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THE NEUROLEPTIC MALIGNANTAND SEROTONIN SYNDROMES

Joseph R. Carbone, MD

THE NEUROLEPTIC MALIGNANT SYNDROME

The advent of nelUoleptic medications in the 1950s led to a revolution in thecare of patients suffering from psychiatric illnesses. Like all phannacothecapeuticagents, however, nelUoleptic agents soon would be fOWld to have unwantedside effects. Among these is an adverse reaction that can be particularly devasta­ting. termed the neuroleptic malignant syndrome (NMS). First described in theFrench medical literature in the 1%05,'° the incidence of NMS is estimated atapproximately 1.0% of patients treated with neuroleptics. The syndrome mostcommonly occurs within the first 3 to 9 days of therapy but can occur after apatient has been taking neuroleptics for a long time. NMS is thought to be anidiosyncratic drug reaction that is not dose related. It has been reported to occurafter a single dose of a neuroleptic agent. A person who has developed NMSduring treatment with a specific nelUoleptic agent can actually be treated withthe same agent at a later time without redeveloping the syndrome;Ml. ~ althoughrecurrences have been reported.

NMS is most closely associaled with the use of the high-potency neurolep­tics, such as haloperidol and thiothixene. It is believed to occur less frequentlyffith the low-potency neuroleptics such as chlorpromazine and mesoridizine,although this finding is controversial. In addition, the newer "atypical" neuro­lepties, such as clozapine, risperidone, and olanzapine, which have been mar­keted as having fewer side effects than do the older neuroleptic agents, alsohave been associated with the NMS.3. 13 The syndrome has been reported in thesetting of treatment with L-dopa agents, as in patients with parkinsonism.2'

From the Departments of Psychiatry and Neurology, Mount Sinai School of Medicine,New York, New York

EMERGENCY MEDIONE CLINICS OF NOItfH AMERICA

VOLUME 18· "-'UMBER 2· MAY 2000 317

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Pathophysiology

The etiology of NMS is related to a dysregulation of the dopaminergicsystem.:ID In the treatment with antipsychotic neuroleptic agents, there is aniatrogenic blockade of dopaminergic transmission,. particularly involving the Ot­receptor system; in the use of L-dopa in parkinsonism there is an iatrogenicenhancement of dopaminergic transmission. In both contexts, the pathophysiol­ogy of NMS is believed to be due to dopaminergic blockade in the basal gangliaand in the hypothalamus.%l Although this seems at first to be counterintuitive intreatment of parkinsonism, NMS usually occurs with sudden decreases in thedosage of l-dopa, amounting to a relative deficiency state compared with whenthe patient was being treated with a higher dose of L-dopa. It has also beenpostulated that the glutamatergic system of neurotransmission could be involvedin NMS. thus explaining the proposed benefit of amantadine, a NMDA S-typeglutamate receptor antagonist, in the treatment of NMS.J.1.

Contributing factors to developing NMS include ambient heat and dehydra­tion; underlying brain damage and dementia (which may have already damageddopaminergic pathways); and high dosing of neuroleptiC'S. although this wouldappear to contradict our understanding of NMS as an idiosyncratic drug reaction(the apparent contradiction could be resolved conceptually by hypothesizingthat there is a genetic dose-dependent vulnerability).

Clinical Features

The constellation of signs and symptoms that comprises the NMS is essen­tiallya triad of hyperthermia (autonomic instability). encephalopathy, and skele­tal muscle rigidity. In addition to rigidity, the patient can have akinesia ordystonia. Autonomic instability is an important feature of the syndrome, and,in addition to causing hyperthermia, it can result in blood pressure instability,diaphoresis, and tachycardia. Oinical features are accompanied by the laboratoryfindings of increased aeatine kinase (CK). leukCK)1osis, and myoglobinuria.s CKelevations of up to 60,000 IUJL have been reported. White blood cell COlUlts aretypically in the range of 10,000 to 40,000 cellsl mmJ and can be accompanied bya shift to tile left.SI One must remain alert to the fact that patients with NMScan develop concurrent infections that could complicate management and resultin a refractory response to treatment. Suspicion of a comorbid process is arousedif a patient continues to be hyperthermic despite decreasing CK levels or ifsymptoms persist past 2 weeks, the average time course of NMS.SI

One of the factors that can delay arriving at the correct diagnosis is theoccurrence of a forme fruste of the syndrome, in which some or all of the classicclinical features are initially absent. Severe NMS, for example, has been reportedto present without hyperthermia or without muscular rigidity.B. ~ Dearly, thisattenuated form of the syndrome poses a diagnostic dilemma, which can becomplicated fwther by its W\predictable time of onset in relation to initiation orwithdrawal of therapy.~

The mortality rate in NMS is estimated at 12% to 20%. 1be most significantcause of morbidity and mortality is renal failure secondary to the large amountsof myoglobin produced by Ihabdomyolysis,S followed by respiratory failureowing to aspiration pneumonia." Aspiration in the setting of NMS can occursecondary to obtundation as well as to dysphagia. Other causes of mortality andmorbidity include sudden cardiac death from myocardial infarction,. acute car­diac failure. or a fatal dysrhythmia. Thrombocytopenia and disseminated intra-

THE NEUROLErnC MAUGNANT AND SEROTONIN SYNDROMES 319

vascular coagulation (Dlq have been reported.!'!· 2~ It is essential to monitor theelectrolyte status of patients with NMS closely because hyperkalemia, hypona­tremia, and hypematremia can occur.D

Differential Diagnosis

One of the many challenges involved in the treatment of NMS involvesmaking the correct diagnosis. Errors can occur in either direction. that is, thetendency to overdiagnose as well as the tendency to underdiagnose the syn­drome. In the case of the overdiagnosis, the principal danger lies in missing aninIectibus process (e.g., meningoencephalitis). The underdiagn9sis can involveunderestimating the associated autonomic instability associated with the syn­drome, or ignoring the potential complications of rhabdomyolysis. In the caseof either the overdiagnosis or underdiagnosis of NMS, the opportunity for themost appropriate treatments to be initiated in a timely fashion is missed.

The differential diagnosis of patients with NMS includes all entities thatcan present with any combination of encephalopathy, fever, and rigidity. Thisincludes central nervous system (CNS) infections, the serotonin syndrome (de­fined later in this article) heat stroke, acute dystonic reactions, and drug toxicities(e.g., monoamine oxidase inhibitor, cholinergic, or lithium toxicities). The differ­ential diagnosis of NMS also includes vasculitis. In the setting of a primary CNSvasculitis, the usual vasculitis work-up can be normal, and, in select cases, brainbiopsy is necessary to confirm the diagnosis. Malignant hyperthermia is anotherdiagnostic entity that should be considered when there is a history of anesthesia.

Lethal catatoniD/· J(J part of the group of entities known as malignant catato­nia,&J deserves special mention in the differential diagnosis of NMS. Like NMS,lethal catatonia and malignant catatonia can present as an encephalopathy ac­companied by fever. 37. '0 Some authors have claimed that it is not possible todistinguish between NMS and lethal catatonia, whereas others have suggestedthat catatonia in general could be a prodrome of NMS. The importance ofdistinguishing the catatonias from NMS lies in the treatment; it is crucial to adda benzodiazepine to the pharmacotherapeutic regimen of any patient suspectedof catatonia.l5. 39. l'I

Diagnostic Testing

NMS poses a tremendous challenge to the clinician. A careful work-up isindicated, which includes the foUowing: serum electrolyte levels, creatinine andblood urea nitrogen levels, complete blood COWlt (including platelet, coagulationstudies, liver, and thyroid functions), serum CK, urine myoglobin, and bloodand urine cultures. A chest radiograph and electrocardiogram are also indicated.An arterial blood gas determination should be considered when pulmonarycomplications are suspected and to help to determine whether pulmonary embo­lism is present.

An emergent, noncontrast head cr is necessary to assess for intracranialprocesses. An electroencephalogram (EEG) can be valuable to assess for noncon­vulsive status epilepticus or viral encephalitis. A lumbar puncture is a routinepart of the work-up of any patient for whom the diagnosis of NMS is beingconsidered."

The patient with NMS must be carefully monitored throughout the courseof the syndrome for possible complications, including. but not limited to, renal

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failure, electrolyte abnormalities, dysrhythmia, aspiration pneumonia. sepsis,and pulInonary embolism secondary to the formation of deep vein thromboses(DVT). In the patient not making a reasonably rapid recovery, it is appropriateto repeat a full diagnostic work-up, including a repeat lumbar puncture.

Management

Management of NMS focuses on withdrawal of the neuroleptic medicationand meticulous supportive care, which includes aggressive hydration. Becauserenal failure is the commonest complication in NMS, strategies must be directedat managing the elevations of CK. with its resulting myoglobin load to thekidneys. Fluid input and output must be monitored carefully, and a urinaryoutput of at least 50 to 100 mL/hc maintained. Autonomic instability results inincreased "insensible losses," with up to an additional 500 mL lost for eachdegree Celsius rise in body temperature.~The use of cooling blankets is essentialto decrease body temperature; antipyretic agents can be helpful if an infectionis a comorbid factor. Vital signs must be monito~ carefully, and a nasogastrictube is indicated given the danger of aspiration.. OVT prophylaxis should bestarted as soon as possible. Patients with NMS should be admitted to anintensive care setting.

In addition to aggressive supportive measures, several specific treatmentsare mentioned in the literature. Dantrolene sodium, 3 to 5 mg/kg IV dividedt.i.d. or q.i.d., has been recommended to treat skeletal muscular rigidity!· 51

Oantrolene sodium exerts its therapeutic effect by means of the blockade ofcalcium release from the muscle fiber's sarcoplasmic reticulum. Bromocriptine,5 mg q..Ld. by nasogastric tube, has also been recommended. ll This can beincreased to a maximum of 40 mg/d. The therapeutic effect of bromocriptine isrelated to its dopamine agonism,. resulting in enhancement of dopaminergictransmission. Some authors have recommended the addition of carbidopa/levodopa, 25/100 by nasogastric tube or intravenous L-dopa.~'·~Other proposedtreatments of NMS include pancuronium,'" G carbamazepine," amantadine,'anesthesi.a,ll and plasmaphezesis.H

An additional mode of treatment that has been used successfully for NMS iselectroconvulsive therapy (ECI}u. Z1.JI Its mechanism of action is not completelyelucidated, but reports of its efficacy are encouraging, especially because it isalso efficacious in the treatment of most types of catatonia.D In preparation forEO, patients are paralyzed.; in NMS, in which there is substantial musclebreakdown. a depolarizing agent is contraindicated owing to its tendency toincrease serum potassium levels.t7 Instead. patients with NMS who receive ECTare paralyzed with a nondepolarizing agent.

Although the various specific treatments presented raise interesting ques­tions regarding various aspects of the pathophysiology of NMS, these treatmentapproaches have not been studied using well-designed methodologies. In fact,most of the proposed therapies are supported by single case reports only. Animportant study by Rosebush et al raises serious questions not only about theefficacy of these treatment measures but also about the suggestion that in somecases, the various specific therapies actually can result in a prolongation of thesyndrome.·1 As a result, p~t1y it is not possible to make dear treatmentrecommendations; management of NMS centers primarily on supportive care,with the role of specific treatment modalities remaining uncertain.

THE NEUROLEPTIC MAUCNANr AND SEROTONIN SYNDROMES 321

THE SEROTONIN SYNDROME

The advent of antidepressant pharmacotherapy with .selective serotoninreuptake inhibitors (SSRls) was greeted with enthusiasm owing to their lowsidHlffeet profile and high degree of therapeutic efficacy. This class of drugs,however. which enhance serotoninergic neurotransmission with only a relativeincrease in the actualleve1 of serotonin.. can result in a toxic state that resemblesNMS. Of note, NMS occurs as an idiosyncratic drug reaction. whereas theserotonin syndrome is a toxic effect that is thought to be due to a hyperstimula·tion of 5-HTlA receptors in the brain and spinal cord."

The serotonin syndrome is characterized by mental status changes an~ avane';' of autonomic and neuromuscular manifestations. In most cases,. two ormore medications known to increase the activity of serotonin are implicated.. Itwas first described in association v.rith the administration of monamine oxidaseinhibitors.:B More recent literature has implicated the tricyclic antidepressants[TCAs) and the SSRls. Increased serotonin activity can result from inlubition ofserotonin metabolism, potentiation of serotonin activity, activation of serotoninreceptors, inhibition of serotonin uptake. or increased substrate supply. Gener­ally, two or more agents possessing at least one of these characteristics must becoadministered for the syndrome to develop, although cases involving singleagents have been reported.u..12 In most cases, symptoms develop soon after theaddition of a new agent or a change in the dose of one already being taken.:R

Monoamine oxidase inhibitors (MAGIs) increase serotonin levels by inhib­iting the breakdown of serotonin. Many of the MAGis cause irreversible enzymeinhibition. Consequently, the serotonin syndrome can result from initiating newtherapies that increase serotonin weeks after an MAOI has been discontinued."Newer MAOIs have tried to obviate this problem by targeting specific subtypesof the enzyme. although toxicities have still been reported when they combinedv.rith SSRIs.:z6, 47 SSRIs are well absorbed, metabolized in the liver. and reach peaklevels v.rithin several hours. Doses should be decreased in patients with liverdisease to prevent inadvertent toxicity. Fluoxetine ms the longest half·life (2-3days). As with the MAOIs, a sufficient drug-free interval must exist between thetime an SSRI (particularly fluoxetine) is discontinued, and use of another drughaving activity at central 5-HTlA receptors is begun.

Clinical Features

The serotonin syndrome consists of a cluster of findings that include enceph­alopathy, hyperreflexia,. nausea and vomiting. and marked autonomic instabil·ity." It can be confused with NMS and other encephalopathic states, thusemphasizing the importance of obtaining a comprehensive medication history.Altered mental status is observed in approximately 40% of patients.22.~ Patientsfrequently present as agitated. restless, or even hypomanic. Less often. they aredrowsy or in coma. Neuromuscular symptoms are seen in 50% of patients andinclude myoclonus, rigidity, and tremor.3Z Hyperreflexia is consistently found.and along with rigidity. is frequently more pronounced in the lower extremities.Diaphoresis and mild elevations in temperature are seen in about 50% of cases.Rhabdomyolosis. hyperkalemia.. renal failure, DIe,. and seizures are all rarebut reported findings. The serotonin syndrome is usually self-limited. with anuneventful resolution once the inciting agent has been discontinued.

Despite the similarities between NMS and the serotonin syndrome, thereare clinical features that can be helpful in distinguishing the two. NMS is

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more likely to present with extrapyramidal signs. very high fevers, dysphagia,incontinence, and sialorrhea. Conversely, patients with the serotonin syndromeare more likely to present with myoclonus, hyperre8exia. and ataxia. Becausethe serotonin syndrome is basically a hyperseroloninergic state, it can be com­pared to a naturally occurring pathologic hyperserotoninergic state (i.e.. thecarcinoid tumor).. thus explaining the occurrence of dianhea. diaphoresis. andvomiting in these patients. It cannot be overemphasized, however. that fre­quently one sees partial forms of these syndromes. in which. for example, onlya mild encephalopathy can be present, perhaps accompanied by mild autonomicinstability. In such cases, the distinction between the syndromes can be veryhard to discern. Likewise, because patients with the serotonin syndrome initiallycan present with complaints of anxiety or mental status alteration. it should beconsidered carefully. especially in patients who have recently had a change intheir phannacologic management.

Management

The treatment of the serotonin syndrome begins with the immediate with­drawal of the offending drug. Analogous to the treatment of NMS, the institutionof aggressive supportive measures, including intravenous hydration. is essential.Careful monitoring of the patient's autonomic parameters and seizure precau*tions are indicated. Muscle contractions should be limited. because if uncheckedthey can lead to fever,. rhabdomyolosis, and respiratory compromise.l,.n Benzodi·azepines are recommended (particularly clonazepam) because they are effectivein controlling myoclonus.»

Syndrome specific treatments have been proposed, including the use ofserotonin antagonists (e.g., cyproheptadine and methysergide); however,. nowell-designed studies have been pedormed..u Treatment with propranolol hasbeen recommended based on the theoretical basis that this is a 5HT*rettptorantagonist,$.< although one case report of a fatality in a patient on propranololhas made some clinicians skeptical of this treatment..Z5 Other interventions ofundetermined benefit include chlorpromazine' (which must be avoided, alongwith metaclopramide and other phenothiazine derivatives, in patients withsuspected NMS), and benadryP Presently, treatment of the serotonin syndromeis based primarily on removing the offending agent, meticulous supportive care,and judicious use of benzodiazepines. Recoaunendations for other treatmentsawait further study.

CONCLUSION

An intensive review of the literature on the NMS and the serotonin syn'drome reveals that these two syndromes have many similarities between eachother and with other entities, such as malignant catatonia. There are manyoverlapping aspects of the clinical presentation. which is complicated further bythe forme fruste of either syndrome. Indeed, the overlapping components of thesesyndromes with each other and with the various types of catatonia have ledsome to propose that they are all within the same spectrum of a single disorder,l'

It might not necessarily be critical. nor even possible, to detennine preciselywith which of these entities one is dealing. Rather, it is essential to remove theprecipitating drugs immediately, and to institute supportive measures, including

nrE NEUROLEmC MAUGNANT AND SEROTONIN SYNDROMES 323

hydration. cooling. and intensive physiologic monitoring. Maintaining il broad­based differential diagnosis throughout the diagnostic evaluation is critical ulti­mately to making the correct diagnosis. Syndrome-speci6c interventions are ofquestionable value and should be used with caution pending the results offurther investigation. Indeed, it has been proposed that initiating syndrome-­specific interventions could even make recovery slower than if aggressive sup­portive measures were used exclusively."

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Address rr:prinl ~ts 10

Ioseph R Carbone. MDMount Sinai School of Medicine

Departments of P5)'chiatry and NewologyOne Gustave Levy Place

New York,. NY 10029