07-05-2025
A 26-Year-Old With Abnormal Eye Movement and Agitated Delirium
Editor's Note:
The Case Challenge series includes difficult-to-diagnose conditions, some of which are not frequently encountered by most clinicians, but are nonetheless important to accurately recognize. Test your diagnostic and treatment skills using the following patient scenario and corresponding questions. If you have a case that you would like to suggest for a future Case Challenge, please email us at ccsuggestions@ with the subject line "Case Challenge Suggestion." We look forward to hearing from you.
Background
A 26-year-old woman presents to the emergency department (ED) with confusion, agitation, sweating, and abnormal involuntary eye movement (diaphoresis and ocular clonus). The symptoms started the previous week; they were mild at first, and the patient attributed them to a week-long heat wave in the city.
The patient felt worse as the week went on and decided to come to the ED because she was not feeling better that morning. She started sweating profusely in the middle of the night, felt her leg muscles become stiff, and was increasingly nauseous. Her fiancé insisted she go to the ED as early as possible because she seemed agitated and confused, pacing around the apartment instead of taking a shower.
The patient's history is reviewed with her fiancé. She has a history of depression, for which she takes fluoxetine; her dose was increased by her psychiatrist 1 month ago. For migraines, she takes sumatriptan and ondansetron. Because her headaches have recently worsened, her neurologist started her on tramadol. She also has had a cough, for which she self-medicated with dextromethorphan. The remainder of her medical history is noncontributory.
She does not smoke, denies drug or alcohol use, and has no allergies or family history of other significant illness.
Physical Examination and Workup
Upon physical examination, her blood pressure is 165/105 mm Hg, pulse 128 beats/min, respiratory rate 20 breaths/min, pulse oximetry 98% on room air, and temperature 100.6°F (38.1°C).
The patient is a thin woman who seems agitated and restless but complies with the examination. The lung examination reveals clear breath sounds in all fields. Her heart has a regular rhythm, and no murmur is appreciated.
Upon neurologic evaluation, she is alert and oriented to date but not to time or place. Her speech is clear and fluent, with good repetition, comprehension, and naming. She recalls 1 out of 3 objects at 5 minutes. No tenderness or signs of trauma are found over the scalp and neck. No proptosis, lid swelling, conjunctival injection, or chemosis is observed.
The patient is able to identify a pen and a clock. She can count fingers and has an intact bitemporal visual field. Extraocular muscles are intact upon examination; she is able to look from right to left as well as up and down. Spontaneous right ocular clonus is observed. Her pupils are 2 mm and are reactive to light. Sensory examination of her face is unremarkable. Her tongue and uvula are midline, with a positive gag reflex. Her hearing test findings are symmetric. Shoulder-shrug findings are equal on both sides. Strength is 5/5 in the upper and lower extremities.
Sensory examination findings reveal symmetry to light touch, pinprick, temperature, vibration, and proprioception. The patient's reflexes are 2+, except in the lower extremities, where bilateral hyperreflexia is observed. She is able to perform rapid alternating movements. The remainder of her physical examination findings are unremarkable.
An ECG reveals normal sinus at a rate of 128 beats/min, without ST-T wave changes. Head CT is performed, and an example similar to the findings in this case is shown below (Figure 1).
Figure 1.
A urine pregnancy test result is negative. Laboratory analyses performed in the ED include a CBC count, metabolic panel, hepatic panel with lipase, and troponin level. Laboratory test findings are remarkable for a WBC count of 12.4 × 103 cells/µL (reference range, 4.2-11.0 × 103 cells/µL), with 69% segmented neutrophils (54%-62%) and bandemia of 2% (3%-5%), and a hemoglobin level of 11.6 g/dL (reference range for women, 12-15 g/dL). Her troponin level is 0.5 ng/mL (reference range, 0-0.4 ng/mL). The remainder of laboratory test findings, including a toxicology screen and creatine phosphokinase level, were within normal limits. Interpretation of the CT scan was normal.
The patient was given acetaminophen for the low-grade fever. Intravenous fluids were started, and she was admitted to the medicine floor.
Discussion
Serotonin syndrome is a potentially life-threatening condition that occurs secondary to serotonin toxicity in the central and peripheral nervous systems. This can be due to a combination of serotonergic agents, an increase in therapeutic dosing of a serotonergic agent, and an overdose or inadvertent interactions of serotonergic agents. Serotonin syndrome is a clinical diagnosis; therefore, a careful and thorough history and physical and neurologic examinations are essential, as is a high level of suspicion.[1]
Serotonin syndrome results from excessive stimulation or agonist activity at postsynaptic serotonin receptors; most often implicated is excessive binding at the serotonin 2A (5-HT 2A ) and serotonin 1A (5-HT 1A ) receptor subtypes. Those two subtypes may be the predominant cause of symptoms.[2] Presenting symptoms can vary widely and range from mild to life-threatening.
Serotonin is produced in the neurons from L-tryptophan, and its concentration is regulated through feedback loops controlling its reuptake and metabolism. Serotonin receptors in the central nervous system regulate attention, behavior, temperature, the sleep/wake cycle, appetite, and muscle tone.[3]
Serotonin receptors are also located in the peripheral nervous system; peripheral serotonin is produced by intestinal enterochromaffin cells and is involved in the regulation of gastrointestinal motility, uterine contraction, bronchoconstriction, and vascular tone. In addition, serotonin in platelets promotes their aggregation.
No specific laboratory test is indicated to diagnose serotonin syndrome, and serotonin levels do not correlate with the severity of symptoms. The Hunter criteria are the most accurate diagnostic set available to diagnose serotonin syndrome, with 84% sensitivity and 97% specificity. The criteria require that a patient be taking a serotonergic agent and meet at least one of the following conditions[4]:
Spontaneous clonus
Inducible clonus with agitation or diaphoresis
Ocular clonus with agitation or diaphoresis
Tremor and hyperreflexia
Hypertonia, temperature > 100.4°F (38°C), and ocular or inducible clonus
A thorough history and physical and neurologic examinations are essential for diagnosis because no specific laboratory test is indicated to diagnose serotonin syndrome. Notably, serotonin levels do not correlate with the severity of symptoms. The Hunter criteria, as outlined previously, are the most accurate diagnostic set available to diagnose serotonin syndrome, with 84% sensitivity and 97% specificity, and the qualifying criteria are independent of one another, not concurrent.
Differential Diagnoses
Besides serotonin syndrome, other differential diagnoses were considered but excluded in this case. Neuroleptic malignant syndrome (NMS) is an idiopathic drug reaction to antipsychotics that has a presentation similar to that of serotonin syndrome; however, NMS presents with bradyreflexia, hyperpyrexia, and lead-pipe rigidity.[5] Myoclonus is rarely seen with NMS, and symptoms typically resolve in days, compared with 24 hours after removal of the offending agent in serotonin syndrome.[6] In addition, patients with NMS have a history of taking a neuroleptic agent (eg, haloperidol, chlorpromazine), atypical antipsychotics, or antiemetic drugs. Vital signs in persons with NMS typically are similar to those in persons with serotonin syndrome and can include hyperthermia, tachycardia, tachypnea, and hypertension.[5] For NMS, dantrolene is the most effective, evidence-based drug treatment available,[6] whereas no evidence-based drug treatments are available for serotonin syndrome.
Malignant hyperthermia is a disorder of skeletal muscle that results from inhalation of halogenated anesthetics (eg, halothane, sevoflurane, desflurane, isoflurane), administration of depolarizing muscle relaxants (eg, succinylcholine), or stressors (eg, vigorous exercise, heat exposure).[7] Malignant hyperthermia is considered a hypermetabolic response of skeletal muscles, and affected patients may present with hyperthermia, tachycardia, tachypnea, increased carbon dioxide production or oxygen consumption, acidosis, hyperkalemia, muscle rigidity, and rhabdomyolysis. Malignant hyperthermia is treated with dantrolene, a specific antagonist that should be available wherever general anesthesia is administered.
Anticholinergic toxicity results from an overdose with an anticholinergic agent and may present with hyperthermia, agitation, altered mental status, mydriasis, dry mucous membranes, urinary retention, and decreased bowel sounds.[8] Patients have normal muscular tone and reflexes in anticholinergic poisoning, compared with serotonin syndrome; the treatment is physostigmine.
Patients with meningitis often have a history of headache, photophobia, neck stiffness, vomiting, and diplopia; they may also present with convulsions, abnormal movements, and/or posturing.
Serotonin syndrome may be distinguished from other causes of agitated delirium on the basis of neuromuscular findings. Patients with sympathomimetic toxicity or infections of the central nervous system typically lack these findings. All the differential diagnoses mentioned can be associated with significant morbidity and mortality without prompt and appropriate treatment; therefore, differentiation based on clinical findings and a high index of suspicion is imperative.
DDx Case Study
A 30-year-old man presents with a 7-month history of worsening hallucinations and delusions. Management initiated by his psychiatrist 1 month ago included risperidone, lithium, olanzapine, and lorazepam. He was brought to the ED because he had been in bed for 3 days in a row and was feeling sluggish, with a temperature of 106°F (41.1°C). Upon examination, the patient is arousable but not oriented to date, time, or place. All extremities are rigid, and reflexes are decreased. His heart rate is 110 beats/min, respiratory rate is 24 breaths/min, and blood pressure is 130/80 mm Hg. No history of illicit drug use is reported.
NMS is an idiopathic drug reaction to antipsychotics that has a presentation similar to that of serotonin syndrome and is characterized by bradyreflexia, hyperpyrexia, and lead-pipe rigidity. Symptoms typically resolve in days compared with 24 hours after removal of offending agent in serotonin syndrome. Patients with NMS have a history of taking a neuroleptic agent (eg, haloperidol, chlorpromazine), atypical antipsychotics, or antiemetic drugs. For NMS, dantrolene is the most effective, evidence-based drug treatment available.
Medications Most Commonly Involved
The medications most commonly involved in serotonin syndrome include selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), opioids, cough medications (eg, dextromethorphan), and antibiotics.[9]
Specific drugs that have the potential to cause serotonin syndrome are as follows[1,6-12]:
SSRIs Citalopram Fluoxetine Fluvoxamine Olanzapine/fluoxetine Paroxetine
SNRIs Duloxetine Sibutramine Venlafaxine
Triptans Almotriptan Eletriptan Frovatriptan Naratriptan Rizatriptan Sumatriptan Zolmitriptan
Miscellaneous Buspirone Carbamazepine Cocaine Cyclobenzaprine Dextromethorphan Ergot alkaloids Fentanyl 5-Hydroxytryptophan Linezolid Lithium L-Tryptophan Meperidine Methadone Methamphetamine Methylene blue Metoclopramide Mirtazapine Ondansetron Phenelzine Selegiline St John's wort Tramadol Tranylcypromine Trazodone Tricyclic antidepressants Valproic acid
Avoid prescribing the following opioids, because they precipitate or worsen serotonin syndrome in patients already receiving SSRIs or MAOIs:
Tramadol
Methadone
Meperidine
Fentanyl
Opioids that have not been linked to serotonin syndrome include morphine, codeine, and hydrocodone; these should be administered if no alternative is available.[10]
SSRIs, SNRIs, MAOIs, certain opioids (eg, fentanyl, tramadol), cough medications (eg, dextromethorphan), and antibiotics are the medication types most commonly involved in serotonin syndrome. Agitation and tremors associated with serotonin syndrome can be treated with benzodiazepines, which are nonspecific serotonin antagonists.
Treatment
Most cases of serotonin syndrome are mild and can be treated by withdrawal of the offending agent and supportive care, with complete resolution of the presenting symptoms.[1] Most cases of serotonin syndrome present for care within 6-24 hours of symptom onset and resolve within the following 24 hours.
Agitation and tremors can be treated with benzodiazepines (which are nonspecific serotonin antagonists); however, in severe cases, patients may require neuromuscular paralysis, sedation, or intubation. Hyperthermia > 106°F (41.1°C) usually is associated with a poor prognosis. Patients presenting with hyperthermia and severe muscle rigidity should be managed with antipyretics, neuromuscular paralysis, sedation, or intubation as indicated.[11]
Serotonin syndrome may be complicated by rhabdomyolysis, disseminated intravascular coagulation (DIC), hepatic or renal dysfunction, and lactic acidosis. Therefore, obtaining urinalysis, renal and hepatic function measurement, and a DIC profile should be part of management. Elicit from the patient a confirmation or denial of illicit or recreational drug use, especially in cases of intentional overdose, because this may complicate the clinical picture and delay diagnosis.
Cyproheptadine is the recognized therapy for serotonin syndrome. Cyproheptadine is a histamine-1 receptor antagonist with anticholinergic and antiserotonergic properties. It is taken orally, and the initial dose is 4-12 mg, repeated every 2 hours, and discontinued if the maximum dose of 32 mg is reached without symptom improvement.[12]
Serotonin syndrome resolves over time if promptly diagnosed and appropriately managed, highlighting the importance of a timely and accurate diagnosis. Polypharmacy also increases the risk for serotonin syndrome; therefore, reconciling a patient's medications is important if serotonin syndrome is suspected. Remember that medications such as fluoxetine have a long half-life and may require 5-8 weeks to be cleared from the system; thus, additional serotonergic medications should be cautiously added.
Cyproheptadine is the recognized therapy for serotonin syndrome, given at an initial dose of 4-12 mg, repeated every 2 hours, not to exceed 32 mg. Physostigmine is the first-line treatment option for anticholinergic toxicity. Serotonin syndrome typically resolves within 24 hours of a patient presenting for care. Typical cases of serotonin syndrome are mild and can be treated by withdrawal of the offending agent and supportive care; neuromuscular paralysis, sedation, or intubation may be considered in severe cases with severe muscle rigidity and hyperthermia.
The patient in this case was successfully managed by discontinuing the inciting agents and was treated with cyproheptadine and supportive care. After complete resolution of all symptoms, the patient was discharged (2 days after admission).
Historical Footnote
Although serotonin syndrome is rare, the case of Libby Zion in 1984 was instrumental in influencing and changing medicine in an unprecedented way. Zion was a patient who had been taking phenelzine, an antidepressant.[13] The therapeutic effects of phenelzine may continue for as long as 2 weeks after discontinuation. Zion was given meperidine for agitation, which led to deadly manifestations of serotonin syndrome. That case led to reforms in the grueling hours of medical residents across the United States.
