Adjunctive lacosamide treatment for adult focal-onset epilepsy: focus on comorbid intellectual/developmental disorders and differing responses

Figures & data

Figure 1 Daily mean doses of background AEDs in the study population.

Note: ^*Sodium channel blockers: carbamazepine, lamotrigine, oxcarbazepine, phenytoin.
Abbreviations: AED, antiepileptic drug; CBZ, carbamazepine; LEV, levetiracetam; LMT, lamotrigine; OXC, oxcarbazepine; PHT, phenytoin; TPM, topiramate; VA, valproic acid; ZNS, zonisamide.

Table 1 Demographic characteristics of the patients

	Value
Age (years)	30 (16–79); 34±14.5a
Gender, n (%)
Male	70 (51.5%)b
Female	66 (48.5%)b
Epilepsy onset (age)	14 (1–65); 19.7±17.7a
Epilepsy duration (years)	11 (1–52); 14.3±11.0a
Lacosamide dose (mg/day)	300 (200–400); 323.5±66.9a
Follow-up duration (months)	11.5 (1–38); 15.3±11.7
Severity of IDDc (n)	46
Mild to moderate	10 (21.7%)d
Severe	28 (60.9%)d
Profound	8 (17.4%)d
Background AEDs (n)
Valproic acid	34 (25.0%)b
Carbamazepine	29 (21.3%)b
Oxcarbazepine	20 (14.7%)b
Lamotrigine	31 (22.8%)b
Levetiracetam	68 (50.0%)b
Topiramate	13 (9.6%)b
Epdantoin	9 (6.6%)b
Zonisamide	22 (16.2%)b
Concomitant antipsychotic medication (n)	17 (12.5%)b

Notes:

a Median (minimum–maximum); mean±SD.

b Number (percentage).

c According to the DSM-V criteria.

d Percentages were calculated according to the total number of patients with IDD.

Abbreviations: AED, antiepileptic drug; DSM-V, Diagnostic and Statistical Manual of Mental Disorders, fifth edition; IDD, intellectual/developmental disorder.

Table 2 Etiologic classification of the patient population

Etiology	n
Birth related and/or genetica	47 (34.6%)
Brain tumor	33 (24.3%)
Mesial temporal sclerosis	18 (13.2%)
Trauma	11 (8.1%)
Cerebrovascular/degenerative disease	8 (5.9%)
Cortical dysplasia	6 (4.4%)
Meningitis sequelae	6 (4.4%)
Tuberous sclerosis	5 (3.7%)
Arteriovenous malformation	1 (0.7%)
Paraneoplastic limbic encephalitis	1 (0.7%)

Note:

a Presumed birth-related complications and/or genetically inherited diseases.

Table 3 Comparison of patients with and without IDD

	IDD (+), n=46	IDD (−), n=90	P-valueb
Age (years)a	26.8±11.0; 23 (16–66)	37.7±14.7; 33.5 (16–79)	<0.001
Gender (male)	22 (47.8%)	48 (53.3%)	0.59
Follow-upa	15.3±12.9; 11 (1–38)	15.3±11.1; 12 (1–38)	0.67
LCM dosea	337.0±67.0; 325 (200–400)	316.7±66.2; 300 (200–400)	0.07
Use of concomitant SCB	30 (65.2%)	48 (53.3%)	0.20
Background AED, na	2.07±0.90; 2 (1–4)	1.62±0.57; 2 (1–3)	0.006
Side effect	16 (34.8%)	23 (25.6%)	0.32

Notes:

a Continuous variables are defined as mean ± SD and median (minimum–maximum), respectively.

b Mann–Whitney U test was used for the comparison of continuous variables.

Abbreviations: Background AED nr, number of initial antiepileptic drugs; IDD, intellectual/developmental disorders; LCM, lacosamide; concomitant SCB, concomitant traditional sodium channel blocking agent.

Figure 2 Kaplan–Meier survival analysis showed that the retention rates were significantly lower in patients with IDD when compared to those in patients without IDD (P=0.04).

Abbreviations: IDD, intellectual/developmental disorder; LCM, lacosamide.

Table 4 Retention rates of LCM treatment during follow-up in patients with and without IDD

Time period (months)	0	6	12	18	24	30	36
Patients at risk (on LCM), n
IDD −	90	70	46	34	22	17	3
IDD +	46	31	22	20	14	9	4
Discontinuation, n
IDD −	7	1	1	1	3	1	1
IDD +	12	2	0	0	1	1	0
Censored patients, n
IDD −	13	23	11	11	2	13	2
IDD +	3	7	2	6	4	4	4
Retention rate, %
IDD −	92	90	88	85	73	66	33
IDD +	73	68	68	68	62	53	53

Abbreviations: IDD, intellectual/developmental disorder; LCM, lacosamide.

Table 5 Daily dosage scheme of LCM and other AEDs at the time of discontinuation and the reasons for discontinuing LCM are shown

No.	Patient no.	Gender	Age (years)	Etiology	Discontinuation reason	Follow-up (months)	Lacosamide dose (mg)	Other AED, dosage (mg)
1	2	M	32	Birth related and/or genetica	Behavioral disorder	1b	300	LEV3,000, OXC900
2	7	M	44	Birth related and/or genetica	GI intolerance	6	300	OXC1,200
3	12	F	34	Brain tumor	Nausea/vomitingc	3	300	LAM300, CRB1,200
4	15	M	36	Birth related and/or genetica	Behavioral disorder	1b	400	LEV3,000
5	16	F	22	Mesial temporal sclerosis	Lack of efficacy	27	400	ZNS300, PHN300
6	22	M	19	Birth related and/or genetica	Behavioral disorder	1b	400	LEV2,000, PHN300
7	23	F	37	Brain tumor	Lack of efficacy	16	200	VAL1,500, PHN300
8	27	F	25	Cortical dysplasia	Pregnancy	37	400	LEV3,000, ZNS200
9	30	M	28	Birth related and/or genetica	Behavioral disorder	1b	350	LEV2,000, VAL1,500, OXC600
10	31	M	20	Meningitis sequelae	Palpitation	1	300	LAM300, PHN300
11	35	M	36	Birth related and/or genetica	Nausea/vomiting	3	300	LEV2,000, VAL2,000, LAM200
12	45	F	50	Birth related and/or genetica	Behavioral disorder	1b	200	LEV2,000, VAL1,000
13	46	F	16	Birth related and/or genetica	Lack of efficacy	34	300	LAM300, OXC1,200, VAL2,000, ZNS200
14	49	M	21	Post-traumatic	Nausea/vomiting	1	300	LAM400, CRB1,200
15	51	F	20	Birth related and/or genetica	Behavioral disorder	1b	300	LEV1,500
16	54	F	22	Birth related and/or genetica	Lack of efficacy	2	200	CRB1,200, ZNS200
17	67	F	16	Birth related and/or genetica	Allergic reaction	2	300	LAM200, OXC1,200
18	69	M	29	Birth related and/or genetica	Palpitation	4	400	LEV3,000, VAL3,000, CRB1,200
19	75	M	33	Mesial temporal sclerosis	Suicidal thoughts	10	300	LEV2,000, PHN200
20	77	F	27	Post-traumatic	Behavioral disorder	1b	300	LEV2,000, OXC1,200
21	78	M	52	Brain tumor	Lack of efficacy	28	300	LEV3,000, CRB1,000
22	83	F	43	Birth related and/or genetica	Palpitation	2	400	LAM350, PHN400
23	86	F	28	Post-traumatic	Lack of efficacy	19	300	LEV2,000
24	91	M	52	Brain tumor	Lack of efficacy	26	300	LEV1,000, CRB400
25	92	F	18	Birth related and/or genetica	Nausea/vomitingd	1	300	VAL750, CRB300
26	113	F	29	Mesial temporal sclerosis	Nausea/vomitingc	1	200	VAL1,500, OXC1,200
27	117	F	18	Birth related and/or genetica	Rash	11	400	LEV3,000, LAM300, CRB600, ZNS200
28	124	F	58	Post-traumatic	Fatigue	30	300	LEV3,000, CRB400
29	128	M	36	Brain tumor	Nausea	4	200	LEV1,500, PHN300
30	129	F	57	Cerebrovascular disease	Nausea/vomiting	2	300	LEV3,000, OXC900
31	136	M	27	Birth related and/or genetic	Lack of efficacy	25	300	LEV1,000, CRB1,200, VAL1,000

Notes:

a Presumed birth-related complications and/or genetically inherited diseases.

b Symptoms appeared in the first 2 weeks.

c Accompanied by vertiginous symptoms.

d Weight loss was observed.

Abbreviations: AED, antiepileptic drug; CRB, carbamazepine; GI, gastrointestinal; LAM, lamotrigine; LCM, lacosamide; LEV, levetiracetam; OXC, oxcarbazepine; PHN, phenytoin; VAL, valproic acid; ZNS, zonisamide.

Table 6 Cox regression analysis showed that use of traditional sodium channel blockers was the only independent predictor of retention rate of LCM treatment

	Odds ratio	95% CI	P-value
Age (years)	1.01	0.98–1.04	0.43
Gender (male)	1.65	0.79–3.43	0.18
Presence of IDD	0.58	0.25–1.32	0.19
Use of concomitant SCB	0.31	0.11–0.89	0.03
Background AEDs, n	1.51	0.94–2.45	0.09

Note: Background AED, initial antiepileptic drug.

Abbreviations: AED, antiepileptic drug; IDD, intellectual/developmental disorder; LCM, lacosamide; SCB, sodium channel blocker.

Table 7 Proposed criteria for forced normalization

Primary (essential) criteria

1. Established diagnosis of epilepsy based on clinical history, EEG, and imaging

2. Presence of a behavioral disturbance of acute or subacute onset characterized by one or more of the following:  • Psychosis with thought disorder, delusions, hallucinations  • Significant mood change, hypomania or mania, or depression  • Anxiety with depersonalization, derealization  • Hysteria: motor, sensory, aphasia

3A. Reduction in the total number of spikes counted in a 60-minute waking-state electroencephalographic recording with a 16-channel machine, using standard 10–20 electrode placement, by over 50% compared with a similar recording performed during a normal state of behavior

OR

3B. Report of complete cessation of seizures for at least 1 week, corroborated by a relative or a carer  Supportive criteria  Recent change (within 30 days) of pharmacotherapeutic regimen  Report of similar episodes of seizure cessation and behavioral disturbance in the past, from a close relative or a carer, or general practitioner, or documentation of this in hospital records with or without electroencephalographic evidence. This may or may not be linked with an anticonvulsant drug

To make the diagnosis

Primary criteria 1, 2, and 3A

OR

Primary criteria 1, 2, and 3B and one supportive criterion