Neuroleptic Malignant Syndrome

By | May 15, 2011

Rare, Unpredictable, Serious, Feared, and Potentially Fatal

Neuroleptic malignant syndrome is a serious, life-threatening side effect of medications that reduce dopami-nergic neurotransmission. In its most lethal presentation, neuroleptic malignant syndrome is characterized by a fulminating onset of delirium, rigidity, immobility, mutism, staring, and tremulousness. Autonomic disturbances are prominent and are manifested by high fever, diaphoresis, tachycardia, and labile or elevated blood pressure. Mental status changes indicated the presence of an encephalopathy that can be demonstrated by diffused EEG slowing. The most common causative agents are antipsychotic drugs, including most of the newer atypical antipsychotics. Cases of neuroleptic malignant syndrome have also been reported with metoclopramide, a dopamine D2 blocking agent used for gastrointestinal symptoms, and with the sudden withdrawal of drugs used to enhance dopaminergic functions, such as levodopa and amantadine. The incidence range of neuroleptic malignant syndrome has been estimated to be between 0.02% to 1.8%. However, there is evidence to support the view that neuroleptic malignant syndrome frequently goes unrecognized and underdiagnosed, especially for those treated with non-anti-psychotic medications.

Haloperidol, for a long time the medication of choice for treating agitation and delirium, was the most common trigger of neuroleptic malignant syndrome. Frequently overlooked, antiemetics and sedatives with neuroleptic properties such as prochlorperazine, metoclopramide, and promethazine can also trigger neuroleptic malignant syndrome.

Factors that increase patients’ risk for neuroleptic malignant syndrome include dehydration, agitation, low serum iron, underlying brain damage, catatonia, and history of prior neuroleptic malignant syndrome episodes. In addition, high room temperature and the diagnosis of affective disorder have been implicated as contributory factors.

The typical case scenario is that of an undernourished, inadequately hy-drated, catatonic or agitated patient on multiple medications who receives a rapid dose increase of a high potency antipsychotic drug. Neuroleptic malignant syndrome was common in the era of rapid neuroleptization and in patients with very high doses of potent antipsychotic drugs. However, neuroleptic malignant syndrome can occur in patients on low doses or in stable antipsychotic regimes, particularly in those receiving polypharmacy Lithium is often implicated in these reactions; SSRIs may also lower the neuroleptic malignant syndrome threshold.

Contemporary experts stress the importance of early detection of neuroleptic malignant syndrome to undertake effective treatment. Although, identifying early signs is difficult, if not impossible in fulminating cases, patients with incipient neuroleptic malignant syndrome show the following symptoms: unexpected mental status changes, new onset catatonia, refractory extrapyramidal side effects, and bulbar signs such as rigidity, dysphagia, or dysarthria. Other researchers have corroborated that mental status changes (especially confusion) and extrapyramidal symptoms usually precede other signs of neuroleptic malignant syndrome, and that temperature elevation may represent a late sign of a potentially fulminating course.

It appears that the neuroleptic malignant syndrome (neuroleptic malignant syndrome) is more frequent with conventional than with atypical antipsychotics. All currently marketed atypicals, except for ziprasidone, have been linked to at least one case of neuroleptic malignant syndrome in adults. Reports in pediatric patients are limited to two adolescent cases treated with risperidone. Probably, there is considerable underreporting of this potentially lethal complication.

In the neuroleptic malignant syndrome clinical course, it is postulated that an acute phase reaction (APR), an immunological reaction, initiates neuroleptic malignant syndrome. APR causes a cascade of events that can be precipitated by infections, muscle injuries, strenuous exercise, burns, surgery, and, perhaps psychological stress. Fever, leukocytosis, muscle breakdown, and low iron serum level are seen in acute phase reaction and are all found in neuroleptic malignant syndrome. The most common immediate causes of death associated with neuroleptic malignant syndrome are cardiac and respiratory arrest, pulmonary emboli, disseminated intravascular coagulation, and myoglobinuric renal failure.

Neuroleptic malignant syndrome is a poorly understood syndrome that usually occurs within hours or days of initiating antipsychotic medications. Besides the risks described above, neuroleptic malignant syndrome is more frequent in men than in women and occurs more often during the summer months. The neuroleptic malignant syndrome risk is also increased by rapid titration, physical restraint, and intramuscular use.

In a review of the pertinent literature, Silva, Munoz, Alpert, Perlmutter, and Diaz (1999) reported that, with few exceptions, the neuroleptic malignant syndrome clinical presentation in children and adolescents was similar to the one described in adults. The triad of fever, tachycardia, and rigidity characterizes the presentation in children and adults; alteration of consciousness was seen in 72%, including coma in 19.4%. Boys are affected twice as often as girls. Children show a higher rate of dystonia (40.8 vs. 29% for all the ages), and a lower rate of tremor (32.7 vs. 48% for all ages). The course could be fulminating or could last up to 18 days.

There are no pathognomonic tests for neuroleptic malignant syndrome but a laboratory profile supports the diagnosis: leukocytosis in the absence of infection, elevated levels of muscle enzymes creatine phosphokinase (CPK), serum alanine aminotransferase (alanine aminotransferase), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH), and low levels of serum iron. Calcium is usually low; BUN and creatinine will increase if renal function is compromised by myoglobinuria. Urine myoglobine is increased.

Silva, Munoz, et al. (1999), report that fatality outcomes have dropped sharply, but underreporting is a concern. Prior to 1986 the mortality rate was 21%; the mortality risk being higher early in the neuroleptic malignant syndrome onset. The authors were unable to locate any neuroleptic malignant syndrome fatalities in children from 1986 until the publication of their article in 1999.

The decrease of neuroleptic malignant syndrome frequency and its apparent better prognosis maybe related to the clinicians growing awareness of early antipsychotic discontinuation and the need for a more aggressive medical treatment approach. Children who had been receiving anticholinergics along with the antipsychotics, and had those medications discontinued at the time of the neuroleptic malignant syndrome onset, had a better outcome than those kept on them. The differential diagnosis of neuroleptic malignant syndrome includes infection plus extrapyramidal side effects, anticholinergic toxicity, serotonin syndrome, heat stroke, retarded catatonia, and malignant hyperthermia.

The neuroleptic malignant syndrome cannot be differentiated from malignant catatonia (MC; previously called lethal catatonia), either clinically or by laboratory testing. The hallmarks of malignant catatonia are acute onset of excitement, delirium, fever, autonomic instability, and catalepsy. Until the advent of ECT most of the patients died. Those clinical features are similar if not identical with the features observed in the neuroleptic malignant syndrome. Both clinical syndromes respond to benzodiazepines and ECT. ECT should be considered early in the course of malignant catatonia. Other conditions commonly associated with catatonic features include delirious mania, benign stupor, and malignant hyperthermia.

It is proposed that simple catatonia, malignant catatonia, and neuroleptic malignant syndrome share a common pathophysiology; this involves a reduction of dopaminergic neurotransmission within the basal ganglia-thalamocortical circuits. Hypodopaminergia may underlie muscle rigidity. Malignant catatonia appears to be a nonspecific syndrome that may occur in association with diverse neurological, medical drug-induced, and psychiatric illnesses. ECT is the preferred treatment for malignant catatonia and its effectiveness and survival rates are better when the treatment is initiated during the first five days of the onset of symptoms. Even severely debilitated patients have tolerated ECT without incident.

Although, the serotonergic or serotonin syndrome shares many clinical features with neuroleptic malignant syndrome, the etiologies of the syndromes are different. The serotonergic syndrome is caused by agents that stimulate specific central and peripheral serotonin receptors, mainly, 5-HT1A and 5-HT2; probably 5-HT3 and 5-HT4 are also involved in causing GI symptoms and affecting dopaminergic transmission. Serotonin syndrome has been reported as a result of interactions between MAOIs, including selegiline and reversible MAOIs inhibitors (RIMAs), and various serotonergic compounds.

LeDoux, Braslow, and Brown (2004) argued about the role of C-reactive protein (CRP) in the pathogenesis of the serotonin syndrome (SS). SS occurs when there is an acute increase in extracellular serotonin in the presence of an impaired serotonin metabolism. Vascular disease and depression are linked to elevated CRR CRP activates platelets, promoting the release of serotonin, and inhibiting the endothelial nitric oxide synthase, which is an “off” signal for the release and action of the platelet-derived serotonin. Thus, C-reactive protein may contribute to the serotonin syndrome by perpetuating the release of serotonin and inhibiting the nitric oxide synthase. They postulate that C-reactive protein may help to predict patients at risk for serotonin syndrome. The serotonin syndrome maybe differentiated from the neuroleptic malignant syndrome clinically as outlined below (see TABLE Differential Diagnosis Between the Serotonin Syndrome and the Neuromalignant Syndrome).

Boyer and Shannon (2005) emphasize that no laboratory tests confirm the diagnosis of serotonin syndrome (SS). However, the presence of tremor, clonus, or akathisia, in the absence of additional extrapyramidal signs should lead clinicians to consider this diagnosis. A history of prescriptions and OTC drugs, use of illicit substances, and dietary supplements may be informative. The physical examination should focus on the assessment of deep-tendon reflexes, clonus, muscle rigidity, ascertaining mydriasis, dryness of oral mucosa, the intensity of bowel sounds, skin color, and the presence or absence of diaphoresis. The evolution of this syndrome is revealing: SS onset is usually rapid, often occurring minutes after ingestion of the injurious agent or of the poisoning substance. Hyperthermia and muscular hypertonia appear late in the syndrome development.

Originally, the serotonin syndrome excluded the addition or increase of antipsychotics prior to the onset of the syndrome. However, serotonin syndrome has been reported with combinations of risperidone and paroxetine; olanzapine, mirtazapine and tramadol, and olanzapine with lithium and citalopram. The 5-HT2 antagonism effect of these antipsychotics may have led indirectly to an overactivation of 5-HT1A receptors resulting in the serotonin syndrome.

TABLE Differential Diagnosis Between the Serotonin Syndrome and the Neuromalignant Syndrome

Serotonin syndrome neuroleptic malignant syndrome
• Psychomotor agitation • Immobility
• Clonus, mioclonic jerking, hyperreflexia, fasciculations • These findings rare in neuroleptic malignant syndrome
• GI disturbances: nausea, vomiting, diarrhea • Constipation and paralytic ilieus
• Antecedent ataxia • No history of ataxia
• Seizures, severe hypotension, ventricular tachycardia, and disseminated intravascular coagulation (DIC) • Rarely present in neuroleptic malignant syndrome

Neuroleptic malignant syndrome cases treated with bromocriptine (a D2 receptor agonist) and dantroline (a peripheral relaxant that interferes with the release of calcium from the sarcoplasmic reticulum) showed no significant benefit over supportive care. When these drugs are used, there is a tendency for a recrudescence of autonomic abnormalities and of elevation of the CPK when these agents are withdrawn.

In our experience with over 50 patients with neuroleptic malignant syndrome, the natural course of the syndrome — even in the most severe cases — has been for the autonomic disturbances, as well as the laboratory abnormalities, to peak in the first 48 hours. They begin to improve significantly within 72 hours solely with cessation of the putative offending agents, administration of antipyretics, application of cooling blankets and replacement of intravenous fluids.

There are anecdotal reports that benzodiazepines are helpful; ASA or acetaminophen are important therapeutic agents.

Fever, EEG abnormalities, and alteration of consciousness appear to be related to a poor prognosis. Complications or neuroleptic malignant syndrome include respiratory failure, deep vein thrombosis with risk of pulmonary embolism, contractures if immobility is prolonged, entrapment neuropathies, renal failure, muscle weakness, and infections such as pneumonia and urinary tract infections,

neuroleptic malignant syndrome residual symptoms included residual rigidity, brachial plexus palsy, residual dysarthria, liver function abnormalities, atelectasis, increase of prolactin levels, and the development of other abnormal movements. Rare sequelae include seizures, DIC, and cerebellar degeneration. Following a neuroleptic malignant syndrome episode patients are at a higher risk of suffering a recurrence if antipsychotic medications are reintroduced within the first two weeks of the full syndrome resolution. Tithium has been reported as precipitating recurrences. After two weeks of full syndrome resolution a single agent maybe reintroduced at a low dose, and slow titration should be continued with regular CPK and vital signs monitoring. The neuroleptic malignant syndrome episode gives the opportunity to evaluate what medications are essential and which ones need to be discarded.

Upon suspicion of neuroleptic malignant syndrome, all antipsychotics, lithium, and SSRIs should be discontinued. Since most psychiatric settings are not equipped to deal with complex, life-threatening conditions, patients should be immediately transported to a medical center where ICU or other life support measures can be provided.

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