Akstinas, J. OMS-IV, Miguel, E. DO
Mesa View Regional Hospital, NV
Rocky Vista University

Abstract

Case Presentation: A 38-year-old woman with a past medical history of depression, vertigo, and a seizure disorder presented to the Emergency Department (ED) with complaints of dizziness for four days. Associated symptoms included nausea, blurry vision, and one episode of difficulty speaking. The patient was alert and oriented x 3 and her vital signs were within normal limits. Horizontal nystagmus was noted on physical exam along with truncal ataxia and unsteady gait.

Results: The patient’s laboratory values revealed a critical elevation in phenytoin levels. Mild leukopenia, megaloblastic anemia, mildly elevated prothrombin time, and hypocalcemia were also noted. Computed tomography of the head without contrast, computed tomography angiography of the head and neck, EKG, and chest X-ray were unremarkable.

Conclusion: The patient was diagnosed with suspected phenytoin toxicity vs. cerebrovascular accident and transferred to a tertiary facility for admission. Brain MRI did not demonstrate evidence of a stroke and the patient was treated with supportive care for elevated phenytoin levels. She was discharged two days after presenting to the ED.

Case Presentation:

A 38-year-old woman with a past medical history of vertigo, depression, and a seizure disorder presented to the ED with complaints of dizziness for four days. She denied ever experiencing anything like this before. She arrived via wheelchair and was transferred to the gurney in the department. The patient described being “unsteady on her feet” and “feeling like the room is spinning”. She described one episode of “difficulty speaking” that lasted “a few minutes” earlier that morning. Associated symptoms included nausea and blurry vision which began at the onset of her dizziness. The patient described the onset as gradual and constant. The patient denied any pain upon presentation. There were no alleviating factors and the dizziness was described as becoming worse upon standing. The patient denied any recent travel or known toxic exposures. The patient denied any fever or chills, syncope, chest pain, shortness of breath, headache or loss of vision.

The patient’s past medical history included vertigo, depression, and a seizure disorder. Her surgical history included a hysterectomy and tonsillectomy. Medications prescribed to her included ativan 2 mg PO PRN, gabapentin 600 mg PO Q 4hrs, escitalopram 20 mg PO QD, trazodone 150 mg PO QHS, and phenytoin 100 mg PO seven times daily. These prescriptions were confirmed by the dispensing pharmacist. The patient had no known drug allergies. She denied any tobacco or illicit drug use and stated that she drank roughly five alcoholic beverages per day, three to four times per week. The patient denied any suicidal ideation or depressed mood.

Vital signs included: blood pressure 124/82 mmHg, pulse 103 bpm, pulse oximetry 98% on room air, temperature 98.2 degrees Fahrenheit and respirations 18 breaths per minute. The patient’s body mass index was 24.69. On the initial physical exam, the patient appeared acutely anxious. She was alert and oriented to person, place, time, and situation. Cardiac and respiratory exams revealed no abnormalities. The neurological exam was positive for pronounced horizontal nystagmus and monocular diplopia of the left eye. Truncal ataxia along with unsteady gait were also observed. The patient had normal finger to nose testing and normal heel to shin testing. Strength and sensation were normal in all four extremities.

The patient was given 4 mg of IV ondansetron to treat her nausea. Initial hematologic laboratories were obtained and were unremarkable. An electrocardiogram revealed normal sinus rhythm with no acute ischemic changes. Chest x-ray, computed tomography of the head without contrast, and computed tomography angiography of the head and neck were all within normal limits.

A neurology consult via telemedicine was obtained. The neurology team recommended obtaining serum phenytoin levels, which were critically elevated at 49.6 mcg/ml, and obtaining an MRI of the brain to investigate for cerebrovascular accident. The patient was then transferred to a tertiary facility under the care of the hospitalist service on the telemetry unit for further workup, neurology consultation and MRI evaluation. The patient was evaluated for cerebrovascular accident via MRI and she received supportive care only during her admission. The patient later stated that she may have accidentally overdosed on her phenytoin, and that she was also experiencing recent memory issues. Poison control was consulted and advised supportive measures after the patient declined activated charcoal. Her phenytoin levels trended down from 49.6 mcg/ml upon admission to 27.9 mcg/ml on her discharge date. The patient was encouraged to follow up with her primary care provider and resume her phenytoin once cleared by her primary care provider.

Discussion

Dizziness is one of the most common complaints seen in the ED¹ and accounts for roughly 4.3 million ED visits per year in the United States.² Moreover, an estimated 15-20% of adults are affected by dizziness in the U.S. every year.³ It is often challenging for the clinician to differentiate life-threatening from benign etiologies of dizziness. Approximately 40% of dizzy patients have peripheral vestibular dysfunction; 10% have a central brainstem vestibular lesion; 15% have underlying psychiatric disorder; and 25% have other problems, such as presyncope and disequilibrium.⁴ Furthermore, there is little available diagnostically to definitively diagnose the myriad benign causes of dizziness in the acute setting. Diagnosis is often initiated by separating peripheral nervous system causes from central nervous system causes of dizziness/vertigo.

Common peripheral causes of dizziness include benign paroxysmal positional vertigo (BPPV), vestibular neuronitis (includes vestibular neuronitis and labyrinthitis), and Meniere’s disease.⁵ Common central causes of dizziness include vestibular migraine, stroke, and vertebrobasilar transient ischemic attack.⁵ The clinician must rely mostly on the history, physical exam, and imaging for proper risk stratification in the acute setting. This case focuses on acute intoxication of phenytoin and a more detailed review of acute dizziness/vertigo can be found elsewhere.

Our patient presented with dizziness in the presence of a history of vertigo and seizure disorder. The onset of the patient’s symptoms was acute, severe, and progressively worsening. At a glance, this presentation paired with the patient’s previous history of vertigo was initially interpreted as a benign recurrence. However, the patient’s subjective description of her symptoms were reported as being “different” from her previous episodes with a slower onset that became progressively worse over several days. In addition, the truncal ataxia was a new symptom that the patient had not experienced in the past. This particular finding in an acute setting is often suspicious for a central lesion.

Her physical exam was positive for horizontal nystagmus, which is often considered physiologic when the beats are bilateral, symmetrical, and only lasting a few beats during lateral gaze.⁴ In contrast, an asymmetrical, more pronounced and prolonged nystagmus may be pathological.⁴ Moreover, our patient lacked any signs of torsional or vertical nystagmus which may be present in central lesions that cause vertigo.^6,7 When assessing visual fields at the bedside, the patient was asked to identify how many fingers the physician was holding up. She identified four fingers when in fact there were two fingers shown. This finding was only present in the left eye. Monocular diplopia is generally not a feature of peripheral vertigo, and is more concerning for central etiologies. When the patient was ambulated in the ED, the patient had a wide-based, staggering gait and declined to continue walking after only a couple of steps due to dizziness.

Given that our patient’s history and physical exam were suspicious for a central lesion, CT imaging of the head along with CT angiography of the head and neck were ordered. These results, along with EKG and blood work, were unremarkable, prompting a bedside neurology consult. Neurology stated that the patient’s phenytoin dose of 700 mg QD was on the high end of what he had encountered in clinical practice. Of note, this prescription was confirmed with the dispensing pharmacist. The typical maintenance dose range of phenytoin for seizure disorder prophylaxis is 300-400mg daily divided into two to three doses. Moreover, dosing is usually adjusted according to clinical response and serum phenytoin levels.

The patient’s phenytoin levels were at a critically high level of nearly 50 mcg/ml. At these levels, most patients can expect neurologic manifestations including ataxia, dizziness, nystagmus, nausea, and vomiting. All of these symptoms were observed in our patient. Furthermore, the episode of dysarthria and diplopia, which are suspicious for a central lesion⁸, can also be explained by phenytoin toxicity. Diplopia is often more concerning for a central lesion as it typically not seen in peripheral lesions.⁸ However, it can be a feature of phenytoin toxicity when serum levels reach over 30-40 mg/L.⁹

Phenytoin was discovered over 100 years ago and is one of the most well-studied anticonvulsants used in clinical practice. It is listed on the World Health Organization’s List of Essential Medicines, and is a rather affordable option for patients with seizure disorder. It is classified as a voltage gated sodium channel blocker, and may be used as an antiarrhythmic agent. Phenytoin is metabolized by hepatic P450 enzymes; it is an inhibitor of CYP2C9 and CYP2C19 and an inducer of CYP3A4.⁷ It is excreted mostly unchanged in the urine and is over 90% bound to albumin in the blood.⁷ Although unbound phenytoin levels often correlate well with symptoms, the total phenytoin is generally ordered in the acute setting. Table 1 below provides a rough correlation to total levels:

• Less than 10 mg/L: Rare side effects
• 10 to 20 mg/L: Occasional mild horizontal nystagmus on lateral gaze
• 20 to 30 mg/L: Nystagmus
• 30 to 40 mg/L: Ataxia, slurred speech, tremor, nausea, and vomiting
• 40 to 50 mg/L: Lethargy, confusion, hyperactivity
• Greater than 50 mg/L: Coma and seizures
  *Table 1. Stat Pearls NCBI⁷

Polypharmacy is a possible factor that may have influenced our patient’s serum phenytoin levels. Trazodone and gabapentin, both of which were prescribed to our patient, may increase the serum levels of phenytoin. In addition, the patient’s alcohol (ethanol) consumption of 20+ drinks per week is far beyond the US dietary guidelines’ recommendation of one per day for females. Ethanol consumption has also been known to potentially increase or decrease serum phenytoin levels.

Eventually, after transfer to tertiary care, the patient believed she may have overdosed on her phenytoin. Given the patient’s polypharmacy burden and her reported phenytoin dosing of seven times per day, it is reasonable to suspect she may have made an error in her medication schedule leading to overdose. During admission her phenytoin was discontinued and she received supportive care only. Although poison control was consulted and recommended activated charcoal to bind any unabsorbed phenytoin in the GI tract, the patient declined. Supportive care is the standard treatment for elevated phenytoin levels as toxicity is rarely fatal.⁷ However, in severe cases, hemodialysis may be performed. With discontinuation and supportive care only, our patient’s phenytoin levels declined by nearly 50% after a two-day admission. She was then instructed to follow up with her primary care physician for follow up.

This case illustrates a patient presenting with the very common complaint of dizziness, that resulted in an extensive workup, consultation and ultimately the diagnosis of phenytoin toxicity.

Learning Points

• Patients experiencing dizziness with a history of vertigo should always be considered for specific toxidromes.
• A thorough medication review may be helpful in the setting of acute vertigo for the effects of polypharmacy.
• Phenytoin toxicity may present similarly to both central and peripheral lesions causing vertigo.
• Helpful clues to phenytoin toxicity may include diplopia, truncal ataxia, and dysarthria.
• Obtain phenytoin levels in the ED on patients prescribed phenytoin with neurological issues.
• Treatment of phenytoin toxicity is usually supportive care only.

References:

• Cappello M, di Blasi U, di Piazza L, et al. Dizziness and vertigo in a department of emergency medicine. Eur J Emerg Med. 1995;2:201–11.
• Saber Tehrani AS, Coughlan D, Hsieh YH, et al. Rising annual costs of dizziness presentations to U.S. emergency departments. Acad Emerg Med. 2013;20(7):689-696. doi:10.1111/acem.12168
• Neuhauser HK. The epidemiology of dizziness and vertigo. Handb Clin Neurol. 2016;137:67-82. doi:10.1016/B978-0-444-63437-5.00005-4
• Uptodate Branch W, Barton J. Approach to the patient with Dizziness. TW Waltham, Inc. https://www-uptodate-com.proxy.rvu.edu/contents/approach-to-the-patient-withdizziness?search=dizziness%20adult&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1 (Accessed September 25, 2020)
• DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. 1995 – . Record No. T922474, Dizziness in Adults – Approach to the Patient; [updated 2018 Nov 30, cited August 31 2020]
• Walls RM, Hockberger RS, Gausche-Hill M, Chang AK. Dizziness and Vertigo. In: Rosen’s Emergency Medicine: Concepts and Clinical Practice. Philadelphia, PA: Elsevier; 2018.
• Iorga A, Horowitz BZ. Phenytoin Toxicity. [Updated 2020 Aug 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482444/
• Eggers SDZ, Kattah JC. Approaching acute vertigo with diplopia: A rare skew deviation in vestibular neuritis. Mayo Clin Proc Innov Qual Outcomes. 2020;4(2):216-222.
• Avcil M, Duman A, Turkdogan KA, et al. Phenytoin intoxication with no symptoms correlated with serum drug level: a case study. Pan Afr Med J. 2015;22:297. Published 2015 Nov 24. doi:10.11604/pamj.2015.22.297.7956