CASE REPORT

Pmg. Neuro-PsychopharmocoL C Biol. Psychiot.1990. Vol. 14, PP. 129-136 Printed in Great Britain. All rights reserved

027&t-584lv90 $0.00 + so @ 1990 Pergamon press plc

~~O~PTIC-~DU~ CATATONIA: NEUROLEPTIC MALIGNANT SYNDROME? JOSE DE LEONl, JERONIMO SAIZ-RUIZ, ADELA ALONSO-ABOLAFIA, ELVIRA PICO-SOLER, JORGE MUNOZ-RUATA and INMACULADA DE LA SERNA Hospital Ramon y Ca-jal,Department of Psychiatry Madrid, Spain

(Final form, Way 1989)

Abstract De Leon, Jose, Jeronimo Saiz-Ruis, Adela Alonso-Abolafia,Elvira Pica-Soler, Jorge MunozRuata and Inmaculada de la Serna: Neuroleptic-InducedCatatonia: Neuroleptic Malignant Syndrome? Prog. Neuro-Psychopharmacol.& Biol. Psychiat. 1990, -14: 129-136 1.

The authors describe a case report of catatonia syndrome after administration of depot neuroleptics. 2. Differential diagnosis was made between neuroleptic malignant syndrome or catatonic syndrome complicated by infection. lhe signs and symptoms observed throughout the patient's course are detailed. 3. A critical review is made of bibliography on the topic, with emphasis on the lack of clear clinical description and poor conceptual definition.

Keywords: catatonic syndrome, extrapyramidalside effects, long-acting neuroleptics, neuroleptic malignant syndrome. Abbreviations: acute confusional state (acs), blood (b), computed axial tomography (CAT), creatinine phosphokinase (CPK), diastolic (d), electroencephalogram(EEG), erratic ocular movements (eom), full-scale intelligence quotient (FSIQ), improvement (imp), mutism (mut), neuroleptic-inducedcatatonic syndrome (NCS), neuroleptic malignant syndrome @MS), obnubilation (obn), performsnce intelligence quotient (PIQ), proteus (prot), psychotic symptoms (psychot,s.),systolic (s), Sequential Multiple Analyzer Computer-24 (SWAG-24), urine (u), urine retention (URT), verbal intelligence quotient &IQ), Weschler Adult Intelligence Scale (WAIS). Introduction Neuroleptic malignant syndrome (IBIS),described by Delay and co-workers (1962), is one of the prominent side effects produced by neuroleptics. Its principal manifestations are: hyperthermia, hypertonia, fluctuating consciousness and autonomic instability (Guse and Baxter, 1985). Early reviews tended to consider it a homogeneous entity (Garaff, 1980: Smego and Durach, 1982; Szabadi, 1984; Gibb and Lees, 1985; Guse and Baxter, 1985; Lwenson, 1985; Kurlan, et al., 19

), but recently the spectrum concept has been introduced (Gonlon, 1986) and

atypical forms have been described (Shaler and Munits. 1986). In a review of 48 cases, Levinson and Simpson (1986) questioned the syndrome's unity, suggesting that many cases can be explained as medical complicationsnot due to neuroleptics. These authors consider this syndrome heterogeneous In nature and propose the alternative designation of extrapyra----------___--1

Present address: Medical college of Pennsylvania at EPPI, Philadelphia, PA, USA 129

130

J.De Leon etal.

midal syndrome with fever. Another picture these drugs produce is akinesia (Rifkin, et al., 1975) which can be accompanied by other symptoms until catatonic syndrome occurs (May, 1959; Cremona-Barbaro,1983). Hyman (1988) considers neuroleptics to be the most common cause of this syndrome in the United States at present. The authors describe the case of a patient given depot neuroleptics who presented a picture similar to NMS, but without fever. This case illustrates the need for differential diagnosis of NMS and neuroleptic-inducedcatatonic syndrome (NCS) accompanied by other complications. Case Report The patient was a 19 year-old male, relatively well adapted to his rural environment. In May 1985, coinciding with his military service away from home (obligatoryin Spain), he began to have problems in relations with companions and superiors. On 5-7-85, the unit doctor referred him to the Central Military Hospital for schizoid conduct and adaptation disorders (he refused to shower with the others and presented "excessive preoccupation with his genitals"). He was evaluated by a psychiatrist who encountered a euphoric and fatuous mood, absence of critical judgement and thought withdrawal phenomena. An EEG showed nonspecific alterations and psychological tests [WAIS (Tea, 1977) and Rorschach (Klopfer, et al., 1960)] disclosed an IQ of 84, schizoid personality and possible paranoid psychosis. Treatment with neuroleptics (maximum doses 7.5 mgfday haloperidol and 50 mg/day levomepromazine) and anticholinergics (6 mg/day biperidine) was prescribed. The patient was discharged three weeks after admission (7-26-85). At this time, he was injected i.m. with 200 mg palmitic ester of pipothiazine and prescribed 25 mglday levopromazine and 4 mglday biperidine. The next day at home, the patient initiated with mutism, negatLvism and episodes of generalized tremor. On 7-31-85, he was seen in his provincial hospital where blood and Wine analyses and an EEG were made, all of which were normal. On 8-8-85, he was referred to the Emergency Service of our center with a nasogastric tube and urinary catheter in place. Figure 1 summarizes his later evolution, including the signs and symptoms observed and treatment given. The examination found: mutism, although the patient followed stimuli visually; intense generalized hypertonia with waxy flexibility, but no conservation of postures. He also presented bilateral pes cavus, syndactyly, muscular atrophy of legs, arreflexia of the Achilles tendon, tachycardia and mild fever of 37.5"C. Analyses shosed metabolic acidosis, 1eukocytcr;is and neutrophilia, leukocyturia and gram-negativebacteriuria. A brain CAT scan was normal. Once diagnosed as possible sepsis of urinary origin, antibiotic treatment was begun. The catatonic syndrome was considered secondary to the depot neuroleptic and 5 mg/12 hr i.m. of biperidine was prescribed. Treatment and Outcome On day 2 of hospitalization,SMAC-24 analyses demonstrated 2350 IU/l CPK. An EEG showed diffuse slowing. We added 15 mg/day i.m. diazepam to the therapeutic regimen. Antibiotic treatment was modified in accordance with a finding of streptococcusgrowth in the blood culture. On day 3, the patient presented alterations in consciousness,mutism, rigidity,

8C8

,

31

eom

Figure I.

I I

I

I

8 6mg

111

15mg

2oOmg

1

1Gmg

2350

4

t

38

5mg

10940

37

..*.*..*a

prot prot

37

37

copious

I

20

25

I

30

5

10

OCTOBER 17

t

38

130

36.5

12Q

*&***.a*

I

I‘*.‘*#*

2.5mg

9300

100

80

t

36.5

90

8-100 5-70

good state of awareness non psych0t.s.

10-120 5-80 120

imp

1

15

SZPT~ER 10

Chronological evolution of the patient'a clinical 8Ttd therapeutic data.

PIPOTEIAZINZ

BROMOCRIPTINZ

DIAEEPAH

BIP~RIDENE

ANTIBIOTICS

CPK (ui/l)

f5830

15600

LE~O~~S

(l/mm'>

atr str and ps ps URT URT

40

INFECTIOUS AGENTS Z U

38

37.5

TEMPERATURE (OC)

abundant

120 160

100 120

HEART RATE

150

12-130 14-150 180 12-150 8-90 7-90 100 6-90

BLOOD PRESSURE S D

SWEATING

5

and flucruatinn

c nener@zed

TRZMORS

imp

f intense and *ene&&gd

obn

I

26

RYPERTONIA

I

21

AUGUST 16

mut acbl

,

11

PSYCHIATRIC SYMPTOMS

8

J.De Leon et al.

attitude, intention and resting tremor, tachycardia, but no fever. The sepsis appeared to have improved. Other diagnostic possibilities considered were neuroleptic malignant syndrome (fever was lacking) and neurological disease. No symptoms suggesting Friedrich's disease were found. Ceruloplasmin and cupremia levels excluded Wilson's disease, coproporphyrin values excluded porphyria, thyroid hormone values excluded hyperthyroidism, complement studies excluded vasculitis and CSF analysis excluded encephalitis. Biperidene (6 mg/d) and diazepam (15 mg/d) were switched to oral administration and fluid therapy was changed to support solutions two days later. On day 6, blood cultures evidenced pseudomona and streptococcus and urine cultures showed pseudomona. An attempt was made to remove the urinary catheter, but the patient retained urine and his fever peaked at 38'C. Diazepam was discontinued in view of the absence of improvement; the patient remained stationary with mutism, varying consciousness,hypertonia, tremor, tachycardia, fever and decubitus of the heels. On day 14, treatment with 5 mglday bromocriptine commenced, in case NMS was present. The patient's fever peaked at 40°C when the urinary catheter became obstructed. The antibiotic was changed in accordance with the antibiogram. Day 17:

the internists recommended discontinuing biperidine because it favors

urine retention. Day 19:

proteus was found in blood and urine cultures and antibiotic

treatment was modified. Day 20:

tachycardia accelerated to 160. The patient was examined

by a cardiologist,who found no underlying heart disease. Temperature was 37.7'C and from a psychiatric standpoint, the patient presented a confusional state with possible auditory hallucinations and delusional ideas of harm.

In the last days of August, intense generalized

fluctuating tremor and erratic bilateral ocular movements were added to the picture. The patient was assessed by both the Infectious Disease Service and Psychiatry, reaching the diagnoses of sepsis by Proteus of urinary origin and possible NMS.

The patient was

transferred to the Infectious Disease Service, although he continued with bromocriptine. At the beginning of September, the patient was afebrile, sweaty, and had improved consciousness. The generalized tremors and rigidity continued, now affecting only the upper extremities, with resting tremor. Episodes of generalized tremor with sweating, tachypnea and tachycardia were noteworthy. On day 37, the patient presented no psychotic symptoms, was partially disoriented in time, could repeat 6 figures directly and none inversely, subtracted 7 from 100 once and answered "I don't know" to more complex questions. The patient controlled urinary incontinence and began to walk with the help of rehabilitation. This improvementwas observed about 50 days after the pipothiazine injection. It has been reported that concentrations usually become undetectable about 30 days after administration (Girard, et al., 1984). The patient returned to the Psychiatry Department at the end of September. He showed no rigidity or psychotic symptoms, but did have echolalia. It was difficult to evaluate the patient's previous psychiatric picture because he was highly suggestionable. In October, his adaptation to the department was better but his mood was infantile and he showed a certain degree of sexual desinhibition. Amantadine was suppressed and a new brain CAT scan was realized, which was normal. Repetition of the analyses proved negative. No test was made for malignant hyperthermia nor was a muscular biopsy obtained. On l/10/85, almost three months after admission, a WAIS showed VIQ 75, PIQ 64 and FSIQ 68.

Neuroleptic inducedcatatonia

133

The Bender test demonstrated, according to Marley's scoring criteria (1982), alterations in quality, angulation difficulty, line extension, rotation, omissions and retrogression,with a raw score of 83.

Corrected for duration of execution (3 min) the score was 33, which is

in the area of non-organicity. The Rorschach evidenced a paucity of ideative content and general interest, with affective lability and absence of psychotic symptoms. The patient was discharged with a diagnosis of possible schizophreniformdisorder (DSM-III)with absence of active symptoms and possible neuroleptic malignant syndrome. Long-Term Follow-Up Six months after discharge (March 1986), the patient was asymptomatic and did not require treatment. In October 1986 (a year after onset), psychological tests were repeated. The WAIS evidenced VIQ 87, PIQ ?7 and FSIQ 80.

In the Bender test, only two criteria were

altered: part workover and omissions. The raw score was thus 25, 12.5 when corrected for time (10 min), within the limits of nonorganicity. In the Rorachach teat he continued to show ideational poverty, but more mobility of interests and more stable affectivity. A certain tendency to fabulation was observed. The examination disclosed no psychotic symptoms, but his family referred having difficultieswith him, in the form of insults, especially because of jealousy toward his older sister. The patient was unaware of having a psychiatric disease and denied receiving treatment. Comments Differential Diagnosis From complementary tests, we could exclude metabolic disorders (hypercalcemia,hepatic encephalopathy,pellagra, porphyria, kidney failure and diabetic cetoacidosis) and brain disease (alterationsin basal ganglia, tumors, cerebra-vasculardiseases, epilepsia and encephalitis) that can produce catatonic syndromes (Magrinat, et al., 1983; Barnes, et al., 1986; Hyman, 1988). The nature of the clinical manifestations eliminated the possibility of a catatonia of affective origin. The patient's course and the fact that the picture appeared after the depot neuroleptic was injected suggested that his catatonia was of pharmacologicalorigin, rather than schizophrenic, that is, that he had NMS or NCS with medical complications. Our patient presented all the major symptoms of NMS described by Guze and Baxter (1985): hyperthermia, hypertonia and fluctuations of the level of consciousness and autonomic instability. However, hyperthermia was related to episodes of urine retention associated with his infection. The patient also presented less common symptoms, like fluctuating tremor and ocular movements. Laboratory tests demonstrated leukocytosis and increased CPK (CPK was only raised in the first determination). Our patient thus satisfied all Levenaon's (1985) major criteria (fever, rigidity and increased CPK), as well as minor criteria (tachycardia,abnormal blood pressure, tachypnea, alterations in consciousness and leukocytosis). If we specify, as Levenson did not, that these symptoms be present in the absence of other disorders that could explain them, our patient had two major criteria and four minor ones that indicate a high probability of NMS.

Robinson, et al., 1985,

reported a case in which an afebrile catatonic syndrome presented after use of metoclorpropamide,which they classify as NMS. The other alternative to consider is NCS accompanied by signs secondary to the infection.

J.De Leon etal.

134

In theory, the akinesia should have responded to the anticholinergicsbut the dosage may have been insufficient. Slow response to these substances has been reported (Hyman, 1988). Aside from this, there was uncertainty as to the duration of the depot effect. Another option to ponder, since the principal differential element between NMS and NCS is high fever, is that our patient presented an intermediate picture between them. Szabadi (1984) has commented that catatonia may be a frustrated form of NMS. Allan and White (1972) describe a patient who after injection of fluphenazine decanoate presented a picture of generalized rigidity, tremor, mutism and decreased consciousnesswith a tendency to somnolence, that is, a catatonic syndrome accompanied by a slight increase in temperature (36.7 C) and neutrophilia in the absence of infection. This picture disappeared when drug cataboliteswere no longer eliminated in urine. Fricchione (1985) establishes an analogy between NCS and its complication,NMS, and catatonia of psychic origin and its complication, lethal catatonia. However, lethal catatonia was described by Stauder (1934) in the preneuroleptic era and it is difficult to determine what the concept really corresponds to. Physiopathologyand Treatment of NMS The physiopathologyof NMS is not well-known, but there is speculation that dopaminergic block may be involved (Caroff, 1980; Henderson and Wooten, 1981; Lazarus, et al., 1989). This theory parts from observations in patients with medical diseases treated with other drugs: alpha-methyl-p-tyrosineand tetrabenazine in a patient with Huntington's chorea (Burke, et al., 1981); after discontinuationof antiparkinson drugs with continued administrationof haloperidol and lithium in a patient with Parkinson's disease and a chronic psychiatric disorder (Henderson and Wooten, 1981); and after suppression of antiParkinson agents in a patient with Parkinson's disease (Toru, et al., 1981). There is still no firm evidence of the specific value of any treatment (Levenson, 1985). Thus it does not seem justified to contrast akinesia pictures, which respond to anticholinergics (Rifkin, et al., 1975) with NMS as responsive to dopaminergic agonists. According to the review by Levinson and Simpson (1986) of patients who actually presented extrapyramidal symptoms and fever, there are cases that recuperate with dopaminergic agonists, anticholinergics,dantralone, loracepam, electroconvulsivetherapy and even without specific treatment. The NCS patients described by Gelenberg and Mandel, (1977) improved with amantadine but not with anticholinergics. Cures have been reported with loracepam in NCS (Fricchione,et al., 1983; Walter-Ryan, 1985). Final Remarks To summarize, our patient poses more questions than answers as to whether there is continuity between NMS and NCS. Along the line of research indicated by Levinson and Simpson, (1986) we have attempted to clearly distinguish symptoms produced by medical complications. Our patient certainly cannot be included in their concept of extrapyramidal symptoms with fever because in our case fever was clearly related to infection. To conclude, we should keep in mind four possible diagnoses in patients who present a catatonic syndrome with fever: schizophrenic or affective catatonia with medical complications (Brenner and Rheuban 1978) organic catatonia with fever (e.g. encephalitis), NCS with a medical complication and NMS. consideration of:

Differential diagnosis is not easy and entails

previous symptoms, relation with neuroleptic treatment, existence of

135

Neuroleptic inducedcatatonia

medical complications and the course. The difficulties involved are mirrorred by the reigning diagnostic confusion. In the pre-neurolepticera, these patients were classified as schizophrenics,although some were surely organic. At the present, there is a tendency to classify them as NMS, although they may really have schizophrenic catatonia or neuroleptic-inducedcatatonia complicated by infection. Conclusions The etiology of catatonic syndromes with fever is very difficult to find. tBefore diagnosing NMS, other possibilities must be thoroughly ruled out , especially NCS complicated by infection. Unless NMS studies become more clear about exclusion criteria, it would be very difficult to reach any meaningful conclusions about this syndrome, even in such important aspects as treatment. References ALLAN, R.N. and WHITE, H-C. (1972) Side effects of parenteral long-acting phenothiazines. Br. Med. .I.1: 221. BARNES, M.P., SAUNDERS, M., WALLS, T.J., SAUNDERS, I. and KIRK, C. (1986) The syndrome of Karl Ludwig Kahlbaum. J. Neurol. Neurosurg. Psychiatry -49: 991-996. 8R~ER, I.R.A. and ~EUB~, 1243-1244,

W.J. (1978) The catatonic dilemma. Am. .I.Psychiatry _135:

BURKE, R.E., FAHN, S., MAYEAUX, R., WIENBVERG, H., LOUI, K. and WILLNER, J.H. (1981) Neuroleptic malignant syndrome caused by a dopamine-deletingdrug in a patient with Huntington's chorea. Neurology -31: 1022-1026 CAROFF, S.N. (1980) The neuroleptic malignant syndrome. J. Clin. Psychiatry -41:

79-83.

CONLON, P. (1986) The spectrum concept of neuroleptic toxicity. Am. J. Psychiatry -143: 811. CREMONA-BARBARO,A. (1983). Neuroleptic-inducedcatatonic symptoms. Br. J. Psychiatry -142: 98-99. DELAY, .I.,PICHOT, P., L~ERIERE, T...ELISSALDE, B. and PEIGRE, P. (1960) Unneuroleptique majeur non phenothiazine et non reserpinique 1 haloperidol dans le traitment des psychoses. Ann. Med. Psychol. -118: 145-152. FRICCHIONE, G.L. (1985) Neuroleptic catatonia and its relationship to psychogenic catatonia. Biol. Psychiatry -20: 304-313. D. and HOBSON, D. (1983) Intravenous lorazepam FRICCHIONE, G.L., CASSEM, N.H., HOOBE~, in neuroleptic-inducedcatatonia. 3. Clin. Psychophar~co~. 3: 338-342. GELFNBERG, A.J. and MANDEL, M.R. (1977). Catatonic reactions to high potency neuroleptic drugs. Arch. Gen. Psychiatry -34: 947. GUZE, B.H. and BAXTER, L.R. (1985). Neuroleptic malignant syndrome. New Engl. .I.Med. -313: 163-166. PETERSON, V.W. and WOOT~, G.F. (1981) Neuroleptic malignant syndrome: a pathogenic role for dopamine receptor blockage? Neurology -31: 132-137. HYMAN, S.E. (1988) Acute psychosis and catatonia. In: Manual of Psychiatric Emergencies, 2nd ed., S.E. Hyman (ed), pp 118-133, Little, Brown and Co., Boston. KLOPFER, B., AINSWOR~, M., ANDERSON, D. and HOLT, R. (1960) Development in the Rorschach Technique. Harcourt, Braze and World, Inc., New York.

136

J.De Leon etal.

LAZARUS, A., MANN, S.C. and CAROFF, S.N. (1989) The Neuroleptic Malignant Syndrome and Related Conditions. APA Press, Inc., Washington, D.c. LEVENSON, J.L. (1985) Neuroleptic malignant syndrome. Am. J. Psychiatry -142:

1137-1145.

LmINSON, D.F. and SIMPSON, G.M. (1986) Neuroleptic-inducedextrapyramidal symptoms with fever. Heterogeneity of the neuroleptic malignant syndrome. Arch. Gen. Psychiatry -43: 839-848. MAGRINAT, G., DANZIGER, J.A., LORENZO, I.C. and FLAMFNBAUM, A. (1983). A reassessment of catatonia. Comp. Psychiatry -24: 218-227. MARLEY, M.L. (1982) Organic Brain Pathology and the Bender-GestaldtTest. Grune and Stratton, New York. MAY, R.H. (1959) Catatonic-like states following phenothiazine therapy. Am. J. Psychiatry 115: 1119-1120. RIFKIN, A., QUITKIN, F. and KLEIN, D.F. (1975) Akinesia: a poorly recognized druginduced extrapyramidal behavioral disorder. Arch. Gen. Psychiatry -32: 672-674. ROBINSON, M.B., KENNET, R.P., HARDING, A.E., LEGG, N.J. and CLARKE, B. (1985) Neuroleptic malignant syndrome associated with metoclopramide. J. Neurol. Neurosurg. Psychiatry -40: 1304-1312. SHALRV, A. and MUNITZ, H. (1986) Akinesia: a poorly recognized drug-induced extrapyramidal behavioral disorder. Arch. Gen. Psychiatry -32: 672-674. SMEGO, R.A. and DURACK, D.T. (1982) The neuroleptic malignant syndrome. Arch. Intern. Med. -142: 1183-1185. STAUDER, H.K. (1934) Die todliche Katatonie. Psychiatr. Nervenka -102:

614-634.

TEA, S.A. (1977) Escala de Inteligencia de Weschler para Adultos. TEA, S.A., Madrid. TORU, M., MATSUDA, D. and MATGUCHI, K. (1981) Neuroleptic malignant syndrome-like state following a withdrawal of anti-parkinsoniandrugs. J. NeN. Ment. Dis. -169: 324-327. WALTER-RYAN, W.G. (1985). Treatment for catatonic symptoms with intramuscular lorazepam. J. Clin. Psychopharmacol.2: 123-124. Inquiries and reprint requests should be addressed to: Jose de Leon, M.D. Medical College of Pennsylvania/EPPI 3200 Henry Avenue Philadelphia, PA 19129 U.S.A.