74-Year-Old Woman With New-Onset Myoclonus

A 74-year-old female nursing home resident with Alzheimer disease was admitted to the hospital with a 5-month history of aggressive behavior, including physically striking other nursing home residents. She had been treated with quetiapine with mild improvement; however, she became tremulous while receiving this medication and so was switched to 0.125 mg/d of risperidone orally. Unfortunately, the patient continued to act aggressively and was brought to the emergency department, where she was unable to follow commands or answer questions appropriately. Laboratory blood tests revealed an elevated serum creatinine level of 1.2 mg/dL (0.6-1.1 mg/dL), compared with a baseline of 0.8 mg/dL. Urine studies showed the presence of gram-negative bacilli and 10 to 20 white blood cells per high-power field, indicating a possible urinary tract infection (UTI). Results for all other diagnostic tests were unremarkable. The patient was treated empirically with a 10-day course of sulfamethoxazole-trimethoprim (SMX-TMP) for a presumed UTI and admitted to the psychiatry unit for behavioral dyscontrol.

The patient's medical history revealed diagnoses of Alzheimer disease, hypothyroidism, hypertension, and previous deep venous thromboembolism. Her medications at the time of admission included memantine (10 mg twice daily), donepezil (10 mg/d), risperidone (0.125 mg/d), citalopram (40 mg/d), levothyroxine (150 μg/d), atenolol (12.5 mg/d), SMX-TMP (2 double-strength tablets daily), and aspirin (81 mg/d).

After admission, the patient's dose of risperidone was increased to 1 mg/d. A few days later, she developed tremor and myoclonus, which were thought to be adverse effects of the increased dose of risperidone, so this medication was discontinued. During the next 4 days, her condition worsened to include increased tremor, myoclonus, and agitation. The patient was transferred to a general internal medicine service for further evaluation.

Physical examination by the general internal medicine service yielded the following findings: temperature, 37.7°C; blood pressure, 122/89 mm Hg; pulse rate, 102 beats/min; respiratory rate, 20 breaths/min; and oxygen saturation, 93% while breathing room air. The patient appeared agitated. She was alert but disoriented to person, place, and time. She was unable to respond to questions appropriately, yet her speech was fluent and comprehensible and she did not have dysarthria. Her skin was pale and damp, but her oral mucosa was dry and there was no jugular venous distention. Her heart rhythm was regular and tachycardic (102 beats/min), without murmurs, rubs, or gallops. Examination of the patient's head and neck revealed that her pupils were normal in shape and size and accommodated appropriately to light. Inspection of the patient's eye movements revealed smooth pursuit, with no signs of ocular clonus or nystagmus. Myoclonus and tremor were present in all 4 limbs, but there was no evidence of muscle spasticity or rigidity. Brisk deep tendon reflexes and inducible clonus were elicited in the upper and lower extremities bilaterally; however, plantar responses were equivocal. Cranial nerves and strength could not be assessed because of poor patient cooperation. Findings on the remainder of the examination were unremarkable.

1. Which one of the following diagnostic tests would be least appropriate in the initial work-up of this patient?

   1. Blood urea nitrogen (BUN) assay

   2. Thyroid-stimulating hormone (TSH) assay

   3. Serum serotonin assay

   4. Serum electrolyte panel

   5. Blood cultures

   The etiology of myoclonus and tremor was uncertain in this patient; however, she initially presented with stage I acute renal failure. Obtaining a BUN level in this patient is warranted because uremia can present with myoclonus and altered mentation. The patient also had a history of hypothyroidism, for which she was receiving synthetic thyroid hormone supplementation. If taken in excessive quantities, the latter can potentially lead to thyrotoxicosis, presenting with elevated temperature, tachycardia, brisk reflexes, and myoclonus; thus, checking a TSH level is important to rule out thyrotoxicosis in this patient.

   An elevated serotonin level in the central nervous system could account for the patient's symptoms, particularly because the patient was taking citalopram, a selective serotonin reuptake inhibitor (SSRI). However, checking a serum serotonin level in the setting of serotonin toxicity has no proven clinical relevance because the level does not correlate with symptoms.¹ Conversely, measuring serum electrolyte levels in this patient is indicated. An electrolyte disturbance, such as hyponatremia, hypomagnesemia, or hypocalcemia, is often a reversible cause of myoclonus and hyperreflexia that should be considered when the etiology of these symptoms is uncertain.

   Another possible cause of the patient's symptoms could be a systemic infection, with the urine as a likely source. Despite being treated with antibiotics for a UTI during this hospitalization, the patient still developed a mildly elevated temperature, tachycardia, tremor, and agitation. These symptoms could indicate early sepsis stemming from an inadequately treated UTI, and therefore obtaining blood cultures to look for bacteremia is justified in this patient.

   Laboratory tests after transfer of the patient to the general internal medicine service yielded the following results (reference ranges provided parenthetically): hemoglobin 12.7 g/dL (12.0-15.5 g/dL); white blood cells, 9.9 × 10⁹/L (3.5-10.5 × 10⁹/L); platelets, 173 × 10⁹/L (150-450 × 10⁹/L); creatinine 1.7 mg/dL (0.6-1.1 mg/dL); BUN, 26 mg/dL (6-21 mg/dL); sodium, 137 mmol/L (135-145 mmol/L); potassium, 4.6 mmol/L (3.6-4.8 mmol/L); bicarbonate, 23 mEq/L (22-29 mEq/L); calcium, 9.4 mg/dL (8.9-10.1 mg/dL); magnesium, 2.5 mg/dL (1.7-2.3 mg/dL); aspartate aminotransferase, 44 U/L (8-43 U/L); alanine aminotransferase, 57 U/L (7-45 U/L); alkaline phosphatase, 84 U/L (55-142 U/L); international normalized ratio, 1.1 (0.9-1.2); total bilirubin, 0.6 mg/dL (0.1-1.0 mg/dL); TSH, 5.2 mIU/L (0.3-5.0 mIU/L); and free thyroxine, 1.2 ng/dL (0.8-1.8 ng/dL). Urine studies revealed a normal urine microscopy, an unremarkable Gram stain, and a fractional excretion of sodium of less than 0.01. Electrocardiography showed sinus tachycardia. Blood cultures were pending.

2. Which one of the following diagnoses is the most likely cause of the patient's presenting symptoms?

   1. Thyrotoxicosis

   2. Acute renal failure

   3. Alzheimer disease

   4. Serotonin syndrome

   5. Neuroleptic malignant syndrome (NMS)

   The level of TSH was only slightly elevated in this patient, and the level of free thyroxine was normal, ruling out thyrotoxicosis as a cause of her symptoms. She had an elevated creatinine level, indicating acute renal failure; however, her BUN level was only slightly elevated to 26 mg/dL and would likely not account for this patient's symptoms, because BUN levels greater than 100 mg/dL are frequently observed when clinical signs of uremia are present. Alzheimer disease can present with myoclonus, but the abrupt onset and nature of her symptoms (ie, brisk reflexes, tremor, damp skin, and elevated temperature) typically are not associated with this disease.

   The serotonin syndrome is the most likely diagnosis for this patient. It is a potentially life-threatening condition that usually presents in patients taking serotonergic agents, such as SSRIs, and manifests primarily as mental status changes, neuromuscular abnormalities, and autonomic hyperactivity.² Although assessment of mental status was difficult in this patient because of her underlying dementia, her increased agitation was a change from her baseline. Furthermore, she presented with neuromuscular abnormalities, including tremor, hyperreflexia, myoclonus, and inducible clonus, as well as autonomic hyperactivity, including tachycardia, damp skin, and elevated temperature, which are most consistent with the serotonin syndrome.

   Initially, NMS was considered for this patient, given her recent use of risperidone, a neuroleptic agent, and the fact that the patient had several of the characteristic features of NMS, including mental status changes and autonomic instability. However, muscle rigidity, which is one of the hallmarks of NMS, was absent in this patient. (Rigidity can also be seen in patients with the serotonin syndrome, but it occurs less frequently).³ Myoclonus, tremor, and hyperreflexia are also not typically observed in patients with NMS. Conversely, NMS usually presents with bradyreflexia and occurs more insidiously, with the onset of symptoms ranging from days to weeks. The sudden progression of symptoms in this patient made NMS less likely.

   After the patient was diagnosed as having the serotonin syndrome, citalopram and all potentially exacerbating medications were discontinued. Nevertheless, the patient's symptoms persisted.

3. Which one of the following is the most important next step in managing this patient?

   1. Oxygen supplementation

   2. Continuous cardiac monitoring

   3. Neuromuscular paralysis

   4. Physical restraint

   5. Intravenous fluid administration

   Oxygen supplementation is usually recommended when oxygen saturation is below 92%; in this case, the oxygen saturation was 93% while the patient was breathing room air, and therefore supplementation with oxygen would not offer any further benefit. Continuous cardiac monitoring is only recommended for patients with the serotonin syndrome who have substantial autonomic instability, as for example those with labile blood pressures. Although this patient had evidence of autonomic instability, including elevated temperature, damp skin, and tachycardia, her blood pressure was stable and her heart rate and rhythm were not sufficiently abnormal to require continuous cardiac monitoring.

   Neuromuscular paralysis is only required in the treatment of severe cases of the serotonin syndrome, involving substantial hyperthermia (ie, a core body temperature of >41°C).¹ These patients should be paralyzed with nondepolarizing agents and then intubated as the increased muscular activity causes an increase in body temperature.¹ Physical restraint has been used to control agitation, but it is not generally recommended in patients with the serotonin syndrome because it can precipitate isometric muscle contraction, leading to lactic acidosis and hyperthermia.⁴

   Supportive care is the mainstay of treatment for patients with the serotonin syndrome. Most patients, particularly those with an elevated temperature, require intravenous (IV) fluid administration to treat volume depletion caused by hyperthermia.⁵ This patient required IV fluids for both her serotonin syndrome and prerenal azotemia. Of note, the patient's elevated creatinine level could have been partially due to treatment with SMX-TMP, but the increase in creatinine level was more than what would be expected from SMX-TMP use alone. In addition, her fractional excretion of sodium was less than 0.01, suggestive of prerenal azotemia.

   Forty-eight hours after discontinuation of the SSRI and administration of IV fluids, the patient's symptoms of the serotonin syndrome, including myoclonus and tremor, had largely resolved; however, she continued to be agitated and her nausea had worsened.

4. Which one of the following medications is the most appropriate at this time?

   1. Ondansetron

   2. Metoclopramide

   3. Benzodiazepines

   4. Trazodone

   5. Olanzapine

   Although ondansetron is an antiemetic agent that blocks serotonin (5-HT) 3 receptors, it can trigger or worsen the serotonin syndrome by paradoxically increasing serotonin levels, particularly when combined with other serotonergic agents such as SSRIs. The mechanism by which it increases serotonin levels is not entirely understood, but it has been postulated that by blocking 5-HT₃ receptors, ondansetron indirectly leads to the activation of another serotonin receptor (5-HT_1A) that is known to play a major role in the serotonin syndrome. Therefore, its use in patients taking SSRIs is contraindicated.⁵ Metoclopramide is an antiemetic agent that primarily blocks dopamine receptors; however, it can also exacerbate the serotonin syndrome (by an unspecified mechanism) and should be avoided in this patient.⁵

   Administration of benzodiazepines is the preferred method to control agitation in patients with the serotonin syndrome. Benzodiazepines, such as diazepam, have been shown to improve survival and dampen the adrenergic response during episodes of the serotonin syndrome in various animal models.⁶ These medications often have the added benefit of decreasing nausea.

   Trazodone is an antidepressant that, at times, is used to treat anxiety and insomnia. It is known to inhibit serotonin uptake, much like SSRIs, and has the potential to cause the serotonin syndrome. Olanzapine is an atypical antipsychotic agent that is often used in the hospital to treat agitation. Similar to ondansetron, atypical antipsychotic agents are thought to increase serotonin levels by indirectly activating 5HT_1A receptors; however, they do this by blocking 5-HT₂ rather than 5-HT₃ receptors.⁷ Thus, olanzapine is not an appropriate choice in this case.

   The patient received low-dose lorazepam to treat her agitation. One day after this therapy was initiated, her agitation and nausea resolved. At approximately the same time, the results of her blood cultures became available and revealed no growth. The patient was finally well enough to be dismissed from the hospital.

5. If the patient had not responded to conservative management, which one of the following medications would have been the most appropriate alternative?

   1. Cyproheptadine

   2. Bromocriptine

   3. Dantrolene

   4. Propranolol

   5. Octreotide

   Cyproheptadine is primarily a histamine receptor antagonist with anti-5-HT_1A receptor and anticholinergic activities. Although generally used to treat allergic conditions, cyproheptadine, with its antiserotonergic properties, is also a recommended therapy for the serotonin syndrome in patients whose symptoms do not improve with supportive care and benzodiazepine administration. However, its true efficacy in treating the serotonin syndrome has not been fully established.⁸

   Bromocriptine is a dopamine receptor agonist that has been used to treat NMS; however, it has no role in the treatment of the serotonin syndrome and in fact may increase serotonin levels and potentiate the effect of SSRIs during the serotonin syndrome.⁵ Dantrolene is a skeletal muscle relaxant used to treat disorders that cause muscle rigidity and hyperthermia, such as malignant hyperthermia, NMS, and rarely the serotonin syndrome. The current patient did not have muscle rigidity or hyperthermia and would likely derive little benefit from dantrolene therapy. Propranolol is a nonselective β-blocker generally used to treat tachycardic conditions. Its use in the serotonin syndrome is not recommended because it can worsen hypotension and lead to shock in patients who already have autonomic instability.⁵ Octreotide, an inhibitor of growth hormone, insulin, and glucagon, is used to treat a number of conditions, including carcinoid syndrome, but has no role in the treatment of the serotonin syndrome.

   Fortunately, this patient's symptoms resolved with conservative measures, including discontinuation of SSRI therapy, initiation of IV fluids, and treatment with low-dose benzodiazepines, obviating the need for cyproheptadine therapy.

DISCUSSION

The serotonin syndrome is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system.⁹ It can be caused by medications that directly or indirectly increase serotonin levels. For example, medications can increase the release of serotonin (amphetamines and cocaine), impair the reuptake of serotonin (SSRIs, serotonin/norepinephrine uptake inhibitors, and tricyclic antidepressants), inhibit serotonin metabolism (monoamine oxidase inhibitors), or act as a serotonin agonist (buspirone and ergot alkaloid). Thus, when the serotonin syndrome is suspected, a detailed reconciliation of prescribed and nonprescribed medications (including changes in dosing and schedule) must be performed. In addition, patients with suspected serotonin syndrome should be questioned about their use of dietary supplements, and clinicians should have a low threshold for screening for illicit drugs.

Diagnosis of the serotonin syndrome is based on clinical findings.¹⁰ Obtaining a detailed history and performing a thorough physical examination of a patient showing signs of this condition are crucial. The serotonin syndrome can present with mental status changes (eg, anxiety, restlessness, agitation, and disorientation), autonomic hyperactivity (eg, tachycardia, hypertension, hyperthermia, diaphoresis, and diarrhea), and/or neuromuscular abnormalities (eg, hyperreflexia, myoclonus, ocular clonus, spontaneous or inducible clonus, tremor, bilateral Babinski sign, and in severe cases, muscle rigidity).^1,9 Several diagnostic scales can be used to define the serotonin syndrome, but one of the most commonly used is the Hunter Serotonin Toxicity Criteria Decision Rule, which is 84% sensitive and 97% specific.¹⁰ To fulfill the criteria of the Hunter scale, the patient should be taking a serotonergic agent and have at least 1 of the following: (1) spontaneous clonus, (2) inducible clonus plus agitation or diaphoresis, (3) ocular clonus plus agitation or diaphoresis, (4) tremor and hyperreflexia, (5) hypertonia, and (6) temperature greater than 38°C plus ocular clonus or inducible clonus. In this case, the patient fulfilled the Hunter Serotonin Toxicity Criteria by taking citalopram, a serotonergic agent, and exhibiting tremor and hyperreflexia.

It is postulated that the serotonin syndrome is mediated by activation of 5-HT_1A receptors. Involvement of other serotonin receptors, including 5-HT_2A receptors, has also been implicated.¹¹ The serotonin syndrome is commonly associated with ingestion of 2 serotonergic agents; however, a single agent can also cause this condition either at the time of initiation or after an increase in dose. It was initially unclear why the patient in this case, who was taking a stable dose of citalopram, developed the serotonin syndrome. It could not be explained simply by her acute renal failure because citalopram is 90% cleared in the liver. However, before developing the serotonin syndrome, the patient had been taking risperidone, an atypical antipsychotic agent, concomitantly with her SSRI. Previous reports have shown that the addition of an atypical antipsychotic agent to the medication regimen of a patient already taking an SSRI can precipitate the serotonin syndrome. Risperidone, specifically, is thought to indirectly activate the 5-HT_1A receptor by blocking 5-HT_2A receptors.¹²

Early recognition of the serotonin syndrome is critical because a delay in the diagnosis of this condition can result in substantial morbidity and possibly death. The first step in managing patients with the serotonin syndrome is the discontinuation of serotonergic agents. In mild cases, conservative management, consisting of IV fluid administration and treatment with low-dose benzodiazepines, is recommended.¹ In cases of moderate severity, cardiac monitoring and correction of any thermal abnormalities are required.^1,11 The use of cyproheptadine is usually indicated in these patients. In severe cases (temperature >41°C), admission to the intensive care unit, with immediate sedation, neuromuscular paralysis, and intubation may be necessary. Generally, symptoms of the serotonin syndrome resolve within 24 to 48 hours after discontinuation of the offending agent. If symptoms persist beyond 72 hours, alternative diagnoses should be sought.⁵

Correct answers: 1. c, 2. d, 3. e, 4. c, 5. a