Patterns of levetiracetam and lacosamide use for treatment of status epilepticus with respect to clinical features and prior antiseizure medications

Abstract

Background

The aim of this study was to evaluate the clinical usage of second-line intravenous antiseizure medications (IV ASMs), particularly levetiracetam (LEV) and lacosamide (LCM), in patients with status epilepticus (SE) in relation to their clinical characteristics and the use of pre-existing ASM. In addition, we examined the ASM responses in relation to one another, an aspect that has rarely been investigated previously.

Methods

This retrospective observational study was conducted at Tampere University Hospital. Data on SE patients aged ≥ 16 years who received IV ASM for the treatment of SE were retrieved from electronic patient register over a one-year period. Patient demographics, epilepsy history, pre-existing ASM therapy, and administered IV ASMs were recorded and SE episodes were classified by SE subtype. Second-line IV ASMs included LEV, LCM, valproate (VPA), and fosphenytoin (FPHT).

Results

A total of 78 SE episodes were identified in 72 patients (median age 68 years, 39% female). Among these, 40 were convulsive SE (CSE), 21 nonconvulsive SE (NCSE), 9 comatose NCSE, and 8 focal aware SE (FASE) episodes. The most used IV ASMs were LCM (47 episodes) and LEV (45 episodes), whereas VPA (7 episodes) and FPHT (2 episodes) were used infrequently. Patients under 68 years had higher response rates than older patients (68% vs. 43%, p = 0.046). Those treated with LEV were significantly older than those treated with LCM (median age 73 vs. 63 years, p = 0.002). Additionally, a prior epilepsy diagnosis was more frequent among patients receiving LCM as the first second-line IV ASM (63% vs. 28%, p = 0.005). Treatment was initiated with pre-existing ASM in 39% of cases. Notably, LCM as first second-line IV ASM demonstrated trend towards higher response rates than LEV (67% vs. 44%, p = 0.057). Following multivariable adjustment for age, sex, SE subtype, etiology, and time from seizure onset to ASM administration, LCM was associated with higher response odds compared to LEV (OR 3.29, 95% CI 1.06–10.19, p = 0.039), with no covariates demonstrating significant independent effects.

Conclusions

The selection of ASM varied according to patients’ clinical characteristics. Patients treated with LCM tended to be younger and were more likely to have a prior diagnosis of epilepsy than those treated with LEV. LCM was associated with higher response rates than LEV, supporting its use as a viable alternative for the treatment of SE.

Introduction

Status epilepticus (SE) is a life-threatening emergency that requires prompt treatment to prevent irreversible neuronal injury, morbidity, and mortality [1]. Clinical guidelines recommend the administration of benzodiazepines (BZDs) as first-line medication for SE. However, if SE control is not achieved with the initial first-line medication, second-line intravenous (IV) antiseizure medications (ASMs) are recommended [2–4].

The 2016 Finnish guidelines for second-line ASM treatment options for SE in adults include fosphenytoin (FPHT), valproic acid (VPA), levetiracetam (LEV), and lacosamide (LCM), whereas the American Epilepsy Society (AES) recommendation does not include LCM in the treatment of convulsive SE (CSE), and the European recommendation only states that LCM has been used to treat SE without providing clear guidance on its use [2–4].

Previous studies indicate that treatment practices vary both across and within countries [5, 6]. Furthermore, LCM appears to be used less frequently than LEV [6, 7]. Clinical characteristics and prior ASM use may influence treatment choice, as concerns persist regarding the potential cardiac adverse effects of LCM [8, 9]. However, evidence on how clinical factors affect treatment choice in this setting remains limited.

Prior studies have demonstrated that LEV is as effective as traditional treatments such as FPHT and VPA. However, most of these studies have primarily focused on patients with CSE rather than other forms of SE [10–14]. LCM has demonstrated efficacy not only in CSE but also across diverse SE presentations [8, 9, 15]. Nevertheless, direct comparative studies assessing the relative efficacy of LEV and LCM remain limited.

This was a population-based, retrospective, single-centre study covering a defined geographical area which included all patients admitted due to SE and treated with second-line IV ASMs. The primary objective was to determine whether clinical characteristics or pre-existing ASM influenced the selection of the primary second-line IV ASM in SE patients. The secondary objective was to determine the response rate to second-line IV ASM treatment in SE. Finally, we examined treatment patterns and outcomes associated with different ASMs, with a specific focus on LCM and LEV, which were the most commonly used ASMs at our institution [6].

Methods

Data collection and patient selection

We collected data from the electronic patient registry of Tampere University Hospital over a one-year period from January 1 to December 31, 2015. We investigated patients from the register identified via searches using the following terms: “seizure”, “epilepsy”, and “SE” that also had the following ICD-10 codes: “G40.X-G41.X” and “R56.X”. In addition, FPHT, VPA, LEV and LCM with all their existing brand names were examined and selected for further examination. Only patients over 16 years old receiving second-line IV ASM for the treatment of ongoing SE within the initial 24 h of the patient’s arrival at the emergency department (ED) were included in the study. The collected data was anonymized prior to any further analysis.

From the obtained patient population, we collected the following data on the administered second-line IV ASMs: the agents used, their doses, and their timing from the onset of the seizure. In addition, we collected the following data: age, sex, prior diagnosis of epilepsy, prior central nervous system (CNS) diseases, pre-existing ASMs, aetiology of SE, administered first-line ASMs (BZDs), administered propofol anaesthesia, and data from the electroencephalogram (EEG) examinations.

Furthermore, we excluded from the study dataset the episodes in which the patient received propofol anaesthesia either prior to or concurrently with the second-line IV ASMs.

Patient classification

The study population was divided into four different groups according to their SE type: CSE, nonconvulsive SE (NCSE), comatose (subtle) NCSE, and focal aware SE (FASE). The same distribution of SE types was used in our previous study identifying indications for use of second-line IV ASM in emergency room settings [6].

In addition, we divided the patients into two groups based on median age to assess its effects in SE outcomes.

Outcome measures

First, we evaluated whether clinical characteristics or pre-existing ASMs influenced the choice of second-line IV ASMs. Second, we evaluated the overall response rates to administered second-line IV ASMs. Third, we examined treatment patterns and response rates associated with the two most commonly used second-line IV ASMs at our institution, LEV and LCM. We further analysed whether age, sex, prior administration of BZDs, prior diagnosis of epilepsy, CNS diseases, or subtype of SE influenced the response rates. Fourth, the responses to FPHT, VPA, and simultaneously administered LEV and LCM were also collected and descriptively evaluated without comparative analysis. LEV and LCM were considered simultaneously administered if given within 30 min of each other.

Responses were assessed under two conditions: when the administered second-line IV ASM represented the initial treatment and when the patient had previously received one or more other second-line ASMs. The therapeutic response to second-line IV ASMs was assessed using three complementary approaches, based on the availability and quality of clinical and neurophysiological data:

1. Clinical assessment of improvement: Response evaluation based solely on clinical assessment only in episodes where an EEG was not performed. A response was classified as positive if the patient records documented a substantial improvement in clinical status within short period of time following administration of the second-line IV ASM. Clinical improvement was inferred when the documentation indicated cessation of overt seizure activity, resolution of confusion, and recovery of orientation and any previously impaired level of consciousness to the presumed baseline state.

2. EEG assessment: All EEG reports obtained after administration of the second-line IV ASM were systematically reviewed. The medication response was considered positive if the EEG showed no findings compatible with ongoing SE.

3. Combined clinical and EEG assessment: This method was applied whenever both clinical and EEG information were sufficiently detailed and concurrently available to allow integrated evaluation of treatment response.

Treatment with the second-line IV ASM was considered unsuccessful if no significant symptom resolution was observed according to patient records and the patient required initiation of an additional ASM for ongoing seizure activity, or if the EEG demonstrated ongoing SE.

Furthermore, we compared the responses to LCM and LEV separately, both in patients with EEG data available and in those evaluated without EEG.

Statistical analysis

The normality of the data distribution was tested using the Shapiro–Wilk test, and kurtosis and skewness values were examined. Descriptive statistics (frequencies and proportions or means, medians, and interquartile ranges) are presented to summarise the clinical characteristics of patients and ASMs. Owing to the positively skewed distribution of continuous variables, the Mann–Whitney U test was applied to analyse differences between two groups. For comparisons involving more than two groups, the Kruskal–Wallis H test was applied. When an association between groups and categorised variables was examined, Pearson’s chi-square test, if assumptions were valid, or Fisher’s exact test was used. In addition, an adjusted odds ratio (OR) for the association between ASMs and response rate was evaluated by a binary logistic regression model adjusted for multiple variables. For all the statistical tests, p values < 0.05 were considered significant. All analyses were conducted using SPSS statistical software version 28.0 for Windows (SPSS, Inc., Chicago, IL, USA).

Ethical considerations

As the study involved no contact with patients, ethical committee approval was not required under the Finnish Law on Research. In accordance with Finnish guidelines, the study was approved by the Head of the Tampere University Science Centre. Data supporting the findings are available from the corresponding author upon reasonable request but are not publicly accessible due to privacy and ethical considerations.

Results

SE types and clinical characteristics of the study population

A total of 80 SE episodes were identified in 74 patients (median age, 68 years; IQR, 61–77 years); 29 patients (39%) were female. Thirty (40.5%) patients had a prior diagnosis of epilepsy and 56 (76%) had a history of CNS diseases. CSE was the most common SE subtype, comprising 40 episodes, followed by NCSE (21 episodes), comatose NCSE (9 episodes), and FASE (8 episodes). One CSE episode and one comatose NCSE episode were excluded due to the concurrent use of propofol with a second-line IV ASM. Thus, 78 episodes (72 patients) were included in the analysis (Fig. 1). There were no significant differences in age or sex among SE subtypes (p > 0.05). Similarly, the proportions of patients with prior diagnoses of epilepsy and prior CNS diseases remained similar.

Fig. 1.

Flowchart showing the administration and responses to ASMs within the first 24 h after admission to the emergency department. Two episodes were treated with three different intravenous (IV) ASMs and are therefore counted twice in the total number of second-line IV ASM administrations. The methods for determining responses and their frequencies of use are described in the Methods and Results sections. Abbreviations: ASM, antiseizure medication; CSE, convulsive SE; FASE, focal aware SE; FPHT, fosphenytoin; N, number of episodes; NCSE, nonconvulsive SE; SE, status epilepticus; *Topiramate was the alternative to second-line IV ASMs used most frequently and was used in 11 episodes; other ASMs included clobazam, zonisamide and oral LCM, VPA and LEV

Total number of administrations of different ASMs

Clinical characteristics and detailed information related to use of second-line IV ASMs were presented in Table 1. As the 1^st second-line IV ASM, LEV was the most frequently used ASM in 39 episodes (50%), followed by LCM in 30 episodes (38%), a combination of LEV and LCM in five episodes (6.4%), VPA in three episodes (3.8%), and FPHT in one episode (1.2%) (Table 2). However, overall, including all second-line IV ASM administrations during the first 24-hour period after ED admission, LCM was the most frequently administered ASM, used in 47 episodes (60%), followed by LEV in 45 episodes (58%), VPA in seven episodes (9%) and FPHT in two episodes (2.6%). Up to three different ASMs from the four available second-line IV options were administered to a single patient within the same 24-hour treatment episode. Specifically, in 26 episodes, patients received two different ASMs, and in two episodes, the patient was treated with three different second-line IV ASMs.

Table 1.

Clinical characteristics and detailed information related to use of second-line IV ASMs

CLINICAL CHARACTERISTICS	Total	LEV	LCM	VPA	FPHT	LEV + LCM	P-value
Episodes / administrations as 1st second-line IV ASM	78	39 (50%)	30 (38%)	3 (4%)	1 (1%)	5 (6%)	NA
Number of patients	72	38 (53%)	28 (38%)	3 (4%)	1 (1%)	5 (7%)	NA
Total number of administrations (% of total episodes)	106	45 (58%)	47 (60%)	7 (9%)	2 (3%)	5 (6%)	NA
Age (median; IQR)	68 (61–77)	73 (64–79)	64 (55–71)	75 (65–76)	47 (NA)	55 (54–67)	0.011 b
Female	29 (39%)	15 (40%)	12 (43%)	3 (100%)	0	1 (20%)	0.211a
Prior epilepsy diagnosis	32 44%)	11 (29%)	18 (64%)	1 (33%)	1 (100%)	2 (40%)	0.013 a
Prior CNS disease	55 (76%)	26 (68%)	24 (86%)	3 (100%)	1 (100%)	3 (60%)	0.254a
Pre-existing same ASM	14 (18%)	8 (21%)	6 (20%)	0	0	0	0.913a
BZD before 2nd line IV ASM	53 (68%)	28 (72%)	18 (60%)	2 (67%)	1 (100%)	4 (80%)	0.815a
EEG response verification	58 (74%)	28 (72%)	22 (73%)	2 (67%)	1 (100%)	5 (100%)	0.137a
Response to 1st second-line ASM administration	43 (55%)	17 (44%)	20 (67%)	1 (33%)	1 (100%)	4 (80%)	0.717a
Time from beginning of SE to ASM (IQR)*	2.49 (1.50–6.26)	2.30 (1.37–4.35)	3.15 (1.52–9.15)	8.30 (6.45–9.11)	2.20 (NA)	2.59 (2.10–17.00)	0.271b
AETIOLOGIES							0.668a
Unknown (cryptogenic)	3 (4%)	1 (3%)	1 (3%)	1 (33%)	0	0
Acute:
Febrile illness	5 (6%)	3 (8%)	2 (7%)	0	0	0
Medication withdrawal / non-compliance	9 (12%)	3 (8%)	5 (17%)	1 (33%)	0	0
Toxic (e.g., alcohol, drugs, poisoning)	6 (8%)	2 (5%)	4 (13%)	0	0	0
Metabolic (e.g., hyponatremia)	9 (12%)	7 (18%)	0	0	1 (100%)	1 (20%)
Acute stroke or hemorrhage	10 (13%)	6 (15%)	4 (13%)	0	0	0
Acute CNS infection	2 (3%)	2 (5%)	0	0	0	0
Remote:
e.g. post-traumatic, post-stroke	21 (27%)	10 (26%)	8 (27%)	1 (33%)	0	2 (40%)
Progressive:
CNS tumor	10 (13%)	4 (10%)	4 (13%)	0	0	2 (40%)
Neurodegeneration	3 (4%)	1 (3%)	2 (7%)	0	0	0

Abbreviations: ASM antiseizure medication, BZD benzodiazepines IQR interquartile range, NA not available, SE status epilepticus, CNS central nervous system, LEV levetiracetam, LCM lacosamide, VPA valproate, FPHT fosphenytoin

*The median time is presented in hours and minutes. Three patients were represented in two different groups. Age, sex, prior epilepsy diagnosis, and previous CNS disease are calculated in relation to the number of patients, and the remaining variables are calculated in relation to the number of episodes

Bold p-values indicate statistical significance

^a Fisher’s exact test

^b Kruskal–Wallis test

Table 2.

Responses to different ASMs by SE subtypes

Response to 1st  second-line IV ASM 43/78 (55%)
SE types, n (%)	LEV	LCM	LEV + LCM	VPA	FPHT
CSE	11/22 (50%)	13/15 (87%)	2/2 (100%)	0/0	1/1 (100%)
Comatose	1/5 (20%)	1/4 (25%)	0/0	0/0	0/0
NCSE	3/8 (38%)	4/8 (50%)	1/2 (50%)	1/3 (33%)	0/0
FASE	2/4 (50%)	2/3 (67%)	1/1 (100%)	0/0	0/0
Total response	17/39 (44%)	20/30 (67%)	4/5 (80%)	1/3 (33%)	1/1 (100%)

Response to 2nd and 3rd second-line IV ASM 9/28 (32%)
CSE	1/1 (100%)	4/8 (50%)	0/0	0/1 (0%)	0/1 (0%)
Comatose	0/1 (0%)	1/4 (25%)	0/0	0/1 (0%)	0/0
NCSE	0/3 (0%)	2/4 (50%)	0/0	1/2 (50%)	0/0
FASE	0/1 (0%)	0/1 (0%)	0/0	0/0	0/0
Total response	1/6 (17%)	7/17 (41%)	0/0	1/4 (25%)	0/1 (0%)

Abbreviations: SE status epilepticus, LEV levetiracetam, LCM lacosamide, VPA valproate, FPHT fosphenytoin, CSE convulsive status epilepticus, NCSE nonconvulsive status epilepticus, FASE focal aware status epilepticus, ASM antiseizure medication

For LEV, the median first second-line IV ASM dosage was 1500 mg (IQR 1000–2000 mg), and for LCM, the median first dosage was 300 mg (IQR 200–400 mg).

In 53 (68%) episodes, BZDs were administrated as a first-line ASM either before or concurrently with the second-line IV ASM.

Influence of clinical characteristics and pre-existing ASM medications on second-line IV ASM treatment

Patients who received LEV as their first ASM for SE were significantly older (median 73 (IQR 64–79) years) than those treated with LCM were (median 63 (IQR 55–70) years, p = 0.002). A greater proportion of patients who received LCM as their first ASM had a prior diagnosis of epilepsy than those who received LEV (63% vs. 28%, p = 0.005). The presence of prior CNS diseases did not influence the choice between LCM and LEV (p = 0.187).

Overall, 36 episodes (46%) involved patients with a prior diagnosis of epilepsy. In 30 of these episodes (83%), at least one of the following ASMs, also commonly used in Finland for the treatment of SE, was part of the pre-existing regimen: LEV (n = 18), LCM (n = 9), or VPA (n = 11). None of the patients had phenytoin as part of a pre-existing treatment. Two of these agents were present as a prior ASM in six episodes (17%), and all three were present in one episode (3%). Notably, patients with pre-existing VPA did not receive it as the 1^st second-line IV ASM during SE. In contrast, in 14 episodes (39%), a pre-existing agent was administered as the 1^st second-line IV ASM. Specifically, eight episodes (21%) involving LEV and six episodes (20%) involving LCM were treated with the same ASM that had been part of the patients’ pre-existing regimen. ASM withdrawal or poor adherence was not identified as an aetiological factor for SE in any of these cases.

Aetiology

In 27% of episodes, the patient had a remote symptomatic aetiological factor for SE, such as post-traumatic or post-stroke epilepsy (Table 1). In 4% of episodes, the aetiology was not known, and in 54%, patients had acute symptomatic aetiological factors. The proportion of remote symptomatic aetiologies was similar between patients receiving LEV (25.6%) and LCM (26.7%). Patients receiving LCM more frequently had a progressive disease as an aetiology (20%) than those receiving LEV (12.8%), whereas patients receiving LEV had more often an acute symptomatic aetiology (61.5%) than those receiving LCM (50%). However, the difference in proportions of these aetiologies between LCM and LEV was not statistically significant (p = 0.310).

Timing of second-line IV ASM administration

The median time from the beginning of the seizure to the administration of the second-line IV ASM was 2 h and 49 min, and this time to treatment varied significantly across SE subtypes (p < 0.001). It was shortest in CSE (2 h and 2 min), followed by comatose NCSE (3 h and 4 min), the FASE (3 h and 59 min), and longest in NCSE (7 hours).

Regarding the timing of ASM administration with regard to seizure onset, LCM was administered 45 min later than LEV (LCM: 3 h and 15 min; LEV: 2 h and 30 min). However, the difference was not statistically significant (p = 0.177). The median delay for FPHT administration was 2 h and 20 min, while VPA was administered substantially later than the others, with a median delay of 8 h and 30 min. Statistical evaluation of FPHT and VPA delays was not performed due to the low number of administrations.

Response rates

Younger patients (< 68 years old) showed a greater response rate to the 1^st second-line IV ASM than older patients (≥ 68 years old) (68% vs. 43%, p = 0.046).

Figure 1 illustrates the treatment responses to the 1^st administered second-line IV ASMs and overall response rates with all given second-line IV ASMs within the first 24 h of admission in cases of CSE, NCSE, comatose NCSE, and FASE. The overall response rate with the 1^st administered second-line IV ASM was 55%.

When administered as the 1^st second-line IV ASM, LCM showed a trend towards improved response rate compared to LEV (67% vs. 44%, p = 0.057). In binary logistic regression, LCM showed a trend to higher odds of treatment response compared to LEV (unadjusted OR 2.59, 95% CI 0.96–6.95, p = 0.059). Following multivariable adjustment for age, sex, SE subtype, aetiology, and time from seizure onset to ASM administration, LCM as the 1^st second-line IV ASM demonstrated significantly higher response odds compared to LEV (OR 3.29, 95% CI 1.06–10.19, p = 0.039), with no covariates demonstrating significant independent effects.

Furthermore, when including cases in which another second-line IV ASM was administered after the failure of a previous second-line IV ASM, LCM demonstrated a higher overall response rate compared to LEV, but the difference was not quite significant (57.4% vs. 40%; p = 0.094). In binary logistic regression, LCM was associated with higher odds of treatment response compared to LEV (unadjusted OR = 2.02, 95% CI: 0.88–4.64, p = 0.096). Following multivariable adjustment for age, sex, prior diagnosis of epilepsy, history of CNS disorders, and previous use of BZDs for SE, LCM remained associated with higher odds of treatment response, although the association did not reach statistical significance (adjusted OR = 1.82, 95% CI: 0.76–4.36, p = 0.177).

Across analyses, LCM consistently showed a higher response rate than LEV, both when used as the 1^st second-line IV ASM and overall. Moreover, LEV and LCM were used in similar proportions across different subtypes of SE, and LCM appeared to have higher response rates across all types of SE than LEV, but these differences were not statistically significant (p > 0.05) (Table 2).

Due to the small number of patients treated with the combination of LCM and LEV, VPA, or FPHT, statistical analysis was not feasible, and the observed responses are presented descriptively. The LEV and LCM combination produced an 80% overall response rate, while FPHT and VPA yielded response rates of 50% and 29%, respectively. Detailed response distributions by treatment stage and seizure subtype are presented in Table 2.

When considering all administered medications, the treatment responses across the different SE subtypes varied as follows: For LEV, the highest response rate was observed in CSE (59.1%), followed by FASE (40%), NCSE (27.3%), and comatose SE (16.7%), in descending order. Similarly, for LCM, the most favourable response was achieved in CSE (73.1%), followed by FASE (50%), NCSE (50%), and comatose SE (25%), respectively.

EEG and response rates

EEG was performed in 58 of 78 episodes (74%). In most cases (47 episodes, 60%), the determination of whether the patient responded to the treatment was based on a combination of clinical findings and supportive EEG results. Decisions based solely on clinical evaluation occurred in 21 episodes (27%), while EEG findings alone guided treatment in 10 episodes (13%).

Among the patients treated with LCM, EEG was used in the response assessment in 73% of cases, and among these, a positive response to the 1^st second-line IV ASM was observed in 60% of episodes. In the cases where the LCM response was based on clinical assessment alone (27%), a positive response was identified in 100% of episodes. Furthermore, among the patients treated with LEV, EEG was used in 72% of the response assessments, and of these, a positive response to the 1^st second-line IV ASM was observed in 47%. In the LEV-treated patients for whom EEG was not available (28%), the assessment was based solely on clinical evaluation, with a positive response documented in 81% of episodes. Finally, among the LCM and LEV episodes in which the response evaluation was based solely on clinical assessment, none of the episodes were of the comatose SE subtype; only one episode was classified as NCSE, and all remaining episodes were classified as CSE or FASE, in which the clinical response is often more evident. In three episodes, patients received anaesthesia, and the decision regarding second-line IV ASM failure was made clinically before propofol administration; EEG was performed afterward. In one episode, topiramate was initiated based on clinical evaluation prior to EEG examination. Additionally, in one episode, EEG was conducted before second-line IV ASM initiation and showed SE findings. However, seizure control was not confirmed by EEG, and treatment response was assessed based on clinical improvement.

EEG was most frequently used in comatose NCSE episodes (9 of 9, 100%), followed by NCSE (19 of 21, 90%), CSE (25 of 40, 63%), and FASE (5 of 8, 63%) episodes.

Alternative ASMs

After the initial failure of second-line IV ASM treatment, subsequent treatment strategies involved either continuation with an alternative IV ASM or switching to alternative treatment options. These included enteral ASM alternatives, of which the most commonly administered was topiramate (TPM) (initiated in 13 episodes), followed by clobazam (one episode), zonisamide (one episode), and orally administered LCM, VPA, and LEV (three episodes), or propofol anaesthesia, which was used in six episodes.

Discussion

Our study provides new information about the influence of clinical features and pre-existing ASMs on the selection of second-line IV ASMs used for treatment of SE. First, certain clinical characteristics such as age and prior diagnosis of epilepsy influenced the choice of a specific second-line IV ASM for individual patients. Second, treatment with second-line IV ASM was initiated relatively often with the same pre-existing ASM used for the treatment of epilepsy. Third, LCM was associated with numerically higher response rates than LEV was. Finally, the administration of BZDs did not significantly alter the effectiveness of subsequent second-line IV ASMs.

Influence of clinical characteristics and pre-existing ASMs to the SE treatment choices

In our unit, older patients were treated more often with LEV than with LCM. This could be attributed to the favourable safety profile of LEV regarding cardiogenic adverse events. In contrast, LCM was used more often in younger patients with a pre-existing diagnosis of epilepsy, possibly because of its perceived efficacy advantage over LEV. Liver or cardiac disease, pregnancy, and drug interactions have been suggested to influence the selection of a second-line ASM in patients with SE, as these conditions could be affected by VPA and FPHT [16, 17]. In contrast, both LEV and LCM have been found to be safe for the treatment of SE. Adverse effects following a single dose are infrequent, although LCM has been notably linked to rare cardiogenic adverse effects [6, 8–10, 12, 13, 15, 18]. No studies to date have specifically examined the determinants influencing the choice between LEV and LCM in clinical practice.

The impact of the patient’s pre-existing ASM usage on second-line IV ASM selection has not often been assessed. Overall, 46% of the study population had a prior diagnosis of epilepsy, and 83% of these had some pre-existing ASM treatment that is also used as a second-line IV ASM. However, episodes with a prior diagnosis of epilepsy relatively infrequently involved patients who had both of the most commonly used second-line IV ASMs at our institution, LEV and LCM, as pre-existing ASMs (17%). In only one episode, the patient had LEV, LCM, and VPA as pre-existing ASMs, leaving FPHT as the only treatment alternative for SE according to the Finnish guideline [3]. Even though alternatives for SE treatment were available, in 39% of episodes with a prior diagnosis of epilepsy, the 1^st second-line IV ASM administered was the same as the pre-existing treatment. Reasons for this may include that the patient’s pre-existing ASM was unknown at the time of second-line IV ASM administration or that the administration was based on the assumption of nonadherence to the pre-existing medication. In a previous study, nonadherence to existing ASM was identified in 39% of seizure patients requiring hospitalization [19].

Response rates of second-line IV ASMs

Previous reports have consistently demonstrated the efficacy of both LEV and LCM in managing SE. Reported efficacy rates for LEV range from 37% to 78% [10–14], whereas those for LCM range between 47% and 70% [8, 9, 15]. In our study, LCM and LEV were effective as the 1^st administered second-line IV ASMs in 67% and 44% of SE episodes, respectively. These findings are in line with previous reports, despite LEV being dosed according to the year 2016 Finnish SE treatment guideline (20 mg/kg and up to 2000 mg), which is remarkably lower compared to the dose recommended in AES SE treatment guideline (60 mg/kg and up to 4500 mg) [2, 3].

Prior studies have indicated that the efficacy of LCM ranges from 56% to 70% in CSE episodes and from 47% to 57% in NCSE episodes [8, 9, 15]. The 42% response rate of LCM in our study was marginally lower in patients with NCSE than in previous studies. However, LCM demonstrated a more favourable response rate of up to 87% in episodes of CSE. We found LEV to be effective in 38% of NCSE episodes, a finding that lacks comparative studies [20]. LEV also demonstrated a 50% response rate in CSE episodes as a 1^st second-line IV ASM, which is in line with previous studies [10–14]. A previous study demonstrated that, within this study population, the diagnosis of NCSE often required EEG prior to the initiation of second-line IV ASM therapy [6]. Since therapeutic efficacy tends to decline with prolonged seizure duration, delays in diagnosis and treatment initiation may partly explain the slightly reduced response to LCM observed in NCSE patients compared with earlier studies [6, 15, 21].

Response rates comparison between LEV and LCM

When directly compared with LEV, LCM was associated with numerically higher response rates as the 1^st administered second-line IV ASM. LCM also appeared to achieve higher response rates across all SE subtypes compared to LEV; however, this observation did not reach statistical significance, likely due to the limited number of cases. The aetiological factors were consistent with those reported in previous reports and did not differ substantially between patients treated with LCM and those treated with LEV. Therefore, the increased response rates observed with LCM cannot be explained by differences in underlying causes [10]. Overall, consistent with previous studies, younger patients achieved a positive response more often than older patients [22]. However, even after adjustment for age and sex, SE subtype, aetiology, and time from seizure onset to ASM administration, the LCM treatment was associated with higher response rates, though this association should be interpreted cautiously given the observational design. Previous direct comparative studies between LEV and LCM are scarce. Administration delays also do not account for the observed difference, as LEV was administered 45 min earlier than LCM, and the delay difference was not statistically significant. Furthermore, the median time (2 h and 49 min) from the onset of SE to the administration of a second-line IV ASM in our study population was similar to that reported in previous studies in Finland (2 h and 40 min) and shorter than the time reported in a study conducted in Spain (overall median 4 h and 30 min) [5, 23, 24]. However, the study design was retrospective, and the response assessment between LCM and LEV was non-blinded, which may introduce bias due to confounding factors. In addition, because the LEV dosage was low compared with the AES recommendation, the response rate results are exploratory and should not be considered definitive.

Other ASMs

Among non-IV second-line ASMs, TPM was administered relatively frequently in this patient population during episodes where second-line IV ASMs failed to achieve the desired therapeutic effect. Previous studies have demonstrated the efficacy of TPM in patients who had already received second-line IV ASMs [25]. However, as the primary focus of this study was on the initial management of SE, the effectiveness of TPM was not evaluated, as it is typically introduced at a later stage of treatment.

Influence of prior BZD treatment on the response rate of second-line IV ASMs

Finally, in our study population, no difference in response rate was detected between patients who had received BZDs before or at the same time as second-line IV ASM and those who had not. This result may be explained by the following observations: A prior study in the same patient population revealed that BZDs were frequently underdosed as first-line ASM, leading to treatment failure with BZDs [26]. Furthermore, the effectiveness of BZDs decreases as the duration of the seizure increases [21, 27]. Therefore, if BZDs as a first-line treatment have failed, it is unlikely that the previously administered BZD would have a significant benefit in an episode once escalation to second-line IV ASMs is needed.

Strengths and limitations

A key strength of this study is the use of comprehensive electronic patient records maintained at Tampere University Hospital, which enabled a robust retrospective analysis and provided detailed information on the drugs administered and their dosages. However, the retrospective nature of the study has certain limitations. Specifically, relying exclusively on medical records to classify patients into distinct SE categories proved challenging and may have led to inaccuracies in how some individuals were categorized. Although the patient population was collected from a large geographical area, the sample size was limited because the study focused specifically on episodes involving SE and patients in need of second-line IV ASM treatment. The small sample size, together with the retrospective observational design of the study, introduces substantial confounding by indication, which must be considered a central limitation when comparing the response rates between LEV and LCM. In addition, the limited sample size reduced the precision and stability of the fully adjusted multivariable logistic regression model; therefore, the findings should be interpreted as exploratory.

Conclusions

The pragmatic approach of this study provides a realistic assessment of the factors influencing second-line treatment choices in SE patients and the response rates of LEV and LCM in the context of real-world SE management. Patients treated with LCM were younger and more often had a prior epilepsy diagnosis than those treated with LEV. In addition, second-line SE treatment was frequently initiated with a pre-existing agent in patients with a prior diagnosis of epilepsy. While LCM was observed to have higher response rates than LEV in this observational cohort, the findings should be regarded as exploratory and hypothesis-generating rather than definitive, given potential treatment selection biases and the limited sample size.

Abbreviations

ASM

Antiseizure medication

CSE

Convulsive status epilepticus

ED

Emergency department

FASE

Focal aware status epilepticus

FPHT

Fosphenytoin

LCM

Lacosamide

LEV

Levetiracetam

NCSE

Nonconvulsive status epilepticus

SE

Status epilepticus

VPA

Valproic acid

Authors’ contributions

The project was carried out in collaboration between all authors. TP, JS and JP conceived and designed the research plan; TP collected the data and PB performed the statistical analyses. TP wrote the first draft and all authors commented on previous versions of the manuscript draft, writing-review and editing. SR and JP helped with project administration, supervision. All authors revised the drafted manuscript. All others read and reviewed the manuscript and approved the final version.

Funding

Open access funding provided by Tampere University (including Tampere University Hospital).

Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Declarations

Ethics approval and consent to participate

As the study involved no contact with patients, ethical committee approval and informed consent were not required under the Finnish Law on Research. In accordance with Finnish guidelines, the study was approved by the Head of the Tampere University Science Centre and followed the tenets of the Declaration of Helsinki.

Consent for publication

None.

Competing interests

T.P, P.B, J.S, and S.R report no conflicts of interest. J.P has participated in clinical trials for Bial, Biohaven, Eisai, and UCB; received research grants from Angelini Pharma, Jazz Pharma, Eisai, Medtronic, UCB, and LivaNova; received speaker honoraria from Angelini Pharma, Eisai, Jazz Pharma, LivaNova, Medtronic, Orion Pharma, Takeda and UCB; received support for travel to congresses from LivaNova, Eisai, Medtronic, and UCB; and participated in advisory boards for Angelini Pharma, Eisai, Jazz Pharma, LivaNova, Medtronic, Novartis, Pfizer, and UCB.