How can I distinguish serotonin syndrome from neuroleptic malignant syndrome in my patient with fever and mental status changes?

Although there is often an overlap between the clinical presentation of serotonin syndrome (SS) and neuromuscular malignant syndrome (NMS), start out with the physical exam. The presence of hyperreflexia, tremors, clonus, hyperactive bowel sounds, and dilated pupils should make you think of SS, whereas hyporeflexia, “lead-pipe” rigidity in all muscle groups, normal pupils, and normal or decreased bowels sounds suggest NMS in the proper context.1-3 The most sensitive and specific sign of SS is clonus.1

Aside from physical exam findings, symptom onset in relation to the implicated drug may also be important. Onset of symptoms within 12-24 h of the initiation or change of an implicated drug suggests SS, whereas a more delayed onset (often 1-3 days) is more supportive of NMS.1-3  SS also tends to resolve within a few days after discontinuation of the offending agent, while NMS usually takes 9-14 days to resolve. 1-3 Although both SS and NMS can be associated with leukocytosis, elevated CK and low serum iron levels are more common in NMS.2

SS is caused by excess serotonin due to a variety of mechanisms—therefore medications— including inhibition of serotonin uptake ( eg, serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, metoclopramide, ondansetron), inhibition of serotonin metabolism (seen with monoamine oxidase inhibitors , including linezolid, methylene blue), increased serotonin release (eg stimulants, including amphetamines, cocaine), and activation of serotonin receptors (eg, lithium), among others. 2

As for medications that can cause NMS, look for neuroleptic agents (eg, haloperidol, olanzapine, quetiapine, risperidone), as well as antiemeics, such as metoclopramide and promethazine.2

 

Bonus Pearl: Did you know that several supplements/herbal products have been associated with serotonin syndrome, including L-tryptophan, St. John’s wort and ginseng?1

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References

  1. Bienvenu OJ, Neufeld K, Needham DM. Treatment of four psychiatric emergencies in the intensive care unit. Crit Care Med 2012;40: 2662-70. https://insights.ovid.com/crossref?an=00003246-201209000-00017
  2. Turner AAH, Kim JJ, McCarron RM, et al. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry 2019;18: 36. https://www.mdedge.com/psychiatry/article/193418/schizophrenia-other-psychotic-disorders/differentiating-serotonin-syndrome
  3. Dosi R, Ambaliya A, Joshi H, et al. Serotonin syndrome versus neuroleptic malignant syndrome: a challenging clinical quandary. BMJ Case Rep 2014. Doi:10.1136/bcr-2014-204154. https://casereports.bmj.com/content/2014/bcr-2014-204154

 

How can I distinguish serotonin syndrome from neuroleptic malignant syndrome in my patient with fever and mental status changes?

When should surgery be considered in my hospitalized patient with divertculitis?

Severe diffuse abdominal pain, fever, tachycardia, leukocytosis or other signs of sepsis and diffuse peritonitis indicative of free perforation requires emergent surgery. Urgent surgery should be considered when your patient fails to improve (eg, abdominal pain or the inability to tolerate enteral nutrition, bowel obstruction, or infection-related ileus) despite medical therapy or percutaneous drainage. 1,2

Lower threshold for surgical intervention is also needed in transplant patients, patients on chronic corticosteroid therapy, other immunosuppressed patients and those with chronic renal failure or collagen-vascular disease because these patients have a significantly greater risk of recurrent, complicated diverticulitis requiring emergency surgery. Overall, up to 20% of patients with acute diverticulitis undergo surgery during the same hospitalization.2

For patients with recurrent uncomplicated diverticulitis, decision regarding future elective surgery should be individualized. Although older guidelines recommended surgery after 2 attacks of uncomplicated diverticulitis, more recent guidelines place less emphasis on the number of episodes and stress the importance of considering the severity of the attacks, chronic or lingering symptoms, inability to exclude carcinoma, overall medical condition of the patient, risks of surgery, and the impact of diverticulitis on the patient’s lifestyle.1,2

Of interest, a decision analysis model suggests that elective resection after a fourth episode may be as safe as earlier resection.3

 

References

  1. Young-Fadok TM. Diverticulitis. N Eng J Med 2018;397:1635-42 https://www.nejm.org/doi/full/10.1056/NEJMcp1800468
  2. Feingold D, Steele SM, Lee S, et al. Practice parameters for the treatment of sigmoid diverticulitis. Dis Colon Rectum 2014;57:284-94. https://www.fascrs.org/sites/default/files/downloads/publication/practice_parameters_for_the_treatment_of_sigmoid.2.pdf
  3. Salem L, Veenstra DL, Sullivan SD, et al. The timing of elective colectomy in diverticulitis: A decision analysis. J Am Coll Surg 2004;199:904-12. https://www.journalacs.org/article/S1072-7515(04)01000-2/fulltext

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When should surgery be considered in my hospitalized patient with divertculitis?

My patient with COPD exacerbation on corticosteroids has an elevated white blood cell and neutrophil count. How can I tell if his elevated neutrophil count is caused by the corticosteroids or an acute infection?

The most helpful lab data favoring corticosteroid-induced granulocytosis (CIG) is the absence of a shift to the left in the peripheral WBC (ie, no more than 6% band forms) and toxic granulation.1 Although the total WBC itself is less helpful, experimental studies have reported a mean maximum neutrophil counts 2.4 times the base line after IV injection of hydrocortisone (200 mg) 2, and a mean increase of 4,000 neutrophils/mm3 after prednisone (20-80 mg). 3

Several possible mechanisms for CIG revolving around altered neutrophil characteristics and dynamics have been proposed4, including

  • Reduced egress from blood into tissues
  • Demargination from vascular endothelial surfaces
  • Delayed apoptosis
  • Enhanced release from the bone marrow.

An experimental animal study reported that only 10% of CIG is related to bone marrow release of neutrophils with the rest related to demargination (61%) and reduced egress from blood or delayed apoptosis (29%).4 This study may explain why high percentage of band forms would not be expected in CIG.

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References

  1. Shoenfeld Y, Gurewich Y, Gallant LA, et al. Prednisone-induced leukocytosis: influence of dosage, method, and duration of administration on the degree of leukocytosis. Am J Med 1981;71:773-78. Link
  2. Bishop CR, Athens JW, Boggs DR, et al. Leukokinetic studies: A non-steady-state kinetic evaluation of the mechanism of cortisone-induced granulocytosis. J Clin Invest 1986;47:249-60. https://www.ncbi.nlm.nih.gov/pubmed/5638121
  3. Dale DC, Fauci AS, Guerry DuPont, et al. Comparison of agents producing a neutrophilic leukocytosis in man. J Clin Invest 1975;56:808-13. PDF
  4. Nakagawa M, Terashma T, D’yachkova YD, et al. Glucocorticoid-induced granulocytosis: Contribution of marrow release and demargination of intravascular granulocytes. Circulation 1998;98:2307-13. PDF

 

 

My patient with COPD exacerbation on corticosteroids has an elevated white blood cell and neutrophil count. How can I tell if his elevated neutrophil count is caused by the corticosteroids or an acute infection?

My patient with ulcerative colitis has had colectomy. Can she still get C. difficile infection?

Yes! Although a common cause of colitis, an increasing number of reports in the literature suggest C. difficile can cause enteritis as well.Antibiotic use is a major risk factor in most reports, with nearly one-half of the cases reported in patients with inflammatory bowel disease, many post-colectomy. 1-3

Mortality of C. difficile enteritis based on the first 83 cases in the literature appears to be 23%,1 but as high as 60%-83% depending on the report!2 Its diagnosis post-colectomy requires a high index of suspicion, as patients may not complain of “diarrhea” with chronically loose stools in the ileostomy bag.  Be particularly on the lookout for C. difficile enteritis in these patients when there is increased stool output, fever, hypotension, and/or leukocytosis2, and when in doubt, send a stool specimen from the ileostomy bag for C. difficile testing.

Although the pathophysiology of C. difficile enteritis is not fully understood, few observations are particularly intriguing: 

  • Small bowel mucosa may be colonized by C. difficile in about 3% of the population, potentially serving as a reservoir.2
  • Patients with ileostomy may develop a metaplasia of the terminal end mimicking colonic environment.4  
  • Exposure of rabbit ileum to C. difficile toxin A also causes significant epithelial necrosis with destruction of villi and neutrophil infiltration.5

 

References

  1. Dineen SP, Bailey SH, Pham TH, et al. Clostridium difficile enteritis: a report of two cases and systematic literature review. World J Gastrointest Surg 2013;5:37-42. https://www.wjgnet.com/1948-9366/full/v5/i3/37.htm
  2. Boland E, Thompson JS. Fulminant Clostridium difficile enteritis after proctocolectomy and ileal pouch-anal anastomosis. Gastroenterology Research and Practice 2008; 2008: Article ID 985658. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633454/pdf/GRP2008-985658.pdf
  3. Freiler JF, Durning SJ, Ender PT. Clostridium difficile small bowel enteritis occurring after total colectomy. Clin Infect Dis 2001;33:1429-31. https://pdfs.semanticscholar.org/333b/d84978cfc4ac8fd21a15bc8fd26ff3160387.pdf
  4. Apel R, Cohen Z, Andrews CW, et al. Prospective evaluation of early morphological changes in pelvic ileal pouches. Gastroenterology 1994;107:435-43. http://www.gastrojournal.org/article/0016-5085(94)90169-4/pdf
  5. Triadafilopoulos G, Pothoulakis C, Obrien MJ, et al. Differential effects of Clostridium difficile toxins A and B on rabbit ileum. Gastroenterology 1987;93:273-279. https://www.ncbi.nlm.nih.gov/pubmed/3596162
My patient with ulcerative colitis has had colectomy. Can she still get C. difficile infection?