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Meidenbauer/Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs. It generally presents with muscle rigidity, fever, autonomic instability and cognitive changes such as delirium, and is associated with elevated creatine phosphokinase (CPK). Treatment is generally supportive.

Signs and symptoms

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The first symptom to develop is usually muscular rigidity, followed by high fever, symptoms of instability of the autonomic nervous system such as unstable blood pressure, and changes in cognition, including agitation, delirium and coma. Other symptoms may include muscle tremors and pharyngitis. Once symptoms do appear, they rapidly progress and can reach peak intensity in as little as three days. These symptoms can last anywhere from eight hours to forty days.

A raised creatine phosphokinase (CPK) plasma concentration will be reported due to increased muscular activity and rhabdomyolysis (destruction of muscle tissue). The patient may suffer hypertensive crisis and metabolic acidosis. A non-generalised slowing on an EEG is reported in around 50% of cases. White blood cells go up in the blood.

Unfortunately, symptoms are sometimes misinterpreted by doctors as symptoms of mental illness, delaying treatment.[1] 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.


  • Increased body temperature >100.4 degrees °F, or >38 °C
  • Confused or altered consciousness
  • Diaphoresis "sweat shock"
  • Rigid muscles
  • Autonomic imbalance

Mnemonic

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A mnemonic used to remember the features of NMS is FEVER.[2]

Causes

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NMS is usually caused by neuroleptic drug use, and a wide range of drug potencies can result in NMS.[3] It has been reported that individuals using haloperidol and chlorpromazine put themselves at greatest risk. NMS may also occur in people (such as patients with Parkinson's disease) who are taking a class of drugs known as dopaminergics (e.g., Levodopa) when the dosage is abruptly reduced. In addition, other drugs which are not used as neuroleptics, but which have anti-dopaminergic activity, can induce NMS (eg, metoclopramide [Reglan]). Even drugs which do not have known anti-dopaminergic activity (e.g., amoxampine [Ascendin] and lithium) have been associated with NMS. Also, the treatment of individuals with desipramine, dothiepin, lithium and phenelezine, tetrabenazine, and reserpine have been known to result in NMS.[4]

Risk Factors

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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.[5]

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.[6]

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.[7]It has also been suggested that postpartum women may be at a greater risk for NMS.[8]

Differential diagnosis

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The differential diagnosis is similar to that of hyperthermia. It includes serotonin syndrome[9]

Features that are present in NMS and not serotonin syndrome are:[10]

  • Bradykinesia
  • Muscle rigidity
  • Laboratory values (WBC & CK)

Pathophysiology

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

However, the failure of D2 dopamine receptor antagonism or dopamine receptor dysfunction to 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,[12] has led to the hypothesis of sympathoadrenal hyperactivity (results from removing tonic inhibition from the sympathetic nervous system) as an etiological mechanism for NMS.[13] 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.

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

Treatment

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NMS is an emergency, and can lead to death if untreated. The first step is to stop neuroleptic drugs and to treat the hyperthermia aggressively, such as with cooling bankets or ice packs to the axillae and groin. Many cases require intensive care and circulatory and ventilatory support. Medications such as dantrolene sodium and bromocriptine may be used[14]. Apomorphine may be used however its use is supported by little evidence.[15] Benzodiazepines may be used to control agitation. Highly elevated CPK can damage the kidneys, therefore aggressive hydration may be required.

Prognosis

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As with most illnesses, the prognosis is best when identified early and treated aggressively. In these cases NMS is usually not 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.[16] Re-introduction to the drug that originally caused NMS to develop may also trigger a recurrence, although in most cases it does not.

Epidemiology

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Occurs in 0.1-0.2% of patients receiving conventional anti-psychotics (e.g., butyrophenones [especially haloperidol], phenothiazines, thioxanthenes). Atypical anti-psychotics are associated with a lower incidence.[16]

History

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NMS was known about as early as 1956, shortly after the introduction of the first phenothiazines.[17] . NMS was first described in 1960 by French clinicians who had been working on a study involving haloperiodol. They characterized the condition that was associated with the side effects of haloperidol “syndrome malin des neuroleptiques”, which was translated to Neuroleptic malignant syndrome.[18]


Research

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While the pathophysiology of NMS remains unclear, the two most prevalent theories with regards to pathopysiology of NMS are:

  • Reduced dopamine activity due to receptor blockade
  • Sympathodrenal hyperactivity and autonomic dysfunction

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. 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. [19]. 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, which do not act on 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 consequently earlier initiation of appropriate treatment. [20] Furthermore, NMS induced by atypical drugs highly resembles "classical" NMS (induced by typical psychotic drugs), which brings their preference to traditional psychotic drugs into question. [21]

References

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  1. ^ Stacy Milbouer, "Quest for the truth", Nashua Telegraph http://www.nashuatelegraph.com/apps/pbcs.dll/article?AID=/20050424/NEWS01/104240081
  2. ^ Identify neuroleptic malignant syndrome. schizophrenia.com URL:http://www.schizophrenia.com/sznews/archives/002054.html. Accessed: July 2, 2006.
  3. ^ Theodore I. Benzer, MD, PhD (2005). "Neuroleptic Malignant Syndrome". Emedicine.{{cite web}}: CS1 maint: multiple names: authors list (link)
  4. ^ Buckley PF and Hutchinson M: Neuroleptic Malignant Syndrome. J. Neurol. Neurosurg. Psychiatry 1995; 58; 271-273
  5. ^ Keck PE Jr, Pope HG Jr, Cohen BM. Risk factors for neuroleptic malignant syndrome. A case-control study. Arch Gen Psychiatry. Oct 1989;46(10):914-8.
  6. ^ Otani K, Horiuchi M, Kondo T. Is the predisposition to neuroleptic malignant syndrome genetically transmitted?. Br J Psychiatry. Jun 1991;158:850-3.
  7. ^ Theodore I. Benzer, MD, PhD (2005). "Neuroleptic Malignant Syndrome". Emedicine.{{cite web}}: CS1 maint: multiple names: authors list (link)
  8. ^ Alexander PJ, Thomas RM, Das A. Is risk of neuroleptic malignant syndrome increased in the postpartum period?. J Clin Psychiatry. May 1998;59(5):254-5.
  9. ^ Christensen V, Glenthøj B (2001). "[Malignant neuroleptic syndrome or serotonergic syndrome]". Ugeskr Laeger. 163 (3): 301–2. PMID 11219110.
  10. ^ Birmes P, Coppin D, Schmitt L, Lauque D (2003). "Serotonin syndrome: a brief review". CMAJ. 168 (11): 1439–42. PMID 12771076.{{cite journal}}: CS1 maint: multiple names: authors list (link) Full Free Text.
  11. ^ Mihara K, Kondo T, Suzuki A; et al. (2003). "Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome". Am. J. Med. Genet. B Neuropsychiatr. Genet. 117 (1): 57–60. doi:10.1002/ajmg.b.10025. PMID 12555136. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  12. ^ Ananth J, Parameswaran S, Gunatilake S, Burgoyne K, Sidhom T (2004). "Neuroleptic malignant syndrome and atypical antipsychotic drugs". J. Clin. Psychiatry. 65 (12): 1722–3. PMID 15119907.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Gurrera RJ (1999). "Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome". Am. J. Psychiatry. 156 (2): 169–81. PMID 9989551.
  14. ^ http://www.ncbi.nlm.nih.gov/pubmed/3804991
  15. ^ http://www.uptodate.com/online/content/topic.do?topicKey=medneuro/5946&selectedTitle=1~123&source=search_result#26
  16. ^ a b Niraj Ahuja and Andrew J. Cole Hyperthermia syndromes in psychiatry Adv Psychiatr Treat 2009 15:181-191. Cite error: The named reference "niraj" was defined multiple times with different content (see the help page).
  17. ^ Friedberg JM. Neuroleptic malignant syndrome. URL: http://www.idiom.com/~drjohn/biblio.html. Accessed: July 3, 2006.
  18. ^ Buckley PF and Hutchinson M: Neuroleptic Malignant Syndrome. J. Neurol. Neurosurg. Psychiatry 1995; 58; 271-273
  19. ^ Gurrera RJ (2002) " Neuroleptic Malignant Syndrome a Neurogenic Form of Malignant Hyperthermial" Clinical Neuropharmacology 25(4): 183-193
  20. ^ Ananth J, Parameswaran S, Gunatilake S, Burgoyne K, Sidhom T (2004) "Neuroleptic malignant syndrome and atypical antipsychotic drugs" J Clin Psychiatry 65(4): 464-70
  21. ^ Samia Hasan and Peter Buckley (1998) "Novel Antipsychotics and the Neuroleptic Malignant Syndrome: A Review and Critique" Am J Psychiatry 155: 1113-111
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