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Brain Injury, June 2006; 20(7): 775778

CASE STUDY

Brain injury following neuroleptic malignant syndrome: Casereport and review of the literature

ANNA LABUDA1 & NORA CULLEN2

1Department of Physical Medicine and Rehabilitation, McMaster University, Hamilton, Ontario, Canada and2Toronto Rehabilitation Institute, University of Toronto, Toronto, Ontario, Canada

(Received 9 January 2005; accepted 11 January 2006)

Abstract

Objective: To report a case of brain injury following neuroleptic malignant syndrome (NMS) and review the literature forsimilar documented cases.Case report: A 30-year old woman presented to the ER with psychotic features and was treated with several anti-psychotics.Subsequently, she developed neurological symptoms and was diagnosed with neuroleptic malignant syndrome. Followinga prolonged course in an acute care facility, she was admitted to a rehabilitation ward, where cognitive and physicalexaminations revealed significant findings. These included marked dysarthria, difficulties comprehending commands,attention problems, as well as abnormalities in her muscle tone, power, reflexes, gait, co-ordination and sensory function.Conclusion: Literature reviews reveal few documented cases of brain injury following neuroleptic malignant syndrome.A further exploration of the effects of NMS on the brain is warranted to elicit whether cerebellar damage is indeed commonfollowing neuroleptic malignant syndrome. Such research could eventually lead to therapeutic interventions aimed atpreventing permanent brain injury in persons with NMS.

Keywords:Neuroleptic malignant syndrome, brain injury, cerebellar injury

Introduction

Neuroleptic malignant syndrome (NMS) is a

potentially fatal idiosyncratic reaction to neuroleptic

agents [1]. Its cardinal manifestations include fever,

extrapyramidal rigidity, a decreased level of

consciousness and autonomic dysfunction [1, 2].

This consequence of anti-psychotic drugs frequently

occurs at the start of neuroleptic treatment admin-

istration or in association with dosage increase.

Haloperidol is the most commonly implicated

agent [3, 4]. Relatively common complications of

NMS have been studied considerably and include

infection, respiratory failure, acute renal failure,

thromboembolism and myocardial infarction [2, 3].

However, the effects of NMS on the brain have not

been well documented, perhaps due to their

infrequency. A review of the 19862004 literature

(PubMed, MEDLINE, PsycINFO) revealed only

four documented cases of cerebellar injury following

neuroleptic malignant syndrome.

Case history

A 30-year-old African Canadian woman, with no

significant past medical history, presented to the ER

with auditory hallucinations, paranoid ideation and

delusions. She had no prior psychiatric history,

no known prior organic brain insult, no family

history of mental illness and no past drug use.

She was admitted to the Psychiatric unit, where

she received Olanzepine, Haloperidol, Cogentin and

Risperidone. Subsequently, she developed neuro-

logical symptoms, including slurred speech, rigidity

and involuntary movements on her left side. She also

Correspondence: Anna Labuda, MD, Department of Physical Medicine and Rehabilitation, Hamilton Health Sciences Corporation, Henderson General

Hospital, 711 Concession Street, Hamilton, Ontario, L8V 1C3, Canada. Tel: (905) 385-9894. Fax: (905) 575 2598. E-mail: alabuda2005@meds.uwo.ca

ISSN 02699052 print/ISSN 1362301X online

2006 Taylor & FrancisDOI: 10.1080/02699050600663022

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developed an elevated temperature, a mildly elevated

white count and her creatinine kinase rose to over

4000. A tentative diagnosis of neuroleptic malignant

syndrome was made and she was treated with

hydration and bromocriptine. She deteriorated

severely enough to warrant admission to the ICU,

where she was intubated and ventilated. Several

investigations were performed, including a CT head,

MRI and a lumbar puncture. All of these results

were negative. There was no history of rash or joint

problems. Various cultures were completed and

none showed definite bacterial or non-bacterial

infection. A 2-D echo showed no evidence of

pericardial effusion or bacterial vegetation. An

EEG test was normal, except for some slowing

activity. She also had a complete rheumatologic

work-up, all of which was negative. At one point, she

was transferred to another hospital for further testing

and repeat investigations were also negative.

The patient spent 14 months in an acute carefacility. For a prolonged period, she remained in a

significantly decreased level of consciousness and

was not rousable. Once this resolved, her commu-

nication skills were very poor. Her rigidity level

varied throughout the hospitalization period. She

gradually improved and was eventually started on

Clozapine. Since then the patients state has

continued to improve slowly, with particularly

significant gains in ambulation and verbal

communication.

Upon her admission to the Toronto Rehabilitation

Institute, cognitive and physical examinations were

completed. On mental status exam, significantfindings included marked dysarthria, inconsistent

difficulties comprehending commands, as well as

basic and sustained attention problems. Specifically,

she had great difficulty recalling more than three to

four digit sequences on digit repetition and exhibited

many omission and commission errors on the

random letter test. Her cranial nerves exam was

normal and unremarkable. On motor examination,

her right lower leg exhibited signs of muscle atrophy,

anteriorly and posteriorly. She also had a slight

increase in tone of her right upper extremity. The

range of motion in her right shoulder was decreased

by at least 50% in all directions. Her power was rated

at 5/5 in all her left extremities, 4 /5 in her right

triceps and 1/5 in her right ankle. Her reflexes were

increased, rated 3/4 in the triceps, biceps and

brachioradialis. Her knees were both 3/4, her left

ankle was 3/4 and the right ankle was 0/4. No clonus

was identified. The plantar response was up going

in her left foot and equivocal in the right.

Co-ordination testing in the upper extremities

showed some dysmetria on rapid alternating move-

ments in both hands, though more marked in her

right. Finger-to-nose testing also exhibited increased

dysmetria and past-pointing on the right. In the

lower extremities, heel-to-knee testing exhibited

mild dysmetria on the left. She had a positive

Rombergs sign. Gait with a walker showed

decreased truncal balance, as well as a high steppage

gait with her right leg; she had obvious difficulty

dorsiflexing her right foot. Sensory examinationrevealed normal sensation to light touch bilaterally

in the upper extremities and normal sensation in her

left lower extremity. There was definite decreased

sensation in the dorsum of her right foot, as well as

over the right lateral malleolus. She also reported no

sensation at all on the plantar aspect of her right foot.

Proprioception was normal in the upper extremities,

as well as in the left lower extremity, but not in the

right lower extremity. On higher sensory testing

stereognosis was preserved bilaterally, while

graphesthesia was 50% present bilaterally. Point

localization was normal.

Discussion

Neuroleptic malignant syndrome is an acute and

potentially lethal reaction to neuroleptic dopamine-

blocking agents. This reaction to anti-psychotic

drugs frequently occurs at the start of treatment

administration, usually within 2 weeks, and often

with an associated increase in medication dosage

[5, 6]. However, this dangerous complication can

also occur during ongoing treatment. Cardinal

manifestations include hyperpyrexia, extrapyramidal

rigidity, a decreased level of consciousness andautonomic dysfunction [1, 2]. Neuroleptic malig-

nant syndrome has a 0.41.4% incidence rate and

it carries a mortality rate of 422% [1, 7].

Pre-disposing risk factors include dehydration,

types and dosages of neuroleptics, organic brain

disease and intra-muscular injection [8, 9].

Complications during the course of NMS are

frequent and include dehydration, infection, respira-

tory failure, acute renal failure, thromboembolism

and myocardial infarction.

The pathophysiology of neuroleptic malignant

syndrome is primarily explained by the theory that

there is an extensive blockade of dopamine receptors

in the basal ganglia and hypothalamus [7, 10]. This

leads to extra-pyramidal muscle rigidity and

impaired central temperature regulation, respectively

[7, 10]. Thus, a hallmark feature of the disorder is a

toxic hyperpyrexia (often over 41C), which results

from a combination of excess heat production and

decreased heat dissipation [10, 11]. Neuroleptics

may lead to this by way of anti-cholinergic, as well

as anti-dopaminergic properties, which interrupt

hypothalamic regulation. Alternatively, symptoms

have also been explained by the theory that

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neuroleptics lead to an increased release of calcium

ions in muscle cells, thus triggering rigidity and

increased thermogenesis [10].

Literature shows that most survivors recuperate

completely, with a mean recovery time of 711 days

[1, 12]. Prevalence of long-term clinical sequelae has

been estimated at 3.33% [1]. Higher estimates have

also been reported, but highly disputed. Although

there is little available data regarding outcome

post-NMS, there exist several documented instances

of long-term complications. Review of the literature

reveals that there are very few current reports, as

most cases of NMS sequelae are from a time when

both the disease and its treatments were poorly

described and only first-generation anti-psychotics

were available. Limb contractures resulting from

sustained extra-pyramidal rigidity have been docu-

mented in a single case study [1, 13]. There are two

case reports of permanent dystonia following

NMS, as well as a case of polyneuritis and coma[1417]. Koponen et al. [6] report persistent

Parkinsonian symptoms in one patient, as well as

ongoing depression. Neuropsychological sequelae,

specifically short-term memory dysfunction were

documented by Rothe et al. [18] in a single case

study. Chen et al. [19] report a case of mild

muscular atrophy, which may have been due to

prolonged acute immobilization rather than the

NMS directly.

There are few articles in the literature relating to

brain injury in NMS. Previous studies have shown

transient or permanent cerebellar deficits following

heat induced CNS injury such as heat stroke, fevertherapy or post-thyroidectomy complications [7].

However, neuroleptic malignant syndrome was first

documented to result in cerebellar complications

in 1989, by Lee et al. [7]. They reported a case of a

32-year-old male, who was diagnosed with haloper-

idol-induced neuroleptic malignant syndrome and

succumbed to cardiopulmonary arrest 4 months

following his initial presentation. On post-mortem

examination, neuropathology of his brain was most

striking in the cerebellum, showing almost complete

loss of Purkinje cells, moderate reduction of granular

neurons and sub-total loss of neurons in the dentate

nucleus. The cerebral cortex, basal ganglia and

hippocampus appeared free of neuronal loss.

Research has shown that the cerebellum is most

vulnerable to hyperpyrexia, followed by the cerebral

cortex, brainstem and spinal cord [11]. In support

of the heat injury theory, studies have shown

preferential heat-induced degeneration of cerebellar

neurons in animals [7]. However, the chemical and

physical properties that account for the selective

cerebellar vulnerability to heat induced injury are

not completely understood. Some studies have

suggested that as various cell lines differ in their

expression of heat shock proteins, response to heat

stress may be, to some extent, a function of cell

type [20].

Studies of cerebellar injury in heat stroke and fever

therapy have shown that the commonest neurologi-

cal sequelae of hyperthermia include ataxia and

dysarthria [11]. From the available literature, itappears that the cerebellar effects are similar in

NMS. Lal et al. [11] reported a case of a 50-year-old

woman, diagnosed with haloperidol-induced neuro-

leptic malignant syndrome, who after the acute

recovery exhibited mutism with normal comprehen-

sion. Acute cerebellar injury has previously been

associated with transient muteness [21]. This is not

surprising, as a primary function of the cerebellum is

to modify the force and rapidity of muscular activity

resulting in finely co-ordinated actions, including

speech. Lal et al. [11] also describe ocular dysmetria

and pronounced ataxia of the limbs and trunk

of their patient, further suggesting cerebellardamage. Similarly, Brown [9] reports the case of

a 17-year-old male, who following a course of

clozapine-induced neuroleptic malignant syndrome,

suffered from severe truncal ataxia, difficulty with

head control, dysmetria and past pointing.

Almost a decade after his discharge, the patient

still had residual hypotonia, dysarthria, trunk and

limb ataxia, as well as balance problems. Manto

et al. [22] have also documented a case of cerebellar

gait ataxia following haloperidol-induced NMS.

Their patient was a 39-year-old male, who following

an episode of NMS, exhibited bilateral dysmetria on

heel-to-shin test, as well as a broad-based ataxic gait.

Upon investigation, a brain CT showed cerebellar

atrophy.

Conclusion

Early identification and intervention in neuroleptic

malignant syndrome are needed. This acute and

potentially lethal reaction to anti-psychotic drugs

frequently occurs at the start of treatment adminis-

tration and is often associated with an increase in

neuroleptic dosage. Presentation signs include

hyperpyrexia, extra-pyramidal rigidity, a decreased

level of consciousness and autonomic dysfunction.

Treatment includes rehydration, dantrolene and

bromocriptine. Neuroleptic malignant syndrome

carries a mortality rate of 422% and an estimated

3.3% of survivors experience long-term clinical

sequelae. Although common systemic complications

of this syndrome have been well documented, the

effects of NMS on the brain have not been well

studied. Literature reviews reveal that only four cases

of cerebellar injury following neuroleptic malignant

syndrome have been described. Review of these

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reports illustrates similarities with the presentation of

our patient, specifically the presence of dysarthria,

dysmetria and truncal ataxia. A main limitation to

this case report is that the patient was not originally

admitted to our hospital and, thus, knowledge of her

initial presentation, treatment and course during the

14 months in an acute care facility is based onavailable documentation. A further exploration of

the effects of NMS on the brain would be warranted

with a two-fold purpose. First, to elicit whether

cerebellar damage is indeed common following

neuroleptic malignant syndrome. Secondly, such

research could eventually lead to therapeutic inter-

ventions aimed at preventing permanent brain injury

in persons with NMS.

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