Neuroleptic malignant syndrome

To the Editor:

I read with great interest the article by Tsai et al (October 2003) (1) about a 68 year-old man with depression who presented with fever, mental status changes, and rigidity that was subsequently diagnosed as neuroleptic malignant syndrome (NMS). The authors suggest that the coincidental increase in the dose of venlafaxine, a dual serotonin and noradrenergic reuptake inhibitor, may have induced the NMS. (1-2) One important distinction that was not mentioned by the authors is the possibility of acute serotonin syndrome (SS).

SS results from the overstimulation of 5-H[T.sub.1]A receptors by selective serotonin reuptake inhibitors, tricylic antidepressants, monoamine oxidase inhibitors, or other serotonergic agents. Clinically, NMS and SS share many features, suggesting different spectrums of a similar disorder. Both syndromes may present with varying degrees of fever, altered mental status, and neuromuscular abnormalities, including leukocytosis, elevated creatinine kinase levels, transaminitis, and low serum bicarbonate levels. Distinctions between the two diagnoses are often difficult to make, having large clinical overlap. However, some authors have suggested that patients with NMS demonstrate higher fevers and more pronounced extrapyramidal effects, while SS patients have lower fevers, myoclonus, and GI dysfunction. (3-4) SS secondary to venlafaxine therapy has been well-described in the medical literature. (5-9) Clearly, the inclusion of SS in the differential diagnosis of this patient is warranted and may suggest an alternate diagnosis. Fortunately, the treatment for both NMS and SS consists of removing the offending agent and providing supportive care. As stated by the authors, (1) there may be a role for both dantrolene and bromocriptine in the treatment of these conditions.

Michael P. Gruber, MD

University of Colorado Health Sciences Center

Denver, CO

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Michael P. Cribber, MD University of Colorado Health Sciences Center, C-272 Division of Pulmonary Sciences and Critical Care Medicine, 4200 East Ninth Ave, Denver, CO 80262; e-mail: michael.gruber@uchsc.edu

REFERENCES

(1) Tsai HC, Kuo PH, Yang PC. Fever, conscious disturbance, and muscle rigidity in a 68-year old man with depressive disorder. Chest 2003; 124:1598-1601

(2) Nimmagadda SR, Ryan DH, Atkin SL. Neuroleptic malignant syndrome after venlafaxine. Lancet 2000; 355:2164-2165

(3) Carbone JR. The neuroleptic malignant syndrome and serotonin syndromes. Emerg Med Clin North Am 2000:18:317-325

(4) Birmes P, Coppin D, Schmitt L, et al. Serotonin syndrome: a brief review. Can Med Asset J 2903; 168:1439-1442

(5) Gutierrez MA, Stimmel GL, Also JY. Venlafaxine: a 2003 update. Clin Ther 2003; 8:2138-2154

(6) Pan JJ, Shen WW. Serotonin syndrome induced lay low-dose venlafaxine. Ann Pharmacother 2003; 37:209-211

(7) McCue RE, Joseph M. Venlafaxine- and trazodone-induced serotonin syndrome. Am J Psychiatry 2001; 158:2088-2089

(8) Perry NK. Venlafaxine-induced serotonin syndrome with relapse following amitriptyline. Postgrad Med J 2000; 76:254-256

(9) Daniels RJ. Serotonin syndrome due to venlafaxine overdose. J Accid Emerg Med 1998; 15:333-334

To the Editor:

We thank Dr. Gruber for his interest in our article (October 2003) (1) describing a case of neuroleptic malignant syndrome (NMS). We agree with Dr. Gruber that serotonin syndrome could be included in the differential diagnosis of our patient. Serotonin syndrome is characterized by serotonergic hyperactivity, and commonly presents with 'altered mental status, myoclonus, hyperreflexia, diaphoresis, nausea, vomiting, and elevations in temperature. Although there are many overlapping aspects of the clinical presentation between the two syndromes, patients with NMS are more likely to present with extrapyramidal signs such as rigidity, very high fever, autonomic disturbance, elevated creatine phosphokinase level, abnormal liver function, and higher possibility of severe complications, such as renal failure, disseminated intravascular thrombosis, and even fatality. The reasons for thinking that NMS is an appropriate diagnosis for our patient included his persistent high fever, the lack of hyperreflexia (which is consistently found in patients with serotonin syndrome), and lack of GI symptoms.

It is natural to think that selective serotonin reuptake inhibitors (SSRIs) could enhance serotonin activity by the inhibition of serotonin uptake, which might lead to the hyperstimulation of 5HT1A receptor and the development of serotonin syndrome. Nevertheless, SSRIs have been shown to inhibit extrapyramidal dopaminergic neurotransmission, and the association of NMS with SSRIs is not uncommon. (2) Serotonin syndrome is most often a toxic effect resulting from the interaction between serotonergic agents and monoamine oxidase inhibitors, while NMS is thought to be an idiosyncratic drug reaction that is more likely to be induced by a single agent. (3)

Currently, there is neither uniform agreement concerning the diagnostic criteria nor specific diagnostic laboratory tests for NMS or serotonin syndrome.4s Some even proposed that these two syndromes are within the same spectrum of a single disorder. It is possible that SSRIs act on both serotonergic and dopaminergic pathways, leading to distinct clinical presentations in different patients. The precise mechanism of how the agent affects neurotransmission requires further investigation. Fortunately, as Dr. Gruber mentioned, this ambiguous status has had relatively little impact on clinical practice, since both syndromes need rapid recognition, prompt withdrawal of use of the offending agent, and aggressive supportive measures.

Hsing-Chen Tsai, MD

Ping-Hung Kuo, MD

National Taiwan University Hospital

Taipei, Taiwan, Republic of China

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Ping-Hung Kou, MD, Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Rd, Taipei, Taiwan, ROC; e-mail: kph@ntumc.org

REFERENCES

(1) Tsai HC, Kuo PH, Yang PC. Fever, consciousness disturbance, and muscle rigidity in a 68-year-old man with depressive disorder. Chest 2003; 124:1598-1601

(2) Caley CF. Extrapyramidal reactions and the selective serotonin-reuptake inhibitors. Ann Pharmacother 1997; 31:1481-1489

(3) Carbone JR. The neuroleptic malignant and serotonin syndromes. Emerg Med Clin North Am 2000; 18:317-325

(4) Radomski JW, Dursun SM, Revely MA, et al. An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria. Med Hypotheses 2000; 55:218-224

(5) Aditynjee, Mathews T, Aderibigbe YA. Proposed research diagnostic criteria for neuroleptic malignant syndrome, hat J Neuropsychopharmacol 1999; 2:129-144

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