NEUROLEPTIC MALIGNANT SYNDROME CURRENT APPROACH TO DIAGNOSIS AND MANAGEMENT

REVIEW ARTICLES NEUROLEPTIC MALIGNANT SYNDROME CURRENT APPROACH TO DIAGNOSIS AND MANAGEMENT 1 Cristian Mihãilescu Abstract: The neuroleptic malignant syndrome (NMS) represents an infrequent but serious condition, an idiosyncratic reaction to a neuroleptic medication. It concerns mainly patients under psychiatric treatment, occuring even after the emergence of the so-called lower-risk atypical neuroleptics. Currently, little is known about risk factors and susceptibility for developing NMS which can practically occur at any age and irrespective of gender and comorbidities. NMS is feared due underdiagnosis and to its poor prognosis, especially when left untreated when it could lead to serious complications and fatalities. An increased level of alertness is necessary for enabling an earlier diagnosis, hence an earlier treatment that can improve its prognosis. Keywords: neuroleptic, malignant, atypical, levodopa, pathogeny, treatment. Rezumat: Sindromul neuroleptic malign (SNM) reprezintã o afecþiune rarã dar gravã, o reacþie idiosincraticã la neuroleptice. Poate sã aparã în special la pacienþi aflaþi sub tratament psihiatric, chiar ºi dupã apariþia neurolepticelor atipice considerate cu risc mai redus de SNM. În prezent, sunt puþine date cu privire la factorii de risc ºi susceptibilitatea pentru a dezvolta SNM ce se poate manifesta practic la orice vârstã ºi indiferent de sex ºi comorbiditãþi. SNM este redutabil datoritã dificultãþii diagnostice ºi prognosticului sãu nefavorabil, mai ales în lipsa tratamentului, când poate conduce la complicaþii severe ºi chiar deces. Este necesarã creºterea nivelului de alertã pentru a facilita diagnosticul mai precoce, deci ºi introducerea mai precoce a tratamentului ceea ce îi poate ameliora prognosticul. Cuvinte-cheie: neuroleptic, malign, atipic, levodopa, patogenie, tratament. INTRODUCTION Delay used this term for the first time in 1960. According to the current conception, the neuroleptic malignant syndrome (NMS) is a rare, but life-threatening, idiosyncratic reaction to a neuroleptic medication. The clinical presentation consists of fever, extrapyramidal signs and symptoms, altered mental status and dysautonomia. EPIDEMIOLOGY The frequency follows closely the rate of antipsychotic medication use, without geographic variations nor related to race. Prospective studies and pooled data from the literature report an incidence of 0.07-0.2% (1). The awareness regarding NMS has increased, hence probably a lower incidence now than in the past. The incidence is higher in men, with a men to women ratio of 2:1 (1, 2). NMS has been diagnosed in ages ranging from 3 to 80 years, reaching a peak before 40 years of age (the maximal incidence of neuroleptic treatment) (2, 3). ETIOLOGY AND PATHOGENY Originally, only the older generation, more potent neuroleptics (eg, haloperidol, fluphenazine) were considered to be able to trigger NMS. Recently, it was aknowledged that all antipsychotic agents, typical and atypical, are able to precipitate the syndrome (1,2). The dopaminergic blockade hypothesis is widely accepted nowadays since medications implicated in NMS have dopamine D2-receptor antagonist properties (1). Pros and cons have been formulated about this hypothesis. Previous studies have induced catalepsy in animals with D2-receptor antagonists. There are also overlapping features of catatonia and NMS (4-6), the former being recognized as a risk factor for NMS. But most convincing for the implication of the dopaminergic blockade in NMS is the occurence of the syndrome after suddenly withdrawing treatment with dopamine, dopamine agonists or Amantadine in patients suffering from Parkinson's disease and the reversal after the reintroduction of such medication. The clinical syndrome is thought to be secondary to decreased dopamine activity in the central nervous system (CNS), as a result of dopamine D2- receptors antagonism or of decreased dopamine availability. Blockade of dopamine neurotransmission in the striatum results in muscular rigidity which leads to pyrexia. At the level of the hypothalamus, the blockade results in altered thermoregulation and reduction of heat dissipation, by interference with the normal role of dopamine as an inhibitor of heat production, process stimulated by serotonin. Blockade at several other levels within CNS (mesocortex, basal ganglia, spinal cord) has been implicated in the occurence of mental status alterations and autonomic disturbancies noted in NMS. 1 1 Internal Medicine, Senior M.D., Psychiatry Clinical Hospital Prof. Dr. Alexandru Obregia, Integrated Outpatient Clinic, Berceni Road No.10-12, sector 4, Bucharest, Romania, Email: cmihai@ping.ro 95

Cristian Mihãilescu: Neuroleptic Malignant Syndrome Current Approach To Diagnosis And Management The peripheral effects include a direct myotoxic effect resulting in an increase of calcium release from the sarcoplasmic reticulum (7), contributing to the increased contractility and to hyperthermia. Dopamine is also known to directly inhibit the skeletal muscle contraction, the dopaminergic blockade resulting in the opposite effect. There are several facts speaking against a single pathogenic hypothesis in NMS. Among these, the fact that NMS occurs after Clozapine (no D2-blocking properties) (8) or after non-neuroleptic medications. Furthermore NMS can have heterogeneous presentations, atypical NMS not including development of rigidity nor fever (1). One particular aspect involves the atypical neuroleptics, associated with a lower risk of NMS. They display less dopaminergic antagonism, reflected in the lower rate of extrapyramidal side effects than the conventional antipsychotics. Even so, their administration doesn't seem to entirely eliminate the risk of NMS (9-15). It has also been claimed that the sympathetic nervous system activation or dysfunction may be involved significantly in the pathogenesis of NMS (1, 16). Normally, the sympathetic nervous system coordinates thermoregulation and represents the main regulator of muscular contraction and thermogenesis. The sympatoadrenal hyperactivity observed on NMS can also be accounted for by the dopaminergic blockade which leads to a reduction in the tonic inhibition of the sympathetic nervous system (16). Other hypotheses for the pathogenesis of NMS include GABA hypoactivity at the level of the GABA A receptor, also based on a similarity with catatonia and on the benefit of benzodiazepines in NMS, increased serotoninergic activity at the 5-HT receptors and 1A decreased at the 5-HT receptors (17, 18) and 2A glutamatergic hypoactivity at the NMDA receptors (19). A low level of serum iron has been reported as a risk factor for NMS (20), predicting the conversion of malignant catatonia to NMS (21). Furthermore, anomalies of the muscle membrane (7, 22) have been described as a possible substrate for the peripheral manifestations of NMS. The most important risk factor for the development of NMS is represented by the treatment with typical neuroleptics (e.g. haloperidol, chlorpromazine, fluphenazine, levomepromazine) but also, even to a lesser degree, the atypical neuroleptics (e.g. clozapine, quetiapine, olanzapine, aripiprazole risperidone, perospirone, zuclopenthixol) (9-15, 23). Development of NMS was observed even with the use of non-neuroleptic drugs like metoclopramide, amoxapine, lithium and some antidepressants which can block central dopaminergic pathways. Approximately 17% of NMS cases develop within 25 hours from the start of antipsychotic treatment, 66% within the first week and almost all cases within 30 days (1). The risk remains high even in the first 22 days after withdrawal of the causing drug (1) and was not associated with the serum level of the drug which was considered therapeutic (3). There is still uncertainty surrounding the association of NMS with a recent increase in dosage, high dosages, the duration of exposure and the type of neuroleptic (long-acting versus short-acting) (3). A genetic predisposition was observed (1) in homozygots for mutations of the citochrome P4502D. Further risk factors are male gender (NMS is twice as frequent in men), dehydration (7), concomitant medication, exposure to cocaine, possible concomitant illnesses and/or debilitated state, hyponatremia, stress, malnutrition, cerebral trauma and organic disorders (3). In our experience, alcohol withdrawal may also be a contributing factor to development of NMS. There is still controversy regarding the impact of high environmental temperature and humidity as risk factors for NMS (20). DIAGNOSIS Symptoms usually set in insidiously over days, although occasional fulminant onsets have been reported (20). The clinical presentation includes hyperthermia, extrapyramidal effects and signs of autonomic dysfunction. The diagnosis of NMS is difficult because manifestations are very nonspecific, and is only made by corroborating history, clinical criteria and laboratory findings together with a thorough differential diagnosis. A multispeciality team approach, including a careful neurological and psychiatric examination, is usually needed, Relevant to diagnosis is a history of neuroleptic treatment, in the last 1 to 4 weeks for oral agents and 2 to 4 weeks for long-acting, depot agents. Physical examination reveals generalised lead-pipe muscular rigidity and pyrexia (usually above 38C, in the absence of another known cause). Also, more than 5 of the following features have to be fulfilled for making the diagnosis of NMS: alterations of the mental status, tachycardia, hypertension or hypotension, tachypnea or hypoxia, diaphoresis and sialorrhea, tremor, incontinence, increased levels of creatine-kinase or myoglobinuria, leukocytosis and metabolic acidosis (1, 2, 3). NMS with atypical presentations have also to be taken into account. Muscular rigidity and hyperthermia are not always present at onset and may set in later or not at all (1, 2). Other associated signs and symptoms and laboratory findings (including those from electromyography, electroencephalography, cerebral computed tomography, muscular biopsy) may be helpful especially with the differential diagnosis but do not contribute significantly to the diagnosis of NMS (3). DIFFERENTIAL DIAGNOSIS A detailed presentation of the differential diagnosis in NMS is beyond the scope of this article. A list of possible differential diagnoses can be found in table 1. The most common causes of NMS-like symptoms, and thus most frequently needing differentiation from NMS are: Parkinson's disease, meningitis, encephalitis, delirium, depression / mania with catatonic features, catatonic schizophrenia / psychosis, serotonin syndrome, drug-induced extrapyramidal reactions, anticholinergic poisoning, heat stroke. 96

Romanian Journal of Psychiatry, vol. XII, No.3, 2010 Neuromuscular Parkinson's disease Meningitis Encephalitis (especially acute viral) Multiple system atrophy (Shy-Drager syndrome) Epilepsy and status epilepticus Stroke Space-occupying lesions, including CNS neoplasm Cerebral vasculitis Malignant hyperthermia Severe dystonia Stroke Metabolic Hyperthyroidism (thyrotoxicosis) Hypocalcemia Hypomagnesemia Pheochromocytoma Infectious Rabies Sepsis Tetanus Botulism Psychiatric Delirium Depression / mania with catatonic features Catatonic schizophrenia / psychosis Lethal catatonia Toxic exposures Heat stroke Amphetamines Anticholinergic agents Cocaine Excess serotonin (serotonin syndrome) Extrapyramidal drug reactions Monoamine oxidase inhibitors Salicylates (Aspirin overdose) Heavy metal poisoning (e.g. lead, arsenic) Strychnine Side-effects associated with atypical antipsychotics Rapid withdrawal of dopaminergic medications (e.g., L-dopa) Dopamine depleting medications (e.g., reserpine, tetrabenazine) Lithium toxicity Allergic drug reactions Phencyclidine intoxication Alcohol / sedative (benzodiazepine, barbiturate) withdrawal Strychnine poisoning Miscellaneous Acute intermittent porphyria Systemic lupus erythematosus Table 1. Differential diagnosis of NMS. TREATMENT NMS represents a medical emergency where time to diagnosis and treatment is of the essence. In order to achieve these goals, due to the complexity and severity of manifestations, NMS requires a multidisciplinary approach. The proposed medical treatment of the syndrome is: elimination of neuroleptic treatment, general measures as supportive therapy and pathogenic, specific treatment. Initially, general measures address the lowering of body temperature in order to fight hyperthermia. In case of rhabdomyolysis, special attention must be paid to hydration (7), urine alkalinization and correction of electrolytic disorders. In some cases with life-threatening hiperkalemia, acidosis, uremic encephalopathy and fluid overload, dialysis may become an option even if it would not influence the serum levels of myoglobin. Other measures may include circulatory support consisting of an adequate hydration, cardiac monitoring and even hemodynamic support, sometimes intubation with ventilation and venous thromboembolism prophylaxis with heparins. Controversies remain with regard to the efficacy and value of particular specific NMS treatments. This is due to the fact that NMS is a fairly rare, life-threatening condition and difficult to diagnose due to its well-known mimicry. All these features didn't allow the conduct of double-blind or placebo-controlled clinical trials in order to identify the most appropriate treatment. As a result, current practice is based on case-studies and no treatment protocol exist so far. The main drugs used in NMS are the dopaminergic medication, benzodiazepines, Amantadine and peripheral myorelaxants. The indicated doses may vary significantly from one case to another, therefore they are adapted and personalized for each particular case. There is no proof that combinations of drugs are associated with an increased efficacy, therefore they cannot be routinely recommended. Another challenge in NMS treatment is the route of administration since the use of the usual oral products is limited by trismus and the general condition of the patients. Especially in the acute phases, the parenteral route is advisable or the use of dispersible formulations that can be readily administered orally. The use of dopaminergic drugs reflects the essential role of the dopaminergic blockade in the pathogenesis of NMS. The most widely used dopaminergic agonists are apomorphine, bromocriptine. Apomorphine administered subcutaneously is considered first-line therapy, useful even as monotherapy (13). Bromocriptine acts by the activation of the postsynaptic dopaminergic D2 receptors, thus increasing the production of dopamine and contributing mainly to the improvement of an altered mental status and of rigidity. It may be associated with side effects like hypotension, nausea, psychosis. It is administered with caution in renal and liver diseases and it's contraindicated in ischemic heart disease and peripheral arterial disease. Levodopa is usually administered in combination with carbidopa or benserazide. There is recent information and is also our experience that a levodopa-based treatment may be effective as a first-line treatment in NMS, irrespective of the severity of presentation, by addressing most of the NMS features. There have also been reports concerning the presence of active glucocorticoid receptors within the ventral tegmental area and substantia nigra. Glucocorticoid medication can benefit NMS patients through an increase of the dopaminergic activity but also through their well-known lysosome membrane stabilization effect (24). Benzodiazepines are supposed to act through potentiation of the GABAergic activity and by indirectly increasing the dopaminergic activity through their actions at the level of basal ganglia and substantia nigra (26). 97

Cristian Mihãilescu: Neuroleptic Malignant Syndrome Current Approach To Diagnosis And Management They don't have a preventative effect (20, 26) but their use, mainly parenterally but also orally, reduces rigidity, improves the mental status and reduces psychomotor agitation. Dysautonomia, including diaphoresis, and pyrexia are not influenced by their use. Amantadine mainly reduces hyperthermia and acts as an antagonist of the NMDA receptor and is thought to facilitate dopamine release from intact dopaminergic terminals, increasing dopamine concentration at dopaminergic terminals. Peripheral myorelaxants are mainly used to correct the increased muscle tone and hyperthermia. Dantrolene sodium is supposed to bind and shut down the ryanodine receptors within the sarcoplasmic reticulum, thereby decreasing the calcium release (3). In the acute phase it should be administered intravenously, then orally. It can be associated with liver toxicity, therefore it's contraindicated in advanced liver disease, photosensitivity. Caution is warranted in heart failure and pulmonary conditions. It's value has been challenged with regard to its real therapeutic value and safety (1,25). Other intravenous myorelaxants have been proposed and used in the treatment of NMS (pancuronium, rocuronium, mivacurium). Electroconvulsive therapy (ECT) represents an alternative in cases where the medications detailed above failed, in severe NMS with a high risk of complications, when NMS is manifested mainly through or cannot be differentiated from catatonic syndrome, in case of persistent residual catatonia and parkinsonism after resolution of the acute metabolic symptoms of NMS (1) or in patients with high risk of relapse after the reintroduction of neuroleptics (27). ECT influences favorably hyperthermia, diaphoresis, mental status, conscioussness and the underlying psychiatric pathology when patients can no longer take neuroleptics but has no impact on delirium and should not be used in clinically unstable patients and with high risk of cardiac arrest or ventricular fibrillation (27). After treating NMS, especially in patients that need ongoing neuroleptic treatment, secondary prophylaxis measures become essential. Firstly, these patients have to be informed that they will continue to have an increased risk of NMS recurrence. When possible neuroleptics have to be avoided or, in cases where reexposure to neuroleptics is deemed necessary, it would be better to avoid depot neuroleptics and use a class of neuroleptics different from that of the causing drug. The new neuroleptic has to be started approximately 2 weeks after the NMS resolution (3,20), with the lowest possible dose and with subsequent slow gradual uptitrating, under close monitoring and avoiding dehydration. EVOLUTION The complications associated with NMS are usually severe and unpredictable and are the ones responsible for its poor prognosis (see table 2). Rhabdomyolysis can induce hydroelectrolytic disorders like hyperkalemia, hyperphosphatemia and hypocalcemia and can contribute to the occurence of acute renal failure. The development of acute renal failure represents a factor of poor prognosis, being associated with a 50% mortality rate (1). Acute respiratory failure can be explained by 98 pulmonary embolism, aspiration pneumonia, acute pulmonary edema or the occurence of acute respiratory distress syndrome. (1, 3). Rhabdomyolysis Acute renal failure Acute respiratory failure Myocardial infarction Brain lesions Seizures Hepatic failure Disseminated intravascular coagulation Escherichia coli fasciitis Sepsis Table 2. The most frequent complications of NMS Other possible complications have been reported: gastrointestinal bleeding as a consequence of commonly accepted medical treatments (especially the use of cyclooxygenase inhibitors as antipyretic agents) and NMS-induced changes in blood coagulation status (28), diffuse intravascular coagulation, lactic acidosis, arrhythmias, cardiac arrest, liver failure, muscular and peripheral nerves lesions. Also, the psychiatric illnesses treated with neuroleptics may decompensate after their withdrawal. The development of NMS complications adversely impact the evolution and prognosis. Thus, they need special attention and a case-by-case approach to treatment. In case of an early diagnosis and treatment and in the absence of complications, NMS prognosis is good, the duration of NMS being approximately 7-10 days after the withdrawal of oral neuroleptics and up to 22 days for depot neuroleptics (1). There have been cases reported where amnesia, permanent parkinsonism, ataxia or even dementia remain after NMS (29, 30). Mortality, historically as high as 22-30%, is now estimated at 5-11,6% (1) possibly due to an increased awareness, earlier diagnosis and treatment. The occurence of acute renal failure increase the mortality rate to 50% (1). Events leading to death are usually respiratory, cardiovascular or acute renal failure, arrhythmias or diffuse intravascular coagulation. CONCLUSION NMS is an infrequent but severe condition that may lead to life-threatening complications. Its nonspecific and heterogeneous presentation explains why it remains a diagnostic and therapeutic challenge. 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