Seizure Exacerbation with Anti-Seizure Medications in Adult Patients with Epilepsy

Abstract

There are numerous reports of seizure exacerbation related to specific anti-seizure medications (ASMs); however, a quantitative analysis with clearly defined parameters for seizure exacerbation in an outpatient setting is lacking. This retrospective study examines adult patients starting a single ASM and follows patient outcomes over the course of treatment, with quantitative evaluation of the incidence of paradoxical seizure exacerbation. In this study, outpatient encounters with five epileptologists at the Baylor College of Medicine Comprehensive Epilepsy Center were evaluated over a 10-month period. Seizure exacerbation was defined as an increase in seizure frequency at least 2 times greater than the baseline seizure frequency after initiation of an ASM, with return to baseline after ASM discontinuation. Patients were stratified into four categories: (1) probable ASM-induced seizure exacerbation; (2) possible ASM-induced seizure exacerbation; (3) non-ASM induced seizure exacerbation; or (4) no seizure exacerbation. Out of a total of 236 encounters where an ASM was initiated, we found that 5.5% of patients experienced some form of seizure exacerbation. However, only 1.3% of patients had probable ASM-induced seizure exacerbation. Consistent with prior studies, our data indicate seizure exacerbation in adults is rare with the initiation of ASMs. However, further studies with a larger sample size are necessary to better understand what factors may predispose patients to potential medication-induced seizure exacerbation.

1. Introduction

It has been widely documented that certain anti-seizure medications (ASMs) may exacerbate seizures in some patients with epilepsy (Chaves and Sander, 2005; Genton, 2000; Sazgar and Bourgeois, 2005; Snead and Hosey, 1985; Somerville, 2002). The mechanism for paradoxical seizure exacerbation, however, is not clearly understood. Possibilities include a disproportionate blocking of inhibitory neurons leading to enhanced excitation or disruption of the spatial and temporal interactions between excitatory and inhibitory neurons (Vergens et al., 1984). With over 20 FDA-approved ASMs, studies investigating the pathophysiology of paradoxical seizure exacerbation have found ASMs with a broad spectrum of action less likely to exacerbate seizures (Chaves and Sander, 2005) while those with a narrow mechanism of action, such as enhanced GABAergic transmission (Liu et al., 2006; Vergens et al., 1984) or blockade of voltage-gated sodium channels (Gao et al., 2017; Liao et al., 2010), are more likely to exacerbate seizures, especially in genetic generalized epilepsies. Several anecdotal accounts detail exacerbation of generalized epilepsy, while studies show exacerbation of focal epilepsy is less common (Somerville, 2009). However, it remains unclear how best to define seizure exacerbation, what ASMs are most likely involved, and what types of epilepsy may be most susceptible.

There are difficulties designing a quantifiable placebo-controlled study examining seizure exacerbation, namely due to ethical concerns regarding a study designed to intentionally exacerbate seizures in patients with epilepsy. Therefore, many documented descriptions of paradoxical seizure exacerbation have been anecdotal accounts presented without a quantifiable baseline of seizure frequency or a clear definition of what constitutes seizure exacerbation (Somerville, 2002). Here we examine a diverse population of adult patients taking a wide range of ASMs and follow seizure frequency over the course of treatment, presenting a unique opportunity to evaluate the incidence of seizure exacerbation with a quantifiable return to baseline after drug withdrawal.

2. Materials and Methods

This retrospective study was approved by the Baylor College of Medicine Institutional Review Board (H-32620). We reviewed all patients who visited five epileptologists as an outpatient in the Baylor College of Medicine Comprehensive Epilepsy Center (Houston, Texas; United States) between August 1, 2018 and May 31, 2019. Only patients presenting to the clinic during this time period were considered; however, their full history was evaluated, including any encounters before or after this time window. The epileptologists were faculty at Baylor College of Medicine, board certified by the American Board of Psychiatry and Neurology in both Neurology and Epilepsy. Exclusion criteria included: failure to begin a trial of a single ASM at an encounter, ASM cross-titration during a new ASM trial, or non-compliance with medication instructions. Inclusion criteria included patients with a documented encounter in which the clinician made a single change to the medication regimen by beginning a trial of an ASM followed by at least one subsequent follow-up encounter. Patients were then stratified into four categories: (1) probable ASM-induced seizure exacerbation: patients with an increase in seizure frequency by at least two times the baseline after ASM initiation, meeting additional criteria adapted from previously published guidelines (Somerville, 2009), including occurrence soon after introduction of the drug, persistence through the treatment periods, resolution when the drug is stopped, and no alternate etiology (Table 1); (2) possible ASM-induced seizure exacerbation: patients with an increase in seizure frequency by at least two times the baseline after ASM initiation meeting some but not all remaining applicable criteria; (3) non-ASM induced seizure exacerbation: patients with seizure exacerbation due to an alternate etiology such as a known trigger, stress, or poor documentation; and (4) patients without seizure exacerbation.

Table 1.

Somerville criteria for seizure exacerbation (Somerville, 2009).

Occurrence soon after introduction of the drug

Persistence through the treatment period

Resolution when the drug is stopped

Recurrence with rechallenge*

Repeated observation by many clinicians*

Syndrome-specificity*

Appearance of a new seizure type not expected from the natural history of the epilepsy syndrome

Occurrence within minutes of intravenous injection and time-course consistent with the pharmacokinetics of the drug*

No alternative explanation

^*not applicable to this study

Basic demographic and clinical factors were recorded for all patients, including age at encounter, gender, and handedness. Patients meeting all exclusion and inclusion criteria were then categorized based on the extent of the description of their reported seizure exacerbation. Variables analyzed include age at onset of seizures, EEG and MRI findings, family history of epilepsy, epilepsy classification, seizure frequency before and after starting the ASM, current ASM regimen, patient compliance, patient side effects, neurosurgical intervention (such as resective surgery, responsive neurostimulation [RNS] and vagus nerve stimulation [VNS]), whether or not exacerbation resolved with withdrawal of the drug, and other active diagnoses.

3. Results

Out of 1,212 encounters (1,173 patients) seen by 5 epileptologists between August 1, 2018 and May 31, 2019, 236 encounters (222 patients) met the inclusion criterion of having added a single ASM to their medication regimen at a clinical encounter (Figure 1). Gender, handedness, and family history of seizures showed no association with likelihood of having seizure exacerbation (Table 2). 13 patients (5.5%) met the inclusion criterion of having added a single ASM to their medication regimen at a clinical encounter with documented seizure exacerbation. After excluding alternate etiologies such as stress and illness, 3 patients (1.3%; Tables 3 and 4) taking 2 ASMs (Table 4) described seizure exacerbation that met all inclusion and exclusion criteria. 5 patients (2.1%; Table 5) in the context of taking 4 different ASMs described seizure exacerbation meeting some but not all remaining applicable criteria. The remaining 5 patients experienced seizure exacerbation attributable to alternate etiologies (2.1%; Table 6) in the context of taking 4 different ASMs (Table 6). Two of the cases of ASM-attributable seizure exacerbation were in patients with generalized-onset seizures, and one patient had focal-onset seizures (Table 3). The remaining 223 encounters (94.5%) did not experience seizure exacerbation with ASM initiation. Of note, two patient encounters described worsening seizure intensity; however, because they did not meet the twice greater than baseline seizure frequency threshold, they were excluded from the study. One of these encounters occurred with lacosamide in a 20-year-old right-handed female with focal epilepsy. The other occurred with perampanel in a 59-year-old right-handed female with generalized epilepsy.

Figure 1.

Flowchart of inclusion and exclusion criteria.

Table 2.

Baseline characteristics

		Category 1: Probable ASM-Induced Seizure Exacerbation		Category 2: Possible ASM-Induced Seizure Exacerbation		Category 3: Non-ASM Induced Seizure Exacerbation		Category 4: No Seizure Exacerbation With ASM Initiation		Total n	p-value
		N	%	n	%	n	%	n	%
Gender	M	3	100	2	40	3	60	114	51.1	122	0.355
	F	0	0	3	60	2	40	109	48.8	114
Handedness	Right	3	100	5	100	5	100	163	73.1	176	0.860
	Left	0	0	0	0	0	0	29	13	29
	Ambidextrous	0	0	0	0	0	0	3	1.4	3
	Unclassified	0	0	0	0	0	0	28	12.6	28
Epilepsy Type	Focal	1	33.3	3	60	3	60	114	51.1	121	0.493
	Generalized	2	66.7	2	40	2	40	60	26.9	66
	Unknown	0	0	0	0	0	0	49	22.0	49

(M = male, F = female)

Table 3.

Characteristics of patients with Probable ASM-Induced Seizure Exacerbation

	Case No.	Age	Sex	Handedness	MRI	EEG	Epilepsy Type	Seizure Types	Seizure Exacerbation Type	Associated Medication	Magnitude of Increase in Seizure Frequency	Other Medications
Probable ASM-Induced Seizure Exacerbation	1	20	M	Right	Normal	Generalized spike-wave discharges	Generalized	Generalized Tonic-Clonic, Absence	Generalized Tonic-Clonic	Ethosuximide	2x	None
	2	60	M	Right	Unavailable (CT head – normal)	Generalized spike-wave discharges	Generalized	Generalized Tonic-Clonic, Myoclonic	Generalized Tonic-Clonic	Lamotrigine	4x	Primidone, Gabapentin, Zonisamide, Albuterol, Atorvastatin, Aspirin, Clopidogrel, Empagliflozin, Insulin Lispro, Isosorbide Mononitrate, Levothyroxine, Losartan, Metoprolol
	3	34	M	Right	Right MTS, s/p L ATL	R temporal sharp waves	Focal	Focal to Bilateral Tonic-Clonic	Focal Impaired Awareness	Lamotrigine	2x	Levetiracetam, Zonisamide
Possible ASM-Induced Seizure Exacerbation	4	41	M	Right	Left frontal cortical dysplasia	Left frontal sharp waves	Focal	Focal to Bilateral Tonic-Clonic,	Focal Impaired Awareness	Cannabidiol	6x	Carbamazepine, Clobazam, Topirimate, Cyanocobalamin, Lactulose, Loratadine, Sennosides-docusate, Cholecalciferol
	5	60	M	Right	Normal	Normal	Focal	Focal to Bilateral Tonic-Clonic	New Daily Sensory Auras	Lamotrigine	New Aura	Clonazepam, Lisinopril
	6	40	F	Right	Right MTS	Right temporal spikes	Focal	Focal to Bilateral Tonic-Clonic	Psychic Aura	Lamotrigine	3.6x	Lacosamide, Progesterone Micronized, Norethindrone, Magnesium Gluconate
	7	38	F	Right	Unavailable (metal in body)	Right temporal spikes	Focal	Focal to Bilateral Tonic-Clonic	Focal Impaired Awareness	Levetiracetam	12x	Oxcarbazepine, Topiramate, Carvedilol
	8	40	F	Right	Normal	Generalized spike-wave discharges	Generalized	Generalized Tonic-Clonic, Atypical Absence	Atypical Absence	Zonisamide	3x	Rufinamide, Citalopram, Ergocalciferol
Non-ASM Induced Seizure Exacerbation	9	24	F	Right	Hypoxic-ischemic changes	Mild diffuse slowing	Focal	Focal to Bilateral Tonic-Clonic,	Focal Impaired Awareness	Cannabidiol	4x	Clonazepam, Lacosamide, Levetiracetam, Oxcarbazepine, Baclofen
	10	20	F	Right	Bilateral diffuse cortical T2 hyperintensities	Right temporal spikes	Generalized	Generalized Tonic-Clonic, Absence	Generalized Tonic-Clonic	Cannabidiol	2x	Rufinamide, Zonisamide, Clonazepam,
	11	23	M	Right	Generalized volume loss, periventricular leukomalacia	Generalized spike-wave discharges	Generalized	Generalized Tonic, Atonic, Absence	Generalized Tonic	Clobazam	2x	Lamotrigine, Tacrolimus
	12	21	M	Right	Right posterior cingulate resection	Right central focal slowing	Focal	Focal to Bilateral Tonic-Clonic	Focal to Bilateral Tonic-Clonic	Lacosamide	8x	Clonazepam, Perampanel, Cetirizine
	13	26	M	Right	Possible left MTS	Generalized spike-wave discharges	Generalized	Generalized Tonic-Clonic, Absence	Generalized Tonic-Clonic	Perampanel	3x	Oxcarbazepine, Lamotrigine, Ergocalciferol, Cetirizine

(M = male, F = female); MTS = mesial temporal sclerosis; ATL = anterior temporal lobectomy

Table 4.

Characteristics of drugs associated with Probable ASM-Induced Seizure Exacerbation

ASM	# of Patients Affected	# of Patients Initiated on ASM	% of Patients Affected	Sex		Handedness		Epilepsy Type
				M	F	R	L	Focal	Generalized
Ethosuximide	1	1	0.4	1	0	1	0	0	1
Lamotrigine	2	48	0.8	2	0	2	0	1	1
Total	3		1.3	3	0	3	0	1	2

(M = male, F = female, R = right, L = left)

Table 5.

Characteristics of drugs associated with Possible ASM-Induced Seizure Exacerbation

ASM	# of Patients Affected	# of Patients Initiated on ASM	% of Patients Affected	Exacerbation Degree	Sex		Handedness		Epilepsy Type		Unmet Somerville Criteria
					M	F	R	L	Focal	Generalized
Cannabidiol	1	15	0.4	x6	1	0	1	0	1	0	Poor documentation due to lack of history and continued seizures despite stopping medication
Lamotrigine	2	48	0.8	x3.6, new aura	1	1	2	0	2	0	Poor documentation, continued increase in auras despite stopping medication
Levetiracetam	1	45	0.4	x12	0	1	1	0	1	0	Possible alternate etiology
Zonisamide	1	20	0.4	x3	0	1	1	0	0	1	Poor documentation
Total	5		2.1		2	3	5	0	4	1

(M = male, F = female, R = right, L = left

Table 6.

Characteristics of drugs associated with Non-ASM Induced Seizure Exacerbation

ASM	# of Patients Affected	# of Patients Initiated on ASM	% of Patients Affected	Exacerbation Degree	Sex		Handedness		Epilepsy Type		Etiology of Exacerbation
					M	F	R	L	Focal	Generalized
Cannabidiol	2	15	0.8	2x, 4x	0	2	2	0	1	1	VNS adjustment/Diarrhea/Nausea
Clobazam	1	14	0.4	2x	1	0	1	0	0	1	Insomnia
Lacosamide	1	10	0.4	8x	1	0	1	0	1	0	Medication toxicity (associated dizziness)
Perampanel	1	3	0.4	3x	1	0	1	0	0	1	VNS out of service
Total	5		2.1		3	2	5	0	2	3

(M = male, F = female, R = right, L = left)

4. Discussion

Pharmacotherapy is the standard of care as the first option to control seizures in patients with epilepsy (Fang et al., 2011). Despite the current availability of 23 ASMs (Billakota et al., 2020; Löscher and Schmidt, 2011), anti-seizure medications (ASMs) may rarely exacerbate seizures in some patients with epilepsy (Chaves and Sander, 2005; Sazgar and Bourgeois, 2005). The phenomenon of seizure exacerbation has been described in several case series and anecdotal reports; however, few studies have systematically reviewed cases of exacerbation in an outpatient setting to establish a quantifiable baseline, monitor for return to baseline, and evaluate the relevant clinical characteristics.

In this study, the ability to view changes in drug response over time offered a unique perspective into the likelihood of a particular case of seizure exacerbation truly being attributable to an ASM. This study met most criteria previously described to ensure probable medication-induced seizure exacerbation (Somerville, 2009) with the exception of: recurrence with rechallenge (due to ethical concerns), repeat observation by many clinicians (not standard of care in the outpatient setting), syndrome-specificity (not applicable), and time course from IV injection (not applicable due to the focus on an outpatient setting, Table 1). Seizure exacerbation was considered to be an increased seizure frequency greater than twice a patient’s baseline seizure frequency (or the appearance of a new seizure type), improvement in exacerbation with removal of the ASM, no other changes in the patient’s treatment regimen (including medications or adjustments to neuromodulatory devices), and no other documented life stressors, known triggers, or illnesses that may have led to the exacerbation.

Our results indicate that seizure exacerbation is rare with initiation of ASMs in the setting of an adult outpatient clinic, occurring at a rate of 1.3% and consistent with prior studies (Chaves and Sander, 2005; Genton, 2000; Sazgar and Bourgeois, 2005; Snead and Hosey, 1985; Somerville, 2009, 2002). Only 3 out of 222 patients experienced probable ASM-induced seizure exacerbation. The two ASMs associated with exacerbation were lamotrigine and ethosuximide. Lamotrigine was associated with seizure aggravation in one patient with generalized epilepsy and one with focal epilepsy. A recent study evaluating risk factors for paradoxical reactions to ASMs in adults with genetic generalized epilepsy found lamotrigine to be the most common ASM associated with seizure exacerbation, especially with a diagnosis of Juvenile Myoclonic Epilepsy (JME) (Gesche et al., 2021). However, further study in a larger population is necessary to evaluate to what degree lamotrigine may be a risk factor for seizure exacerbation in focal epilepsy. Ethosuximide aggravated seizures in one patient with generalized epilepsy, which has also been previously described (Chaves and Sander, 2005).

Since non-ASM induced seizure exacerbation and possible ASM-induced seizure exacerbation were found nearly as frequently as probable ASM-induced seizure exacerbation (2.1% vs 2.1% and 1.3%, respectively), it is important to obtain a thorough history when seizure frequency increases significantly in the outpatient setting. This data highlights the importance of using strict criteria to attribute seizure exacerbation to an ASM. The alternative causes of seizure exacerbation included sleep deprivation, illness, alcohol and/or other recreational drugs, drug-drug interactions with either over-the-counter medications or other prescribed medications, hormonal changes, or alternative changes to the seizure treatment regimen (such as reduction or discontinuation of another ASM or changes to seizure modifying devices such as VNS or RNS devices). ASM toxicity has also been previously reported to paradoxically exacerbate seizures (Bartolini and Sander, 2019; Guerrini et al., 1998), which was the presumptive alternate explanation for one of our patients (Table 6). Additional recommendations in the setting of seizure exacerbation include: (1) Attempt to document a reliable frequency of seizures over time; (2) Distinguish between ASM-induced seizure exacerbation and natural fluctuation of seizure frequency; and (3) return to a previous treatment regimen in the setting of severe seizure exacerbations (Somerville, 2009).

There were several limitations to this study. The first limitation is sample size, including patients from a single institution. With 3 cases of probable ASM-induced seizure exacerbation, 5 cases of possible ASM-induced seizure exacerbation, and 5 cases of non-ASM induced seizure exacerbation, there remains limited power to determine clinical characteristics that might identify significant risk factors for drug-induced seizure exacerbation. In some cases, seizure exacerbation was not quantifiable with a pre- and post-treatment seizure frequency, excluding these patients from subsequent analysis. Additionally, in many cases, cross-titrations of more than one medication limited the ability to attribute changes in seizure frequency to the addition of a single ASM. We also could not exclude the possibility that reported events were non-epileptic in nature, since these accounts were not performed in the setting of video-EEG monitoring. Finally, there may have been alternate etiologies for seizure exacerbation that were either not documented or not elicited from the patient, which could have led to false attribution of seizure exacerbation to an ASM.

Further study should evaluate the incidence of seizure exacerbation in the setting of a multicenter prospective trial with a standardized checklist for establishing probable medication-induced seizure exacerbation. In addition, a global registry for the collection of data from a variety of sources could increase study power to an even greater degree, as seen, for example, with the North American Antiepileptic Drug Pregnancy Registry (“North American Antiepileptic Drug Pregnancy Registry,” 2020).

5. Conclusions

Consistent with prior studies, our data indicate seizure exacerbation is rare with initiation of anti-seizure medications. Here, we uniquely describe rare exacerbation with initiation of a single ASM in an outpatient clinic setting. However, further study with a larger sample size is necessary to better understand what factors may predispose patients to potential ASM-induced seizure exacerbation.

Highlights:

• Seizure exacerbation is rare with initiation of anti-seizure medications (ASMs).

• Only two ASMs were associated with probable paradoxical seizure exacerbation: lamotrigine and ethosuximide.

• Probable seizure exacerbation was found in two patients with generalized epilepsy and one patient with focal epilepsy.