Recent onset of confusion, limited mobility, and disturbed sleep-wake cycle

A 66-year-old woman has a 6-day history of confusion, reduced food intake, and limited mobility. Although the patient has no recent history of fever, rigors, cough, shortness of breath, chest pain, urinary frequency, or burning micturition, she does report a disturbed sleep-wake cycle. A week before, the patient was discharged from a local hospital where she was treated for community-acquired pneumonia with moxifloxacin 400 mg daily, and for paranoia with haloperidol 2 mg twice a day and mirtazapine 15 mg daily. Her family reports escalating confusion and tremor of her hands over the past week.

Q How would you focus your initial assessment?

Additional medical history

• The patient’s medical history is significant for deep venous thrombosis, coronary artery disease, hypertension, chronic obstructive pulmonary disease (COPD), atrial fibrillation, major depressive disorder, and agoraphobia.
• In addition to the haloperidol and mirtazapine she was recently prescribed, the patient is taking paroxetine 20 mg daily, furosemide 40 mg twice daily, domperidone 10 mg 4 times daily, amlodipine 10 mg daily, atorvastatin 20 mg daily, warfarin 2 mg daily, trazodone 50 mg daily, oxycodone 5 mg twice daily, meloxicam 15 mg daily, tramadol 37.5 mg 3 times a day, and imipramine 25 mg daily.

Physical examination

• The patient is oriented to person, but not to time or place.
• Oral temperature is 37.3°C.
• Pulse rate is 97 beats/min.
• Respiratory rate is 28 breaths/min.
• Blood pressure is 118/83 mm Hg.
• Cardiovascular and abdominal systems are unremarkable.
• Neurological examination demonstrates increased tone and tremor (resting and postural) in arms and legs, as well as brisk reflexes in the upper limbs but not in the lower limbs.

Laboratory results

• Blood and serum levels are normal for hemoglobin, platelets, sodium, potassium, and phosphorus.
• Several blood or serum values are abnormal:

Radiographic findings

• A chest x-ray shows extensive ill-defined interstitial markings in the right upper lobe, suggestive of pneumonia.
• Computed tomography shows hypodense areas of the subcortical white matter of the cerebral hemispheres in the brain, indicative of age-related ischemic demyelination.

Q What is your presumptive diagnosis?

Remove the precipitating agent

The first step in treating serotonin syndrome is to withdraw the offending agent—often a medication that was recently added or whose dosage was recently increased. After this step, symptoms usually resolve within 24 hours. But they may persist for days if the drug involved has a long half-life. Administering a 5HT_2A antagonist, such as cyproheptadine, may be useful when more aggressive treatment is required. Cyproheptadine, a histamine 1 receptor antagonist, is given orally (or crushed and administered through a nasogastric tube) at an initial dose of 12 mg, and subsequently at 4 to 8 mg every 6 hours.⁷ Alternatively, another 5HT_2A antagonist, chlorpromazine, can be given 50 to 100 mg intravenously.⁸

Ensure that the patient receives supportive care. Administration of intravenous (IV) fluids and correction of electrolyte and metabolic abnormalities are the mainstays of supportive treatment.

Benzodiazepine may need to be administered if the patient exhibits uncontrolled agitation. Hyperthermia (usually due to muscle hyperactivity) typically resolves itself and does not require antibiotics or antipyretics. However, severe cases of serotonin syndrome with uncontrolled hyperthermia may require sedating the patient, inducing neuromuscular paralysis, and initiating orotracheal intubation and ventilation.

Take precautions. Bromocriptine and dantrolene, which are used to treat neuroleptic malignant syndrome, are contraindicated in serotonin syndrome and may worsen serotonergic signs.⁹ Extreme caution is therefore warranted with patients who may be taking both serotonergic and antipsychotic medications, or in cases when the diagnosis is in doubt.

The patient’s outcome

After our initial assessment, we discontinued all antidepressant and antipsychotic medications, administered IV fluids, and monitored the patient’s electrolytes. Treatment with lorazepam and cyproheptadine led to improvement. Her confusion and tremors subsided, and her CK values normalized within 48 hours. After a psychiatric consultation, we began slow-release venlafaxine at a dose of 37.5 mg/d. At discharge, we arranged a follow-up appointment for the patient in the community.

CORRESPONDENCE
Habib U. Rehman, MB, Department of Medicine, Regina Qu’Appelle Health Region, Regina General Hospital, 1440 14th Avenue, Regina, SK, S4P 0W5, Canada; [email protected]

A 66-year-old woman has a 6-day history of confusion, reduced food intake, and limited mobility. Although the patient has no recent history of fever, rigors, cough, shortness of breath, chest pain, urinary frequency, or burning micturition, she does report a disturbed sleep-wake cycle. A week before, the patient was discharged from a local hospital where she was treated for community-acquired pneumonia with moxifloxacin 400 mg daily, and for paranoia with haloperidol 2 mg twice a day and mirtazapine 15 mg daily. Her family reports escalating confusion and tremor of her hands over the past week.

Q How would you focus your initial assessment?

Additional medical history

• The patient’s medical history is significant for deep venous thrombosis, coronary artery disease, hypertension, chronic obstructive pulmonary disease (COPD), atrial fibrillation, major depressive disorder, and agoraphobia.
• In addition to the haloperidol and mirtazapine she was recently prescribed, the patient is taking paroxetine 20 mg daily, furosemide 40 mg twice daily, domperidone 10 mg 4 times daily, amlodipine 10 mg daily, atorvastatin 20 mg daily, warfarin 2 mg daily, trazodone 50 mg daily, oxycodone 5 mg twice daily, meloxicam 15 mg daily, tramadol 37.5 mg 3 times a day, and imipramine 25 mg daily.

Physical examination

• The patient is oriented to person, but not to time or place.
• Oral temperature is 37.3°C.
• Pulse rate is 97 beats/min.
• Respiratory rate is 28 breaths/min.
• Blood pressure is 118/83 mm Hg.
• Cardiovascular and abdominal systems are unremarkable.
• Neurological examination demonstrates increased tone and tremor (resting and postural) in arms and legs, as well as brisk reflexes in the upper limbs but not in the lower limbs.

Laboratory results

• Blood and serum levels are normal for hemoglobin, platelets, sodium, potassium, and phosphorus.
• Several blood or serum values are abnormal:

Radiographic findings

• A chest x-ray shows extensive ill-defined interstitial markings in the right upper lobe, suggestive of pneumonia.
• Computed tomography shows hypodense areas of the subcortical white matter of the cerebral hemispheres in the brain, indicative of age-related ischemic demyelination.

Q What is your presumptive diagnosis?

Remove the precipitating agent

The first step in treating serotonin syndrome is to withdraw the offending agent—often a medication that was recently added or whose dosage was recently increased. After this step, symptoms usually resolve within 24 hours. But they may persist for days if the drug involved has a long half-life. Administering a 5HT_2A antagonist, such as cyproheptadine, may be useful when more aggressive treatment is required. Cyproheptadine, a histamine 1 receptor antagonist, is given orally (or crushed and administered through a nasogastric tube) at an initial dose of 12 mg, and subsequently at 4 to 8 mg every 6 hours.⁷ Alternatively, another 5HT_2A antagonist, chlorpromazine, can be given 50 to 100 mg intravenously.⁸

Ensure that the patient receives supportive care. Administration of intravenous (IV) fluids and correction of electrolyte and metabolic abnormalities are the mainstays of supportive treatment.

Benzodiazepine may need to be administered if the patient exhibits uncontrolled agitation. Hyperthermia (usually due to muscle hyperactivity) typically resolves itself and does not require antibiotics or antipyretics. However, severe cases of serotonin syndrome with uncontrolled hyperthermia may require sedating the patient, inducing neuromuscular paralysis, and initiating orotracheal intubation and ventilation.

Take precautions. Bromocriptine and dantrolene, which are used to treat neuroleptic malignant syndrome, are contraindicated in serotonin syndrome and may worsen serotonergic signs.⁹ Extreme caution is therefore warranted with patients who may be taking both serotonergic and antipsychotic medications, or in cases when the diagnosis is in doubt.

The patient’s outcome

After our initial assessment, we discontinued all antidepressant and antipsychotic medications, administered IV fluids, and monitored the patient’s electrolytes. Treatment with lorazepam and cyproheptadine led to improvement. Her confusion and tremors subsided, and her CK values normalized within 48 hours. After a psychiatric consultation, we began slow-release venlafaxine at a dose of 37.5 mg/d. At discharge, we arranged a follow-up appointment for the patient in the community.

CORRESPONDENCE
Habib U. Rehman, MB, Department of Medicine, Regina Qu’Appelle Health Region, Regina General Hospital, 1440 14th Avenue, Regina, SK, S4P 0W5, Canada; [email protected]

A 66-year-old woman has a 6-day history of confusion, reduced food intake, and limited mobility. Although the patient has no recent history of fever, rigors, cough, shortness of breath, chest pain, urinary frequency, or burning micturition, she does report a disturbed sleep-wake cycle. A week before, the patient was discharged from a local hospital where she was treated for community-acquired pneumonia with moxifloxacin 400 mg daily, and for paranoia with haloperidol 2 mg twice a day and mirtazapine 15 mg daily. Her family reports escalating confusion and tremor of her hands over the past week.

Q How would you focus your initial assessment?

Additional medical history

• The patient’s medical history is significant for deep venous thrombosis, coronary artery disease, hypertension, chronic obstructive pulmonary disease (COPD), atrial fibrillation, major depressive disorder, and agoraphobia.
• In addition to the haloperidol and mirtazapine she was recently prescribed, the patient is taking paroxetine 20 mg daily, furosemide 40 mg twice daily, domperidone 10 mg 4 times daily, amlodipine 10 mg daily, atorvastatin 20 mg daily, warfarin 2 mg daily, trazodone 50 mg daily, oxycodone 5 mg twice daily, meloxicam 15 mg daily, tramadol 37.5 mg 3 times a day, and imipramine 25 mg daily.

Physical examination

• The patient is oriented to person, but not to time or place.
• Oral temperature is 37.3°C.
• Pulse rate is 97 beats/min.
• Respiratory rate is 28 breaths/min.
• Blood pressure is 118/83 mm Hg.
• Cardiovascular and abdominal systems are unremarkable.
• Neurological examination demonstrates increased tone and tremor (resting and postural) in arms and legs, as well as brisk reflexes in the upper limbs but not in the lower limbs.

Laboratory results

• Blood and serum levels are normal for hemoglobin, platelets, sodium, potassium, and phosphorus.
• Several blood or serum values are abnormal:

Radiographic findings

• A chest x-ray shows extensive ill-defined interstitial markings in the right upper lobe, suggestive of pneumonia.
• Computed tomography shows hypodense areas of the subcortical white matter of the cerebral hemispheres in the brain, indicative of age-related ischemic demyelination.

Q What is your presumptive diagnosis?

Remove the precipitating agent

The first step in treating serotonin syndrome is to withdraw the offending agent—often a medication that was recently added or whose dosage was recently increased. After this step, symptoms usually resolve within 24 hours. But they may persist for days if the drug involved has a long half-life. Administering a 5HT_2A antagonist, such as cyproheptadine, may be useful when more aggressive treatment is required. Cyproheptadine, a histamine 1 receptor antagonist, is given orally (or crushed and administered through a nasogastric tube) at an initial dose of 12 mg, and subsequently at 4 to 8 mg every 6 hours.⁷ Alternatively, another 5HT_2A antagonist, chlorpromazine, can be given 50 to 100 mg intravenously.⁸

Ensure that the patient receives supportive care. Administration of intravenous (IV) fluids and correction of electrolyte and metabolic abnormalities are the mainstays of supportive treatment.

Benzodiazepine may need to be administered if the patient exhibits uncontrolled agitation. Hyperthermia (usually due to muscle hyperactivity) typically resolves itself and does not require antibiotics or antipyretics. However, severe cases of serotonin syndrome with uncontrolled hyperthermia may require sedating the patient, inducing neuromuscular paralysis, and initiating orotracheal intubation and ventilation.

Take precautions. Bromocriptine and dantrolene, which are used to treat neuroleptic malignant syndrome, are contraindicated in serotonin syndrome and may worsen serotonergic signs.⁹ Extreme caution is therefore warranted with patients who may be taking both serotonergic and antipsychotic medications, or in cases when the diagnosis is in doubt.

The patient’s outcome

After our initial assessment, we discontinued all antidepressant and antipsychotic medications, administered IV fluids, and monitored the patient’s electrolytes. Treatment with lorazepam and cyproheptadine led to improvement. Her confusion and tremors subsided, and her CK values normalized within 48 hours. After a psychiatric consultation, we began slow-release venlafaxine at a dose of 37.5 mg/d. At discharge, we arranged a follow-up appointment for the patient in the community.

CORRESPONDENCE
Habib U. Rehman, MB, Department of Medicine, Regina Qu’Appelle Health Region, Regina General Hospital, 1440 14th Avenue, Regina, SK, S4P 0W5, Canada; [email protected]