Neuroleptic Malignant Syndrome (NMS)

Haloperidol (Haldol)[1]

Neuroleptic malignant syndrome is a drug-induced neurological disorder characterized by hyperthermia, rigidity, autonomic dysfunction and an altered mental status. It may cause rhabdomyolysis and renal failure or lead to aspiration pneumonia and is associated with mortality rates of up to 10%.

Neuroleptic Malignant Syndrome emerges due to the following process: Poison.

Presentation

Major symptoms of NMS are hyperthermia, rigidity, autonomic dysfunction and an altered mental status, and NMS may be suspected if anamnestic data include therapy with neuroleptics, other psychotropic drugs, or if treatment with such compounds has recently been discontinued. Symptom onset is subacute; NMS develops in the course of several days or weeks [11] [6]. Manifestation is as follows:

In general, the severity of single symptoms may vary in the course of the day and until resolution, e.g., patients may present with high fever, their body temperature may decrease and eventually rise again. Muscle tone may vary from mild hypotonia to manifest hypertonia, rigidity and opisthotonus.

Workup

Anamnestic data and clinical presentation may prompt a strong suspicion of NMS, and laboratory analyses of blood and urine samples are usually carried out to confirm this tentative diagnosis. The following findings are characteristic of NMS:

While the patient remains hospitalized, those parameters should be re-evaluated periodically.

Treatment

Withdrawal of the causative drug and supportive therapy to remedy and relieve neurological deficits are the mainstays of treatment; due to the possibility of life-threatening complications, NMS patients need to be hospitalized.

  • Discontinuation of the causative treatment is of utmost importance. Even if the patient depends on psychotropic drugs, it is recommend to interrupt the corresponding therapy for at least two weeks. If an episode of NMS has been induced by the cessation of dopaminergic therapy, it should be reinitiated. Patients who suffer from neuroleptic-induced NMS may also benefit from amantadine or bromocriptine [12].
  • Hydration is critical and may require fluid therapy. In mild cases, patients will be able to drink sufficiently. Patients who present with dysphagia may receive fluids and nutrients by means of a nasogastric tube. In severe cases, fluids have to be administered intravenously. Aggressive fluid therapy is necessary to avoid renal failure in case of rhabdomyolysis and aims at reducing serum concentrations of myoglobin. Sodium bicarbonate may be required in case of metabolic acidosis.
  • With regards to hyperthermia, physical cooling seems to be more effective than antipyretic drugs. Sedation and intubation may be necessary in case of body temperatures >41°C [11].
  • In order to induce muscle relaxation, benzodiazepines or dantrolene may be employed. The latter are also effective against psychomotor agitation and may be employed to achieve sedation, as mentioned above. However, benzodiazepines may exacerbate dyspnea and delirium. Still, they are often preferred over dantrolene as first-line therapeutics.
  • Electroconvulsive therapy has occasionally been reported to be effective in NMS.

Treatment should be continued until few days past full recovery in order to avoid an immediate relapse.

Prognosis

An individual patient's prognosis highly depends on their condition upon the initiation of treatment. In general, resolution can be expected within one or two weeks if adequate care is provided [11]. Recovery times are prolonged in case depot medication triggered NMS. Rhabdomyolysis, myoglobinuria and subsequent renal failure, aspiration pneumonia, disseminated intravascular coagulation and thromboembolic events, as well as multiple organ dysfunction syndrome are severe, potentially life-threatening complications; they are also the most common causes of death in NMS patients. To date, the overall mortality associated with NMS is approximately 10% [2]. The average outcome for patients who present with any of the aforementioned complications is considerably worse, though. Recurrence is likely if the causative drug is administered again while alternative psychotropic compounds are usually well tolerated. Ideally, such treatment is discontinued entirely.

Etiology

NMS is a drug-induced disorder that has first been described by the French psychiatrist Jean Delay and his colleagues who associated it with haloperidol [1]. By now, a myriad of psychotropic drugs has been related to this symptom complex, some others even state that NMS has been associated with "every single antipsychotic compound" used so far [2]. Most cases are ascribed to the administration of dopamine D2 receptor antagonists and it is generally assumed that antidopaminergic effects account for the majority of symptoms shown by NMS patients. Other drugs related to NMS mediate only minor alterations of dopaminergic pathways or none at all. In detail, the following compounds may trigger NMS:

  • First-generation antipsychotics, e.g., flupentixol, fluphenazine, haloperidol, trifluoperazine, zuclopenthixol
  • Second-generation antipsychotics, e.g., aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone
  • Antidepressants like amoxapine and phenelzine
  • Antiemetics, e.g., metoclopramide, prochlorperazine, and promethazine
  • Lithium

Patients who are administered highly potent drugs at high doses, or who are subjected to sudden changes of medication, e.g., treatment with more potent compounds, dose increase, or withdrawal of dopamine agonists, are at high risks of developing NMS. This also applies to individuals who receive parenteral treatment or who receive more than one drug.

Available data don't allow for the deduction of dose-response relationships and additional factors, presumably genetic, developmental and environmental influences, are likely to predispose and contribute to NMS. A few studies have been published on the genotype of NMS patients [3], but large-scale analyses have not yet been carried out. With regards to environmental factors, high temperatures, dehydration and physical restraint have been proposed to contribute to the onset of NMS [2]. Infectious diseases, ileus, stroke and trauma have also been listed as precipitating events [4].

Epidemiology

NMS is a rather uncommon side effect of antipsychotic and related treatment, with an estimated 0.2 to 30 per 1,000 patients receiving such therapy developing this disorder [5]. However, the respective drugs are prescribed to large numbers of people and thus, NMS is regularly seen by neurologists and emergency physicians. Incidence rates have been decreasing though, and this trend may reflect changed prescription habits due to an increased awareness, or improved pharmacovigilance. With regards to the class of drugs most commonly associated with NMS, a literature review yields contradictory results. To date, it cannot be concluded that NMS incidence diminished owing to the preferential prescription of second-generation antipsychotics.

A predilection for males has been reported, but race seems unlikely to influence the individual risk of NMS. The mean age of onset is 50 years [6].

Sex distribution
Age distribution

Pathophysiology

The pathophysiological mechanisms underlying NMS are only partially understood. Administration of high doses of dopamine D2 receptor antagonists ensues a sudden inhibition of dopaminergic signaling in distinct brain regions, namely in the hypothalamus (associated with hyperthermia), the nigrostriatal bundle (related to rigidity and tremor), and the mesolimbic and mesocortical pathways (accounting for the altered mental state) [7], and it is generally agreed on that NMS is the result of these events. This hypothesis is further supported by the fact that NMS may be triggered by withdrawal of dopamine agonists, which are generally prescribed to patients suffering from Parkinson's disease [8]. However, NMS has been described in patients on psychotropic drugs that are not known to interfere with dopaminergic pathways. In this context, involvement of the sympathetic nervous system in NMS pathogenesis has been studied. In fact, autonomic dysfunction as well as hyperthermia and rigidity may be related to such effects [9], and NMS patients often show enhanced levels of urine and plasma catecholamines. Moreover, it has been speculated that serotonergic signaling cascades may be compromised in NMS patients. Lithium, for instance, may trigger NMS and does modulate noradrenergic and serotonergic signaling. Despite the fact that serotonin syndrome is considered a different entity, there are etiological, pathophysiological and clinical similarities between this disorder and NMS [10].

Prevention

To date, the etiology of NMS is only partially understood. Consequently, the risk of NMS should be considered in any patient treated with psychotropic drugs, particularly if neuroleptics are administered. Thus, prescription of such drugs should be considered carefully. Patients with a history of NMS are at risk of recurrence, and because discontinuation of therapy is often not an option, alternative treatment regimens should be applied in such cases. Furthermore, patients should be advised of this uncommon side effect and should be encouraged to inform their physician upon first perception of symptoms.

Summary

Neuroleptic malignant syndrome (NMS) is a severe neurological disorder; it is also an uncommon side effect of treatment with antipsychotic drugs, antidepressants, antiemetics and lithium. Symptom onset is generally ascribed to high doses of the corresponding pharmaceuticals, to sudden dose increase or even withdrawal of medication mediating contrary effects. To date, it is not possible to predict the development of NMS in an individual patient, though, and additional, as-of-yet unknown factors are likely to play a pathogenetic role.

The clinical hallmarks of NMS are hyperthermia, rigidity, autonomic dysfunction and an altered mental status. A thorough analysis of the patient's medical history, recent changes in medication, as well as laboratory analyses of blood and urine samples are the mainstays of NMS diagnosis. An early initiation of therapy is crucial for survival, since NMS patients may suffer rhabdomyolysis and renal failure, aspiration pneumonia and coagulation disorders in advanced stages of the disease. If such complications are developed, the patient's prognosis worsens significantly.

Treatment consists in withdrawal of the causative agent and measures to relieve symptoms. In this context, fluid therapy, muscle relaxants and dopaminergic agents are most frequently applied. Most patients recover within two weeks after symptom onset. Continuation of neuroleptic therapy has to be re-evaluated thereafter since patients with a history of NMS are more likely to suffer additional episodes of this disease. In many cases, change to an alternative treatment regimen is sufficient to prevent new bouts of NMS.

Patient Information

Neuroleptic malignant syndrome (NMS) is a drug-induced neurological disorder characterized by high fever, rigidity, autonomic dysfunction and an altered mental status. It is most frequently related to medication prescribed to patients suffering from schizophrenia, bipolar disorder and other forms of psychosis, but antidepressants and antiemetics have also been reported to induce NMS. Commonly, the onset of symptoms is associated with a recent change in medication or increased doses. The majority of the aforementioned compounds inhibits dopaminergic signaling pathways in the brain, i.e., they reduce the availability of the neurotransmitter dopamine for brain functions. Of note, patients who are diagnosed with Parkinson's disease suffer from dopamine deficiency, and they are generally treated with drugs that stimulate dopaminergic signaling. Therefore, sudden discontinuation of antiparkinson treatment may result in NMS, too.

Symptom onset is subacute and complaints develop gradually in the course of several days. Besides the abovementioned cardinal symptoms of NMS, affected individuals may also develop tremor and gait disturbances, difficulties in breathing, speaking and swallowing, palpitations, fluctuations in blood pressure, incontinence, hallucinations, disorientation, psychomotor agitation and delirium. In severe cases, breakdown of muscle proteins with subsequently increasing serum concentrations of myoglobin may impair kidney function. This process does indeed account for a considerable share of NMS-associated mortality. Since renal failure does generally not occur in early stages of the disease, the initiation of treatment in a timely manner is crucial for a favorable prognosis.

Treatment with the psychotherapeutic drug that induced the episode of NMS has to be discontinued, but may be restarted at a later point in time. Then, a change to an alternative treatment regimen should be considered. Most patients recover within about two weeks if adequate symptomatic therapy is provided.

Self-assessment

References

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  7. Berman BD. Neuroleptic malignant syndrome: a review for neurohospitalists. Neurohospitalist. 2011; 1(1):41-47.
  8. Fiore S, Persichino L, Anticoli S, De Pandis MF. A neuroleptic malignant-like syndrome (NMLS) in a patient with Parkinson's disease resolved with rotigotine: a case report. Acta Biomed. 2014; 85(3):281-284.
  9. Gurrera RJ. Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome. Am J Psychiatry. 1999; 156(2):169-180.
  10. Dosi R, Ambaliya A, Joshi H, Patell R. Serotonin syndrome versus neuroleptic malignant syndrome: a challenging clinical quandary. BMJ Case Rep. 2014; 2014.
  11. Katus LE, Frucht SJ. Management of Serotonin Syndrome and Neuroleptic Malignant Syndrome. Curr Treat Options Neurol. 2016; 18(9):39.
  12. Reulbach U, Dutsch C, Biermann T, et al. Managing an effective treatment for neuroleptic malignant syndrome. Crit Care. 2007; 11(1):R4.

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Media References

  1. Haloperidol (Haldol), CC BY-SA 3.0
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