Risperidone, neuroleptic malignant syndrome and probable dementia with Lewy bodies

2000, Vol.24,pp 1043-1051 CopyrIght 0 2000 Elsewer Scxmce Inc.

Prog. km-Psychophamacol.

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RISPERIDONE, NEUROLEPTIC MALIGNANT SYNDROME AND PROBABLE DEMENTIA WITH LEWY BODIES GIANPIETRO SECHI, VIRGILlO AGNElTI, RAFFAELLA MASURI, GIOVANNI A. DEIANA, MAURA PUGLIAlTI. KAI S.M. PAULUS and GIULIO ROSATI

Department of Neurology, University of Sassari, Sassari, Italy

(Final form, July 2000)

Abstra

Sechi, GianPietro, Virgilio Agnetti, Raffaella Masuri, Giovanni A. Deiana, Maura Pugliatti, Kai S.M. Paulus and Giulio Rosati: Risperidone, Neuroleptic Malignant Syndrome and Probable Dementia with Lewy Bodies. Prog. Neuro-Psychopharmacol. & Biol. Psychiat.

2ooo,~,

pp. 1043-1051.02000

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Conflicting reports are available regarding the sensitivity of patients with Dementia with Lewy bodies (DLB) to risperidone. 2. The authors studied a rare familial case of probable DLB, who developed a documented episode of neuroleptic malignant syndrome (NMS) following the exposure to risperidone. Previously, the patient had had an episode of NMS on trifluoperazine. 3. The discontinuance of risperidone, in combination with a mild increase of dopaminergic therapy, led to a complete recovery in few days. 4. In patients with DLB, a continued vigilance for extrapyramidal side effects, including NMS, would be advisable during the use of risperidone. 1

Keywords: familial risperidone.

dementia

with

Lewy bodies,

neuroleptic

malignant

syndrome,

. revrw: central nervous system (CNS), dementia with Lewy bodies(DLB), neuroleptic malignant syndrome(NMS), Parkinson’s disease (PD).

1043

1044

G. Sechi et al.

Risperidone, multicenter

a relatively

new atypical

neuroleptic,

has been reported

trials to have a side effect profile comparable

in several

with that of placebo when

used in doses of 6 mg/day or less (Borison et al., 1992, Marder and Meibach, Peuskens,

1995). Moreover,

early reports suggested

1994,

that this drug may be a useful

agent in the treatment both of patients with Parkinson’s

Disease (PD) and psychosis

(Meco et al., 1997) and in psychotic

symptoms

Lewy bodies

(DLB)

(Allen

(Lavretsky and Sultzer,

and behavioural

et al., 1995).

1998, Rosebush

effect profile of risperidone

However,

several

and Mazurek,

in dementia

other

recent

1999) indicate

may be very similar to that of typical

with

studies

that the side

neuroleptics,

in

particular in PD (Ford et al., 1994), and in DLl3 (Ballard et al., 1998). In addition, the occurrence

of neuroleptic

the initiation

malignant

of risperidone

(Webster and Wijeratne,

syndrome

has been reported

1994, Raitasuo

in few elderly

shortly

and young

after

patients

et al., 1994, Hasan and Buckley,

The authors studied a patient with probable several days of initiation

(NMS) that developed

1998).

DLB in which a NMS appeared

within

of risperidone.

Case Retmt

A 63-year-old language

with a 6-year

disorder with paraphasia,

in attention

and alertness,

hallucinations, neuroleptics,

parkinsonism

psychotic

et al.,

1999),

diagnosed

of progressive

cognition

behavioural

and exaggerated

cognitive

with pronounced

disturbances

decline, variations

with recurrent

visual

adverse response to standard doses of criteria for probable DLB (McKeith et al.,

was admitted

parents were first cousins,

have been variously

history

fluctuating

meeting the clinical diagnostic

1996, McKeith patient’s

woman

to hospital

in February

and six family members

as depression

(brothers,

(2 members), or psychotic

1997. The or sisters) behavioural

Risperidone,

disturbances

NMS and probable

(3 members), or parkinsonism

DLB

1045

(1 member). The pedigree

of the family

is reported in Fig. 1. In the past, she had been treated with thioridazine one depot injection which

caused

severe

trifluoperazine, developed

of fluphenazine

(25 mg), or trifluoperazine

extrapyramidal

amitriptiline,

maprotiline

NMS with extreme

(50-150 mg daily, per OS), or

rigidity,

side-effects.

In

(6 mg daily, per OS)

June

and low bromocriptine hyperthermia

1996, doses,

bromocriptine

trifluoperazine

doses kept unchanged.

within few days. Madopar daily,

was

cogwheel

doses reduced

administered rigidity

from

and bradykinesia.

per OS), and paroxetine

1996 because

From January

and maprotiline and

related to NMS disappeared

100 mg; benserazide

September

the patient

from 6 mg to 2 mg daily,

The symptoms

HBS (levodopa

on

and a rise in serum creatine

kinase (CK) levels up to 5326 IU/L (normal c 250 IU/I). Amitriptiline were discontinued,

while

25mg), five times

of moderately

severe

1997, amitriptiline

(40 mg daily,

(20 mg daily, per OS) were added because

of a moderate

depression.

I:1 B.D.

II:1

II:2 B.D.

II:3 P.

II:4 B.D.

I:2

II:.5 B.D.

II:6 D.

II:7 D.

II:8

Fig 1. Pedigree of the family. Squares represent males and circles represent females. /= deceased; B.D.= psychotic behavioural disturbances; D.= depression; P.= parkinsonism.

Paroxetine

was discontinued

after 20 days.

On this therapeutic

delusions worsened and, in February 1997, risperidone

regimen,

the

2.5 mg daily was introduced.

1046

G. Sechi ef

Ten days

later,

muscle rigidity,

the patient

showed

which progressed

al.

marked

functional

further following

disability

and increased

a mild reduction,

by mistake, of

Madopar HBS doses: from five times daily to four times daily.

g

40

it { 39 b 1

38 CK: <250ILJll

+f 31 m P 36 5 s ‘c: k! 9

2 g

E

I I II 0 2

I I II

I I I I I /

4

8

6

10

12

I I I : , , / 16

14

18 20

Fig 2. Temporal relationship between risperidone body temperature elevation, and CK serum levels.

She was hospitalized stupor, marked akinesia, 38.7X), following between Complete

diaphoresis hours

and on admission, muscle rigidity,

ranged

I I I I,

I

26

therapy,

30 Days

28

risperidone

withdrawal,

the clinical picture was characterized hyperthermia

between

95/70

80 and 110 beats per minute. blood cell count with differential

and

150/80

No systemic

(axillary,

Serum

CK

increased

to

displayed 2374

during the

rate

ranged

was found.

a mild leukocitosis:

The blood cell count was

examination

urine cultures were normal. Electroencephalogram

heart

site of sepsis

polymorphonucleocytes).

by

peak temperature,

mmHg;

cell count showed

within normal limits two days later. Radiologic

rhythm.

I

24

and oliguria. Repeated blood pressure measurements

WBC count of 14.380/mm3(80%

dominant

I

22

IUA

of the chest, blood and nonspecific the

seventh

slowing

of

day

of

Risperidone,

hyperthermia. withdrawal,

The temporal

NMS and probable DLB

relationship

body temperature

between

elevation,

risperidone

electrocardiogram

therapy,

risperidone

and CK serum levels are detailed

Repeated complete blood count, serum electrolytes, tests, urinalysis,

1047

in Fig 2.

liver, renal and thyroid function

and brain CT were normal. A diagnosis

of NMS

was made. Madopar HBS doses were given six times daily, whereas risperidone discontinued. nutrition.

The

patient

Extrapyramidal

risperidone, improved

CK levels becoming

was treated signs

improved

returned more

with

isotonic

within

saline

6 days

i.v.

from

and

parenteral

discontinuance

to normal over 11 days and the patient

alert

and verbal.

The

patient

was

of

gradually

in the following

days

remained afebrile. No antibiotic was given.

DLB is usually

considered

a sporadic

disorder,

as there are few pathologically

confirmed patients with affected relatives (Denson et al., 1997, Ohara et al., 1999). Our patient fits the clinical

diagnostic

DLB, according

to the criteria

McKeith

1999).

et al.,

variability

typical

depression, McKeith

criteria

for a rare familial

of the consortium

Indeed,

her other

and one patient’s

siblings

behavioural

brother showed

et al., 1999). Moreover,

on DLB (McKeith

affected

of DLB: three had psychotic

case of probable

the clinical

disturbances,

parkinsonism

like others familial

showed

et al., 1996,

(McKeith

two had

et al., 1996,

reports on this disorder,

patient’s parents were first cousins (Ohara et al., 1999) and through analysis pedigree, an autosomal

dominant

inheritance

the

of our

appears to be the most likely genetic

pattern. Pharmacologic

management

by an exaggerated mortality

(McKeith

extrapyramidal fluphenazine,

of neurobehavioral

response to neuroleptics, et al.,

symptoms trifluoperazine

1992). following

Our

and risperidone,

in DLB is complicated

which causes excessive

patient

mild

symptoms

showed

to moderate

a severe doses

and two documented

morbidity

and

worsening

of

of thioridazine, episodes of NMS,

1048

G. Sechi et al.

according

to the

Hutchinson,

recent

1995)

The biological

criteria

respectively

following

factors responsible

defined. Failure to up-regulate reduced dopaminergic

been also documented

trifluoperazine

for neuroleptic

syndrome

(Buckley

and

and risperidone.

sensitivity

in DLB are not well blockade or a

in the striatum seem play a critical role (Piggot et

hypoactivity

in patients

1990), as a possible consequence 1981)

of this

D2 receptors in response to neuroleptic

innervation

al., 1998). A dopaminergic

and Wooten,

for diagnosis

in the central

susceptible

nervous

system

to NMS (Nishijima

(CNS), has

and Ishiguro,

either of dopamine receptor blockade (Henderson in critical

areas of

CNS (Sechi et al. 1984, Sechi et al., 1996) with respect to the activity

of other

neurotransmitters noradrenaline;

involved

serotonin)

Preliminary behavioural

or of a shift decrease

reports

in the control

in dopamine

of movement

activity

and thermoregulation

(Green, 1989, Sechi et al., 1996). indicated

symptoms

risperidone

in DLB (Allen

failed to confirm these findings

as a useful

lack of balance

at higher doses (Livingston,

and is antihistaminic

among these

amitriptiline of these vigilance

may

neurotransmitters

the recent exposure

have

for extrapyramidal

the use of risperidone,

search of

caused

it also has

1994). In our patient, by risperidone

favourite

this

may have played a role in inducing

to paroxetine,

neurochemical

side effects, including

particularly

the

in critical

it should be noted that, in the patient, the concomitant

and levodopa, drugs

this is the

at low doses, and potent

1994). In addition,

(Livingston,

areas of CNS (e.g., basal ganglia; hypothalamus) the NMS. Moreover,

studies

reported case of NMS related

displays central 5HT2 receptor antagonism

activity

A computerized

and

cases were found; one died.

dopamine D2 antagonism noradrenergic

subsequent

(Ballard et al., 1998).To our knowledge,

several database was conducted to find the previously to this drug: twenty-one

drug for psychotic

et al., 1995), however

first reported case of NMS in DLB induced by risperidone.

Risperidone

(i.e.,

and the manipulation imbalance.

Continued

NMS, would be advisable

in patients with DLB.

use of

during

Risperidone, NMS and probable DLB

1049

We report the first case of NMS in DLB induced by low doses of risperidone. findings

indicate

a particular

sensitivity

of patients

Our

with DLB also to this atypical

neuroleptic.

ences_

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Inquiries and reprint requests should be addressed to: GianPietro Sechi, M.D. Neurological Clinic Viale S. Pietro 10 07100-Sassari, Italy tel: 0039-79-228.231 fax: 0039-79-228.423 e-mail address: [email protected]

neuroleptic