ABSTRACT | PDF

RESEARCH

Comparative efficacy of antiepileptic drugs and lacosamide in patients with epilepsy due to an underlying brain lesion

Jai Singh Yadav, Maheshwar Nath Tripathi1, Samiksha Kaur2, Tej Bali Singh3

Assistant professor, 1Ex-Senior Resident, Department of Psychiatry, Institute of Medical Sciences, Banaras Hindu University, 2Psychologist, SRLM Hospital,3Professor, Division of Biostatistics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

 

Abstract

Aim: We aimed to compare the efficacy of other antiepileptic drugs (AEDs) to lacosamide (LCM) in patients with epilepsy due to an underlying brain lesion.

Methods: Total fifty patients were screened for the study. The sociodemographic data, side effects, frequency of seizures recorded and neurocognitive rating scales were applied in all patients fulfilling the inclusion criteria. Patients were given LCM in doses range of 6-8 mg/kg body weight. Follow up were done at monthly interval for three months.

Results: We found prevalence of seizures and encephalitis of brain was more common in rural and low socioeconomic status patients in all age groups. Maximum patients were receiving add-on AEDs therapy of two or more drugs. The patients with seizures in post encephalitis of brain and sequelae were less tolerated to higher doses AEDs and its combinations. 86.25% patients had severe neurological/systemic side effects and the mean seizures control were <50%.

Conclusions: The seizures of these patients can be effectively controlled by LCM in comparison to other AEDs.

 

Yadav JS, Tripathi MN, Kaur S, Singh TB. Comparative efficacy of antiepileptic drugs and lacosamide in patients with epilepsy due to an underlying brain lesion. Dysphrenia. 2013;4:127-31.

Keywords: Neurons. Drug resistance. Seizures. Quality of life.

Correspondence: dr.maheshwar@gmail.com

Received on 7 December 2012. Accepted on 28 January 2013.

 

 

Introduction

In a study of 160 patients diagnosed with organic mental disorders, seizure disorder represented maximum number of cases.[1] Among 70%  patients  with epilepsy, causative factors are head trauma,  malformation  of brain, brain tumours, stroke, cerebral haemorrhage, lack of oxygen during birth, encephalitis, post encephalitic sequelae, or other physical and chemical insult.[2] High proportions of post encephalitis sequelae are resistant to medical treatment. The possible underlying causes can be (i) decrease numbers of gamma aminobutyric acid (GABA)-ergic neurons, (ii) increase secretion of glutamate in degenerative area of brain, (ii) changes in intrinsic properties of aberrant neurons, and (iv) aberrant connection of degenerative neurons have high propensity to develops epilepsy. Higher metabolism of diseased area in brain is related to continuous epileptic activity.[3] About 30% of patients do not become seizure free with antiepileptic drug (AED) therapy and are considered refractory or drug resistant patients.

Lacosamide (LCM) is effective in seizure reduction as adjunctive therapy in patients with uncontrolled partial onset seizures.[4,5] It acts through enhancement of slow activation of voltage gated sodium channels and also through functional interaction with collapsin response mediator protein-2 (CRMP2). It may also prevent the formation of inappropriate neuronal connections by binding to CRMP2 modulator of axon development.[6] LCM is approved as adjunctive therapy in 17 years and older for partial onset seizures. In randomised, double-blind, placebo-controlled clinical trials of adult patients with uncontrolled partial onset seizures with or without secondary generalisation, LCM produced significantly greater reduction in seizure frequency than placebo.[4,7,8]

Aim: To compare the efficacy of other antiepileptic drugs to LCM in patients with epilepsy due to an underlying brain lesion.

Methods: Eighty patients were screened for study from neurology clinic of Sir Sunderlal Hospital, Banaras Hindu University, Varanasi, Uttar Pradesh, India from January 2011 to January 2012. The diagnoses of all patients were done by consultant in charge of outpatient department (OPD). The patients fulfilling the following inclusion criteria were included in study:

1. Age between17-60 years.

2. Patients had no additional brain diseases like tumour, trauma, systemic illness.

Table 1. Diagnosis, radiographical findings and receiving treatment at the time of initial visit

Age groups

(years)

Number of patients in each group

Investigative

finding (CT scan/MRI)

Medical/neurological findings with seizure

Combined/single AEDs therapy and

dose range

17-27

10

3

5

CA

PES

TA/DE

MR, CP, MD

MD, OBS/BD

MD, OBS/BD

V+Le/Le+C

Ox+E+Lam/C+Lam

E+C+Lam/V/E

28-38

6

4

CA/PES

TA/DE

MR, CP, MD

MD, OBS/BD

V+Le/E

C+Lam

39-49

4

5

PES

TA/DE

MR, MD, OBS/BD

MD, OBS/BD

V+Le/Le+C

C

50-60

11

TA/DE

MD, OBS/BD

V+Le

CA=Congenital anomalies; PES=Post encephalitic sequelae; TA/DE=Trauma/degenerative; MR=Mental retardation; CP=Cerebral palsy; MD=Movement disorder; OBS/BD=Other psychotic/behaviour disorder; V=Valproate; Le=Levetiracetam; Ox=Oxcarbazepine; E=Phenytoin; C=Carbamazepine; Lam=Lamotrigine

V: 30-40mg/kg, Le: 30-35mg/kg, C: 15-20mg/kg, OX: 30-35mg/kg, E: 5-10mg/kg, Lam: 3-4mg/k

3. Patients were on single or combined AEDs treatment for at least two months duration in adequate doses.

4. Their seizures were not controlled.

5. They were not able to tolerate the side effect of other AEDs.

6. Further increase in dose of either drug was not possible for desirable effects.

7. Patients were willing to give consent for treatment.

The baseline investigations such as routine examination of blood, cerebrospinal fluid (CSF) examination, computed tomography (CT) scan/magnetic resonance imaging (MRI) further excluded patients. Finally fifty patients fulfilled the selection criteria. Neurocognitive tests were administered on all 50 patients. Sociodemographic information was summarised. Patients were admitted for one month and they underwent complete physical and neurological examinations. The AEDs of all patients were gradually withdrawn in care within two weeks. During gradual withdrawal if any patient developed seizure they were given parenteral lorazepam. The dose of LCM was given 6-8 mg/kg body weight and the doses of LCM titrated depending on seizure control and eventual adverse events on maximum doses. The titration of LCM was done on basis of International League Against Epilepsy (ILAE) guideline and technical file of therapy. Patients stabilised on LCM for two weeks in indoor then they were discharged after applying rating scales. The patients/attendants of patient were given seizure recording diary. The subsequent follow up of all patients were done at minimum one month interval up to three months and they were asked to contact if seizure occurred. The seizure count, side effects were noted and neurocognitive testing scales were applied on each visit. Two patients dropped out because they did not turn up for follow up, therefore finally forty eight patients completed the study.

Neurocognitive testings: All patients were applied Bhatia’s Battery of Performance Test of Intelligence,[9] International Cooperative Ataxia Rating Scale for measurement of ataxia (ICARS),[10] Ashworth and modified Ashworth scales for spasticity(ASAS),[11] quality of life in epilepsy, McNemar test[12] to compare the presence of seizures at baseline and during follow up.

Statistical analysis: Statistical analysis was done to check for significant differences in terms of seizure count and adverse events.

Results

 We found that the prevalence of seizures in patients with underlying brain lesion was higher in rural people and people of low socioeconomic status. Eighty per cent patients of seizures were receiving add-on therapy of two or more AEDs (Table 1). 86.25% patients had severe neurological side effects and the mean seizures control was <50%. On biochemical/CT scan/MRI finding, we observed post encephalitic brain degeneration was common and these patients were less tolerated to higher single or in combination AEDs’ doses (Table 1).

 The mean frequencies of seizures were 5.9/day in 15 patients of different age group, 3.4 seizures/week in 21 patients and 1.8 seizures/month in 14 patients. Therapies with LCM mean dose range was 5-8 mg/kg body wt. The average rate of response was found >90% in all age groups with minimal side effects after three months of therapy. The mean scores of quality of life in epilepsy scale for all epileptic patients were higher than the initial scores (Table 2).

 

 

Table 2. Seizure frequency and their types after LCM therapy

Age

group

Total

patients

Frequency and

types of seizure at initial visit (frequency/patients)

Frequency and

types of seizure at second month (frequency/patients)

Frequency and

types of seizure at third month (frequency/patients)

Efficacy after

month

 

 

 

 

 

Second

Third

17-27

18

D-7/8

 

GTCS-4

PGC-3

P-1

 

 

 

 

 

 73.5%

91.5%

 W-5/6

 

GTCS-1

PGC-3

P-2

W-3/7

 

GTCS-2

PGC-3

P-2

 

 

M-2/4

 

PGC-3

P-1

M-2/2

 

PGC-2

M-2/4

PGC-2

P-2

 

 

F-9

 

F-16

 

T-94

 

T-25

 

T-8

 

28-38

10

D-5/4

GTCS-1

PGC-3

 

 

 

 

 

 

 

83.3%

89%

W- 3/4

PGC-3

P-1

W-2/2

PGC-2

 

 

 

M-2/2

 

PGC-1

PM-1

M-1/2

 

PGC-2

M-2/2

 

PGC -2

 

 

 

F-6

 

F-8

 

T-36

 

T-6

 

T-4

 

39-49

10

D -4/3

GTCS-2

PGC-1

 

 

 

 

 

82.76%

93.12%

W-3/5

GTCS-2

PGC-2

PGC-1

W-2/2

GTCS-1

PGC-1

W- 1/1

 

M-1/2

PGC-2

M-1/1

PGC-1

M-1/1

PGC-1

 

 

F-7

 

F-8

 

T-29

 

T-5

 

T-2

 

50-60

10

W-1/4

GTCS-2

PGC-2

 

 

 

 

93.8%

100%

M-2/6

GTCS-4

PGC-2

M-1/1

P-1

 

 

 

 

 

F-9

 

F-10

 

T-16

 

T-1

 

 

 

D-Day; W-Week; M-Month; T-Total; GTCS-Generalised tonic clonic seizure; PGC-Partial generalised seizure; P-Partial seizure; CPS-Complex partial seizure; F-Seizure free.

 

 

 

 

Discussion

Patients with post encephalitic sequelae are special group of patients and require special medical support along with seizure management. These groups are also more vulnerable to tolerate the drug side effects and easily develop serious problem. Therefore choice of drug requires more precaution, especially in patients having comorbid problem of resistant seizure. These patients mainly show poor academic, social performances and failure of thrive. In attempt to control resistant seizures of many cases, we are bound to increase dose or prescribe add-on therapy, but there are certain stages where these practice of increasing doses of AEDs becomes less effective and patients develop serious side effects. Tripathi et al.[13] called for cautious use of lamotrigine in patient’s already on valproic acid and highlighted the importance of patient education, prompt recognition and treatment for preventing mortality and morbidity associated with serious cutaneous reactions like Stevens-Johnson syndrome or more fatal, toxic epidermal necrolysis. Therefore there are hopes on new AEDs in these directions, but unfortunately these drugs are also unable to fulfill these needs in this special group.[14] Our study is single study in which we took special groups of patients. In this study we found that the mean score of recovery was 98% in patients after three months follow-ups and 50% were found seizure free. The response can be explained on basis of (i) double mode of action with LCM in seizure prevention and (ii) LCM checks the new formation of aberrant neurons those can be responsible for new focal formation of epilepsy.

In quality of life rating scale in epilepsy, we found significant improvement from baseline with LCM group, because many patients taken for this study had more problems in their quality of life due to associated problems of neurological deficit, mental subnormality, movement disorder, spasticity, decrease alertness, side effects of other AEDs and uncontrolled seizures. Improvements in all symptoms were observed with decrease in seizure frequency. Epilepsy is chronic and disabling illness; poor subjective well-being in this population seems to be associated with less effective self-care, more severe physical symptoms, greater functional impairment and disability as well as increased healthcare utilisation and expenditure.[15] Moreover, poor coping make it more difficult to treat the illness, since poor coping may make sufferers not to take care of themselves and follow prescribed treatment.[15]

We did not find any severe adverse reaction that amounts to stop the therapy. However one patient complained of gastric upset and nausea during first week of titration and one reported dizziness. These findings further support that LCM therapy shows almost minimum side effect on cognitive function. Although in higher dose it can impair some cognitive function but the overall finding after treatment with LCM was favourable in terms of symptomatic improvement. The reason for good compliance could be that previous therapy had more side effects and patients got adopted on AEDs. We also found that the percentage of seizure reduction were more in post encephalitic sequelae. The findings further support the suppressive effect of aberrant neuronal growth in epilepsy of these groups. There were two studies done on adult patients receiving LCM in brain tumour-related epilepsy with seizures, the findings were similar to our study.[16,17] There were report of 42.9% seizure free and >50% reduced frequency in seizure,[18] as well as 46% seizure free and 77% reduced frequency in seizure. Few studies of LCM in patients reported good response but unfortunately not enough studies are carried out that could support guideline recommending LCM for treatment in resistant seizures. This study encourages hope in patients due to underlying brain lesion related resistant epilepsy in patient. The limitations of study were small sample size and short duration of follow up. We address more studies with large sample size to assure the efficacy and safety in this special group of patients.

Acknowledgment: This study was neither funded nor assisted by any agency directly or indirectly. All work was done in interest of patients.

Ethics: This clinical work has been approved by the Banaras Hindu University ethics committee and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

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