INDIAN PSYCHOSOCIAL FOUNDATION
 
   INDIAN PSYCHOSOCIAL FOUNDATION
         
IJPS >
IJPS April 2011
IJPS October 2011
IJPS April 2012
IJPS October 2012
IJPS April 2013
IJPS October 2013
IJPS Apirl 2014
IJPS October 2014
IJPS Apirl 2015
IJPS Apirl 2016
IJPS October 2016
IJPS Apirl 2017
 
 
 
ADD-ON THERAPY TO LACOSAMIDE IN

ADD-ON THERAPY TO LACOSAMIDE IN FUNCTIONALLY COMPROMISED BRAIN WITH RESISTANT EPILEPSY IN CHILDREN.

1 J.S. Yadav, 2 S Kaur, 3 T.B. Singh 4K Singh,

Assist. Professor,  Deptt. Of Psychiatry, AIIMS New Delh,1 Psychologist, SRLM Hospital, Varanasi,2  Prof. Division of Biostatistics, IMS, BHU,3Associate Professor, Deptt. Of Neurosurgery, IMS, BHU. 4


Abstract

Background: Compromised brain function is condition of brain when it not able to function optimally due to underlying disease, congenital malformation, harmful environmental exposure or side effects of the course of treatment. Malformation of cortical development are brain lesions that have been associated with increased level of excitability and often co-exist with very severe epilepsies1

Aim: Children with functionally compromised brain are more prone to develop seizures and these groups are poorly tolerating the side effects of existing Antiepileptic Drugs (AEDs). Despite of best efforts 30% are refractory and this figure may be more in children, therefore for management of these groups our more hopes one to use newer AEDs.

Methodology: Twenty children of resistant seizure with functionally compromised brain have been recruited from neurosurgery and child guidance clinic of a S. S. Hospital BHU. There socio-demographic data were taken and baseline investigations/radiological examinations were done. Patients were rated on scales and were admitted for two weeks, all the AEDs were gradually withdrawn in care within one week, at the same time valproate were titrated up to 30-35mg/kg body weight depending upon their tolerability, in between if any patient developed seizure they were given parentrel valproate. LCM was added in the range of 3-5mg/kg body weight, if patients did not respond to adequate dose of valproate in the subsequent week. Patients stabilized on AEDs for two weeks in indoor then they were discharged after applying rating scales. All patients were monthly follow up and they were asked to contact if seizure occurred. The seizure count did on baseline.  Follow up duration was three month at the one month interval, in each follow up details were noted and scales were applied.  

Results: Twenty patients in age groups 7-21years were evaluated, we find prevalence of seizures and brain anomalies were more common in rural and low socio economic status children in all age groups. Maximum patients were receiving add-on AEDs therapy of two drugs, 86.25% patients had severe neurological/systemic, side effects and the mean seizures control were <50%. On biochemical/ radio graphical findings we find brain anomalies, callosal agenesis were common and these were less tolerated the AEDs combination. The add-on therapies of lacosamide with valproate were shown mean 98% response and two patients have minimal systemic side effects.                                                                                                              Conclusion: this study we find that callosal agenesis was common brain anomalies in these patients and were less tolerated to the AEDs combination. The Combined therapy of lacosamide and valproate was more effective in children than add- on therapy of other AEDs. This combination can given safely in children with special group those having resistant seizures.

Key words: Resistant epilepsy, Compromised brain, Anti epileptic

Introduction


Compromised brain function is condition of brain when it not able to function optimally due to underlying disease, congenital malformation, harmful environmental exposure or side effects of the course of treatment. Malformation of cortical development are brain lesions that have been associated with increased level of excitability and often co-exist with very severe epilepsies1. Among 70% infant /children with epilepsy, causative factors are head trauma, malformation of brain, brain tumors, stroke, cerebral hemorrhage, and lack of oxygen during birth, encephalitis, or meningitis, other physical and chemical insult 2. High proportions of children with malformation present with epilepsy are often resistant to medical treatment. The underlying causes may be (i) - Decreases numbers of GABA nergic neurons.( ii)- Increases secretion of glutamate in dysplastic area (iii)-Changes in intrinsic properties of aberrant neurons( iv)-Aberrant connection of dysplastic and normal structure has high propensity to develops epilepsy like infantile spasm TLE Lennox gas tout syndrome. Higher metabolism in dysplastic area in brain related to continuous epileptic activity 3. About 40% of children do not fined seizure free with antiepileptic drug therapy and are considered refractory, intractable or drug resistant patient. Lacosamide 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). The plasma level of AEDs those acts on cytochrome P-450 (carbamzepine and valproate) not markedly affected when given in combined therapy with LCM. It may also prevent the formation of inappropriate neuronal connections by binding to CRMP2 modulator of axon development 6 Lacosamide (LCM) is approved as adjunctive therapy in 17 years and older for partial onset seizures.  In randomized, double-blind, placebo-controlled clinical trials of adult patients with uncontrolled partial-onset seizures with or without secondary generalization, addition of lacosamide to other AEDs produced significantly greater reduction in seizure frequency than placebo 6,7. In retrospective study of 16 children with drugs resistant focal seizure mean age 14.9 years demonstrated good response to adjunction lacosamide without severe adverse effects 8. In a prospective study on 17patients mean age was 8+4.7years and follow up mean duration was 9.1 4 months, the mean seizure reduction was76% 9.  Little is known about the use of LCM in children, studies suggest that LCM benefit in children who have failed to respond to previous antiepileptic drugs (AEDs),8 In retrospective study of 16 children with drug-resistant focal epilepsy demonstrated good response to adjunctive lacosamide therapy median seizure reduction of 39.6%; 37.5% with ≥50% seizure reduction without severe adverse events8. Lacosamide can be used with extreme caution in children younger than 17 years old as there safety and efficacy have not been fully confirmed. Therefore we concentrated in our study to see the efficacy and safety of lacosamide in compromised brain with resistant seizure (CBRS) groups of children.

Aim

1.       To find out the difficult conditions in functionally compromised brain of children where management of seizures are more challenging.

2.       Asses the efficacy of combined therapy of Lacosamide and valproate in functional compromised brain with resistant seizure in children

Methodology

Sample selection was taken from neurosurgery and child guidance clinic S.S. Hospital BHU between 2010-2011 investigations of all children were done, and on the basis of CT scan/MRI findings they were further excluded or included.  Neuro -cognitive testing applied.  Socio demographic information is summarized in TABLE-1. Twenty two patients who met the resistant seizure criteria with functional compromised brain have been taken for the study, inclusion criteria was between the age 7-21 year, patients having addition brain deformities, post encephalitic sequelae, all has taken single or combined AEDs treatment  at least  4 months minimum duration in  higher doses, their seizures were not controlled, their parents were willing to give consent for treatment,  they were not able to  tolerate the side effect  of other AEDs, therefore further  not possible to increase the doses of either drug or the patient were receiving maximum doses but desirable effects have not been obtained. The patients were excluded who has other systemic side effects. Two patients were drop out because they not turned up in OPD. Finally twenty patients included in the study.TABLE-2.

 Neuro cognitive Testing

1.       All the patients were applied Wechsler intelligence scale for children (WISC) (Wechsler et al., 1991).9, International cooperative Ataxia Rating scale (ICARS) (Storey et al., 2004)4, Ashworth and scale for modified Ashworth scale for plasticity (ASAS) (Pandean et al., 1999), quality of life in epilepsy scale-89 in epileptic children10 McNamara test (Near et al., 1947)11 to compare the presence of seizures at baseline and during follow up.

Procedure

Each patient got admitted and they were underwent complete physical and neurological examinations. The parents/attendants of patient were given seizure recording diary. The diagnostic criteria of seizure based on International league against epilepsy. The titration of doses of valproate and LCM were done on basis of ILAE guideline and technical file of add on therapy of doses 3-5kg/body wt. of LCM respectively. At first all the AEDs were gradually withdrawn in care within one week, in between if any patient developed seizure they were given parentrel valproate. The doses of valproate were titrated up 30-35mg/kg body wt. depending upon their tolerability. The doses of LCM were also given 3-5mg per kg body wt. and the doses of LCM titrated depending on seizure control and eventual adverse events on maximum doses. Patients stabilized on AEDs for two weeks in indoor then they were discharged after applying rating scales. Subsequent follow up of all patients were done at minimum one month interval up three months and they were asked to contact if seizure occurred. The seizure count did on baseline. The side effects were noted and neuro-cognitive testing scales were applied on each visit.  

Statistical Analysis

Data score of all scales were analyzed, the mean scores on WISC were divided into three groups (70_+ 10, 50 + 10, 20+_10) of submental disorders. Majority of patients in severe mental retardation group has congenital abnormalities of brain. There were no significant changes in WISC scores find after LCM therapy but total scores were slightly higher than the previous. The mean Scores of quality of life in epilepsy scale- 89 for all epileptic patients were higher than the previous scores. Total scores reduction on (ASAS)  were significant lower, the mean quality of life in epilepsy scale-89 were higher and on McNemar test  seizures at baseline significantly reduced at end of three month follow up.

Results

Twenty children were received either combined or only single AEDs in maximum dose. The frequencies of seizures were variable in each age groups, the mean frequency of seizures were two /day in nine patients, 1.4 seizures/week in seven, and 1.5 seizures/months in four children. In addition on therapies with LCM and valproate mean dose range was 5mg/kg body wt., and 30mg/ kg body wt. respectively. We find prevalence of seizures and brain anomalies were more common in rural, low socio economic status group children in all age groups. Eighty percent patients were receiving add-on therapy of two or more AEDs drugs. 86.25% patients had severe neurological/systemic side effects and the mean seizures control was<50%. On biochemical/CT-scan/MRI finding we observed brain anomalies, callosal agenesis were common and these patients were less tolerated the AEDs combination. The add-on therapy of lacosamide with valproate was shown 98% response with minimal side effect after three months of therapy. The mean Scores of quality of life in epilepsy scale- 89 for all epileptic patients were higher than the initial scores.


Table-1: Socio –Demographic Profile of study subjects

 

Age groups

(in years)

Total patients

 

Male

Female

Urban

rural

Low S.E

Middle S.E

High S.E

Family history of seizure

07/10/12

12

(60)

8

(66.7)

4

(33.3)

2

(16.7)

10

(83.3)

8

(66.7)

4

(33.3)

-

5

(41.7)

11-13

4

(20)

3

(75)

1

(25)

1

(25)

3

(75)

3

(75)

1

(25)

-

2

(50)

14-17

3

(15)

2

(66.7)

1

(33.3)

-

3

(100)

3

(100)

-

-

2

(66.7)

18-21

1

(5)

1

(100)

--

1

(100)

-

-

1

(100)

-

-

Figures in parenthesis shows the percentage

 

TABLE-2 : Radio graphical findings and receiving treatment at the time of initial visit

 

Age groups

(in years)

Numbers of patient in each group

Investigative

finding(CT Scan/MRI)

Medical/neurological findings with seizure

Combined/single AEDs

therapy and

doses range

7-10

6

3

3

 

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

11-13

3

 

1

CA /PES

 

TA/DE

MR,CP,MD/

MR, MD,OBS/BD MD,OBS/BD

V +Le/E/

Ox+ E+ lam

C +lam

14-17

2

1

PES

TA/DE

MR, MD,OBS/BD

MD,OBS/BD

V +Le / Le+c

C

18-21

1

TA/DE

MR, 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/behavior disorder V-valproate, Le-leveteracetam, Ox- oxmcarbmazipine, E- Phenytoin, C-carbazepine 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

 

Table 3: Seizure frequency and their types after Valproate and LCM therapy

 

Age group

Total patients

Frequency and types of seizure at initial

Frequency and types of seizure at second month

Frequency and types of seizure at third month

Efficacy after month

second

third

7-10

12

D- 5/6

 

W-3/4

 

M-4/2

T-900

GTCS-6

PGC-3P-2

PM-1

W-1-3/5

M-2-3/6

F—1

T-58

GTCS-1

PGC-6

P-3

PM-1

W-1-2/2

M-1-2/4

F-6

T-18

 

PGC-4

P-2

 

 

93.5%

 

98%

11-13

4

D 3-5/1

W-1- 3/1

M-2/2

T-132

GTCS-3

PGC-1

W-1-2/1

M-1/2

F-1

T-8

PGC-3

M-1-2/2

F-2

T-3

P-2

 

93.9%

 

97.7%

14-17

3

D -10/2

W-3/1

T-612

GTCS-2

PGC-I

W-1-2/2

M- 1/1

T-13

GTCS-2

PGC-1

W- 1/1

M-1-2/1

F-1

T-5

PGC-1

P-1

 

97.9%

 

99.2%

18-21

1

W-1/1

T-4

PGC-I

M-1/1

T-1

P-1

F-1

T-0

-------

 

75%

 

100%s

D-day, W-week, M-month T-Total

GTCS-generalized tonic clonic seizure, PGC-partial generalized seizure,

P- Partial seizure, PM- psychomotor epilepsy

F- Seizure free                                                                                                        

Conclusion


Children with functionally compromised brain are special group of children those needs special medical support along with seizure management. These groups are also more vulnerable to tolerate the drug side effects and easily develops serious problem. Therefore before choice of any drug more precaution needs, especially in children those having co morbid problem of resistant seizure. These children mainly show poor academic, social development 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 became less effective and child developed serious side effects. 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 10, 11, 12 our study is single study in which we took special groups of children. In this study we find that the mean score of recovery was 98% in patients after three months follow-ups and 50% found seizure free The good response can be explained that i) almost non interaction of LCM with valproate in combination therapy ii) double mode of action with LCM in seizure prevention iii) LCM checks the newly formation of aberrant neurons those are responsible for new focal formation of epilepsy.  In quality of life rating scale in epilepsy, we found significant improvement from baseline in add-on with LCM region can be, many children taken for this study has more problems in their quality of life due to associated problems of


neurological deficit, mental subnormal ties, movement disorder, spasticity, decrease alertness, side effects of other AEDs and  uncontrolled seizures. Improvements were noticed in all symptoms after decreases with seizure frequency. We did not find any severe adverse reaction that could need to stops the therapy these finding further supports the almost non side effect on cognitive function. Although combination with valproate can impair the some cognitive function but overall finding after improvement in seizure of combined therapy were favorable symptomatic improvement. We observed minimal side effect in patient taking add-on therapy with LCM, one patient complained gastric upset and nausea during first week of valproate titration and one patient dizziness. The region for good compliance could be that previous therapy had more side effects and patients got adopted on AEDs.  We also find that the percentage of seizure reduction were more in children with congenital anomalies and 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 received LCM in BTRE with seizures, reported 42.9% seizure free and >50% reduced frequency in seizure 10.  Other study Supported this result that 46% becomes seizure free and 77% patient reduced frequency in seizure 13. Few study of LCM in children reported good response but unfortunately no enough studies carried in children those could support guideline recommending for treatment in children. This study encourages hope in functionally compromised brain related resistant epilepsy in children. 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 special group children.

 


 

References

  1. André Palmini, Peter Halasz, Ingrid E. Scheffer, Yukitoshi Takahashi, Angeles Perez Jimenez, François Dubeau, Frederick Andermann, Eliseu Paglioli-Neto, Jaderson Costa da Costa, Felix Rosenow, and Brita Fritsch. Reflex Seizures in Patients with Malformations of Cortical Development and Refractory EpilepsyEpilepsia 2005:46(8):1224-1234.
  2. Cendes F, Andermann F, Carpenter S, Zatrorre RJ, Cashman NR, Temporal lobe epilepsy caused by domoic acid intoxication:evidence for glutamate –mediated excitotoxicity in humans. Ann Neurol 1995; 37:123-6.
  3. A.G. de Volder, J.F.A. Gadisseux, C.J. Michel, J.M.V. Maloteaux, A.C. Bol, C.B. Grandin.Brain glucose utilization in band heterotopia: synaptic activity of “double cortex”Pediatr Neurol, 11 (1994), pp. 290–294.

  1. Ben-Menachem E, Biton V, Jatuzis D, Abou-Khalil B, Doty P, Rudd GD (2007). "Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures". Epilepsia 48 (7): 1308–17

 

  1. Cross SA, Curran MP.1.Drugs 2009; 69(4):449-459.

 

  1. Storey E, Tuck K, Hester R, Hughs A, Churchyard A. Inter-rater reliability of the international corporation Ataxia rating scale(ICARS) Mov Disord 2004;19:1261-62.

 

  1. Heyman E  , Lahat L , Levin N, berkovitch Preliminary  efficiently and safety of lacosamide in children with refractory epilepsy; Eur j paediatr  neurol :2011 14 September {epud ahead of print

 

  1. C,Breau L,Camfield, P.Impact of pediatric epilepsy on the family: a scale for clinical      and research use. Epilepsia2001; 42:104-12.

 

  1. Maschio M, Dinapoli L,Vidri A Vidiri, A Pace, A Febi, A.Pompili, M.C. Caraplla and B. Jandolo (2009) The role side effect play in the choice of antiepileptic therapy in brain tumour related epilepsy: A comparative study on traditional antiepileptic drugs versus oxcarbazepine. J Exp cli cancer Res. 28:60.

 

  1. Maschio M, Dinapoli L,Saveriano F, Jandolo B. (2009) Efficacy and tolerability of zonisamide as add-on in brain tumour related epilepsy: Prelimary report. Acta Neurol scand 120:210-212.

 

  1. Maschio M, Dinapoli L, Mingoia M,Sperati F.  Lacosamide as add-on in brain tumor-related epilepsy: preliminary report on efficacy and tolerbilityJ Neurol (2011) 258:2100–2104.

 

  1. Newton HB,ConnellyJ, Lima J, Cunnigham H, Pearl D, MallKin M. Lacosamide in brain tumour patients with refractory seizure: efficacy and tolerability. J Nerol (2010) 25 (suppl.1): S1-s246, P476.

 

  1. Ben Menachem E, Biston V, jatuzis D, abou khalil B, Doty P, Rudd GD(2007) Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial onset seizure. Epilepsia 48:1308-1317.

 

  1. Keleman A, Halasz P (2010) Lacosamide for the prevention of partial onset seizure in epileptic adult. Neuropsychiatry. Dis Treat 6:465-471.