Epilepsy & Behavior 111 (2020) 107284 Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh Misdiagnosis of lamotrigine toxicity as posterior circulation transient ischemic attack or stroke☆ Patsy Ramey, Melissa Osborn, Howard Kirshner, Bassel Abou-Khalil ⁎ Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, United States of America a r t i c l e i n f o Article history: Received 25 February 2020 Revised 12 June 2020 Accepted 22 June 2020 Available online xxxx Keywords: Lamotrigine Toxicity Vertebrobasilar insufficiency Stroke Stroke workup a b s t r a c t Purpose: Lamotrigine (LTG) is one of the most used antiseizure medications (ASMs). Titration is indicated for incomplete seizure control, but toxicity with vertigo, ataxia, and diplopia may ensue. Lamotrigine concentration would be the optimal diagnostic test. However, patients often receive a stroke evaluation when presenting to the emergency department (ED), leading to unnecessary cost and delayed management. We investigated the frequency of stroke evaluation for symptoms associated with LTG toxicity and attempted to identify factors leading to this expensive evaluation. Methods: We identified adult patients treated with LTG who presented to an emergency room with dizziness, ataxia, or diplopia and received a negative stroke evaluation, between 2003 and 2018. They were among 972 patients treated with LTG for epilepsy. We collected age at time of occurrence, symptoms presented, imaging studies performed, LTG dose and serum concentration, and the time the result was available. As a denominator, we also identified patients who developed clinical LTG toxicity during the same time period. Results: Thirteen patients with LTG toxicity had 16 negative stroke evaluations in the emergency room. Their mean age was 62 years (range: 43–79) as compared with 47 years for all patients treated with LTG (p b 0.0005). The mean daily LTG dose was 621 mg (range: 300–900 mg). A LTG serum concentration was requested on the day of evaluation in 7 instances, though the result was never available until at least the next day. In 4 instances, the LTG level was drawn 1–3 days after presentation. Five of the patients in this group were among 71 patients with clinical LTG toxicity and LTG concentration N 20. Conclusion: Emergency departments will frequently call a stroke alert for patients taking LTG and presenting with symptoms consistent with LTG toxicity, particularly in seniors at greater risk of stroke. This adds not only expense but also radiation and contrast exposure from computed tomography (CT) studies. We recommend that a rapid LTG assay be made available and always ordered in patients receiving LTG, avoiding the considerable expense of an unnecessary stroke evaluation. © 2020 Elsevier Inc. All rights reserved. 1. Introduction Lamotrigine (LTG) is one of the most frequently used antiseizure medications (ASMs), with a broad spectrum of efficacy, a favorable safety profile, and a generally good tolerability. Clinical trials demonstrated LTG efficacy at doses of 300–500 mg per day [1–4]. However, some patients require higher doses to achieve optimal seizure control, potentially exposing them to toxic adverse effects [5,6]. The most common adverse effects in adjunctive therapy trials were dizziness, ataxia, and nausea [7]. In a practice-based study comparing effectiveness of ASMs, the most common reason for LTG intolerability was unsteadiness [8]. ☆ This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ⁎ Corresponding author at: A-0118 MCN, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, United States of America. E-mail address: bassel.abou-khalil@vumc.org (B. Abou-Khalil). https://doi.org/10.1016/j.yebeh.2020.107284 1525-5050/© 2020 Elsevier Inc. All rights reserved. In patients using the immediate-release LTG formulation, dizziness and ataxia corresponding to peak levels can be paroxysmal, causing emergency room visits. Patients presenting to the emergency room with acute ataxia and diplopia are suspected of having posterior circulation ischemic symptoms, particularly if they are in the age group most at risk for stroke. Patients are often subjected to an extensive stroke evaluation, without considering the possibility of LTG peak toxicity. Lamotrigine serum concentration may not be ordered, or may be ordered as an afterthought, following a negative stroke workup. Even if ordered in a timely manner, the LTG concentration is often not available until days later. We reviewed our database of patients with epilepsy to identify a group of patients who received a stroke evaluation for symptoms associated with peak LTG toxicity. We analyzed characteristics of patients in this group, symptoms of toxicity, and sequence of events that led to stroke evaluation. We also strived to identify factors that led to this expensive evaluation, and to suggest standard of practice improvements for patients at risk of LTG peak toxicity. 2 P. Ramey et al. / Epilepsy & Behavior 111 (2020) 107284 2. Methods The study investigated patients treated for epilepsy at the Vanderbilt University Medical Center, a large referral center with a large geographical catchment area, including Tennessee, Southern Kentucky, Northern Alabama, Northern Mississippi, and Northern Georgia. We searched the patient database of the senior author to identify adult patients treated with LTG who underwent a negative stroke evaluation after presenting to the emergency room with symptoms of LTG toxicity that could also be seen with posterior circulation ischemia, namely dizziness/vertigo, unsteadiness, and diplopia. Emergency room evaluations were either at Vanderbilt University Medical Center or at various local hospitals. The database included electronic medical records starting in 2003 up to 2018. We excluded patients who had known history of vertebrobasilar insufficiency, posterior circulation stroke, or vestibular disease. We recorded demographic parameters including age at time of occurrence and symptoms at emergency room presentation. We also recorded dose and dosing schedule of LTG, concomitant medications, last serum concentration prior to emergency room presentation, serum concentration at emergency room presentation, if that was ordered, and the days it took before results were available. We reviewed the stroke evaluation, including imaging studies performed such as head computed tomography (CT), brain magnetic resonance imaging (MRI), brain and cervical MR angiography (MRA), head and neck CT arteriography (CTA), or CT perfusion (CTP). We reviewed factors that may have precipitated the LTG toxicity and factors that may have influenced the patients to present to the emergency room rather than call the neurologist. This information facilitated our development of practice recommendations to help avoid unnecessary stroke evaluations in these patients. To determine how commonly LTG toxicity precipitates a stroke workup, we also identified all patients who had clinical LTG toxicity in association with a LTG serum concentration N20mcg/ml, above which patients are likely to experience toxicity [5]. 2.1. Statistical analysis We used the Wilcoxon rank sum test to compare the patient group age with the age of all patients treated with LTG. 2.2. Standard protocol approvals, registrations, and patient consents The study was approved by the Vanderbilt Human Research Protections Program (IRB # 131947). 3. Results 3.1. Patients Out of 972 patients on LTG, 13 patients met the inclusion/exclusion criteria (Table 1). The patients included 8 women and 5 men. At the time of the events, the patients' ages ranged from 43 to 79 with a mean of 62, whereas the average age of all patients receiving LTG was 47 (p b 0.0005, Wilcoxon rank sum test). 3.2. Treatment All patients were taking LTG for chronic focal epilepsy. The mean total daily LTG dose was 621 mg (range: 300–900 mg). At the time of the event, nine patients were taking the extended-release preparation (3 used three daily doses and 6 used two daily doses), and five were taking the immediate-release preparation (2 patients used three daily and 3 patients used two daily doses). Five were on LTG monotherapy, five were on one other ASM, and three were on two other ASMs. Concomitant ASMs were levetiracetam in five patients, pregabalin in two, clonazepam in two, zonisamide in one, and gabapentin in one patient. 3.3. Stroke evaluations in the emergency department (ED) for lamotrigine toxicity Eleven patients had a single negative stroke evaluation. One patient had two separate negative stroke evaluations two years apart. A second patient had three evaluations, 3 years apart then 10 months apart. Each evaluation was considered a separate instance. 3.4. Symptoms and cause of lamotrigine toxicity at ED visit The most common symptoms prompting emergency department (ED) evaluation were ataxia (12 instances), dizziness/vertigo (9 instances), confusion/altered mental status (6 instances), slurred speech (5 instances), weakness (4 instances), diplopia (3 instances), and nausea/vomiting (2 instances). The symptoms came on acutely in 9 instances. In the remaining instances, symptoms of toxicity increased over more than one day before presentation. The cause of toxicity was not clear in the majority of instances. In five instances, there was an increase in the dose of LTG in the preceding weeks prior to presentation. In one instance, the patient may have accidentally taken an extra dose. In the remaining ten instances, there was no change in dose to account for the toxicity. 3.5. Stroke evaluation The stroke evaluations included 14 head CT, 11 brain MRI, 6 MRA, 6 CTA, and 4 CTP scans (Table 1) as well as echocardiograms and carotid ultrasounds in some patients. A LTG serum concentration was requested on the day of evaluation in 5 patients (7 instances), but the result was not available until at least the next day (delay range: 1–12 days, mean: 3.9 days). The serum concentration ranged from 17 to 28 mcg/ml, always higher than it had been prior to the instance of toxicity. In 8 patients (9 instances of toxicity), the level was not performed on the day of presentation; in 3 of these (4 instances of toxicity), the LTG level was drawn one to three days after presentation, and in 5 patients (5 instances of toxicity), a LTG level was not drawn. 3.6. Estimating the incidence of stroke evaluations for lamotrigine toxicity We identified 129 patients (67 women and 62 men) who had a serum LTG concentration measurement of ≥20 mg/L (range: 20–40.3; mean: 24.54 mg/L). Their mean age was 44.4 years. Among these patients, 71 (55%) had clinical manifestations of toxicity, including five patients (7%) in the current series who had stroke evaluations. Thus, we estimate that 7% of patients with LTG toxicity received a negative stroke evaluation in the ED. The clinical manifestations of toxicity in the larger group of 71 patients included (in order of frequency) gait disturbance/disequilibrium, dizziness, tremor, diminished energy, sleepiness, memory loss, blurred/double vision, nausea/vomiting, difficulty concentrating, headache, irritable mood, depression, and insomnia. 4. Case reports 4.1. Patient #4 This patient with temporal lobe epilepsy and migraine developed seizures at age 28 following a head injury with loss of consciousness. Seizures were drug-resistant, so that she underwent presurgical evaluation then a right temporal lobectomy at age 41. She was seizure-free for 3 years postoperatively then had seizure recurrence in the setting of stress. She was treated with divalproex and gabapentin until age 49 years; because of side effects, she was switched to LTG, titrated to 300 mg per day. At age 55, she developed episodes of confusion. Her LTG level was 8.1. Because of the possibility that the confusional episodes were seizures, her dose of extended-release LTG was increased to 400 mg per day. One month later, her LTG concentration was 16 mcg/ml, and she was free of P. Ramey et al. / Epilepsy & Behavior 111 (2020) 107284 3 Table 1 Instances of stroke evaluations for symptoms related to LTG toxicity. Patient # Age/gender Symptoms prompting evaluation for stroke/TIA Imaging performed LTG daily dose (mg) LTG serum concentration (mcg/ml) Lag time between event and LTG serum concentration results 1 2 3 4 5 67/F 64/M 58/M 55/F 64/F 67/F 68/F 64/M 66/M 66/F 57/M 55/F 52/F 66/F 43/F 79/M Ataxia (falls), dizziness Confusion, N/V, vertigo, somnolence Ataxia, dizziness Ataxia, dizziness, altered mental status Ataxia, diplopia, weakness Ataxia Ataxia, dizziness Ataxia, slurred speech, confusion Ataxia, dizziness Confusion, N/V, dysphagia, vertigo Ataxia, diplopia, slurred speech Slurred speech, lower extremity weakness Slurred speech, altered mental status Ataxia (falls), vertigo, confusion Ataxia, slurred speech, weakness Ataxia, vertigo, diplopia MRI, MRA CT, CTA, CTP MRI CT, MRI, MRA, CTA CT, MRI CT, MRI, MRA CT, MRI, MRA CT, CTA, CTP CT, CTA CT, CTA, CTP CT, MRI, MRA CT, MRI, CTA, CTP CT, MRI, MRA CT, MRI CT CT, MRI 600 600 750 400 600 600 600 800 800 600 900 600 350 300 700 425 Not done 20.3 18.7 21.2 24.6 18 22.4 19.8 24.9 Not done Not done 28.0 Not done 23.4 17.2 Not done N/A 5 days 2 days 2 days 3 days 3 days 8 days 4 days 5 days N/A N/A 2 days N/A 3 days 12 days N/A 6 7 8 9 10 11 12 13 M = male; F = female; TIA = transient ischemic attack; LTG = lamotrigine; MRA = magnetic resonance angiography; CTA = computed tomography angiography; CTP = computed tomography perfusion; N/V = nausea and vomiting; N/A = not applicable. confusion events. Two days later, she was transferred to our facility for altered mental status and ataxia. Computed tomography ordered at the outside facility demonstrated only the expected postsurgical encephalomalacia. At the time of admission to our ED, a LTG level was requested. Brain MRI, MRA, and CTA, and neck MRA were obtained the next day. The radiological studies were all determined to be normal. The LTG level drawn on the day of admission was not available until two days later; it was 21.2 mcg/ml. Her LTG dose was reduced to 350 mg per day, with a LTG concentration of 14.1 three weeks later. 4.2. Patient #5 This is a 64-year-old woman with familial mesial temporal lobe epilepsy. Her seizures started at age 27 with isolated auras of a funny feeling, like a numbness that goes up the body from the toes to the head. She did not seek medical attention until she had her first bilateral tonic–clonic seizure in sleep at age 29. Following that, her most common seizure type became focal impaired awareness seizures in waking, starting with a 30-second aura. She was treated with phenobarbital, then phenytoin, but continued to have an average of two focal impaired awareness seizures and one isolated aura per month, as well as two to three focal to bilateral tonic–clonic seizures per year. A video-electroencephalography (EEG) study indicated a right inferomesial temporal seizure onset. She was switched to carbamazepine, with markedly improved seizure frequency. Because of occasional breakthrough seizures and the finding of osteopenia on a bone density measurement, she was switched from carbamazepine to LTG at age 60. Her LTG dose was progressively increased to 300 mg twice a day because of occasional breakthrough seizures, resulting in a LTG concentration of 7.5 mcg/ml. She became seizure-free after the addition of extended-release levetiracetam 500 mg at bedtime at age 64. However, she experienced rare episodes of unsteadiness, one of which was severe with diplopia and inability to walk. She was taken to a local emergency room and was admitted. She had a head CT and brain MRI that showed no evidence of acute stroke, only nonspecific white matter punctate high signal areas. Electroencephalography was normal. A LTG level was drawn. The initial diagnosis was a posterior circulation transient ischemic attack (TIA). After the LTG level was found to be 24.6 three days later, the diagnosis was changed to LTG toxicity. A follow-up LTG level obtained two days after discharge on the same dose was 13.1 mcg/ml. She had another episode of unsteadiness at age 67, in which she needed assistance to walk. Again, she went to the local emergency room, was admitted and received a stroke workup. Head CT was normal, and brain MRI with contrast was negative for stroke, showing only atrophy and chronic white matter microvascular disease. Brain MRA and brachiocephalic MRA were negative. The episode lasted 2 h; she was diagnosed with a TIA. She was switched from aspirin to clopidogrel. A LTG level was obtained; the level returned three days later, after she was already discharged, at 18 mcg/ml. When seen in clinic 5 months later, she was asymptomatic at the same dose. Her LTG level was 15.3 mcg/ml. At age 68, another episode of unsteadiness caused her to be readmitted to her local emergency room for another stroke workup. Head CT and brain MRI again showed no definite abnormalities, other than nonspecific white matter disease. Carotid ultrasound was also negative. She also had an echocardiogram with a bubble study that was negative. Lamotrigine level was again obtained. The result returned 8 days later and was 22.4 mcg/ml. When she was seen in clinic two weeks later, her dose of LTG was reduced to 250 mg twice daily. 5. Discussion We present a series of patients who underwent expensive stroke evaluations, including exposure to radiation and contrast, for what was eventually diagnosed as LTG toxicity after LTG levels were reported, usually days later. The symptoms came on acutely in 9 instances, which raised concern for cerebrovascular origin, specifically posterior circulation ischemia. Inappropriate stroke evaluation was common, estimated to occur in about 7% of patients with LTG toxicity. The patients' decision to go to an emergency room is likely related to acuteness and debilitating severity of the symptoms, causing concern for the possibility of stroke. The timing of events may have also played a role if they occurred after clinic hours or on weekends. Emergency room physicians' decision to call a stroke alert may have been related to the known increased risk of stroke with age. Our patient group had a mean age of 62 at the time of the event, as compared with a mean age of 47 for the whole group of patients with epilepsy treated with LTG. Posterior circulation ischemia is understandably on the differential diagnosis in patients presenting with acute vertigo, ataxia, and diplopia, particularly when symptoms are abrupt in onset [9]. However, it is important to consider LTG toxicity in patients receiving this medication. Lamotrigine toxicity commonly manifests with dizziness/vertigo, ataxia, and diplopia, which can imitate posterior circulation ischemia. Seniors are more likely to experience LTG toxicity [10]; in particular, imbalance is more common in this population. Lamotrigine clearance decreases with increasing age in seniors [11]. It is also likely that seniors are more susceptible to experience rapid onset of peak LTG adverse effects. One pharmacokinetic study in the elderly reported median time 4 P. Ramey et al. / Epilepsy & Behavior 111 (2020) 107284 to maximal LTG concentration at 1.25 h [12]. Two prior studies in younger patients with epilepsy found time to maximal concentration of 1.97 h (range: 0.31 to 4.45 h) in patients aged 17–62 (mean: 36 years) [13] and 1.71 h (range: 0.75 to 4.02 h) in patients aged 18–55 (mean: 32.5 years) [14]. A rapid rise in LTG serum concentration may account for the acuteness of toxicity symptoms seen in some patients in the current study. The therapeutic LTG concentration is usually considered to be between 2 and 20 mcg/ml. Most patients will experience LTG toxicity with concentrations exceeding 20 mcg/ml, but some individuals experience symptoms of toxicity with concentrations over 15 mcg/ml [5]. Unexplained spikes in LTG concentration have been reported, suggesting nonlinear kinetics in some individuals [15]. This could further contribute to the rapid rise in LTG concentration in select patients. Lamotrigine concentration needs to be monitored more closely in seniors, to identify trends that may lead to toxicity and to make adjustments proactively. It is important that the clinician considers potential stroke mimics when evaluating acute ataxia and ponder the cost implications of an unnecessary stroke evaluation [16,17]. While the cost of imaging studies may vary significantly from facility to facility and region to region, it is always considerable [18–21]. Head CT cost (USD) ranged from $300 to $6750, brain MRI cost ranged from $504 to over $5000, head CTA cost varied from $500 to $6200 or greater, and brain MRA ranged from $500 to $10,800. These figures generally do not include radiologist professional fees or the cost of sedation. Costs can continue to escalate as more tests and consults are added, while the cost of a LTG serum concentration is generally less than $100. Radiation and contrast exposure are additional factors to be considered with CT brain imaging, CT angiography, and CT perfusion. Overtesting in EDs has also been reported in other conditions, stimulating the development of protocols to increase the proportion of true positive tests [22]. A LTG serum concentration should be essential in the evaluation of patients taking LTG and presenting with ataxia, dizziness, and diplopia. The availability of a serum concentration in a timely fashion could obviate additional expensive testing. Rapid assays for LTG serum concentration have been validated [23–27] and should become widely available and utilized in the acute care setting. 6. Conclusion A stroke workup is common when patients taking LTG, particularly seniors, present to the emergency room with symptoms consistent with LTG toxicity. This adds unnecessary expenses as well as radiation and contrast exposure from CT studies. 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