What’s the first thing that pops into your head when you see an older woman presenting to the ED from a nursing facility with atraumatic altered mental status? If you’re like me, ‘UTI’ comes quickly to mind. I then banish the thought of a UTI and force myself to go through a worst-first differential diagnosis to exclude, either through the history and clinical assessment or through testing, more dangerous causes. This is a case of a 67-year-old woman with an unusual cause of altered mental status… and a UTI.

HPI

She had a history of moderate to severe dementia and had been placed in an Alzheimer’s facility 4 days previously. When she had moved into the facility she was ambulatory and conversant with family members, with her baseline cognitive impairment, which involved moderate limitations in ADLs, and frequent hallucinations. She was brought into the ED with severe mental status changes that had been worsening since she moved to the facility.

Medications

Her medications included trazodone, citalopram (Celexa), quetiapine (Seroquel), divalproex (Depakote), levothyroxine (Synthroid), simvastatin (Zocor), valsartan/HCTZ (Diovan), and haloperidol (Haldol). The trazodone and quetiapine had been titrated up during the previous month. She had also received extra doses of prn trazodone and haloperidol at the facility initially because of her increasing agitation and aggressive behavior but they were both then discontinued 2 days prior to presentation.

Exam and Labs

On arrival, her vitals were: T 36.7, BP 140/70, HR 85, 97% on RA, RR 16. She was lying in bed moaning, would not follow commands or answer questions, but was able to withdraw all 4 extremities to stimuli, and had no facial droop. She did not have any clonus or hyper-reflexia, but she had markedly increased tone in her upper and lower extremities. Her UA showed positive nitrites, positive leukocyte esterase, and 24 WBC/hpf.

Clinical course

The patient’s UTI was treated, but she clearly had another cause for the dramatic change in mental status and the increased motor tone. Her citalopram, trazodone, quetiapine, citalopram, and divalproex were held, and the next day her rigidity had decreased, unmasking hyper-reflexia and induced clonus. Her mental status improved and 15 days later she was discharged at her mental baseline.

What was the cause?

Serotonin syndrome likely from a combination of citalopram, trazodone, and quetiapine. Her UTI was a red herring.

What was the precipitant?

The patient had been on a long-term, stable dose of citalopram. Her trazodone and quetiapine had been titrated up during the previous month. Our best guess is that the patient had not been taking her medications as prescribed while at home. When she was admitted to the Alzheimer’s facility, she suddenly started receiving all her medications. She initially received extra PRN doses of the trazodone and haloperidol, but these were discontinued two days prior to presentation. Despite this she continued to worsen (still on citalopram and quetiapine) until her visit to the ED.

Diagnosis: Serotonin Syndrome

Signs and Symptoms

The “classic” triad of serotonin syndrome consists of: 1

  1. Mental status changes
  2. Autonomic hyperactivity
  3. Neuromuscular changes

However, as with most classic triads, all three components are not present in the majority of patients. The vague and variable presenting symptoms make this a particularly difficult diagnosis in the elderly, who may have underlying dementia. It is a diagnosis you will miss if you don’t have it in the back of your mind.

Patients often present within 6 hours of initial use of a causative medication or overdose. However, cases can be more indolent as in the patient above with several days of worsening symptoms to the point of near catatonia. Typical symptom progression is as follows: 1

  • Akathisia
  • Tremors
  • Altered mental status
  • Inducible clonus
  • Sustained clonus (+/- ocular clonus)
  • Muscular rigidity
  • Hyperthermia
  • Death

Patients may also have diaphoresis, agitated delirium, mydriasis, diarrhea, tachycardia, and autonomic instability. The clonus and rigidity is often more pronounced in the lower extremities, and once the patient has developed severe muscular rigidity, it may mask the clonus or hyper-reflexia as in the case above. The differential diagnosis should include neuroleptic malignant syndrome (many older adults are on antipsychotic agents), anti-cholinergic toxicity, sepsis, and malignant hyperthermia. Depending on the constellation of symptoms, the medication list, and recent medication changes, it may be easy or challenging to establish the etiology.

Causes of Serotonin Syndrome

Polypharmacy and complications of medication interactions are a major problem in older adults. It places them at risk for serotonin syndrome because of the many medications that can cause or contribute to it. 2 Some medications are obvious risks for serotonin syndrome, such as SSRIs that directly increase the serotonin concentration in the synaptic cleft. However, there are many medications associated with serotonin syndrome that you may not think of as having anything to do with serotonin, including opioid analgesics, anti-emetics, antibiotics, OTC medications, and herbal supplements. The list included here shows some of the more common medications but is by no means exhaustive (adapted from a great review article 1 and UptoDate).

High Risk Medications

  • SSRIs: citalopram (Celexa), sertraline (Zoloft), fluoxetine (Prozac), paroxetine (Paxil)
  • Anti-depressants: trazodone (Oleptro), buspirone (BuSpar), clomipramine (Anafranil), and venlafaxine (Effexor), MAOIs such as phenelzine (Nardil), and tricyclic antidepressents
  • Anticonvulsant: valproate (Depakene)
  • Analgesics: fentanyl (Sublimaze), tramadol (Ultram)
  • Anti-emetics: ondansetron (Zofran), metoclopramide (Reglan)
  • Migraine: sumatriptan(Imitrex)
  • Antibiotics: linezolid (Zyvox) – has MAOI activity
  • Over-the-counter (OTC) and herbal remedies: dextromethorphan, St John’s wort, ginseng
  • Other: Lithium

A patient does not have to overdose to develop serotonin syndrome. They may be on a stable dose of an SSRI, but then when a new medication such as linezolid is started, or if the patient starts taking OTC meds such as dextromethorphan, it could tip them over to a dangerously high serotonin activity level. Taking a good medication history in patients with any symptoms of serotonin syndrome is imperative! Patients may not think to mention OTC meds or herbal remedies.

The interplay of medications, agonists, antagonists, and reuptake inhibitors in the development of serotonin syndrome is complicated. For example trazodone inhibits serotonin reuptake but also antagonizes 5-HT2A/C receptors, and is known to cause serotonin syndrome. Atypical antipsychotics such as quetiapine (Seroquel) has serotonin 5-HT2 antagonist properties, but paradoxically has been reported to enhance the serotonergic effect of other serotonin modulators and contribute to serotonin syndrome in case reports. 3,4  It is thought that antagonism of certain 5-HT receptors (eg by atypical antipsychotics) may lead to increased sensitivity of other 5-HT receptors. 5

Treatment of Serotonin Syndrome

  1. Discontinue the causative agents: Management of these patients primarily lies in stopping the causative agents, and avoiding any other medications that could contribute to serotonin syndrome.
  2. Supportive care: For mild cases, care is primarily supportive with IV fluids, and benzodiazepines for muscular rigidity. Muscular rigidity causes the hyperthermia of serotonin syndrome, so anti-pyretics such as acetaminophen (Tylenol) are not useful. Physical restraints should be avoided or minimized because of the risk of isometric contractions against the restraints, worsening the hyperthermia and risk of rhabdomyolysis.
  3. Benzodiazepines: In mild to moderate cases, benzodiazepines should help reduce rigidity and therefore hyperthermia. Benzodiazepines should be used with caution and at lower doses than usual in older adults, however, as they can paradoxically worsen agitation and can be deliriogenic. However, they are recommended for patients with muscular rigidity.
  4. 5-HT2A antagonists (cyproheptadine): Moderately ill patients may also benefit from 5-HT2A antagonists (cyproheptadine – initial dose 12 mg orally or crushed and NGT). Chlorpromazine (50-100 mg IM), or olanzapine (10 mg sublingual) also have 5-HT2A antagonist activity and have been used, but there is limited evidence for all of these agents.
  5. Consider intubation, sedation, and paralysis: Severely ill patients (e.g. those with a temperature greater than 41.1C), may require intubation, sedation, and paralysis to stop the muscular rigidity. Succinylcholine is not recommended for RSI because of the increased risk of hyperkalemia and rhabdomyolysis. Patients may have fluctuating vital signs and autonomic instability. Hypotension can be treated with low doses of norepinephrine or epinephrine. Patients with hypertension and tachycardia can be treated with a short-acting beta-blocker such as esmolol.
  6. Consult a toxicologist or poison control center: For moderate or severely ill patients in particular, it is helpful to speak with a toxicologist or poison control center. In the U.S., the poison control center (1-800-222-1222) can provide guidance, medication recommendations, and will continue to follow the patient after admission.

See Paucis Verbis card on Serotonin Syndrome.

Serotonin Syndrome Awareness

You have to be aware of serotonin syndrome and the potential precipitants if you are going to make the diagnosis. A study in 1999 in England reported that over 85% of general practitioners surveyed were not even aware of serotonin syndrome. 6 Hopefully understanding of the syndrome has improved since that time. Some key risk factors that might help trigger you to think about it in older adults include multiple risky medications. However, you should also be aware of how changes in living situation could affect how the medications are being taken. In this patient’s case, she may not have been receiving her scheduled doses at home, and on moving to a facility received those doses as well as extra PRN doses.

Take-Home Points

  1. Think about serotonin syndrome as a possible cause of altered mental status in older adults, particularly those with hyperthermia, muscular rigidity, clonus, recent changes in medications, or new medications.
  2. Take a good medication history, as many medicationss other than SSRIs and MAOIs cause serotonin syndrome, including antibiotics, analgesics, OTCs, and herbal medications.
  3. Medications you may not think of as potential culprits, such as atypical antipsychotics, may precipitate serotonin syndrome when used in combination with other serotoninergic agents, although this has mainly been reported as case reports and is not fully understood.
  4. Treat with symptomatic support including IV fluids, benzodiazepines (low dose for older adults) for muscular rigidity, and in moderate to severe cases, cyproheptadine. In severe cases, they may require intubation, sedation, and paralysis.
  5. Phone a friend for help! The poison control center can help with treatment recommendations and put you in touch with a toxicologist if needed for severe cases.

Image

1.
Boyer E, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120. [PubMed]
2.
Poeschla B, Bartle P, Hansen K. Serotonin syndrome associated with polypharmacy in the elderly. Gen Hosp Psychiatry. 2011;33(3):301.e9-11. [PubMed]
3.
Kohen I, Gordon M, Manu P. Serotonin syndrome in elderly patients treated for psychotic depression with atypical antipsychotics and antidepressants: two case reports. CNS Spectr. 2007;12(8):596-598. [PubMed]
4.
Marlowe K, Schirgel D. Quetiapine and citalopram: aetiological significances in serotonin syndrome. N Z Med J. 2006;119(1237):U2058. [PubMed]
5.
Dvir Y, Smallwood P. Serotonin syndrome: a complex but easily avoidable condition. Gen Hosp Psychiatry. 2008;30(3):284-287. [PubMed]
6.
Mackay F, Dunn N, Mann R. Antidepressants and the serotonin syndrome in general practice. Br J Gen Pract. 1999;49(448):871-874. [PubMed]

Expert Peer Review

Dr. Shenvi makes some excellent points. The most important thing is to “First Think Drugs” when evaluating an older adult with non-specific symptoms. Serotonin toxicity is easy to miss. It is almost always caused by an interaction between multiple medications and much less commonly from a single serotoninergic agent. Even in overdose attempts, only 15% of patients will have significant clinical manifestations.  Serotonin syndrome is better classified as “Serotonin Toxicity” – it is always the result of too much serotonin in the central nervous system and is NOT an idiosyncratic drug reaction.  Serotonin can be increased by multiple mechanisms, and the list of potential medications is long.

Although cyprohepatadine can be used, the evidence for this is actually lacking [1] and care must be taken in older patients who may be more susceptible to the sedation and anticholinergic effects of this agent. The key to treatment is to stop all potentially offending medications – and given the long list [2], I would opt to stop everything. Yes, everything.

For this patient, the team opted to stop all of her medications. Remember that many of the drugs that you may be tempted to use to control the agitation and jumpiness that are clinical features of the diagnosis can actually make serotonin toxicity worse! I would not use atypical antipsychotics or any other medications with psychotropic effects.

The key to treatment is early recognition. In 1984, an inexperienced intern did not recognize the classic features of serotonin toxicity in a young college girl named Libby Zion. The intern and the resident then treated her symptoms of tremor, shaking and agitation by placing her in physical restraints and giving her meperidine --- her symptoms worsened, her fever climbed to 107, and she was dead before the morning. The case of Libby Zion is often cited in the lead up to the Bell report that changed work hour and supervision regulations for resident education[3].

But I believe that the case of Libby Zion, like our patient that Dr. Shenvi presents, has a few other important lessons for all of us when treating patients who present with confusion:

  1. Do not assume the patient is “as billed”. Dr. Shenvi did not assume this was just delirium due to a urinary tract infection.
  2. First Think Drugs (especially in our older patients who are on multiple medications) .
  3. Do No Harm— Behavioral changes associated with dementia can be challenging for patients, families and staff, but we have to use caution when treating these symptoms with medications that have significant central nervous system effects.  Polypharmacy is associated with bad outcomes for older adults. Before adding an additional agent to control a symptom, make sure that the symptom is not a side effect of another medication. In this case, the patient was becoming more and more agitated at her facility – likely because of developing serotonin toxicity. The treatment initiated was to increase the dose of her medications and add another antipsychotic, interventions that made the clinical syndrome worse.

 References

  1. Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with cyproheptadine. The Journal of emergency medicine. Jul-Aug 1998;16(4):615-619. PMID: 9696181.
  2. Boyer EW, Shannon M. The serotonin syndrome. The New England journal of medicine. Mar 17 2005;352(11):1112-1120. PMID: 15784664.
  3. Asch DA, Parker RM. The Libby Zion case. One step forward or two steps backward? The New England journal of medicine. Mar 24 1988;318(12):771-775. PMID: 3347226.
Debra Bynum, MD
Associate Professor of Medicine Program Director, Geriatric Medicine Fellowship
Christina Shenvi, MD PhD
ALiEM Associate Editor
Assistant Professor
Assistant Residency Director
University of North Carolina
www.gempodcast.com