Abstract
Mild forms of serotonin syndrome can potentially be fatal, if not recognized. The increased use of serotonergic agents makes the awareness of its prevalence, various presentations, diagnostic evaluation, and treatment a clinical imperative. It is important to note that serotonin syndrome can only be diagnosed clinically in the presence of 3 clinical criteria: mental status changes, autonomic manifestations, and neuromuscular abnormalities. This case report describes a patient who underwent an uncomplicated closed nasal fracture reduction and subsequently developed serotonin syndrome.
1
Case description
A 42-year-old woman with no significant medical history had recently been struck at work sustaining a nasal fracture. The patient had a depressive disorder for which she was taking quetiapine (atypical antipsychotic), citalopram (selective serotonin receptor inhibitor), and Adderall (central nervous system [CNS] stimulant). Clinical examination confirmed the nasal fracture. She underwent an uncomplicated closed nasal fracture reduction. Intraoperatively, she had received a single dose of ondansetron.
Upon emergence from anesthesia, the patient evidenced a form of clonus with movement of the head rhythmically to the left and right. Her vital signs remained stable. As time progressed, her condition worsened. She became agitated, restless, and did not follow commands. Her blood pressure began to fluctuate from 180 to 90 mm Hg. Her legs appeared more rigid, and her eyes evidenced vertical movements, a form of ocular clonus. She was mildly febrile with skin temperature of 38.5°C. Benzodiazepines were administered, which did not appear to have much effect. Cyproheptadine treatment resulted in greater alertness and less rigidity. After 2 hours, the ocular clonus resolved, and blood pressure swings were less pronounced and finally stabilized.
2
Discussion
Serotonin syndrome is described as a triad of neuromuscular abnormalities, autonomic hyperactivity, and mental status changes. It can range from a benign to a life-threatening condition and is seen in all age groups from newborns to elderly. This condition can only be diagnosed clinically with laboratory test being used to diagnose the severity of the disease. The incidence of this condition is increasing, secondary to the increased amount of serotonergic agents prescribed .
It usually manifests when 2 serotonergic agents are administered simultaneously, although it can occur after the administration of a single serotonergic drug or after increasing the dose ( Table 1 ). A reported mechanism is the addition of drugs that inhibit the cytochrome P450 2D6 and/or 3A4 (CYP3A4) isoenzymes to serotonin reuptake inhibitors (SSRIs), although reported drug classes implicated in causing serotonin syndrome are multiple .
| Class | Drugs |
|---|---|
| Antidepressants | Monoamine oxidase inhibitors , TCAs , SSRIs , SNRIs , bupropion , nefazodone , trazodone |
| Atypical antipsychotics | Zyprexa, Risperdal, Seroquel |
| Opioids | Tramadol , pethidine , fentanyl , pentazocine , buprenorphine , oxycodone , hydrocodone |
| CNS stimulants | Phentermine , diethylpropion , amphetamine , sibutramine , methylphenidate , methamphetamine , cocaine |
| 5-HT1 agonists | Triptans |
| Psychedelics | MDMA , MDA , 5-Methoxy-diisopropyltryptamine |
| Herbs | St John’s Wort , Syrian rue , Panax ginseng |
| Others | Tryptophan , valproate , buspirone , lithium , linezolid , dextromethorphan , chlorpheniramine , ondansetron , granisetron , metoclopramide , ritonavir |
The patient in this case was on 3 different classes of drugs: citalopram increased extracellular serotonin by inhibiting the reuptake neuronal serotonin 5HT1A . Adderall stimulates CNS activity by blocking the reuptake and increases the release of dopamine norepinephrine and serotonin in extraneural space . Although the exact mechanism of action of Seroquel is unknown, Seroquel has antagonist properties at serotonin type 2A (5HT2A) and dopamine type 2 (D2) receptor high affinity and potent inhibitory effects that norquetiapine (the active metabolite of quetiapine) exhibits for the norepinephrine transporter . A randomized, 8-week, double-blind study provides evidence that when Seroquel is taken with an antidepressant, it works to enhance the efficacy of antidepressants .
Serotonin has an important role in regulating mood, personality, appetite, wakefulness, emesis, temperature regulation, and sexual behavior . Serotonin syndrome is purely a clinical diagnosis with laboratory studies providing supportive but not diagnostic evidence . Awareness of the condition is limited with more than 85% of physicians in 1 recent study unaware of the diagnosis . Clinically, a history of exposure to 1 or more serotonergic agents and the presence of appropriate symptoms should prompt consideration of the diagnosis. When the triad of symptoms mental status changes, autonomic manifestations, and neuromuscular abnormalities are present, the diagnosis is easier to recognize. For the triad of symptoms, mental status changes include anxiety, delirium, confusion, and restlessness . Autonomic manifestations include diaphoresis, tachycardia, hypertension, hyperthermia, vomiting, and diarrhea. Neuromuscular abnormalities include hyperreflexia and clonus, particularly ocular clonus, muscle rigidity (seen more often in the lower extremities), tremor, and bilateral Babinski sign .
Differences between mild and moderate manifestations of the condition are relative and should be viewed as a general grouping along a continuum of escalating manifestations of the condition. Signs and symptoms of the condition embrace a spectrum of presentations from mild to severe: restlessness to psychosis, gait abnormality to muscle rigidity. Mild manifestations include tremor, trouble concentrating, dysarthria, dysphagia, sleep disturbances, gait abnormalities, and uncontrolled muscle movements of the extremities or face including arm or leg jerking or twitching of the face or tongue. Abnormal limb movements or Parkinson-like features, which were not noted before initiation of serotonin agonists or uptake inhibitors or which appear after a recent increase in medication dosage, should prompt consideration of serotonin toxicity . Moderate symptoms are distressing to the patient and include hypertension and hyperthermia, and severe symptoms are life threatening and include shock and multiorgan failure ( Table 2 ).
| Mild | Moderate | Severe |
|---|---|---|
| Tachycardia | Hyperactive bowel sounds | Severe hyperthermia |
| Diaphoresis | Hypertension | Muscle rigidity |
| Dilated pupils | Hyperthermia (40°C) | Multiple organ failure |
| Myoclonus | Shock | |
| Increased DTR | Hyperthermia (41.1°C) | |
| Restlessness | ||
| Anxiety | ||
| Gait abnormality | ||
| Difficulty concentrating | ||
| Sleep disturbances | ||
| Muscle twitching |
Two diagnostic criteria have been identified as acceptable for the diagnosis of serotonin syndrome: Sternbach’s and Hunter’s toxicity criteria . Hunter’s toxicity criteria decision rules are more sensitive and specific than Sternbach’s but is useful only in predicting serotonin toxicity in patients who are known to have taken a serotonergic agent ( Table 3 ) . The severity of the symptoms is believed to be associated with the degree of serotonin activity. Most of the cases present within 24 hours, most within 6 hours of a change or initiation of a new drug. Anticholinergic syndrome, malignant hyperthermia, and neuroleptic malignant syndrome are the primary considerations diagnostically. An accurate history of the timing, dose, and medications taken facilitates the identification of the correct diagnosis. Laboratory testing, although not diagnostic, maybe useful to rule out alternative explanations of the presenting symptoms.
| Classification | Hunter toxicity criteria | Sternbach criteria |
|---|---|---|
| Diagnosis | 1. Must have taken a serotonergic agent and have ONE of the following: A. Spontaneous clonus B. Inducible clonus plus agitation or diaphoresis C. Ocular clonus plus agitation or diaphoresis D. Tremor and hyperreflexia E. Hypertonia F. Temperature above 38°C plus ocular clonus or inducible clonus | 1. Recent addition or increase in a known serotonergic agent 2. Absence of other possible etiologies 3. No recent addition or increase of a neuroleptic agent 4. At least 3 of the following symptoms: mental status changes, agitation, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, fever |
| Sensitivity | 84% | 75% |
| Specificity | 97% | 96% |
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