Neuroleptic malignant syndrome

Neuroleptic malignant syndrome

Haloperidol, a known cause of NMS
Classification and external resources
Specialty Critical care medicine, Neurology
ICD-10 G21.0
ICD-9-CM 333.92
DiseasesDB 8968
eMedicine emerg/339 med/2614ped/1581
Patient UK Neuroleptic malignant syndrome
MeSH D009459

Neuroleptic malignant syndrome (NMS) is a life-threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs. NMS typically consists of muscle rigidity, fever, autonomic instability,[1] and cognitive changes such as delirium, and is associated with elevated plasma creatine phosphokinase.[2] The incidence of neuroleptic malignant syndrome has decreased since it was first described, due to changes in prescribing habits, but NMS is still a potential danger to patients being treated with antipsychotic medication. Because of the unpredictability of NMS, treatment may vary substantially but is generally based on supportive care and removal of the offending antipsychotic drug.

Signs and symptoms

The first symptoms of neuroleptic malignant syndrome are usually muscle cramps and tremors, fever, symptoms of autonomic nervous system instability such as unstable blood pressure, and alterations in mental status (agitation, delirium, or coma). Once symptoms appear, they may progress rapidly and reach peak intensity in as little as three days. These symptoms can last anywhere from eight hours to forty days.[2] The muscular symptoms are most likely caused by blockade of the dopamine receptor D2, leading to abnormal function of the basal ganglia similar to that seen in Parkinson's disease.[3]

A raised white blood cell count and creatine phosphokinase (CPK) plasma concentration will be reported due to increased muscular activity and rhabdomyolysis (destruction of muscle tissue).[4] The patient may suffer hypertensive crisis and metabolic acidosis. A non-generalized slowing on an EEG is reported in around 50% of cases.

The fever is believed to be caused by hypothalamic dopamine receptor blockade. The peripheral problems (the white blood cell and CPK count) are caused by the antipsychotic drugs. They cause an increased calcium release from the sarcoplasmic reticulum of muscle cells which can result in rigidity and eventual cell breakdown. No major studies have reported an explanation for the abnormal EEG, but it is likely also attributable to dopamine blockage leading to changes in neuronal pathways.[1]

Symptoms are sometimes misinterpreted by doctors as symptoms of mental illness, delaying treatment.[5] NMS is less likely if a person has previously been stable for a period of time on antipsychotics, especially in situations where the dose has not been changed and there are no issues of noncompliance or consumption of psychoactive substances known to worsen psychosis.

Differential diagnosis

Differentiating NMS from other neurological disorders can be very difficult. It requires expert judgement to separate symptoms of NMS from other diseases. Some of the most commonly mistaken diseases are encephalitis, toxic encephalopathy, status epilepticus, heat stroke, and malignant hyperthermia. Due to the comparative rarity of NMS, it is often overlooked and immediate treatment for the syndrome is delayed. Drugs such as cocaine and amphetamine may also produce similar symptoms.[2][6]

The differential diagnosis is similar to that of hyperthermia, and includes serotonin syndrome.[7] Features which distinguish NMS from serotonin syndrome include bradykinesia, muscle rigidity, and elevated white blood cell count.[8]

Causes

NMS is usually caused by antipsychotic drug use, and a wide range of drugs can result in NMS.[1] Individuals using butyrophenones (such as haloperidol and droperidol) or phenothiazines (such as promethazine and chlorpromazine) are reported to be at greatest risk. However, various atypical antipsychotics such as clozapine, olanzapine, risperidone, quetiapine, and ziprasidone have also been implicated in cases.[9]

NMS may also occur in people taking dopaminergic drugs (such as levodopa) for Parkinson's disease, most often when the drug dosage is abruptly reduced.[10] In addition, other drugs with anti-dopaminergic activity, such as the antiemetic metoclopramide, can induce NMS.[11] Even drugs without known anti-dopaminergic activity have been associated with NMS; examples include amoxapines and lithium. Also, desipramine, dothiepin, phenelzine, tetrabenazine, and reserpine have been known to trigger NMS.[12] At the molecular level, NMS is caused by a sudden, marked reduction in dopamine activity, either from withdrawal of dopaminergic agents or from blockade of dopamine receptors.

Risk factors

One of the clearest risk factors in the development of NMS is the course of drug therapy chosen to treat a condition. Use of high-potency neuroleptics, rapid increase in dosage of neuroleptics, and use of long-acting forms of neuroleptics are all known to increase the risk of developing NMS.[13]

It has been purported that there is a genetic risk factor for NMS, since identical twins have both presented with NMS in one case, and a mother and two of her daughters have presented with NMS in another case.[14]

Demographically, it appears that males, especially those under forty, are at greatest risk for developing NMS, although it is unclear if the increased incidence is a result of greater neuroleptic use in men under forty.[1] It has also been suggested that postpartum women may be at a greater risk for NMS.[15]

An important risk factor for this condition is Lewy body dementia. These patients are extremely sensitive to neuroleptics. As a result, neuroleptics should be used cautiously in all cases of dementia.

Pathophysiology

The mechanism is thought to depend on decreased levels of dopamine activity due to:

It has been proposed that blockade of D2-like (D2, D3 and D4) receptors induce massive glutamate release, generating catatonia, neurotoxicity and myotoxicity.[17][18] Additionally, the blockade of diverse serotonin receptors by atypical antipsychotics and activation of 5HT1 receptors by certain of them reduces GABA release and indirectly induces glutamate release, worsening this syndrome.[19]

However, the failure of D2 dopamine receptor antagonism or dopamine receptor dysfunction does not fully explain the presenting symptoms and signs of NMS, as well as the occurrence of NMS with atypical antipsychotic drugs with lower D2 dopamine activity.[20] This has led to the hypothesis of sympathoadrenal hyperactivity (results from removing tonic inhibition from the sympathetic nervous system) as an etiological mechanism for NMS.[21] Release of calcium is increased from the sarcoplasmic reticulum with antipsychotic usage. This can result in increased muscle contractility, which can play a role in breakdown of muscle, muscle rigidity, and hyperthermia. Some antipsychotic drugs, such as typical neuroleptics, are known to block dopamine receptors; other studies have shown that when drugs supplying dopamine are withdrawn, symptoms similar to NMS present themselves.[2]

There is also thought to be considerable overlap between malignant catatonia and NMS in their pathophysiology, the former being idiopathic and the latter being the drug-induced form of the same syndrome.[22]

Treatment

NMS is a medical emergency, and can lead to death if untreated. The first step is to stop the antipsychotic medication and treat the hyperthermia aggressively, such as with cooling blankets or ice packs to the axillae and groin. Supportive care in an intensive care unit capable of circulatory and ventilatory support is crucial. The best pharmacological treatment is still unclear. Dantrolene has been used when needed to reduce muscle rigidity, and more recently dopamine pathway medications such as bromocriptine have shown benefit.[23] Amantadine is another treatment option due to its dopaminergic and anticholinergic effects. Apomorphine may be used however its use is supported by little evidence.[3] Benzodiazepines may be used to control agitation. Highly elevated blood myoglobin levels can result in kidney damage, therefore aggressive intravenous hydration with diuresis may be required. When recognized early NMS can be successfully managed; however, up to 10% of cases can be fatal.[2]

Should a patient subsequently require an antipsychotic, trialling a low dose of a low-potency atypical antipsychotic is recommended.[2]

Prognosis

The prognosis is best when identified early and treated aggressively. In these cases NMS is not usually fatal. In previous studies the mortality rates from NMS have ranged from 20%–38%; however, in the last two decades, mortality rates have fallen below 10% due to early recognition and improved management.[24] Re-introduction to the drug that originally caused NMS to develop may also trigger a recurrence, although in most cases it does not.

Memory impairment is a consistent feature of recovery from NMS, and usually temporary, though in some cases, may become persistent.[25]

Epidemiology

Pooled data suggest the incidence of NMS is between 0.2%–3.23%.[26] However, more physician awareness coupled with increased use of atypical anti-psychotics have likely reduced the prevalence of NMS.[1] Additionally, young males are particularly susceptible and the male:female ratio has been reported to be as high as 2:1.[1][26][27]

History

NMS was known about as early as 1956, shortly after the introduction of the first phenothiazines.[28] NMS was first described in 1960 by French clinicians who had been working on a study involving haloperidol. They characterized the condition that was associated with the side effects of haloperidol "syndrome malin des neuroleptiques", which was translated to neuroleptic malignant syndrome.[12]

Research

While the pathophysiology of NMS remains unclear, the two most prevalent theories are:

In the past, research and clinical studies seemed to corroborate the D2 receptor blockade theory in which antipsychotic drugs were thought to significantly reduce dopamine activity by blocking the D2 receptors associated with this neurotransmitter. However, recent studies indicate a genetic component to the condition.[29] In support of the sympathoadrenal hyperactivity model proposed, it has been hypothesized that a defect in calcium regulatory proteins within the sympathetic neurons may bring about the onset of NMS.[30] This model of NMS strengthens its suspected association with malignant hyperthermia in which NMS may be regarded as a neurogenic form of this condition which itself is linked to defective calcium-related proteins.

The introduction of atypical antipsychotic drugs, with lower affinity to the D2 dopamine receptors, were thought to have reduced the incidence of NMS. However, recent studies suggest that the decrease in mortality may be the result of increased physician awareness and earlier initiation of treatment rather than the action of the drugs themselves.[20] NMS induced by atypical drugs also resembles "classical" NMS (induced by "typical" antipsychotic drugs), further casting doubt on the overall superiority of these drugs.[31]

References

  1. 1 2 3 4 5 6 Neuroleptic Malignant Syndrome at eMedicine
  2. 1 2 3 4 5 6 Strawn JR, Keck PE, Caroff SN (2007). "Neuroleptic malignant syndrome". The American Journal of Psychiatry 164 (6): 870–6. doi:10.1176/ajp.2007.164.6.870. PMID 17541044.
  3. 1 2 http://www.uptodate.com/online/content/topic.do?topicKey=medneuro/5946&selectedTitle=1~123&source=search_result#26[]
  4. ↑ Latham J, Campbell D, Nichols W, Mott T (2008). "How much can exercise raise creatine kinase level—and does it matter?". The Journal of Family Practice 57 (8): 545–7. PMID 18687233.
  5. ↑ Stacy Milbouer, "Quest for the truth", Nashua Telegraph http://www.nashuatelegraph.com/apps/pbcs.dll/article?AID=/20050424/NEWS01/104240081
  6. ↑ Sachdev PS (2005). "A rating scale for neuroleptic malignant syndrome". Psychiatry Research 135 (3): 249–56. doi:10.1016/j.psychres.2005.05.003. PMID 15996751.
  7. ↑ Christensen V, Glenthøj B (2001). "[Malignant neuroleptic syndrome or serotonergic syndrome]". Ugeskrift for Lægerer 163 (3): 301–2. PMID 11219110.
  8. ↑ Birmes P, Coppin D, Schmitt L, Lauque D (2003). "Serotonin syndrome: a brief review". CMAJ 168 (11): 1439–42. PMC 155963. PMID 12771076.
  9. ↑ Khaldi S, Kornreich C, Choubani Z, Gourevitch R (2008). "Antipsychotiques atypiques et syndrome malin des neuroleptiques : brève revue de la littérature" [Neuroleptic malignant syndrome and atypical antipsychotics: A brief review]. L'Encéphale (in French) 34 (6): 618–24. doi:10.1016/j.encep.2007.11.007. PMID 19081460.
  10. ↑ Keyser DL, Rodnitzky RL (1991). "Neuroleptic malignant syndrome in Parkinson's disease after withdrawal or alteration of dopaminergic therapy". Archives of Internal Medicine 151 (4): 794–6. doi:10.1001/archinte.151.4.794. PMID 1672810.
  11. ↑ Friedman LS, Weinrauch LA, D'Elia JA (1987). "Metoclopramide-induced neuroleptic malignant syndrome". Archives of Internal Medicine 147 (8): 1495–7. doi:10.1001/archinte.147.8.1495. PMID 3632154.
  12. 1 2 Buckley PF, Hutchinson M (1995). "Neuroleptic malignant syndrome". Journal of Neurology, Neurosurgery, and Psychiatry 58 (3): 271–3. doi:10.1136/jnnp.58.3.271. PMC 1073359. PMID 7897404.
  13. ↑ Keck PE, Pope HG, Cohen BM, McElroy SL, Nierenberg AA (1989). "Risk factors for neuroleptic malignant syndrome. A case-control study". Archives of General Psychiatry 46 (10): 914–8. doi:10.1001/archpsyc.1989.01810100056011. PMID 2572206.
  14. ↑ Otani K, Horiuchi M, Kondo T, Kaneko S, Fukushima Y (1991). "Is the predisposition to neuroleptic malignant syndrome genetically transmitted?". The British Journal of Psychiatry 158: 850–3. doi:10.1192/bjp.158.6.850. PMID 1678666.
  15. ↑ Alexander PJ, Thomas RM, Das A (1998). "Is risk of neuroleptic malignant syndrome increased in the postpartum period?". The Journal of Clinical Psychiatry 59 (5): 254–5. doi:10.4088/JCP.v59n0509a. PMID 9632037.
  16. ↑ Mihara K, Kondo T, Suzuki A, Yasui-Furukori N, Ono S, Sano A, Koshiro K, Otani K, Kaneko S (2003). "Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 117B (1): 57–60. doi:10.1002/ajmg.b.10025. PMID 12555236.
  17. ↑ Kornhuber J, Weller M, Riederer P (1993). "Glutamate receptor antagonists for neuroleptic malignant syndrome and akinetic hyperthermic parkinsonian crisis". Journal of Neural Transmission. Parkinson's Disease and Dementia Section 6 (1): 63–72. PMID 8105799.
  18. ↑ Chatterjee A (2014). "Glutamate-based magnetic resonance spectroscopy in neuroleptic malignant syndrome". Annals of Indian Academy of Neurology 17 (1): 123–4. doi:10.4103/0972-2327.128579. PMC 3992752. PMID 24753679.
  19. ↑ Odagaki Y (2009). "Atypical neuroleptic malignant syndrome or serotonin toxicity associated with atypical antipsychotics?". Current Drug Safety 4 (1): 84–93. PMID 19149529.
  20. 1 2 Ananth J, Parameswaran S, Gunatilake S, Burgoyne K, Sidhom T (2004). "Neuroleptic malignant syndrome and atypical antipsychotic drugs". The Journal of Clinical Psychiatry 65 (4): 464–70. doi:10.4088/JCP.v65n0403. PMID 15119907.
  21. ↑ Gurrera RJ (1999). "Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome". The American Journal of Psychiatry 156 (2): 169–80. doi:10.1176/ajp.156.2.169. PMID 9989551.
  22. ↑ Northoff G (2002). "Catatonia and neuroleptic malignant syndrome: psychopathology and pathophysiology". Journal of Neural Transmission 109 (12): 1453–67. doi:10.1007/s00702-002-0762-z. PMID 12486486.
  23. ↑ Dhib-Jalbut S, Hesselbrock R, Mouradian MM, Means ED (1987). "Bromocriptine treatment of neuroleptic malignant syndrome". The Journal of Clinical Psychiatry 48 (2): 69–73. PMID 3804991.
  24. ↑ Ahuja, N.; Cole, A. J. (2009). "Hyperthermia syndromes in psychiatry". Advances in Psychiatric Treatment 15 (3): 181–91. doi:10.1192/apt.bp.107.005090.
  25. ↑ Mendhekar DN, Duggal HS (2006). "Persistent amnesia as a sequel of olanzapine-induced neuroleptic malignant syndrome". The Journal of Neuropsychiatry and Clinical Neurosciences 18 (4): 552–3. doi:10.1176/jnp.2006.18.4.552. PMID 17135384.
  26. 1 2 Pelonero AL, Levenson JL, Pandurangi AK (1998). "Neuroleptic malignant syndrome: a review". Psychiatric Services 49 (9): 1163–72. doi:10.1176/ps.49.9.1163. PMID 9735957.
  27. ↑ Hernández JL, Palacios-Araus L, Echevarría S, Herrán A, Campo JF, Riancho JA (1997). "Neuroleptic malignant syndrome in the acquired immunodeficiency syndrome". Postgraduate Medical Journal 73 (866): 779–84. doi:10.1136/pgmj.73.866.779. PMC 2431511. PMID 9497946.
  28. ↑ Friedberg JM. Neuroleptic malignant syndrome. URL: http://www.idiom.com/~drjohn/biblio.html. Accessed: July 3, 2006.
  29. ↑ Velamoor VR (1998). "Neuroleptic malignant syndrome. Recognition, prevention and management". Drug Safety 19 (1): 73–82. doi:10.2165/00002018-199819010-00006. PMID 9673859.
  30. ↑ Gurrera RJ (2002). "Is neuroleptic malignant syndrome a neurogenic form of malignant hyperthermia?". Clinical Neuropharmacology 25 (4): 183–93. doi:10.1097/00002826-200207000-00001. PMID 12151905.
  31. ↑ Hasan S, Buckley P (1998). "Novel antipsychotics and the neuroleptic malignant syndrome: a review and critique". The American Journal of Psychiatry 155 (8): 1113–6. doi:10.1176/ajp.155.8.1113. PMID 9699705.

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