The neuroleptic malignant syndrome (NMS) is a potentially lethal complication of antipsychotic drug therapy characterized by fever, muscular rigidity, altered consciousness, and autonomic dysfunction.1,2 Delay and Deniker first coined the term "neuroleptic malignant syndrome" in the 1960s,3 although the condition had been previously encountered but not formally recognized. Indeed, as evidence of its undcrrecognition, the clinical entity "neuroleptic malignant syndrome" does not appear on the list of Medical Subject Headings in the Cumulated Index Medicus as of 1984.
At the time of a 1980 review, there were only about 60 reported cases of NMS in the literature.1 Since then there has been a proliferation of NMS case reports,* suggesting that the syndrome is just beginning to enter clinical awareness. If. however, the incidence (0.5% to 1.0%) attributed to NMS is accurate, then, as Caroff notes: "This percentage would indicate that the NMS is a neglected clinical problem of major proportions considering the large number of patients treated with neuroleptics."1 The clinician must therefore be alerted to its manifestations and treatment modalities. The purpose of this article is to present two illustrative cases of NMS and to review the current status of procedures for the detection and management of this serious disorder.
Mr. A. a 20-year-old white male, presented to the emergency room of Temple University Hospital in a catatonic stupor. The patient had a well-substantiated diagnosis of paranoid schizophrenia. There was no previous history of medical illness, aside from a premature birth with respiratory distress syndrome.
Six weeks before coming to Temple Hospital. Mr. A became acutely psychotic. Symptoms included persecutory delusions and auditory hallucinations. He was subsequently hospitalized at two different facilities and treated with various neuroleptics including lluphenazine. haloperidol. and thioridazine. In all. 225 mg (9 ce) of lluphenazine decanoate was administered over this 6week period.
One week prior to hospitalization. Mr. A's condition began to deteriorate while hospitalized al a private facility. Accompanying records mentioned that he was febrile and manifested stiffness, tremor, hypersalivation, urinary and fecal incontinence, and an irregular pulse. His sensorium was clouded. He became progressively mute and was unable to eat. The clinical picture did not improve with anticholinergic therapy. He was transferred to Temple Hospital for further evaluation.
On admission. Mr. A"s rectal temperature was 38° C, respirations were 20/min. blood pressure was 154/98 mmHg, and the pulse was 100 beats/min. He was alert and responsive to deep-pain stimuli, but not to verbal discourse. The skin was warm and moist. Neurological examination revealed hypertonicity in all muscle groups, especially those of the neck. He exhibited blepharospasm, hyperreflexia, and generalized plastic rigidity. Plantar responses were flexor. Cranial nerves were intact. No abnormalities were found on examination of the heart, lungs, and abdomen.
The values for the following admission laboratory tests were within normal limits, hemoglobin, hematocrit. WBC count and differential, platelet estimate, partial thromboplastin time, sodium, potassium, chloride, bicarbonate, glucose, creatinine, calcium, phosphorus, uric acid, cholesterol, total protein, albumin, bilirubin, alkaline phosphatase, lactic dehydrogenase, aspartate amino-transferase, thyroxine (T4), and T-, resin uptake. Blood urea nitrogen was slightly elevated (23 mg/dL). Urinalysis showed trace ketones. 0-3 RBC/HPF, 4-9 WBC/HPF, and mucous threads. Urine and blood cultures did not demonstrate bacterial growth. The ECG and chest X-ray were normal.
Initial treatment consisted of intravenous half-normal saline solution. All medications were discontinued except benztropine, 2 mg IM or orally three to four times daily. The temperature returned to normal during the first 24 hours after admission. Urinary retention and incontinence developed on the second hospital day and required temporary placement of an indwelling catheter. He was placed on a I week course of amoxicillin oral suspension. 250 mg every 8 hours, for prevention of urinary tract infection. A cystometrogram. performed to rule out an atonic bladder, was normal.
Marked clinical improvement occurred 1 week after hospitalization, at which time Mr. A began to eat. converse, and walk by himself. However, he remained very rigid and tremulous. Therapy was initiated with amantadine. 100 mg twice daily, and gradually resulted in further resolution of extrapyramidal signs. Benztropine was discontinued.
The patient's paranoid psychosis reemerged during the second hospital week and he became agitated, hostile, and delusional. Repeat serum electrolytes, blood chemistries, and complete blood count, were normal. Mr. A was treated with slowly increasing dosages of thioridazine up to 200 mg three times a day with no recurrence of neurologic symptoms. By the fifth hospital week mental status revealed an alert, oriented, cooperative patient with blunted affect and residual stiffness. Psychotic symptoms were in remission. Thirty-eight days alter hospital admission Mr. A was discharged home on thioridazine and amantadine for aftercare at a local mental health center.
Ms. B, a 38-year-old mentally retarded white female, was acutely psychotic and brought by police to the Temple University Hospital "Crisis Center." She reportedly was breaking furniture at home, walking incessantly, dressing inappropriately, not eating or sleeping properly, "hearing voices," and threatening to commit suicide. Despite a long outpatient record, she had never before been psychiatrically hospitalized. Past medical history was significant for a positive tuberculin PPD test, but she was never treated for tuberculosis.
In the Crisis Center the patient received the following medication over a 12-hour period: haloperidol, 25 mg IM; haloperidol, 20 mg orally; chlorpromazine. 75 mg IM; and chlorpromazine, 1.200 mg orally. Also, she had received an injection of fluphenazine decanoate. 50 mg (2 ce) IM, 3 days earlier at her community mental health center.
Ms. B was transferred to the inpatient psychiatry service for continuing treatment. Physical examination disclosed a mute, febrile, profusely diaphoretic female with cogwheel rigidity, generalized muscle hypertonicity, and coarse resting tremor. There was severe orthostatic hypotension; blood pressure was 100/60 mmHg when supine and 60/40 mmHg when standing. Other medical problems included a candidiasis skin rash and trichomonas vaginitis.
Initial management was directed toward stabilizing her blood pressure. She was hydrated intravenously and kept at bed rest with legs elevated. All medications were held except acetaminophen as needed for fever. During the next 3 days, however, Ms. B's condition worsened. She became increasingly rigid and catatonic. When sitting, she manifested typical waxy flexibility, a fixed gaze, and a masked face. Her mouth was open and she drooled continuously. The patient was intermittently incontinent of urine and feces. Occasionally, Ms. B would utter "I'm cold. I'm cold." but usually she did not communicate verbally.
Benztropine. 2 mg orally once daily, and amantadine. 100 mg orally three times daily, were added. In addition, daily physiotherapy was ordered. The laboratory evaluation consisting of blood chemistries, electrolytes, thyroid studies, serology. CSF analysis, EEG. CT brain scan. ECG. chest X-ray, and throat, sputum, urine, and blood cultures, was normal. A low-grade fever and leukocytosis persisted despite treatment for the trichomonas and candidiasis infections.
Ms. B remained catatonic and virtually immobile for about 3 weeks. She was unable to walk or feed herself without assistance. Fortunately, her neuromuscular symptoms resolved by the fourth hospital week. She began to speak short sentences and to care for herself. Her temperature and WBC count returned to normal. No obvious mental status abnormalities were noted besides deficient social skills. The patient continued to improve steadily, so that she could leave the hospital 7 weeks after admission. On discharge there were only minimal signs of rigidity.
These two cases share many features in common with NMS as described in other comprehensive reviews1,2,4 (Table 1). Typically, there are extrapyramidal signs such as tremor, diffuse muscular rigidity, dyskinesias, or akinesia. Hypertonic involvement of pharyngeal musculature may result in dysarthria, dysphagia, sialorrhea, and respiratory complications. Less frequent neurological findings are oculogyric crisis, opisthotonus, trismus, chorea, Babinski responses, and seizures.5 Hyperthermia develops concomitantly with or shortly after extrapyramidal signs. Temperatures may exceed 42° C,6 but commonly hover between 38° to 40° C (rectally). Other autonomic disturbances include pallor, excessive perspiration, labile blood pressure, incontinence, tachycardia, and tachypnea. The level of consciousness may vary over the course of NMS from an alert but unresponsive mutism to stupor, obtundation, and coma in severe cases.
CLINICAL FEATURES OF NEUROLEPTIC MALIGNANT SYNDROME
As seen in these cases, NMS usually develops explosively over a few days. Its onset, however, is unrelated to the length or dosage of neuroleptic therapy - NMS can occur hours or months after treatment.1 Furthermore, many patients with NMS have previously taken the offending neuroleptic without difficulty and have tolerated the same or a similar drug after resolution of the syndrome. Apparently, variables other than the neuroleptic itself are operating to produce this toxic reaction.
Itoh et al postulated that intramuscular administration of neuroleptics and marked physical exhaustion with dehydration favor the development of NMS; these features were common to all 14 patients in their series.4 High ambient temperature may also be a contributing factor,7 but is not a necessary condition. Additionally, certain patient subgroups seem to be at increased risk. Among these are young adult males,1 adolescents,8,9 patients with organic brain disease,1.3.5 and those treated with high potency neuroleptics or longacting depot preparations. 1.10-12 The latter is sometimes injudiciously and overaggressively employed, eg, in psychiatric emergency centers. Clinicians in these settings may potentiate the development of NMS if they arc unaware that psychotic patients whom they are treating will go on to receive, or have already received, neuroleptic therapy elsewhere, as was the case with Ms. B. To make matters worse, treatment with high potency antipsychotics often results in extrapyramidal signs that may be an early clue to recognizing NMS; this can be mistaken for further functional decompensation, and the clinical condition may be aggravated by continued antipsychotic treatment.15 Similarly, the emergence of dystonias in patients prophylactically treated with anticholinergics may be a warning of impending NMS mandating cessation of the antipsychotic or reduction of dosage.14
Since most persons who receive neuroleptics arc psychotic, NMS is usually seen in patients with a major psychiatric disorder - schizophrenia, manicdepressive illness, character disorder, or organic brain disorder. However, the presence of a psychiatric illness is not a prerequisite for NMS. There are notable exceptions in which non-psychiatric patients developed the syndrome as well.15 |q Prompt detection of NMS therefore requires not only knowledge of its clinical manifestations, but also a high level of suspicion for its occurrence in susceptible patients.
NMS presents a wide differential diagnosis that encompasses psychiatric, infectious, vascular, neoplastic, traumatic, neurologic, and toxic-metabolic conditions (Table 2). Physicians should consider the diagnosis of NMS in any patient taking neuroleptics who develops fever and CNS abnormalities. On the other hand, patients should never be assumed to be suffering from NMS unless all possible organic illnesses are vigorously ruled out by physical, neurological, and laboratory examinations. Leukocytosis and elevated serum CPK are common in NMS.1 Other laboratory studies are frequently normal.4,5 Disease states that can mimic NMS, eg, CNS infections, focal brain lesions, and metabolic derangements, often reveal specific laboratory abnormalities not found in NMS.
Catatonia, comprised of catalepsy, mutism, stereotypy, waxy flexibility, and muscular rigidity, strongly resembles NMS.10,15,20,21 Catatonia is a nonspecific symptom complex that appears in psychiatric disorders other than schizophrenia, such as manic-depressive illness, conversion disorders, dissociative states, and reactive psychoses. Differentiating NMS from "Bell's mania"22 or Stauder's "lethal catatonia"23 may be difficult.* Moreover, many patients presenting with catatonic signs and symptoms have organic causes.25 Too frequently the physician assumes that a patient who presents with "catatonia" has a psychiatric disorder and, regrettably, medically-ill catatonic patients are prematurely referred for psychiatric disposition. The misdiagnosis of NMS as a psychiatric disorder can have fatal results.
Many syndromes occurring in connection with the use of psychotropic medications may complicate and obscure accurate diagnosis in NMS. For example, combined neuroleptic-lithium treatment may cause a severe reaction associated with fever and neurotoxicity.20,27 Neuroleptics alone can induce a catatonic syndrome indistinguishable from NMS except for the presence of hyperthermia in the latter.28*31 Major tranquilizers, especially in conjunction with anticholinergics, may cause a drug fever similar to NMS by interfering with central and peripheral mechanisms of body temperature regulation.7 Characteristic features of NMS also have been seen with the concomitant use of MAO inhibitors and tricyclic antidepressants.1 Interestingly, both a sedative-hypnotic withdrawal state and the complications resulting from the neuroleptic treatment of such a condition can resemble NMS.1,17 The demarcation between NMS and all of these closely allied iatrogenic conditions is not clearly defined. Caroff concludes: "The NMS may be the neuroleptic-induced subtype of a more generalized set or spectrum of disorders that can be induced in susceptible patients by a variety of pharmacological agents."1
Another condition that may be easily misidentilicd as NMS is heatstroke, which manifests in hyperpyrexia, increased pulse rate, hot Hushed skin, and unconsciousness.7,32,53 Factors associated with increased risk of heatstroke - alcoholism, living on the higher tloors of multistory buildings, inability to care for oneself, and using major tranquilizers - predispose chronic psychiatric patients to its development.34 However, in heatstroke, the muscles are flaccid, rather than rigid as in NMS. Also, the skin is dry, not diaphoretic. Because different management is required, it is important to distinguish these two syndromes.
NMS has been associated with both phenothiazine and non-phenothiazine antipsychotics. High potency neuroleptics (eg, haloperidol and lluphenazine) are the most frequent offenders, but cases also have been reported with chlorpromazine,4,20,35,36 thioridazine,37,38 thiothixene,39 trifluoperazine,40 loxapine,41 and others. Some antipsychotics were employed together or in combination with other medications. Although treatment with neuroleptics is usually considered sine qua non in the pathogenesis, "neuroleptic malignant syndrome" has been reported in association with drugs that do not have antipsychotic properties.15,19 Perhaps such cases represent NMS-like states, but ascribing the diagnosis of "neuroleptic malignant syndrome" is probably a misnomer unless symptoms arise specifically as a result of neuroleptic administration per se.
The pathogenesis of NMS is presently under investigation. It is thought that altered thermoregulation in NMS is due to neuroleptic-induced dopamine receptor blockade in the basal ganglia and hypothalamus, thus increasing heat generation through muscle contraction and by impairing heat dissipation.5 Likewise, many of the neurologic and autonomic disturbances in NMS can be explained on the basis of interferences with dopaminergic neurotransmission of striatal and hypothalamic neurons. However, the occurrence of NMS-like states caused by dopamine depleting agents in a patient with Huntington's disease,15 and also following the abrupt withdrawal of levodopa and carbidopa in a patient with Parkinson's disease,19 indicates that dopaminergic hypoactivity. in addition to dopamine receptor blockade, may play an important role in this syndrome.
DIFFERENTIAL DIAGNOSIS OF NEUROLEPTIC MALIGNANT SYNDROME
Other etiological explanations have been raised by virtue of a close relationship between NMS and malignant hyperthermia (MH). MH is a rare multifactorial genetic disorder caused by certain depolarizing muscle relaxants and inhalational anesthetics.42 Like NMS, it is characterized by hyperpyrexia, rigidity, autonomic instability, elevated serum muscle enzymes, and improvement with dantrolene sodium. These striking similarities between NMS and MH suggest that they may share a common pathophysiology.
Currently, there is a reliable screening test to detect persons who are susceptible to MH.4' The test involves the use of a muscle biopsy specimen that has been exposed in vitro to halothane or caffeine (or both). In comparison with normal persons, those who are MH-susceptible exhibit increased muscle tension in response to low concentrations of these drugs.44 Utilizing a similar approach, evidence of pathophysiological link between NMS and MH, recently presented by Caroff et al,45 can be found in the following: 1) a recovered NMS patient had an abnormally sensitive in vitro muscle contracture response to fluphenazine as well as halothane, and 2) three patients with susceptibility to MH were no more sensitive to fluphenazine-induced muscle contractions than were eight normal controls. The first finding suggests that NMS patients are at risk to develop MH, whereas the second finding indicates the converse is not necessarily true. Thus, "vulnerability to one syndrome may not automatically mean vulnerability to the other."40
Some investigators15,47,49 have theorized distinct pathogenic mechanisms operating in NMS and MH. Tollefson's49 study of muscle contractility in a recovered NMS patient failed to corroborate the findings of Caroff and associates.45 Moreover, Lotstra et al,48 reported the case of a recovered NMS patient who subsequently underwent general anesthesia in conjunction with ECT (for treatment of a psychotic depression) without any difficulty. Hence, there has been some doubt cast on the relationship between NMS and MH. Because data are scanty, we must await additional studies to confirm or disprove their putative etiological similarity. It seems likely, however, that elucidation of the physiologic and biochemical parameters underlying MH will further our understanding of factors responsible for NMS.
TREATMENT AND PROGNOSIS
There is no clearly established treatment for NMS other than immediate withdrawal of all psychotropic medications when typical signs of the syndrome develop. An investigation into possible neurologic, toxic-metabolic, and infectious illnesses should be carried out concurrently. Supportive care must be instituted promptly to control hyperthermia (eg, with antipyretics and cooling blankets), stabilize blood pressure, correct fluid and electrolyte imbalance, and treat secondary complications such as thromboembolism, aspiration pneumonia, arrythmias, rhabdomyolysis, and renal insufficiency. Tube feedings may have to supplement decreased food intake resulting from impaired deglutition. Some patients may require respirator support for tachypneic hypoventilation.5 Others have needed intensive cardiac care following myocardial infarction.6 In a dramatic case of NMS complicated by gas-producing Escherichia coli fasciitis, bilateral below-the-knee fasciotomies were necessary.50
In general, anticholinergic agents, antibiotics (in the absence of specific infection), amobarbital sodium interviews, and renal dialysis are ineffective. Although dialysis is necessary if renal failure ensues,51 it cannot remove the offending drug from serum because neuroleptics are highly membrane or protein bound.52 ECT, used in the treatment of acute catatonic excitement,55 has not been advocated in the therapy of NMS.1 However, lessee and Anderson54 recently reported two cases of NMS with severe fever in which ECT resulted in rapid defervescence and the beginning of overall clinical improvement. They suggested a possible role for ECT in cases where there is continued clinical deterioration or life-threatening fever.
Within the past few years specific pharmacologic interventions have been tried in NMS on a limited basis. Dantrolene, used in the treatment of heatstroke,55 malignant hyperthermia,5059 and spasticity,60 has been effective in at least six patients with NMS.61-65 (Additional case reports appear in the French literature.) It works by inhibiting intracellular calcium release from muscle sarcoplasmic reticulum.66 By quickly counteracting thermogenesis induced by tonic skeletal muscle contraction, dantrolene may prevent lethal complications of NMS related to the duration of hyperthermia.1·63
Amantadine37·67 and bromocriptine,68 70 both dopamine agonists, also have been used successfully in NMS, although in some instances improvement may have been spontaneous.46 They presumably offset the central dopamine receptor blockade caused by neuroleptics. Amantadine has previously been shown to be effective in treating neuroleptic-induced catatonia, and seems to be superior to anticholinergic drugs in this type of reaction.28 Alternatively, bromocriptine may offer a more effective strategy since it acts postsynaptically, rather than presynaptically. as does amantadine.71 While pharmacotherapy appears promising with amantadine, bromocriptine, and especially dantrolene, more clinical experience is needed to determine whether any can be recommended as definitive treatment in NMS. either alone or in combination. At present, physicians may want to employ them in more serious cases or in those which do not respond to supportive measures.
Symptom resolution in NMS occurs usually within IO days after discontinuation of the neuroleptic and institution of adjunctive therapy. It may take several weeks for symptoms to remit if depot injections are responsible. Tragically, the disturbances end fatally in about 20% of cases.1 Death from respiratory, renal, and cardiovascular causes has been cited. Post-mortem examinations have failed to demonstrate any specific gross or microscopic CNS abnormalities.4,35 If, as Peele and von Loetzen72 have suggested, many sudden, unexplained, autopsy-negative deaths in patients receiving neuroleptics are actually acute cardiac deaths among the general population and cases of lethal catatonia among the mentally ill. then fatalities from NMS may reflect a predisposition for its occurrence in heterogeneous groups of patients treated with major tranquilizers, as previously mentioned.
NMS presents a dangerous complex of neurologic and psychiatric symptoms. When the diagnosis of NMS is suspected, the following steps should be taken: 1) stop all psychotropic drugs; 2) provide supportive care; 3) pursue an investigation into organic illnesses; and 4) consider the use of amantadine, bromocriptine, or dantrolene.
The fact that the two cases described herein were encountered over a relatively short time (1979 to 1981) indicates that NMS may not be as rare as originally believed. Hopefully, increased appreciation of the syndrome will lead to early recognition and prompt institution of therapeutic measures, thereby reducing morbidity and avoiding death.
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CLINICAL FEATURES OF NEUROLEPTIC MALIGNANT SYNDROME
DIFFERENTIAL DIAGNOSIS OF NEUROLEPTIC MALIGNANT SYNDROME