Epidemiology
The true incidence of NMS is not known because the available evidence is inconclusive.[14] Estimates range from 0.02% to 3%.[15] An important limitation when considering published estimates is that they are almost exclusively incidence proportions (number of new cases over a period of time divided by number of persons at risk at the beginning of the time period) rather than true incidence rates (number of new cases over a period of time divided by the person-time at risk).[14] Reported incidence has declined over the last 20 years, which may reflect greater awareness with heightened vigilance and more prompt clinical intervention. Other possible factors may include systematic reporting bias, an evolving practice trend toward the use of second-generation antipsychotic medications (SGAs), and caution in using high initial doses of antipsychotics.[14]
NMS has been reported to be more common in male than in female patients, but larger studies have not consistently found this.[16] A systematic review and meta-analysis that specifically examined sex and age distribution in NMS found a male to female ratio of 1.5.[17]
Preexisting structural brain abnormality, catatonia, and older age are associated with an increased risk.[3][18] Mortality associated with NMS appears to vary.[3][5][6][14][19][20][21] Two large studies reported a rate between 8% and 9%.[16][22] A subsequent systematic review found that respiratory difficulties, hyperthermia severity, and older age were associated with increased mortality.[23]
Risk factors
NMS has been reported in association with every antipsychotic medication, presumably through their antagonism of dopamine D2 receptors.[24]
Administration of high doses of antipsychotics at onset of treatment and intramuscular administration may increase the risk.
No single drug is associated with a greater risk than another. Some believe that risk for NMS is less with second-generation antipsychotics (SGAs) than with first-generation antipsychotics (e.g., haloperidol, pimozide), especially high-potency first generation agents. One large case-controlled study found the opposite to be true.[16] Other large studies have found that rigidity is more frequent and mortality is higher with first generation agents.[22][34]
Almost all patients develop symptoms within 30 days, with 16% developing symptoms within 24 hours after drug initiation and 66% within 1 week.[1][35]
Patients with agitation require antipsychotics to be given intramuscularly.[29] Whether the clinical setting (physical agitation and emotional turmoil) predisposes to the development of NMS is not currently known.
Motor restlessness is considered a risk factor for developing NMS.[29]
A systematic review and meta-analysis that specifically examined sex and age distribution in NMS found that males are approximately 50% more likely to be diagnosed with NMS at any age (male to female ratio of 1.5).[17]
It has been suggested that low serum iron may contribute to acute hypodopaminergia.[31][32]
Although acute hypoferremia has been observed in a significant proportion of NMS cases, iron does not readily cross the blood-brain barrier, so it is unlikely that acute changes in serum iron play a causative role in NMS. However, chronically low iron levels could affect brain dopamine function over time.
This may be an independent risk factor, secondary to prolonged agitation and/or diaphoresis with poor oral intake, or may be linked by association to sepsis.[29]
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