Medical Forum

A Veteran Presenting With Altered Mental Status and Clonus

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Case Presentation: A 69-year-old male veteran with a medical history of chronic obstructive pulmonary disease (COPD), coronary artery disease, heart failure with reduced ejection fraction, and significant tobacco use presented to the VA Boston Healthcare System (VABHS) emergency department with shortness of breath. Additional history included bipolar disorder, for which he took olanzapine and duloxetine, and a history of opioid use disorder, for which he took buprenorphine/naloxone. On initial evaluation, his blood pressure was 168/81 mm Hg with an oxygen saturation of 100% on 5 L of supplemental oxygen.

A physical examination was notable for a confused gentleman in no acute distress. He had endexpiratory wheezing, and his skin was noted to be diaphoretic. He was found to have 3 beats of inducible clonus at his ankles bilaterally, and 3+ reflexes at his biceps and patellae bilaterally. Laboratory tests were notable for a leukocytosis to 12.5 K/uL and an elevated bicarbonate of 40 mEq/L (Table). A chest X-ray showed hyperinflated lungs without any masses, consolidation, or fluid. Shortly after arriving on the medicine floor, he became progressively more confused with visual hallucinations. Further history elicited from the patient’s wife revealed that the patient had developed twitching of his extremities for several days prior to this admission, resulting in the patient spilling and dropping things.



►Zachary Reese, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC) :Dr. Weller, the differential diagnosis for altered mental status is quite broad. How does the presence of clonus change or focus your approach to altered mental status?

►Jason Weller, MD, Instructor of Neurology, Boston Medical Center (BMC) and VABHS :The presence of clonus does not significantly narrow the differential. It does, however, suggest a central component to the patient’s altered mental status. Specifically, it implies that the underlying process, whether systemic or neurologic, interferes with central nervous system (CNS) control of the neuromuscular system. 1 The differential is still quite broad and includes metabolic derangements (eg, uremia, electrolyte disturbances, hypercarbia, and thyroid dysfunction), medication toxicity from olanzapine or duloxetine, and vascular processes (eg, CNS vasculitis). Infectious etiologies, both within the CNS and systemically, can cause encephalopathy, as can autoimmune processes, such as immune-mediated encephalitis. Finally, primary neurologic conditions such as myoclonic epilepsy can be considered. Given the patient’s medical history, serotonin syndrome must be considered.

Dr. Reese: Given the concern for serotonin syndrome, the admitting medical team discontinued the patient’s duloxetine. Dr. Weller, what is the pathophysiology of serotonin syndrome, and how is it diagnosed?

Dr. Weller: Serotonin is ubiquitous throughout the body and brain. Serotonin syndrome is caused by excess endogenous or exogenous serotonin, and this is usually caused by a variety of medications. The symptoms range from tachycardia, agitation, and diaphoresis to sustained clonus, hyperthermia, and shock. 2,3 The extent of serotonin syndrome is typically thought to reflect the degree of serotonergic activity. 4

Serotonin syndrome is a clinical diagnosis. While there are no tests that can confirm the diagnosis, the Hunter criteria can be used to assist with making the diagnosis. 5 Per the Hunter criteria, a patient can be diagnosed with serotonin syndrome if they have taken a serotonergic agent and have at least 1 of the following: spontaneous clonus, inducible or ocular clonus with agitation or diaphoresis, tremor and hyperreflexia, or hypertonia with fever and clonus. This patient had taken duloxetine and had inducible clonus and diaphoresis, thus suggesting a diagnosis of serotonin syndrome.

Dr. Reese: Aside from selective serotonin reuptake inhibitors (SSRIs), are there other medications that we typically prescribe that can cause serotonin syndrome?

Dr. Weller: In addition to SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), other commonly prescribed medications that can cause serotonin syndrome are 5-HT3 antagonists (eg, ondansetron), 5-HT agonists (eg, triptans), and opioids (eg, fentanyl and tramadol). There are also case reports of atypical antipsychotics (eg, olanzapine) causing serotonin syndrome because of their antagonism of the 5-HT2 and 5-HT3 receptors. 2 Additionally, linezolid is commonly overlooked as a cause of serotonin syndrome given its action as a monoamine oxidase inhibitor. 4 In this patient, it would be prudent to discontinue olanzapine and duloxetine.

Dr. Reese : Duloxetine, olanzapine, and buprenorphine/naloxone were discontinuedgiven concern for serotonin syndrome. Although there are not strong data that buprenorphine/ naloxone can cause serotonin syndrome, the team discontinued the medication in case it might be contributing to the patient’s encephalopathy, while closely monitoring the patient for withdrawal. There was a rapid improvement in the patient’s symptoms over the 24 hours after discontinuation of the 3 medications.


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