Neuroleptic Malignant Syndrome in an Older Woman With Schizophrenia: Page 2 of 2

February 19, 2013

Pathophysiology of NMS 

It has been suggested that the cause of NMS may be multifactorial.6 The pathophysiology of NMS is not entirely understood, although it has been established that acute reduction of dopamine activity in the brain is the basic underlying mechanism.13-16 Currently, NMS is thought to be caused by central or peripheral dopaminergic blockade resulting in muscle rigidity and core temperature elevation.14 Dopamine blockade in the nigrostriatal pathway is the source of the muscular rigidity or lead-pipe rigidity (ie, a type of increased muscle tone in which pathologic resistance to passive extension of a joint is constant throughout the range of motion21), while blockade in the hypothalamus can result in hyperthermia.16 It is unlikely the dopaminergic blockade theory is the sole explanation given serotonergic, noradrenergic, and cholinergic pathways are also implicated.14 It is thought that glutamate also plays a role, which explains why the drug amantadine (an N-methyl-D-aspartate S-type glutamate receptor antag-onist) is used to treat NMS.14 

Diagnosing NMS  

There has been controversy surrounding the diagnostic criteria of NMS largely due to the varying symptoms and degrees of severity in presentations.12 There are several sets of criteria by which to diagnose NMS: the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV)22; the Adityanjee Criteria23; the Levenson Criteria24; and the Pope Criteria.25 According to the DSM-IV, a diagnosis of NMS requires two essential features to be present: severe muscle rigidity and fever (temperature >99ºF).22 Two or more other symptoms must also be present, such as diaphoresis, dysphagia, tremor, incontinence, altered levels of consciousness with increased confusion, mutism, tachycardia, elevated or labile blood pressure, hypersalivation, leukocytosis, or laboratory evidence of muscle injury, as in the case of elevated CPK levels.21 

Muscle rigidity and fever are essential diagnostic features of these four sets of criteria. Rigidity is usually generalized throughout the body and is described as lead-pipe or unbreakable in quality.14,15 However, the classic symptom of muscular rigidity has been absent in some documented cases of NMS,14 or in other cases, has been localized to the tongue, facial muscles, or masticatory muscles, causing dysarthria or dysphagia.7,12 Temperature elevations are usually accompanied by profuse diaphoresis, and it is the febrile state that constitutes NMS as a medical emergency because it can lead to brain damage of the cerebellum or death.15 However, fever can instead be mild, delayed in presentation, or absent entirely.12,14 

While elevated CPK levels and leukocytosis are thought to be characteristic of NMS, they are not required to make the diagnosis, as was the case described by Murray and colleagues.26 Although elevated CPK levels are commonly noted during the progression of NMS and are considered an essential symptom to diagnose NMS per the Levenson Criteria,24 this symptom is generally considered to be nonspecific and not pathognomonic for the syndrome.6,23,25 The duration of reported symptoms varies from 1 to 44 days and does not appear to be dose-related.14 In addition, these symptoms can occur when drug concentrations in the blood are in therapeutic ranges, rather than at toxic levels.13 

Though not included specifically on any of the diagnostic criteria lists, patients can present with a fixed gaze resembling mutism, while others can be agitated, more psychotic, or delirious.13 Furthermore, it has been reported in more than 80% of cases that mental status changes or muscular rigidity preceded other signs and symptoms of NMS, suggesting an incipient form of NMS may exist.15

Differential diagnosis. Because the symptoms of NMS are nonspecific, the differential diagnosis of NMS has been described as “baffling,”13 encompassing a broad range of disorders that are beyond the discussion of this case report. It is important to note that as NMS progresses and remains undiagnosed, patients may show more severe symptoms of agitation, psychosis, or delirium, and clinicians may mistakenly assume the patient is experiencing an exacerbation of his or her primary psychiatric illness. For example, Kohen16 reported a case of a 66-year-old woman with Alzheimer’s dementia who resided in a skilled nursing facility and whose NMS was misdiagnosed as a UTI. The case patient experienced restlessness, confusion, and agitation, for which her attending physician added quetiapine 12.5 mg twice daily to her medication regimen. Within 2 days of taking quetiapine, the patient’s symptoms worsened and an elevated CPK level was noted. Quetiapine was discontinued immediately, leading to resolution of her NMS. This mistake may lead to inappropriate treatment, such as erroneous prescription of further antipsychotic medication, which would only worsen the patient’s clinical picture. 

Nursing home personnel often have limited formal education and training in psychiatric disorders and psychopathology.5 With regard to our case patient, the nursing personnel recognized a change in her status, but were limited in understanding all the possible explanations for this change. The
patient presented with symptoms during a summer with record high temperatures, which may have explained the diaphoresis. A documented UTI may have led staff to attribute behavioral or mental status changes to the infection, similar to the Kohen16 case report. Muscle rigidity with mutism or psychosis may have been erroneously interpreted as a worsening of the patient’s schizophrenia or Alzheimer’s disease. What follows is an explanation of the diagnoses that were considered as part of the differential diagnosis for our case patient and why they were ruled out; these included heat stroke, serotonin syndrome, and anticholinergic delirium. 

Heat stroke is characterized by pyrexia, confusion, rapid breathing, and agitation, and it typically occurs during the summer months, which is when our case patient exhibited her symptoms.27 However, patients with heat stroke have skin that is dry. In cases of NMS, patients present with diaphoresis and noticeably wet skin.12 

Patients with serotonin syndrome present with altered mental status, similar to NMS; however, they are typically restless and agitated,28 whereas akinesia and muscular rigidity are hallmarks of NMS. Patients with serotonin syndrome have demonstrated rigidity in rare cases. Nausea, vomiting, and diarrhea are characteristic of serotonin syndrome but are not typically present in NMS. Further, serotonin syndrome has a rapid onset, usually within 24 hours, whereas NMS develops over the course of 24 to 72 hours, or longer, after administration of a neuroleptic agent.12,14  

Anticholinergic delirium was considered given the patient’s medication regimen. The features of anticholinergic delirium include confusion, pyrexia, dry skin, mydriasis, and decreased secretion of body fluids.7 In contrast, diaphoresis and wet skin are typically present with NMS.12 


Once a diagnosis of NMS is established, discontinuation of the causative antipsychotic medication is widely considered the first step toward amelioration.12-15 Once the agent is discontinued, NMS remits in approximately 7 to 10 days, and nearly all patients recover within 30 days.15 Our case patient’s clozapine was not discontinued when NMS was suspected because the treating psychiatrist was concerned about a relapse of her schizophrenia. In addition, NMS is not an absolute contraindication to continued antipsychotic therapy. 

Because complications of NMS and of withdrawal of the neuroleptic agent can be severe and life-threatening, emergency transfer to a hospital for supportive care is often warranted.15 General supportive measures should be initiated, including daily monitoring of CPK levels, rehydration and cooling, stabilization of blood pressure, correction of fluid and electrolyte imbalances, deep venous thrombosis prophylaxis, and nutritional support.12-15 These measures are often sufficient to resolve NMS. Patients who must be restarted on their neuroleptic medication should be carefully monitored to minimize the risk of recurrence. Precautionary measures include waiting at least 2 weeks to resume therapy, using less potent therapies, starting with a lower dose of medications and titrating upward gradually, avoiding concomitant administrating of lithium, and avoiding dehydration.29 

There are conflicting reports of the benefit of using dopamine agonists (ie, bromocriptine, amantadine) and muscle relaxants (ie, dantrolene) as treatment.12 Dantrolene, bromocriptine, or amantadine may be considered for patients with CPK elevations or hyperthermia upon presentation, or those who do not respond to withdrawal of the neuroleptic agent with supportive care within a couple of days.29 Dantrolene can be prescribed to reduce core body temperature and peripheral muscle rigidity by inhibiting calcium release from the muscle sarcoplasmic reticulum.13-15 Amantadine has been effective in some cases, as reported by Lazarus and colleagues,13 and it is thought to reverse the dopamine receptor blockade associated with NMS. Bromocriptine may reduce hyperthermia and alleviate rigidity and heat production via action on thermoregulatory centers in the hypothalamus.13 


Although NMS is a rare disorder, patients are at risk of developing it whenever dopamine antagonists are prescribed. Because the symptoms are nonspecific, staff can easily overlook NMS and its milder, partial form, yet the condition can become life-threatening if left untreated. Thus, NMS should remain a concern of staff at LTC facilities, which will house increasing numbers of older adults with chronic and persistent mental illness. It is important for healthcare professionals to become familiar with this potentially lethal adverse event of neuroleptics and be vigilant to its early signs and symptoms to ensure early and optimal intervention. 


1. PubMed Health. Schizophrenia. Updated February 13, 2012. Accessed January 21, 2013.

2. Nicholson D, Chiu W. Neuroleptic malignant syndrome. Geriatrics Advisor. 2004;59(8):36-40. 

3. Grabowski DC, Aschbrenner KA, Feng Z, Mor V. Mental illness in nursing homes: variations across states. Health Affairs. 2009;28(3):689-700. Accessed January 29, 2013.

4. World Health Organization. Schizophrenia. Accessed January 24, 2013. 

5. Reichman WE, Katz PR, eds. Psychiatry in Long-Term Care. 2nd ed. New York, NY: Oxford University Press; 2009:427-445.

6. Rosenberg I, Woo D, Roane D. The aging patient with chronic schizophrenia. Annals of Long-Term Care: Clinical Care and Aging. 2009;17(5):20-24.

7. Hall RCW, Hall RCW, Chapman MJ. Anticholinergic syndrome: presentations, etiological agents, differential diagnosis, and treatment. Clinical Geriatrics. 2009;17(11):22-28.

8. Raaska K, Raitasuo, V, Arstila M, Neuvonen PJ. Bacterial pneumonia can increase serum concentration of clozapine. Eur J Clin Pharmacol. 2002;58(5):321-322.

9. Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007;76(3):391-396.

10. Foatelli FM, Gernay P, Lievens I, Ansseau M. Neuroleptic malignant syndrome and general paralysis: a clinical case [in French]. Rev Med Liege. 2006;61(12):807-811.

11. Delay J, Deniker P. Drug-induced extrapyramidial syndrome. In: Vinken PJ, Bruyen GW, eds. Handbook of Clinical Neurology: Diseases of the Basal Ganglia. Amsterdam: North Holland Publishing; 1968:248-266.

12. Haddad PM, Dursun SM. Neurological complications of psychiatric drugs: clinical features and management. Hum Psychopharmacol. 2008;23(suppl 1):15-26.

13. Lazarus A, Mann SC, Caroff SN. The Neuroleptic Malignant Syndrome and Related Conditions. Washington, DC: American Psychiatric Press; 1989:3-56.

14. Hall RC, Appleby B, Hall RC. Atypical neuroleptic malignant syndrome presenting as fever of unknown origin in the elderly. South Med J. 2005;98(1):114-117.

15. Caroff SN, Campbell EC, Sullivan KA. Neuroleptic malignant syndrome in elderly patients. Expert Rev Neurother. 2007;7(4):423-438. 

16. Kohen I. Neuroleptic malignant syndrome in a skilled nursing facility resident. Annals of Long-Term Care: Clinical Care and Aging. 2008;16(9).

17. Ananth J, Parameswaran S, Gunatilake S, Burgonye K, Sidhom T. Neuroleptic malignant syndrome and atypical antipsychotic drugs. J Clin Psychiatry. 2004;65(4):464-470. 

18. Molina D, Tingle LT, Lu X. Aripiprazole as the causative agent of neuroleptic malignant syndrome: a case report companion. J Clin Psychiatry. 2007;9(2):148-150. 

19. Raaska K, Neuvonen PJ. Ciprofloxacin increases serum clozapine and N-desmethylclozapine: a study in patients with schizophrenia. Eur J Clin Pharmacol. 2000;56(8):585-589.

20. Brouwers EE, Sohne M, Kuipers S, et al. Ciprofloxacin strongly inhibits clozapine metabolism: two case reports. Clin Drug Investig. 2009;29(1):59-63.

21. MediLexicon. Lead-pipe rigidity. Accessed January 29, 2013. 

22. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:735, 795-798.

23. Adityanjee, Singh S, Singh G, Ong S. Spectrum concept of neuroleptic alignant syndrome. Br J Psychiatry. 1988;153:107-111.

24. Levenson JL. Neuroleptic malignant syndrome. Am J Psychiatry. 1985;142(10):1137-45.

25. Pope HG Jr, Keck PE Jr, McElroy SL. Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital. Am J Psychiatry. 1986;143(10):1227-1233.

26. Murray ME, Gregory S, Franco K. Neuroleptic malignant syndrome in a medically ill older woman. Clinical Geriatrics. 2004;12(9):32-36. 

27. Mayo Clinic. Heatstroke. Update September 2, 2011. Accessed January 21, 2013.

28. PubMed Health. Serotonin syndrome. Accessed January 21, 2013.

29. Wijdicks EFM. Neuroleptic malignant syndrome. UpToDate. Updated April 10, 2012. Accessed January 21, 2013.


The authors report no relevant financial relationships.


Address correspondence to:

Julie Pullen, MS, GNP-C

St. Vincent’s Long-Term Care Services

1101 North 27th Street, Suite 101

Billings, MT 59101