The retention of lacosamide in patients with epilepsy and intellectual disability in three specialised institutions

Seizure 52 (2017) 123–130

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The retention of lacosamide in patients with epilepsy and intellectual disability in three specialised institutions J. Brennera , H.J.M. Majoieb,c,1, S. van Beekd,2 , J.A. Carpaye,* a

University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands Department of Neurology, Academic Center of Epileptology Kempenhaeghe, Sterkselseweg 65, 5591 VE Heeze, The Netherlands School of Mental Health & Neuroscience and School of Health Professions Education, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands d SEIN Epilepsy Centre, Achterweg 5, 2103 SW Heemstede, The Netherlands e Department of Neurology, Tergooi Hospital, Rijksstraatweg 1, 1261 AN Blaricum, The Netherlands b c

A R T I C L E I N F O

A B S T R A C T

Article history: Received 3 July 2017 Received in revised form 1 September 2017 Accepted 27 September 2017 Available online xxx

Purpose: We describe the effectiveness of lacosamide as adjunctive therapy in patients with epilepsy and an intellectual disability. This information is relevant, as few data exist pertaining to this population with a high prevalence of (intractable) epilepsy. Methods: We performed a retrospective study in three specialised institutions. Inclusion criteria were (1) focal onset or symptomatic generalized (2) therapy-resistant epilepsy, (3) intellectual disability and (4) residence in a care-facility for people with intellectual disabilities (PWID). The primary outcome variables were the retention rates of lacosamide, estimated through Kaplan-Meier survival analysis. Secondary outcomes were reported seizure control, side effects and clinical factors influencing discontinuation. Results: One hundred and thirty-two patients were included. The median retention time of lacosamide in our cohort was four years. The estimated one-, two- and three-year retention rates of lacosamide were 64%, 57% and 56% respectively. Severity of intellectual disability and seizure type did not influence whether lacosamide was continued. In 48.5% of patients, a reduction of seizure activity was reported. Side effects were at least part of the reason for discontinuing treatment in 26.5% of all patients. Common side effects were tiredness/somnolence (in 30.3%), aggression/agitation (24.2%), and instable gait (15.2%). Five deaths during follow-up were considered unlikely to be related to the use of lacosamide. One patient died unexpectedly within two months of treatment onset, probably this was a case of SUDEP. Conclusion: These retention rates of lacosamide in PWID are similar to rates of previously registered antiepileptic drugs in PWID. Behavioural side effects were noted in a high proportion compared to the general literature on lacosamide. Other side effects were in line with this literature. Lacosamide seems effective and safe for PWID and refractory epilepsy. © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Keywords: Lacosamide Retention Refractory epilepsy Intellectual disability Institutionalised

1. Introduction The prevalence of epilepsy in the general population is estimated at 0.5%. Approximately 50% of patients with newly

Abbreviations: PWID, people with an intellectual disability; AED, anti-epileptic drug; RCT, randomised controlled trial; SUDEP, sudden unexplained death in epilepsy. * Correspondiong author at: Postbus 10016, 1201 DA, Hilversum, The Netherlands. E-mail addresses: [email protected] (J. Brenner), [email protected] (H.J.M. Majoie), [email protected] (S. van Beek), [email protected] (J.A. Carpay). 1 Postal address: Postbus 61, 5590 AB, Heeze, The Netherlands. 2 Postal address: Postbus 540, 2130 AM, Hoofddorp, The Netherlands.

diagnosed epilepsy become seizure free with initially prescribed anti-epileptic drugs (AED’s). Despite the registration of new antiepileptic drugs, 30% of patients will continue to have seizures after treatment with at least two different AED’s, successively or concomitant (refractory epilepsy) [1]. In people with intellectual disabilities (IQ less than 70), the prevalence of epilepsy is estimated to be substantially higher than in the general population: 10–30% [2]. With increasing severity of intellectual disability, the prevalence of epilepsy increases as well. Intellectual disability is associated with multiple seizure types within an individual and a poorer prognosis for seizure control – with refractory epilepsy in up to 75% of patients [3,4]. The refractory nature of epilepsy in this population often provides the need for polypharmacy, including new AED’s [4].

https://doi.org/10.1016/j.seizure.2017.09.017 1059-1311/© 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

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Whilst the prevalence of epilepsy is high in people with intellectual disabilities (PWID), they are typically excluded from randomised controlled clinical trials (RCT’s) with new AED’s, on account of ethical concerns about the capacity to consent, and of foreseen problems with diagnostics, seizure count, assessment of adverse effects and compliance to therapy [5]. As a result, there is little evidence on optimal treatment of epilepsy in PWID. Clinical guidelines for the management of epilepsy in adults with an intellectual disability recommend the same AED’s as prescribed in the general population – which include sodium valproate, lamotrigine and potentially carbamazepine or levetiracetam as first options for treatment of focal onset and symptomatic generalized seizures – taking special consideration of potential adverse cognitive and behavioural effects of AED’s [6]. A Cochrane review of 14 RCT’s on pharmacological interventions for epilepsy in PWID concluded that lamotrigine, topiramate, clobazam, rufinamide and felbamate seem effective and tolerable as adjunctive therapy, and consider this to be evidence supporting the use of similar AED’s in PWID as in the general population. The review reports that pharmacological interventions are still under-

investigated in the population of PWID [7]. More recently, retrospective studies have addressed the duration of treatment (retention rate) and – if applicable – the reason for discontinuation of several new anti-epileptic drugs in PWID. The retention rate was used as an indication for efficacy and tolerability of AED’s in intellectually disabled patients, where precise registration of seizure frequency is notoriously difficult. The studies present twoyear retention rates of 40–75% for lamotrigine, levetiracetam, topiramate and perampanel and of 85% for oxcarbazepine [5,8–10]. Two of these articles concluded gabapentin to seem less effective. Lacosamide was registered in Europe in 2008, as an adjunctive AED in the treatment of refractory partial-onset seizures with or without secondary generalization. Its mechanism of action is believed to be blockage of sodium channels. Three randomised controlled trials on the efficacy of lacosamide as an adjunctive AED in partial-onset seizures showed a reduction (>50%) in seizure frequency in 30–40% of patients, and a median reduction of seizure frequency of 14 to 45% [11–13]. Three prospective studies and two retrospective studies estimated one-, two- and three-year retention rates of lacosamide to be 62–77%, 45–71% and 35–52.9%

Table 1 Demographic and clinical characteristics of all included patients (n = 132). Characteristic Sex, % of all patients Male Female Age in years, mean (SD; min – max) Weight in kilograms, mean kg (SD) Severity of intellectual disability, nr. of patients (% of patients) Mild (IQ 50–70) Moderate (IQ 35–50) Severe (IQ 20–35) Profound (IQ <20) Unknown Aetiology of epilepsy, nr. of patients (% of patients) No known aetiology Genetic Perinatal pathology Post-infectious Vascular Posttraumatic Metabolic Neoplastic Post-vaccination Inflammatory Intoxication Seizure type, nr. of patients (% of patients) Focal onset (Multi)focal onset with secondary generalization Generalized onset Unknown Daily dose of lacosamide in milligrams, mean (SD; min – max) Number of preceding AED’s used, mean (SD; min – max) Number of concomitant AED’s, mean (SD; min – max) Sodium Valproate Carbamazepine Lamotrigine Clobazam Levetiracetam Topiramate Oxcarbazepine Phenytoin Other concomitant AED’s Concomitant vagal nerve stimulator, nr. of patients (% of patients) Concomitant behavioural medication, nr. of patients (% of patients) Antipsychotics Benzodiazepines Antidepressants Follow-up time in years, mean (SD; min – max) AED’s = antiepileptic drugs.

Value 56.8% 43.2% 41.7 (15.0; 18.0–78.0) 69.1 (16.5) 31 (23.5%) 20 (15.2%) 31 (23.5%) 10 (7.6%) 40 (30.3%) 54 (40.9%) 24 (18.2%) 19 (14.4%) 16 (12.1%) 7 (5.3%) 4 (3.0%) 2 (1.5%) 2 (1.5%) 2 (1.5%) 1 (0.8%) 1 (0.8%) 4 (3.0%) 77 (58.3%) 31 (23.5%) 20 (15.2%) 243.7 (104.9; 50.0–450.0) 7.0 (3.3; 2–19) 2.0 (0.9; 1–6) 66 (50.0)% 55 (41.7%) 43 (32.6%) 38 (28.8%) 37 (28.0%) 17 (12.9%) 16 (12.1%) 15 (11.4%) 39 (29.5%) 19 (14.4%) 39 (29.5%) 24 (18.2%) 11 (8.3%) 9 (6.8%) 4.6 (2.1; 0.1–7.7)

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respectively [14–18]. Estimated median retention times vary from 196 days, in another retrospective large cohort study, to 3.2 years [14,16,19]. In two of the studies, about 20–30% of all patients reported a period of significant reduction (>50%) in seizure activity [14,15], the other two studies mentioned a 50% reduction of seizure frequency in 50% [16,17]. Frequently mentioned side effects were dizziness (24.2–55%), headache (12.7–20.8%), diplopia (10.3– 18.6%), ataxia (4–23%) and nausea (10–18%)[12,13,16,17]. The efficacy and tolerability of lacosamide was researched in a small group of patients with Lennox-Gastaut syndrome [20]. The median retention time of lacosamide was 90 days, retention rates were not given. Lacosamide reduced seizure frequency by more than 50% in only 10.5% of patients. Lacosamide increased seizure activity in 78.9% of patients. Behavioural side effects were reported in 47.7% of patients, the most common were aggressiveness and irritability or somnolence. A recent monocenter study assessed the use of lacosamide in a heterogeneous population of patients with intellectual disabilities [21]. A median retention time of 1.5 years and one-, two- and three-year retention rates of 62.0%, 43.7% and 29.1% respectively were described. The most common reason for discontinuation was lack of efficacy, 11% of patients experienced side effects. In the current study, we retrospectively assessed estimated one-, two- and three-year retention rates of lacosamide for refractory epilepsy in PWID in every-day clinical practice, using the data from three specialised institutions for PWID and epilepsy. 2. Methodology We performed a retrospective study, with the estimated retention of lacosamide as an adjunctive AED as primary outcome variables. Data were acquired from electronic patient files available in the two large epilepsy clinics of the Netherlands, SEIN and the academic center of epileptology (ACE) Kempenhaeghe, and a large institution for intellectually disabled patients (de Amerpoort/ Sherpa). All patients of these centres with an intellectual disability (IQ less than 70) and epilepsy were included, provided they were currently taking lacosamide for epilepsy or had used it in the past. In all three institutions all patients with epilepsy are seen in an outpatient setting by a neurologist with special interest in epilepsy, at least once a year, and more often when indicated. Normally, the neurologist has an appointment with the legal representative and/ or the primary professional caretaker of the patient. The local medical ethics committee of the ACE Kempenhaeghe approved this study and decided it did not require further evaluation based on the Medical Research Involving Human Subjects Act (WMO). Due to the retrospective nature of the data and anonymous data handling and analysis, formal consent was not required. Included patients did give a general consent to future use of their data for research purposes at their admission to the clinics. For the purpose of this study, data were considered on age, sex, weight, severity of intellectual disability (categorised according to the DSM-V criteria), aetiology of epilepsy, seizure type (according to the ILAE 2017 criteria), duration of treatment with lacosamide, dosage of lacosamide, previous and concomitant anti-epileptic medication (stratified into sodium channel and non-sodium channel medication), concomitant behavioural medication, changes in seizure frequency and severity with lacosamide, adverse effects of lacosamide, and reason for discontinuation. The reason for discontinuation could be lack of efficacy, the occurrence of adverse effects or a combination. Data were gathered from the onset of treatment until either the date of discontinuation of lacosamide or the date of data collection. The primary outcome variable of the study was the retention of lacosamide, estimated through Kaplan-Meier survival analysis.

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Patients still using lacosamide at their last follow-up were censored from that moment on in the survival analysis. To promote comparability to literature, we specified one-, two- and three-year retention rates. The statistical package we used was SPSS. Secondary outcome measures were efficacy – as reported by the neurologist and categorised as ‘effective in reducing seizure frequency’, ‘effective in reducing seizure severity’, ‘not effective’ or even as a further increase of seizure activity after starting lacosamide –, adverse effects of lacosamide – as reported by patients, carers or the neurologist –, and – if lacosamide was discontinued – the reason for discontinuation. Furthermore, we investigated the relationship of severity of intellectual disability, seizure type, dosage and efficacy of lacosamide, and number of preceding and concomitant AED’s with the probability of discontinuation of lacosamide and the occurrence of adverse effects, and the relationship of adverse effects with the probability of discontinuation. We applied Chi-square tests for categorical data and Mann-Whitney U tests in case of continuous independent variables. To reduce the chance of a type-II error, we adhered to an alpha level of 5% and did not apply corrections for multiple testing. 3. Results One hundred and thirty-two intellectually disabled adults who had ever used lacosamide were included in the study. Demographic and clinical characteristics are displayed in Table 1. Patients were aged between 18 and 78 years, with a mean age of 42 years. The severity of intellectual disability was categorised as being ‘mild’, ‘moderate’, ‘severe’ or ‘profound’. Included patients had a wide spectrum of seizure types and aetiologies. The most frequent etiological classifications of epilepsy were genetic, post-infectious and perinatal hypoxia, although the aetiology was classified as unknown in the largest

Fig. 1. Kaplan-Meier survival curve of lacosamide. The vertical axis represents the estimated probability that patients are still taking lacosamide after a given period of time. Short orthogonal lines represent censored patients.

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proportion of patients (40.9%). Established genetic causes included tuberous sclerosis (n = 6), Down syndrome (n = 2), DCX related disorders (n = 2), Dravet syndrome, Rett syndrome and ring chromosome 20 (each n = 1). Vascular causes included ischemic and haemorrhagic stroke and vascular structural abnormalities. More than half of the patients had (multi)focal onset seizures with secondary generalization, while 23.5% had generalized onset seizures and for 15.2% seizure type was unknown. On average, patients had received seven different AED’s before lacosamide was prescribed, including on average two other sodium channel blockers. An average of two AED’s were prescribed alongside lacosamide, excluding escape medication. The most common prescribed AED’s alongside lacosamide were sodium valproate, carbamazepine, lamotrigine, clobazam and levetiracetam. Generally one other sodium channel blocker was prescribed alongside lacosamide. About a third of the patients used concomitant behavioural medication; either antipsychotics, benzodiazepines or antidepressants. 3.1. Retention of lacosamide Estimated retention rates of lacosamide are depicted in KaplanMeier survival in Fig. 1. The median retention time of lacosamide was four years (SD  0.8 years). The one-, two- and three- year retention rates of lacosamide were 64%, 57% and 56% respectively (Table 2). Of 132 included patients, 63 patients (47.7%) eventually stopped taking lacosamide during follow-up, fifty-five (85.7%) of which in the first two years after onset. The mean follow-up time for all patients was 4.6 years and was not significantly different between patients who continued lacosamide versus patients who discontinued lacosamide (Table 3).

Lack of efficacy was at least part of the reason for discontinuation in 73.0% of patients that discontinued lacosamide; in about half of these patients side effects also played a role in the decision to discontinue (Table 2). Severity of intellectual disability, seizure type, number of previously used AED’s and number of concomitant AED’s were not associated with whether lacosamide was continued (Table 3). Patients who used another sodium channel blocker were more likely to discontinue lacosamide. 3.2. Efficacy and adverse effects Lacosamide was reported to be effective in 48.5% of patients, in reducing seizure frequency, severity or both. These patients were more likely to continue taking lacosamide (p < 0.001). The mean maintenance dosage of lacosamide was significantly higher in patients who continued taking lacosamide than in patients who did not. No patients became completely seizure free after starting lacosamide. In 7.6% an increase in seizure frequency was reported. In total, 83 (62.9%) patient files mentioned adverse effects related to the use of lacosamide. These adverse effects were classified into behavioural (in 51.5% of all patients) and somatic side effects (in 33.3% of patients). On the contrary, 10.6% of PWID expressed more initiative and alert behaviour whilst taking lacosamide. The frequency of occurrence of specific side effects is displayed in Table 2. Multiple side effects could be mentioned in a single patient file. The occurrence of adverse effects attributed to lacosamide was not different depending on severity of intellectual disability (p = 0.87), dosage (p = 0.83) or efficacy of lacosamide (p = 0.27), or depending on the concomitant use of other AED’s (p = 0.58) or behavioural medication (p = 0.07; Table 4). The largest proportion

Table 2 Primary outcome measures. Characteristic

Outcome

Estimated retention time in years, median (SD) 1-year retention rate, estimated% 2-year retention rate, estimated% 3-year retention rate, estimated% Number of patients that discontinued lacosamide, nr. of patients (% of patients) Of which due to; number of patients (% of all patients): Lack of efficacy Side effects Lack of efficacy and Side effects Unknown Efficacy; number of patients (% of patients) Increased seizure activity No effect on seizures Reduction in seizure frequency Reduction in seizure severity Reduction in frequency and severity Unknown Adverse effects – Behavioural; number of patients (% of all patients) Fatigue/somnolence Aggression/rebellion/agitation Withdrawn/depressive mood Anxiety Other Adverse effects – Somatic; number of patients (% of all patients) Instable gait Dizziness Gastro-intestinal problems Aphasia/difficulty finding words Headache Increased appetite Allergic reaction/skin rash/prurigo Ataxia/tremor Visual disturbances Drooling

4.0 (0.8) 64% 57% 56% 63 (47.7%) 25 (18.9%) 14 (10.6%) 21 (15.9%) 3 (2.3%) 10 (7.6%) 52 (39.4%) 39 (29.6%) 11 (8.3%) 14 (10.6%) 6 (4.6%) 40 (30.3%) 32 (24.2%) 8 (6.1%) 4 (3.0%) 3 (2.3%) 20 (15.2%) 10 (7.6%) 10 (7.6%) 5 (3.8%) 4 (3.0%) 4 (3.0%) 4 (3.0%) 4 (3.0%) 3 (2.3%) 2 (1.5%)

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Table 3 Characteristics of patients who continued or discontinued lacosamide. Characteristic

Continued lacosamide (n = 69)

Discontinued lacosamide (n = 63)

Severity of intellectual disability; number of patients (% of patients that continued or discontinued lacosamide)a Mild (IQ 50–70) 20 (29.0%) Moderate (IQ 35–50) 9 (13.0%) Severe (IQ 20–35) 15 (21.7%) Profound (IQ <20) 5 (7.2%) Seizure type; number of patients (% of patients that continued or discontinued lacosamide) (Multi)focal onset, with or without secondary generalization 48 (69.6%) 14 (20.3%) Generalized onset Number of preceding AED’s, mean (SD) 7.1 (3.5) Of which sodium channel blockers, mean (SD) 2.7 (1.4) Dosage of lacosamide per day (mg), Mean (SD) 271.7 (104.5) Number of concomitant AED’s, mean (SD) 2.5 (0.9) Of which sodium channel blockers, mean (SD) 1.0 (0.7) Efficacy; number of patients (% of patients that continued or discontinued lacosamide) No effect on seizures 20 (29.0%) Seizure reduction 45 (65.2%) Adverse effects; number of patients (% of patients that continued or discontinued lacosamide)e Somatic side effects 24 (34.8%) Behavioural side effects 30 (43.5%) Follow-up time in years, mean (SD) 3.8 (2.2)

P-value P = 0.48b

11 (17.5%) 11 (17.5%) 16 (25.4%) 5 (7.9%) P = 0.21b 33 (52.4%) 17 (27.0%) 7.1 (3.1) 2.7 (1.2) 213.0 (97.1) 2.5 (1.0) 1.3 (0.6)

P = 0.89c P = 0.83c P < 0.001c P = 0.97c P = 0.05c P < 0.001d

42 (66.7%) 19 (20.2%) 20 (31.7%) 38 (60.3%) 4.5 (1.8)

P = 0.43b P = 0.04f P = 0.14c

a Percentages do not always add up to 100% because severity of intellectual disability and seizure type were not always known. These cases were not included in the tests for difference between groups. b Chi-square test, two-tailed. c Mann-Whitney U test, two-tailed. d Mann-Whitney U test, one-tailed. e Percentages do not add up to 100% because not all patients that (dis)continued lacosamide experienced side effects. f Chi-square test, one-tailed.

of the patients that discontinued lacosamide experienced behavioural side effects (p = 0.04; Table 3). Six patients died during treatment with lacosamide, these cases are described in Table 5. Four patients died at least six months after commencing treatment with lacosamide of causes clearly not related to the use of lacosamide. The death of the fifth patient – a 30-year old female with a refractory Dravet syndrome – seven months after the start of treatment with lacosamide, was classified as a SUDEP. An ECG performed a year before lacosamide was added to her medication, showed no abnormalities. No autopsy has been

done. The sixth patient – a 35-year old female with symptomatic focal onset seizures of unknown aetiology – died unexpectedly, two months after the start of treatment with lacosamide. In the first month of treatment, lacosamide had a positive effect on the patient’s seizures and no side effects were noted. The dose was then increased from 50 mg once to 50 mg twice a day. Less than a week later, the patient suffered from headache, vertigo, nausea, somnolence and high blood pressure (RR 187/132). The patient died two days later of unknown causes. The patient was not known to have heart disease (e.g. arrhythmia’s or conductive disorders),

Table 4 Characteristics of patients who did or did not experience adverse effects. Characteristic Severity of intellectual disability; number of patients (% of patients with or without adverse effects)a Mild (IQ 50–70) Moderate (IQ 35–50) Severe (IQ 20–35) Profound (IQ <20) Seizure type; number of patients (% of patients that continued or discontinued lacosamide) (Multi)focal onset, with or without secondary generalization Generalized onset Number of preceding AED’s, mean (SD) Of which sodium channel blockers, mean (SD) Dosage of lacosamide per day (mg), Mean (SD) Number of concomitant AED’s, mean (SD) Of which sodium channel blockers, mean (SD) Efficacy; number of patients (% of patients with or without adverse effects) No effect on seizures Seizure reduction Number of patients with concomitant behavioural medication; number of patients (% of patients with or without adverse effects) Follow-up time in years, mean (SD)

Adverse effects (n = 83)

No adverse effects (n = 49)

21 (25.3%) 13 (15.7%) 18 (21.7%) 6 (7.2%)

10 (20.4%) 7 (14.3%) 13 (26.5%) 4 (8.2%)

48 (57.8%) 22 (26.5%) 8.5 (3.5) 2.9 (1.3) 243.6 (111.7) 2.5 (0.9) 1.2 (0.7)

33 (67.3%) 9 (18.4%) 7.5 (3.1) 2.5 (1.4) 243.9 (93.3) 2.4 (1.0) 1.1 (0.7)

36 (43.4%) 44 (53.0%) 27 (32.5%)

26 (53.1%) 20 (40.8%) 12 (24.5%)

P = 0.07b

4.4 (1.9)

3.7 (2.3)

P = 0.09d

p-value P = 0.87b

P = 0.28b

P = 0.15c P = 0.92c P = 0.98c P = 0.27c P = 0.55c P = 0.27b

a Percentages do not always add up to 100% because severity of intellectual disability and the effect on seizures were not always known. These cases were not included in the tests for difference between groups. b Chi-square test, two-tailed. c Mann-Whitney U test, one-tailed. d Mann-Whitney U test, two-tailed.

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Table 5 Deceased patients. Characteristic

Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

Sex Aetiology of epilepsy

Male Unknown

Male Down syndrome

Female Perinatal cerebral haemorrhage

Female Female Encephalopathy, possibly due to Unknown perinatal asphyxia

Dosage of lacosamide Concomitant AED’s

300 mg/day

Female Dravet syndrome (SCN1A-gene mutation) 400 mg/day

200 mg/day

300 mg/day

200 mg/day

100 mg/day

Levetiracetam and phenytoin (n = 2)

Valproate (n = 1)

Topiramate and valproate (n = 2)

Carbamazepine, pregabalin, valproate (n = 3)

Valproate, lamotrigine, carbamazepine (n = 3)

Time between onset of lacosamide and death Age at death (years) Cardiac history ECG before onset

4.5 years

7 months

1 month

7 years

3.5 years

Oxcarbazepine, clobazam, phenobarbital (n = 3) 2 months

72

30

54

63

51

35

No Yes, sinus rhythm

No Yes, sinus rhythm SUDEP

No No

No No

No No

No No

Severe dementia and abstaining treatment policy

Pneumonia followed by heart failure in a patient with a palliative treatment policy

Sigmoid volvulus and a large goitre pressing on the trachea, palliative treatment policy

Unknown

No

No

No

No

No

Cause of death (as in file)

Autopsy

Severe dementia, pneumonia and palliative treatment policy No

but used lisinopril and metoprolol for hypertension. No further diagnostic tests (e.g. lab, ECG, brain scan) and no post-mortem examinations were done. 4. Discussion In this multicentre cohort of PWID and refractory epilepsy, with a mean follow-up of almost five years after initiating lacosamide, we report an estimated two-year retention rate of lacosamide of 57% which is comparable to the published two-year retention rates of lamotrigine (57–75%), levetiracetam (46–59%) and topiramate (38–63%) in previous studies in PWID and epilepsy [5,8,9]. Previously published two-year retention rates of oxcarbazepine were higher, and those of tiagabine and gabapentin were lower than those of lacosamide. Although classification of seizures in our sample was based on limited data, we included 23.5% with seizures of presumed generalized origin, which are formally not within lacosamide’s registered indication. However, we found no association between the continuation of lacosamide and seizure classification. The high prevalence of refractory epilepsy in PWID implies that new AED’s are often prescribed. With few data from RCTs available, the retention rate of an AED in clinical practice is considered a useful measure to reflect efficacy and tolerability in this population. The assumption is that, after starting an AED, the neurologist decides to continue treatment when tolerance is at least acceptable and when a meaningful reduction in seizure activity is achieved, albeit that in clinical practice this subjective assessment is not always backed up with objective data [10]. As expected, lacosamide was reported to be more effective in patients who continued lacosamide. Higher doses of lacosamide were prescribed in patients who continued using it, probably reflecting better tolerance. Retention rates of lacosamide have been studied before in the general population and in PWID. The median retention time of lacosamide in our study, of four years, was higher than in similar studies of lacosamide retention, where median retention times varied from a little over half a year to about three years

Patient 6

[14,16,19,21]. However, the median retention time as a measure also reflects the number of patients at risk. The discontinuation of treatment in one patient may evince a larger impact on the estimated retention rate when the number of patients at risk is low and Kaplan-Meier survival analysis should be interpreted with caution when an increasing number of patients are censored [22]. Whilst the two-year retention rate of 57% in the current study in PWID is comparable to that of the general population, reported to be between 45 and 71%, the three-year retention rate of 56% in the current study is a little higher than the reported values for the general population, namely 35–53% [14–18]. This might be due to the influence of the amount of censored patients on estimated retention, as explained for the median retention time. Another possible explanation may lie in the difference in frequency or method of assessing efficacy in PWID compared to the general population. In the general population, seizure frequency was significantly reduced in 30–40% of patients [11–13]. A significant effect in the general population was usually defined as a 50% reduction in seizure frequency [16]. In our population, neurologists reported lacosamide to be effective in 48.5% of all patients, although we did not attempt to register exact effect sizes, since acquiring reliable data on seizure frequency is notoriously difficult in PWID. The higher long-term retention rates in our study in comparison with that of the general population, might therefore reflect that smaller gains were considered to justify the continuation of lacosamide, especially if lacosamide was well tolerated. The retention rates in our study also compare favourably to the results of two studies on the use of lacosamide in PWID, one small but more homogenous group of adults with Lennox-Gastaut syndrome [20] and another more heterogeneous cohort of about the same proportions as in our study [21]. The shorter median retention time in the Lennox-Gastaut study may point to lacosamide being less useful in such generalized forms of epilepsy, although we did not evince a difference in likelihood of treatment continuation between patients with generalized and partial onset of seizures. The difference in median retention time, as well as the steeper decrement of retention rates over time in the latter study with PWID [21] – with a one-year retention rate of 62.0%,

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comparable to ours, and increasingly lower two- and three-year retention rates –, may again be influenced by the faster decrement of the number of patients at risk. Alternatively, it might be based on a difference in outcome assessment and decisions to discontinue between centres. Eighty-three of 132 (63%) patients experienced adverse effects of lacosamide, which were at least part of the reason for discontinuation in 26.5%. Higher doses of lacosamide were prescribed in patients who continued using it, probably reflecting better tolerance. The most common adverse effects were ‘tiredness/somnolence’, ‘aggression/agitation’ and ‘instable gait’, in line with the most common adverse effects in patients with Lennox-Gastaut syndrome [20]. In the general population, somatic side effects such as dizziness, headache, diplopia, ataxia and nausea are more common [12,13,16,17]. Behavioural side effects are less common in the general population, with a reported incidence of about 4% [23]. Behavioural side effects generally appear to occur more often in PWID than in the general population [2]. In our study behavioural side effects were associated with discontinuation of lacosamide. We also noted positive behavioural effects in 10.6% of our subjects. A positive effect of lacosamide on mood has been reported in other studies as well [24]. Somatic side effects were reported less often in PWID than in the general population, which may indicate under-reporting due to limitations in communication skills. The dosage of lacosamide and number of concomitant AED’s were not significantly related to the incidence of side effects. The concomitant use of other sodium channel blockers also did not influence the incidence of side effects, however it did influence whether lacosamide was continued, possibly reflecting the tolerability of the side effects. This association might not be significant if we applied corrections for multiple comparisons and should therefore be interpreted with care. It is however in line with literature and an implication for further research in this population. Six patients, died during treatment with lacosamide. In four cases a clear cause of death was established, unrelated to epilepsy. Two deaths were ‘unexplained’. One of these two patients died seven months after starting treatment with lacosamide from Sudden Unexplained Death in Epilepsy (SUDEP) as classified by the treating physician and we feel this latency suggests it was unrelated to the medication [25]. The other patient died unexpectedly within two months of starting treatment with lacosamide, after experiencing symptoms of headache, vertigo, nausea, somnolence and high blood pressure. The patient was not known to have a cardiac disease and did not take concomitant medication associated with PR prolongation. Apart from the (preexistent) hypertension, all of these symptoms have been registered as possible side effects of lacosamide [26]. There have been sporadic reports of sudden cardiac death or severe cardiac complications as a result of high-dose lacosamide [27–29] and the EMA advise caution when prescribing lacosamide to patients with known conduction problems, concomitant medication associated with PR prolongation or patients with a history of severe cardiac disease (e.g. myocardial infarction and heart failure) [30]. However cardiac complications have never previously been attributed to treatment with the low dosage of lacosamide that was prescribed to our patient. Therefore we feel this case might also represent a case of SUDEP. Two SUDEPs in a sample of 132 therapy-resistant epilepsy patients, during a median follow-up period of over 4.5 years, do not exceed published estimates of SUDEP in this setting [31,32]. In the three centres that participated in the current study, routine ECGs are not performed before commencing lacosamide treatment. The yield of screening for cardiac abnormalities by routine ECG in this setting seems low [21].

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5. Conclusion Lacosamide seems effective and well-tolerated as an adjunctive anti-epileptic drug in this study of PWID and refractory epilepsy, irrespective of seizure classification and severity of intellectual disability. We found retention rates comparable to other adjunctive AED’s in this population, and to recently published rates of lacosamide in PWID. Frequent side effects were tiredness or somnolence, aggression or agitation and instable gait, which were the reason for discontinuation in a little over a quarter of all patients. Behavioural side effects were more common in our sample than in the general population. One patient died unexpectedly within two months after commencing treatment with lacosamide, possibly to be classified as a SUDEP. In conclusion, our data suggest lacosamide is an effective and safe treatment option in PWID and epilepsy who fail to respond to first-line AED’s, but special attention should be paid to behavioural adverse effects. Declaration of interest UCB Pharma Nederland BV provided an unrestricted grant for this study, covering travel costs and the work of JB. UCB or its employees had no involvement in the study design, data collection, analysis and interpretation or in the writing and submission of the article. References [1] Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. Lancet Neurol 2011;10:446–56. [2] Mattson RH. The role of the old and the new antiepileptic drugs in special populations: mental and multiple handicaps. Epilepsia 1996;37(Suppl. 6):45– 53. [3] Coulter DL. Epilepsy and mental retardation: an overview. Am J Ment Retard 1993;98(Suppl. 1):1–11. [4] Sunder TR. Meeting the challenge of epilepsy in persons with multiple handicaps. J Child Neurol 1997;12:38–43. [5] Carpay JA, Aalbers K, Graveland GA, Engelsman M. Retention of new AEDs in institutionalized intellectually disabled patients with epilepsy. Seizure 2009;18(2):119–23. [6] National Institute for Health and Clinical Excellence. Epilepsies: diagnosis and management. NICE guideline (CG137). . [7] Jackson CF, Makin SM, Marson AG, Kerr M. Pharmacological interventions for epilepsy in people with intellectual disabilities. Cochrane Database Syst Rev 2015;9:1–60. [8] Simister RJ, Sander JW, Koepp MJ. Long-term retention rates of new antiepileptic drugs in adults with chronic epilepsy and learning disability. Epilepsy Behav 2007;10:336–9. [9] Snoeijen-Schouwenaars FM, van Ool JS, Tan IY, Schelhaas HJ, Majoie MH. Evaluation of perampanel in patients with intellectual disability and epilepsy. Epilepsy Behav 2016;66:64–7. [10] Bootsma HP, Ricker L, Hekster YA, Hulsman J, Lambrechts D, Majoie M, et al. The impact of side effects on long-term retention in three new antiepileptic drugs. Seizure 2009;18:327–31. [11] Halász P, Kälviäinen R, Mazurkiewicz-Beldzinska M, Rosenow F, Doty P, Hebert D, et al. SP755 Study Group. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia 2009;50(3):443–53. [12] Ben-Menachem E, Biton V, Jatuzis D, Abou-Khalil B, Doty P, Rudd GD. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partialonset seizures. Epilepsia 2007;48(7):1308–17. [13] Chung S, Sperling MR, Biton V, Hebert D, Rudd GD, et al. SP754 Study Group. Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia 2010;51(6):958–67. [14] Novy J, Bartolini E, Bell GS, Duncan JS, Sander JW. Long-term retention of lacosamide in a large cohort of people with medically refractory epilepsy: a single centre evaluation. Epilepsy Res 2013;106:250–6. [15] Flores L, Kemp S, Colbeck K, Moran N, Quirk J, Ramkolea P, et al. Clinical experience with oral lacosamide as adjunctive therapy in adult patients with uncontrolled epilepsy: a multicentre study in epilepsy clinics in the United Kingdom (UK). Seizure 2012;21:512–7. [16] Rosenow F, Kelemen A, Ben-Menachem E, McShea C, Isojarvi J, Doty P. SP774 Study Investigators. Long-term adjunctive lacosamide treatment in patients with partial-onset seizures. Acta Neurol Scand 2016;2(133):136–44. [17] Rosenfeld W, Fountain NB, Kaubrys G, Ben-Menachem E, McShea C, Isojarvi J, et al. SP615 Study Investigators. Safety and efficacy of adjunctive lacosamide

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