was a neuroleptic in all but one of the patients. That particular patient had been treated with neuroleptics in the past, was currently taking lithium, and ultimately was diagnosed with lethal catatonia. The acute medical problems of patients in our comparison group were varied but generally serious. Three of the comparison patients died before recovering from the non-NMS;

neuroleptics

ill.9’14

which clinical from those who while receiving of this goal, we ill patients who

acute lowing

medical illness. These diagnoses: aspiration

monia,

and

patients

lethal

were

pneumocystis

METHODS

cords

were

not

available;

those

cases

were

excluded.

A

total of four private and three public hospitals treated the patients included in the study. One of the authors (D.S.) reviewed all the charts personally. The manner in which charts

were

reviewed

and

information

was

reported

was

designed to mask completely the identities of the individuals being studied. In each case, the patient’s primary physician at the time of the acute illness was contacted to obtain any further relevant information. In general, each subject had extensive medical evaluation during the acute medical illness. For the 24 NMS patients and was available

the 10 non-NMS patients, regarding the following:

documentation complete physical

function tests, all patients; at least kinase (CK) measurement, 22 NMS, 8 non-NMS (most patients had a series of CK measurements); at least one white blood cell count, all NMS, 8 non-NMS; urinalysis, 23 NMS, all non-NMS; toxicologic studies of the blood and/or urine, 13 NMS, 7 examination one serum

266

catatonia.

and

creatine patients

liver

tardive EPSE

carinii

dyskinesia and

signs

listed

diagnoses

acute

and

tuberculosis;

and

etiology. data on demographics, in Levenson’s’5

and

obstruc-

Alzheimer leukocytosis; infarction”;

of the

origin; EPSE and “rule out myocardial

increased

symptoms,

CK

and

and

Pope’s revised3 criteria risk factors for NMS mentioned at article. In most cases, in order for a

and on the putative the beginning of this sign or symptom to be recorded actual word for the symptom had Sometimes

chronic

dementia

other

reaction

EPSE,

and

the folpneu-

of the

dystonic

pneumonia;

disseminated

of undetermined We obtained

The

as follows:

tive pulmonary disease, type; fever of unknown

We sought to identify as many cases of possible NMS as we could during a 21-month period. We contacted the medical directors of all the psychiatric hospitals and general hospital psychiatric units in San Diego County. We asked if they or any of the physicians on their staffs had been involved in the treatment of a patient in whom a diagnosis of NMS had been considered. We also notified members of our department of our study. These efforts yielded 41 cases. In 7 cases, medical re-

three patients had pneumonia, bacterial

a synonymous

word

as being to appear or phrase

present, the in the chart. was

accepted

in lieu of the specified word. For example, “increased activity, irritability, and sleeplessness” was coded as agitation even though the patient’s chart did not contain the word “agitation.” Maximum vital signs were defined as the highest recorded measurements during the acute medical problem. Baseline vital signs in almost all the cases were defined as the last complete set of vital signs recorded prior to discharge, which always occurred after resolution of the acute medical illness. In a few cases, admission vital signs had to be substituted because discharge vital signs were either not available or, in three cases, because the patient died. Psychiatric diagnoses recorded in the charts were typically based on DSM-III or on DSM-ffl-R.24 We used the Fisher’s exact probability test to evaluate categorical data and Student’s t-test for continuous data. Depot neuroleptic doses were converted to average daily dose

equivalents.26

All

VOLUME

daily

4

neuroleptic

#{149} NUMBER

doses

3

SUMMER

#{149}

were

1992

SEWELL

then converted to mg chlorpromazine lents.n’ Data for maximum neuroleptic transformed using natural logarithm a normal distribution of the data.

dose

(CPZ) equivaand CK were

in order

1 summarizes

demographic

and

to achieve

clinical

informa-

tion

for the two groups. We found no significant differences in regard to demographic information, mean daily neuroleptic

dose

in mg

CPZ

equivalent,

neuroleptic

JESTE

Another limitation in our study deserves mention. It is possible that some of our cases might have been misclassified. For example, it is possible that some of the cases classified as non-NMS in fact had NMS but that crucial clinical features required by the diagnostic criteria were not documented. This would yield false negatives. There is also the possibility of false positives, cases classified as NMS that might have been diagnosed otherwise if a more complete prospective assessment had been undertaken and documented. In addition, some patients might have had both NMS and some other acute medical illness. It is

RESULTS Table

AND

po-

find significantly more dehydration in the NMS group. We found no significant differences in mean baseline vital signs between the groups or in the following mean maximum recorded vital sign ± SD measurements (NMS versus non-NMS): temperature in degrees Fahrenheit (101.6 ± 2.2 vs. 101.7 ± 2.8), pulse in beats per minute (127 ± 25 vs. 124 ± 26), and respirations in breaths per minute (29±10 versus 26± 7). There were several interesting differences in clinical manifestations (Table 2). The mean maximum diastolic blood pressure was significantly greater in the NMS group. In addition, the following signs and symptoms were found more commonly in the NMS group: cogwheeling, diaphoresis, disorientation, drooling, dysphagia, and rigidity. The mean maximum recorded CK levels ± SD for the NMS and non-NMS groups in IU/ml were 4,295 ± 8,372

TABLE

and

Note: NS = not significant. Continuous data were analyzed using Student’s t-test. Categorical data were analyzed using the Fisher’s exact probabffity test. bOne patient (with lethal catatonia) was not on neuroleptic. “In mg of chlorpromazine equivalents/day at onset of acute medical illness.

tency,

or frequency

4,674

± 7,732,

of lithium

use.

respectively,

and

recorded white blood cell counts 6,000 cells/cc and 14,000 ± 7,000 (differences

ization was

not significant).

We

The

the

did

mean

(WBC) cells/cc, mean

maximum

were 14,000 respectively

length

of hospital-

in days

± SD for the NMS and non-NMS and 36±20, respectively (difference

46±56

±

patients not sig-

1.

Baseline without

Age,

years

(mean

Gender,

limi-

may be unavailable and have been consistently documented. These and other factors make it difficult to obtain a sample size large enough to allow for valid tations.

For

factors

under

comparisons.

retrospective a large recent

example,

study

records

might

not

In addition to the study, we were also

sample because work by Keck

NMS

usual

limitations

of a

hindered in obtaining occurs infrequently. In fact,

et al.1’ suggests

that

the

OF NEUROPSYCHIATRY

44.9±18.3

49.1±21.8

NS

19:5

10:0

NS

4

1

4

3

Schizophrenia

6

3

Other

9

3

disorder

Neuroleptic

potency

high:only

Only

PValuea

Neuroleptic

NS

low:both (mean

dose’

13:2:9

± SD)

log transformed

Natural

1,228±1,551

579±718

6.31±1.46

5.42±1.62

Number

on lithium

6

Number

dehydrated

20

2.

Signs without

and

symptoms neuroleptic

or Symptom recorded

mmHg

(mean

blood

4:2.3k

in patient malignant

groups syndrome

with

NMS

Non-NMS

Group

Group

86±13

166±23

152±26

Drooling

(n) (n) (n) (n)

Dysphagia Rigidity

PValuea

pressure, 103±9

Disorientation

and (NMS)

± SD)

Systolic

Diaphoresis

NS

30.006

Diastolic

Cogwheeling

NS

2

(n) (n)

0.019 NS

15

1

0.007

18

3

0.016

21

4

0.009

13

0

0.002

10

0

0.015

22

4

0.003

frequency

of NMS may be decreasing, probably because of increasing clinical awareness of the syndrome that has led to earlier intervention and to a reduction in risk factors.

JOURNAL

Non-NMS Group (n = 10)

Dementia

Maximum

encounter

with and (NMS)

diagnosis

Bipolar

Sign

studies

± SD)

male:female

Psychiatric

DISCUSSION clinical

groups syndrome

Group (n = 24)

Variable

TABLE

all retrospective

for patient malignant NMS

nificant).

Almost

information neuroleptic

Note: Continuous data were

NS

not significant. data were analyzed analyzed using Fisher’s =

using exact

Student’s probability

t-test. test.

Categorical

267

NEUROLEPTIC

MALIGNANT

also possible have

had

that some mild

diagnostic

NMS.

or

errors

of our comparison NMS. We tried

early by

SYNDROME

relying

on

patients

might

to reduce

published

before

such

criteria

Furthermore,

believe

that

our

findings

are

of interest

because,

from

their

acute

medical

illnesses

sug-

that the illnesses that resemble NMS may often be quite serious. It is conceivable that confusion about the diagnosis of NMS may delay appropriate interventions and contribute to the high mortality in the non-NMS group. Our findings suggest that when a patient on neuroleptic develops fever, tachycardia, tachypnea, and elevated CK and WBC, it is just as important to consider NMS as it is to rule out other acute medical illnesses such as pneumonia. Error in either direction can be potentially fatal. Certain manifestations such as diastolic hypertengests

for

all subjects selected had extensive medical evaluations during their acute illnesses, reducing the chances of misdiagnosis. We

recovering

to

our knowledge, this is the only study of NMS that included a comparison group of acutely medically ill patients. Our results may begin to clarify what factors put a patient at higher risk for the development of NMS. Contrary to expectations, our NMS group did not have an over-representation of the following putative risk factors: affective illness, agitation, male gender, high-potency neuroleptic, or concurrent lithium use. Our results do support the notion that dehydration may be a risk factor for NMS’5”6 To our surprise, certain signs, symptoms, and laboratory values were not significantly more common in our NMS group even though they were included in the operational criteria3 we used to classify the patients. These were tachycardia, fever, tachypnea, increased CK, and increased WBC. The signs and symptoms that were significantly more common in the NMS subjects were cogwheeling, diaphoresis, disorientation, drooling, dysphagia, rigidity, and diastolic hypertension. The clinical similarities we found between the NMS and the non-NMS groups suggest that a patient with apparent NMS may actually have some other medical illness, as has been suggested by Levinson and Simpson.16 The fact that three of the non-NMS patients died

sion

and

cogwheeling

may

favor

a diagnosis

of NMS.

We thank the following people who helped with various aspects of this study: Dominick Addario, M.D.; Allan Adler, M.D.; David B. Bergman, M.D.; Phil Botkiss, M.D.; Michael P. Caligiuri, Ph.D John Castro, M.S. W.; Alice Cleghorn, Ph.D.; Larry Denny,M.D.; Stephen Groban,M.D.;Jackuelyn Harris, M.D.; Jack Hughes; Alice Krull, M.D.; Lou Ann McAdams, Ph.D.; Fran McMillan; David McWhirter, M.D.; Sahbuddin Mollah, M.D.; Robert Sanders, M.D.; Susan Shuchter, M.D.; Stephen V. Sobel, M.D.; J. Robert Swenson, M.D.; and Susan Westin, M.D. This work was supported in part by NLMH Grants 5R37 MH43693, IROI MH45131, 1P50 MH45294, and 5R01 MH45298 and by the Department of Veterans Affairs. A version of this article was presented at the Annual Meeting of the American Psychiatric Association, New York, May 12-17, 1990. .;

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