neuropsychological and language evaluation in children...

Neuropsychological and Language Evaluation in

children with Benign Childhood Epilepsy with

Centrotemporal Spikes and its Functional MRI

correlation

Thesis submitted in fulfillment of the rules and regulations for DM

Degree Examination of Sree Chitra Tirunallnstitute for Medical

Sciences and Technology, Thiruvananthapuram

By Dr. Haseeb Hassan

Resident in Neurology

·Month and Year of Submission: October 2011

CERTIFICATE

I, Dr. Haseeb Hassan hereby declare that I have actually carried out the

project under report.

Date: 05-10-2011 ~Ha~ Place: Thiruvananthapuram Resident in Neurology.

Forwarded. He has carried out the project under report.

Dr. Sanjeev V Thomas (Guide),

Professor,

Department of Neurology,

SCTIMST.

~ Dr. Muraleedharan Nair,

Professor & Head,

Department of Neurology,

SCTIMST.

ACKNOWLEDGEMENTS

i express my heartfelt gratitude and indebtness to my esteemed teacher and guide Dr. Sanjeev V Thomas, Professor of Neurology, SCTIMST, Thiruvananthapuram. In spite of multifarious demand on his precious time, he constantly helped, guided and encouraged me in completing this work. His indepth knowledge, vast experience and dedication to research inspired me at every step of the study.

I am indebted to Dr. M. D. Nair, Senior Professor and Head, Department of Neurology for the constant support and encouragement.

I take this opportunity to sincerely thank Dr. K Radhakrishnan, Director & Senior Professor of Neurology, SCTIMST for providing me the opportunity to do this study.

I am grateful to Dr. C Kesavadas, Additional Professor, Department of IS & IR, SCTIMST, for supervising and guidance on functional MRI.

I express my special thanks to Dr. Neelima Gopinath (Neuropsychologist} and Mrs. Anu Mohan (Speech pathologist) for neuropsychological and language evaluation of the subject.

My special thanks to Dr. Ruma Mathur, Assistant professor, Department of Radiology, Medical college, Trivandrum for her help on designing language paradigm and helping in fMRI analysis.

I am thankful to Mrs. Jija S James (PhD student) and Mr. Diljit Singh (M.Tech Student) for their help on fMRI and DTI analysis.

My thanks to Mr. Venugopal and team (Electrophysiology lab) and Mr. Sabarinathan S (Medical social worker) for their support.

Lastly, I would like to thanks all the parents who consented to their child's participation in the study.

~~ Dr. Haseeb Hassan

CONTENTS

SL. NO. DESCRIPTION PAGE NO.

1. INTRODUCTION 1 -3

2. REVIEW OF LITERATURE 4-17

3. AIMS AND OBJECTIVES 18

4. MATERIALS AND METHODS 19-28

5. RESULTS AND ANALYSIS 29-43

6. DISCUSSION 44-49

7. CONCLUSION 50

8. REFERENCES 51-60

9. Appendix I: Study proforma 61-63

10. Appendix II: Handedness Inventory 64

INTRODUCTION

INTRODUCTION

INTRODUCTION

Benign childhood epilepsy with centro-temporal spikes (BECTS) is the most

common epilepsy syndrome of childhood and has excellent outcome in the term

of seizure with 98% of children outgrowing the disorder by puberty.1 The absence

of neuropsychological deficit has been considered a prerequisite for the

diagnosis of BECTS.2 However, recent studies suggest that the syndrome can be

associated with significant cognitive and learning disabilities.3•4•5•6 Understanding

the cognitive and behavioral co-morbidities, even in the context of a relatively

benign seizure disorder, remains an important area of concern in BECTS.

The localization of the epileptic focus in the perisylvian language areas has

prompted various investigators to study the relationship between interctal EEG

abnormality and language dysfunction. Some studies have reported side-specific

deficits, that is, impairment in attention and visuospatial tests, but not in verbal

span, in the case of prevalently right-sided interictal EEG abnormality7•8 or in

language tests in the case of a left-sided prevalence.9 Others have reported no

such correlation. 3 Cortical hyperexcitability in BECTS can vary over time in terms

of rate, lateralization and location that can influence pattern and severity of

neuropsychological and language dysfunction that may or may not correlate with

the EEG abnormality at given point of time. Reversal of neuropsychological

abnormality with subsidence of centro-temporal spikes has also been

INTRODUCTION 2

demonstrated by some author. 10 Lack of correlation with EEG abnormality and

persistant cognitive abnormality has been shown in many studies.

Persistence of cognitive abnormalities even after clinical and electrical remission

suggest that there is chronic interruption of neuropsychological function due to

disruption of organization of cortical function or network formation. Weather it is

directly linked to epileptiform discharges or "hereditary impairment of brain

maturation"11 is responsible for both epileptic activity and neuropsychological

abnormality is debatable.

Functional magnetic resonance imaging (fMRI) studies has emerged as

promising non-invasive tool to characterize language function reliably. 12

Language fMRI in refractory focal seizure of childhood have shown alteration of

pattern of language lateralization. However, only a handful studies on BECTS

and functional alteration in cerebral representation of language is available in

literature. Lillywhite et. al. has reported reduced lateralized fMRI related

language activation compared to controls in cohort of 20 BECTS patients.13

Diffusion tensor imaging (DTI) study has demonstrated leftward asymmetry in the

arcuate fasciculus in healthy right handed individual.14 In developmental dyslexia,

reduced fractional anisotropy compared to healthy controls has been

demonstrated.15 No published literature evaluating white matter tract changes in

BECTS are available to best of our knowledge.

INTRODUCTION 3

This study was taken to evaluate neuropsychological and language assessment

of children with SECTS and compare their fMRI and DTI characteristics with

healthy controls.

REVIEW OF

LITERATURE

REVIEW OF LITERATURE 4

REVIEW OF LITERATURE

The benign focal epilepsies of childhood are idiopathic epilepsies, the ILAE's

definition of which is "A syndrome that is only epilepsy, with no underlying

structural brain lesion or other neurologic signs or symptoms. These are

presumed to be genetic and are usually age-dependent"16 Benign childhood

epilepsy with centrotemporal spikes (BECTS) (also called Benign Rolandic

Epilepsy) is the most frequent form of the benign focal epilepsies and probably

most common epilepsy in children after febrile seizure. The reported prevalence

varies from10 to 24%.17•18 The usual age of onset is between 2to 13 years,19

though onset between 6 months and 14 years is reported.1 Younger onset

BECTS is associated with more active disease.1 The sex ratio is approximately

three boys to two girls.1

Seizure characteristics

Three-quarters of seizures occur in non-rapid-eye movement (non-REM) sleep,

usually shortly after sleep commences or before wakening. The most

recognizable seizure manifestations involve oropharyngolaryngeal symptoms

and hemifacial motor, sensory, or more usually sensorimotor symptoms.

Oropharyngolaryngeal symptoms occur in just over one-half of seizures, with

hemifacial sensorimotor manifestations occurring in around one-third of seizures.

Oropharyngolaryngeal symptoms consist of unilateral sensory (numbness and


parasthesia) and motor manifestations affecting the structures inside the mouth

(i.e., tongue, inner cheeks, teeth, and gums) and the pharynx and larynx. The

motor manifestations are responsible for gurgling, grunting, and guttural noises,

sometimes producing a so-called death rattle. The motor manifestations of the

hemifacial seizures consist of sudden, continuous, or burst of clonic contractions

usually localized to the lower lip and often accompanied by ipsilateral tonic

deviation of the mouth. In a minority of cases the motor manifestations are more

widespread with hemifacial clonic activity, sometimes with spread to the

ipsilateral upper limb. The sensory manifestations of the hemifacial seizures are

usually described as numbness or tingling in the corner of the mouth. Speech

arrest is very common in rolandic seizures, occurring in about 40% of patients.

Hypersalivation is reported to occur in around one-third of rolandic seizures In

more than one-half of rolandic seizures consciousness is retained throughout the

seizure, such that the child can often give a vivid description of his or her

experiences after the seizure. However, spread of rolandic seizures is common,

leading to impairment of consciousness and secondarily generalized tonic-clonic

seizures (GTCS). Seizure frequency is low, typically 2-5 total seizures, but also

quite variable, ranging from a single lifetime episode to multiple seizures per

day.1


Electroencephalography

The interictal EEG in children with rolandic epilepsy usually shows a normal

background activity. The hallmark of SECTS is centrotemporal (or rolandic)

spikes. The centrotemporal spikes are typically seen independently on both

sides. They can be unilateral also. They are broad, diphasic, high-voltage (i 00-

microvolts to 300-microvolts) spikes, with a transverse dipole, and they are often

followed by a slow wave. The spikes may occur isolated or in clusters, with a

rhythm of about 1.5 Hz to 3 Hz. The discharge rate is increased in drowsiness

and in all stages of sleep, and in about one third of children, the spikes appear

only in sleep. Sleep architecture is normaL Rolandic spikes are not

pathognomonic of SECTS. 1 to 2% of children between 5 and 12 years old who

do not have seizures also show Rolandic discharges in routine EEG recordings.20

Neuropsychological and language dysfunction in BECTS

Beaumanoir et al. were the first to describe cognitive problems in children with

SECTS. In 1 0 children, tests of cognitive function were performed. One girl had a

low IQ; she had average or below-average scores on all tests. Two children with

a predominantly left-sided focus performed below normal on a recognition test,

and two children with a right-sided focus obtained a low score on visuomotor

coordination (Bender test). However, despite their results, the authors concluded

that there is no evidence to indicate that rolandic spikes in epileptic children are

relevant. 21


Heijbel and Bohman studied 16 children with BECTS. Thirteen children were

seizure-free for more than 1 year. Their mean IQ did not had significantly

different from that of healthy controls. The children with BCECTS had

significantly worse scores on visuomotor coordination (Bender test) compared

with controls. No differences were noted with respect to school adjustment and

behavior. 22

Loiseau et at. studied 168 children with BECTS, 28 ( 16.7%) of whom had a mildly

subnormal IQ, learning difficulties, inattention, hyperactivity, or emotional

liability.23

D' Alessandro et al. reported the neuropsychological data of 44 children with

BECTS. The authors selected children who were seizure-free for more than 6

months and on no medication. Specific cognitive problems were detected on

attention, language, and visuomotor coordination tasks. Children with a bilateral

spike or spike-wave focus had the worst scores. The Wechsler FSIQ, PIQ, and

VIQ were within the normal range. In a follow-up assessment, 11 children were

retested when they were free of both seizures and EEG abnormalities for more

than 4 years. The problems in attention, language and visuomotor coordination

had disappeared in all.24' 25


Deanna et al. reported on three children with BECTS. They all suffered from

speech disturbances like word finding difficulties, poor articulation, phonological

errors, and stuttering. Language comprehension was normal in all.26

Wirrell et al. found that in a group of 42 children with BECTS, 8 (1go/o) had a mild

developmental delay. No neuropsychological testing was done in this study.27

Morooka et al. studied 18 children with BECTS. Eight (44%) children had

developmental disabilities; learning disabilities, hyperkinesis, ADHD, abnormal

behavior, and clumsiness were noted. 28

In a study on language dysfunction in children with BCECTS, Staden et al.

studied 20 children prospectively. Children were selected because of BCECTS,

irrespective of a history of learning or language problems. Thirteen children

(65%) showed language difficulties in 2 or more of 12 language tests. Eight

children had specific language impairment and five had language and

intelligence problems. 3

Croona et al. studied 17 children with BCECTS with typical seizure

manifestations and EEG characteristics, and 10 controls matched for age, sex,

and estimated intelligence. The children with BCECTS did worse on auditory-


verbal memory and auditory-verbal learning as well as some of the executive

functions. 29

GOndOz et al. studied 20 children with SECTS. All were treated with

carbamazepine and were seizure-free. Ten children (50%) had language delay or

learning problems.30

Yung et al. retrospectively analyzed cognitive and behavioral problems in 56

children with seizures and EEG characteristics suggestive of SECTS. Seven

children (12%) manifested mild or moderate intellectual problems, eight (14%)

had behavioral problems, and eight (14%) had specific learning disabilities.

Forty-one children (72%) had no cognitive or behavioral problems.10

Monjauze et al. studied language in 16 children with SECTS. Seven children

were seizure-free and showed no EEG abnormalities for more than 1 year. Six

children repeated a class and nine already had speech-language therapy. The

most affected domains were expressive grammar and literacy skills. No

difference between children with active SECTS and SECTS in remission was

found. However, Monjauze et al. reported that children with a short duration of

epilepsy had better scores in reading and spelling.31


Papavasiliou et al. studied 32 children with SECTS. None of them had atypical

clinical or EEG features or showed cognitive or behavioral regression. Children

were tested on reasoning skills, spelling, reading aloud, reading comprehension,

and dyslexia. In addition, parents were asked about the school performance of

their children. Results were compared with those of 36 controls without epilepsy

or other chronic disease. As a group, children with SECTS scored significantly

worse on spelling, reading aloud, reading comprehension, and dyslexia-type

errors. They frequently had below-average school performance. Eleven children

had severe written language problems; in 9 of them EEG abnormalities and

seizures had resolved after years but the learning problems were persistent.

EEG registrations were made while awake and during sleep. No relation between

EEG characteristics and language problems was observed.32

From our centre, Vinayan et al. studied 50 children with SCECTS. All of them

used antiepileptic drugs. Educational problems were noted in 26 (52%). Deficits

in neuropsychological or language tests were found in 19 children (38%).4

Northcott et al. described 42 children with SCECTS. Children were recruited from

six EEG laboratories. Twenty-seven (64%) children used antiepileptic

medication. Their results scored significantly below normative data in memory

and phonologic processing skills. EEG features were not associated with

cognitive difficulties.33


In conclusion, many series on cognitive and language difficulties in children with

BECTS have been reported in the last three decades. The most consistent noted

observation is language delay, learning disabilities, and academic problems. But

also in series of children with uncomplicated BECTS, lower average results are

reported on neuropsychological tests involving visuomotor coordination, some

executive functions, sustained attention, memory and learning of auditory-verbal

material, delayed recall, and verbal fluency, compared with controls.

Association between EEG abnormality and language and

neuropsychological impairment

The localization of the epileptic focus in the perisylvian language areas has

prompted various investigators to study the relationship between interctal EEG

abnormality and language dysfunction.

Woolf et al. studied correlation between focal lEOs and neuropsychological

deficit in 20 patients of BECTS. Focal spikes were located in the perisylvian

region in 13 children, in the occipital region in seven, and in the frontal region in

one. Five children had bilateral or multiple foci. Children with left perisylvian

spikes did not differ from the others in global IQ, but performed significantly lower

in language tests.9


Massa et al. studied 35 patients of BECTS. 28% had educational performance

and familial maladjustment occurred. These sociofamilial problems were

correlated with impulsivity, learning difficulties, attention disorders, and minor

(7/35 cases, 20%) or serious (3/35 cases, 8%) auditory-verbal or visual-spatial

deficits. Intermittent slow-wave focus, multiple asynchronous spike-wave foci,

long spike-wave clusters, generalized 3-cycles/second "absence-like" spike-wave

discharges, conjunction of interictal paroxysms with negative or positive

myoclonia, and abundance of interictal abnormalities during wakefulness and

sleep correlated with neuropsychological deficit.8

Vinayan et al. reported higher frequency of absence of tangential dipole in

patients with BECTS having educational problem.4

Staden et al. did not found any correlation between EEG abnormality and

cognitive dysfunction in study of 20 patients of SECTS. (rpt reference). No

relation between EEG characteristics and language problems was observed by

Papavasiliou et al. in a study of 32 children with BECTS.3

Weglage et al. studied 40 children with centrotemporal spikes. Twenty had

simple partial seizures, and 20 had undergone EEG because of headache. The

control group consisted of 40 children matched for age, sex, and socioeconomic

status. The children with centrotemporal spikes and rolandic seizures did not


differ from the children with centrotemporal spikes and headache. Combined,

they did significantly worse on the Wechsler FSIQ and PIQ, visual perception,

short-term memory, psychiatric status, and some subtests in a fine motor

performance task, compared with controls. 34

In summary, presence of centrotemporal spikes and its lateralization did not have

consistent correlation with the neurocognitive dysfunction. Atypical EEG

characteristics influence the neuropsychological and language outcome.

Reversal of neuropsychological deficit on subsidence of EEG abnormality is

reported by many investigators. Metz-Lutz et al. prospectively studied 22 children

with BECTS after a first epileptic seizure. Within the first half-year, 9 children

were noted to have academic problems. In 5 children, behavioral problems were

noted as well. In 14 children (64%), neuropsychological testing showed

significant problems in short-term memory, learning, and attention. The children

were retested 18 months later. The children whose EEG had become completely

normal in sleep and while awake achieved significantly higher scores than the

children whose EEG still showed epileptic activity.35

Lindgren et al. studied 32 children aged 7-15 years with BECTS. Twenty-six

children (81 %) were tested again years later, using the same neuropsychological

techniques. A matched group of 25 children without epilepsy was tested twice as


well. During the first assessment, children with SCECTS scored significantly

lower on memory and learning of auditory-verbal material, delayed recall,

executive functions, reading, and writing ability. No difference in immediate

memory, memory and learning of visuospatial material, and intellectual ability

was found. On reexamination, no difference between the children with SCECTS

and the control group was noted, except for verbal fluency.36

Papavasiliou et al. in a study of 32 children with SECTS has reported persistence

of language problem even after subsidence of EEG abnormality.32

Enough evidence is not there to suggest that suppressing EEG abnormality

improve the cognitive outcome in SECTS. Weather it is directly linked to

epileptiform discharges or "hereditary impairment of brain maturation" is

responsible for both epileptic activity and neuropsychological abnormality is

debatable.11


Language lateralization in BECTS patients

The behavioral37 and functional studies38 have shown that language gets

lateralize in early childhood and remains stable thereafter. Although the reason

for this specialization is unknown, it is often assumed that the functional

lateralization of the human brain has an adaptive value and may even present a

prerequisite for the full realization of the linguistic potential. Though atypical

language lateralization (Bilateral or right) is well known in refractory focal

epilepsy with structurallesion,39 there is only handful of study in idiopathic partial

epilepsies like SECTS. The characterization of the language areas can give

functional neuroanatomical correlate for language dysfunction in SECTS

patients.13

Piccirilli et al. selected 22 children with BCECTS to study hemispheric

lateralization of language. A verbal task was given to repeat the names of four

animals. This verbal task was combined with right- or left-hand finger tapping.

Their results suggest involvement of the right hemisphere in language in children

with a left-sided focus. The authors concluded that epileptiform activity in

BCECTS can modify the hemispheric lateralization of language40

Lillywhite et al. studied patterns of language lateralization using fMRI in 20

children with typical SECTS and compared with the healthy controls. The fMRI

analyses revealed that language- related activation was less lateralized to the left


hemisphere in anterior brain regions in the patients relative to the control group

consistent with decreased performance in the BECTS group compared to the

control group on the neuropsychological measure most dependent on the

integrity of anterior aspects of the language axis, namely, sentence production. 13

The intracarotid sodium amobarbital (Wada) test has been the standard method

for lateralizing language before epilepsy surgery. However, because of invasive

nature, the Wada test was limited as pre-operative assessment tool to plan

surgical resection and ascertain risk of post surgical deficit. Functional magnetic

resonance imaging (fMRI) is a newer, relatively safe neuroradiological technique

for localization of cortical function. fMRI detects the BOLD (blood oxygenation

level dependent) signal as an indicator of neuronal activity associated with the

performance of a specific task. 41 The functional activation map illustrates a

network of brain regions that are activated in response to a particular cognitive

task. A high concordance rate between fM Rl and Wad a test for assessment of

language lateralization is report.42• 43• 44


Diffusion tensor imaging of the language network

Language function characteristically involves multiple cortical areas connected

through white matter tracts. The arcuate fasciculus, a subdivision of the superior

longitudinal fasciculus, is a major white matter tract that is one of the primary

fiber bundles involved in human language processing. 45 The arcuate fasciculus

is not only important in language function, but it is also part of a network that has

been repeatedly implicated in reasoning and intelligence tasks.46•47 Using

tractography, DTI parameters such as fractional anisotropy (FA), an indirect

measure of myelination and/or axonal density within white matter,48 can be

measured, along specific white matter tracts, including the arcuate fasciculus.49

DTI studies of the arcuate fasciculus have demonstrated leftward asymmetry for

both structure and diffusion parameters in adults 14, 50 and children. 51 Measure of

laterality of arcuate fasciculus and FA values are found to correlate with cognitive

functions.52 In developmental dyslexia15 and autism,53 reduced fractional

anisotropy compared to healthy controls has been demonstrated. No published

literature evaluating white matter tract changes in BECTS are available to best of

our knowledge. This could be a valuable tool in understanding the underlying

pathomechanism of cognitive impairment in patients of idiopathic epilepsy.

AIMS

AND

OBJECTIVES

AIMS AND OBJECTIVES 18

AIMS AND OBJECTIVES

1. To characterize the neuropsychological and language function of children

with SECTS and compare with matched controls.

2. To assess the language lateralization by means of fMRI and compare with

the control.

3. To study the diffusion tensor characteristics of the arcuate fasiculus and

compare with the controls

·MATERIALS

AND

METHODS

MATERIALS AND METHODS 19

MATERIALS AND METHODS

DEGSIGN:

Cross-sectional observational Study

PLACE OF STUDY

Sree Chitra Tirunallnstitute for Medical Sciences &Technology (SCTIMST),

Thiruvananthapuram

SUBJECTS

CASES:

Fifteen children with BECTS who fulfilled the following criteria were enrolled for

the study as "cases":

• Satisfies both clinical and electrographic criteria for diagnosis of BECTS,

with normal neurological examination and neuroimaging (All response to

checklist part A is "yes" and checklist part B is "No")

• Age between 1 0 years - 16 years

• No additional clinically diagnosed neurological condition

• Malayalam as the native language

• Right handed (Score >+40 on Edinburgh Handedness Inventory). [See

Appendix--, page--]

• · Parents consenting for the study

EXCLUSION CRITERIA:

• Any response to checklist part A is "No" or checklist part 8 is "Yes"

• Contraindication or non-cooperation for MRI


• Visual or hearing impairment that could potentially interfere with fMRI task

performance

Check list (Part A)

l Did the child have at least one witnessed attack with typical features: Yes /No nocturnal, simple partial seizures affecting one side of the body, or on alternate sides; usually oro-facial-pharyngeal, with speech arrest and hypersalivation; secondary generalization may occur.

2 Is the age of onset between 3 and 12 years. Yes /No 3 Is rolandic seizures the first experienced seizure type? Yes /No

(with the exception of childhood absence seizures, occipital seizures, or febrile seizures)

4 Is The child's overall neurodevelopmental milestones within normal Yes /No limits.

5 Is the routine neurolocical examination normal. Yes /No 6 Does atleast one interictal BEG shows focal sharp waves of typical Yes /No

morphology and distribution, and a normal EEG background for age.?

7 Has the neuro imaging study excluded structural, ischemic, Yes /No inflammatory or space occupying lesions.? (Incidental lesions are exempted)

Check list (Part B) Potential patticipants will be excluded if any of the following is true:

I A witnessed history of seizure is not available, even in the presence Yes /No of a suggestive BEG.

2 Only the desctiption of a secondary generalized seizure, even with a Yes /No suggestive BEG.

3 Neurological examination is abnormal. Yes /No 4 Development is deviant or global developmental delay has been Yes /No

diagnosed by the physician. 5 There are atypical features in the history that are inconsistent with a Yes /No

diagnosis of RE or suggest another diagnosis with incidental Rolandic seizures. These include myoclonic or tonic seizure types; static orornotor deficits as in the congenital or acquired opercular syndromes; or a chromosomal dysmorphic syndrome.

6 There is abnormal background EEG pattern. Yes /No 7 Neuroimaging is obviously abnormal (see No.7 above). Yes /No


CONTROLS:

A total of 30 healthy controls (1 :2) were recruited from a single school. Controls

were selected through a stratified randamised sampling. The age and gender

was comparable to the cases. Consent of the parents were taken for neurological

examination and detailed neuropsychological and language assessment was

done at school. Patient with history of epilepsy (except febrile seizures) were

excluded from the study .. Parents of the children who agreed for clinical and

neuropsychological evaluation were invited for MR imaging. Only 4 parents

agreed to subject their children for the imaging study.

Assessment:

1. Clinical: Details history was taken from parents and was recorded in

structured performa (Appendix 1, page 61-63), that included demographic profile,

antenatal, birth and developmental history, details of seizures (Onset, semiology,

duration, type, frequency, drug treatment, response, any adverse events) were

recorded. Details of grade of study, academic performance (grade/ percentage of

marks), parental and teacher assessment of academic performance, any specific

area/ subject of difficulty, repetition of a grade was noted. Handedness was

determined by Edinburgh Handedness Inventory (Appendix 2, page 64).54

Detailed physical examination including general and systemic examination and

detailed neurological examination was performed.


2. Electroencephalography (EEG): All previous EEG tracing available were

reviewed. The patients not fulfilling the EEG criteria were excluded from the

study. A partial sleep deprived interictal digital scalp EEG was done for all the

patients and standard 1 0-20 system of extracranial electrode placement was

used. EEG was read by qualified electroencephalographer. Background activity,

presence or absence of interictal epileptiform discharges (lEOs) in wakefulness

and sleep activation of lEOs were recorded. According to the maximum negativity

(using referential derivations) and diphasic spikes (using bipolar montage), most

prominent focus was determined. Laterality was also noted. Presence or

absence of tangential dipole was also noted.55 Most abnormal EEG and the

current EEG were taken for analysis.

3. Neuropsychological and language assessment:

Subjects underwent a comprehensive neuropsychological and language

assessment. The neuropsychological assessment consisted of the Wechsler

Intelligence Scale for Children-IV (WISC-IV) 56 to obtain individual subset score,

index scores (Verbal Comprehension, Perceptual Reasoning, Working Memory

and Processing Speed) and full scale IQ (FSIQ) was calculated. Verbal learning

and memory were assessed with the Rey Auditory and Verbal learning Test

(RAVL T).57 In addition, Trail Making Test, a semantic fluency test, and the

Wechsler Memory Scale - revised (WMS-R) visual reproduction test were


administered to assess further executive functioning ability, processing speed,

and visual memory.

The language assessment was done using the Clinical Evaluation of Language

Fundamentals-4 (CELF-4).58 Individual subset scores, composite scores for

core language, receptive language, expressive language, language Content

index, language memory and working memory indices were calculated as per the

CELF scoring manual.

The neuropsychological and language assessment were held with sufficient time

gap in between to minimize fatigue for the subjects. Neuropsychological tests

were administered by clinical psychologist (Dr. Neelima Gopinathan) and

language assessment was done by speech and language pathologist (Mrs. Anu

Mohan).

4. MRI scanning

4.1 Subject preparation

Children were explained regarding the task with aid of power point presentation.

They were familarised with the scanner, head coil and scanner noise. Child was

made to rehearse on mock block design sequence of each paradigm with one

task and one rest block prepared on Microsoft power point presentation.


4"2 fMRI language paradigm

Three fMRIIanguage paradigms were administered for each subject.

1. Verb generation task: The paradigm consisted of alternate rest and active

condition. During active condition, subjects were shown picture and ask to

covertly generate related verb. Grey scale picture was used in order to reduce

visual activation. Images were projected through visual projection system to the

scaner screen. The pictures were synchronized to change after 2 imager pulse.

During rest phase, blank slide was alternated with a small 'x' symbol. Subjects

were instructed to look at it but not to generate verb. A total of 5 active and 5

rest blocks were presented alternatively and 1 00 measurements were taken in

total. During each active block, 5 pictures were presented. Each picture was

shown for 7.16 seconds (2 TE pulse).

2. Semantic language processing task: The block design and number of

measurements were same as Verb generation task. The stimuli consist of pairs

of nouns presented visually to the subjects that were either semantically related

or unrelated. The subject was instructed to press the response button of right

hand, if the words are semantically related or to press left button if unrelated.

During each active block, 5 pairs of words were presented.

3. Passive listening: The subjects were presented a story and were instructed

to listen carefully. The paradigm consisted of 10 (5 each) alternating 30 seconds


of active and rest period. During active period, story was presented in vernacular

language (Malayalam) and during rest period, the reverse audio tract of the

active part was played which was not comprehensible.

At the time of final analysis only verb generation task was used as there were

inconsistent results with semantic language and passive listening task.

4.3 Image acquisition:

The image was acquired on a 1.5-T MR imager (Avanto SQ engine, Siemens,

Erlangen, Germany).

1. Anatomical images: The anatomical images of the entire head were obtained

with a 3-D spoiled gradient-recalled acquisition in the steady state sequence (3-D

FLASH; TRITE 11/4.94 ms, flip angle 15 °, field of view 256 mm, slice thickness 1

mm, matrix 256x256). The sequence was used for final coregistration of the fMRI

images to the anatomical images. 3-D FLAIR (TRITE/TI 5,000/405/1,800 ms,

field of view 256 mm, slice thickness 1 mm, matrix 256x256) was also obtained

to coregister DTI tractography image.

2. fMRI: The functional images were collected by using a echoplanar imaging

(EPI) sequence (TRITE 3,580/50 ms, flip angle 90°, field of view 250 mm, matrix

64x64, 33 mm thick slice and 0.8 mm gap). Gradient field map (map of the BO


field) was done to mask the image areas where there was distortion and local

signal loss.

3. Diffusion tensor imaging: A spin-echo echo-planar DTI sequence was

performed with diffusion gradients along 30 noncollinear directions with the

following imag-ing parameters: TR 3500 ms, TE 1 05 ms, matrix 192 x 192, field

of view 230 mm2, 2 mm slice thickness with 1.5 mm gap averaged twice and with

a b factor of 0 and 1400 s/mm2.

4.4 Image processing and analysis

fMRI data were processed and language activation maps were generated using

the Statistical Parametric Mapping software (SPM8: Wellcome Department of

Imaging Neuroscience, London, UK). Preprocessing included realignment for

motion correction followed by co-registration of functional and anatomical image

(3D FLASH). Images were spatially normalized at 3 x 3 x 3 voxel size.

Normalized images were smoothed with an isotropic gaussian kernel filter, 6 x 6

x 6 mm full width, half maximum (FWHM) in x, y, z axes. Subject-specific SPM (t)

maps were computed by using a fixed-effects model with a significance level of

Puncorr < 0.01. Resultant individual activation maps thresholded at Puncorr < 0.01

were visually inspected to determine laterality of language activation.


A 5 point visual rating scale was used: 1 -Well lateralized to right side, 2- Less

lateralized to right side, 3 - Bilateral activation, 4 - Less lateralized to left side

and 5 - Well lateralized to left side. The rating was done by Neuroradiologist

(R.M) blinded for the details of subjects. Only Verb generation task was used for

analysis of language laterality. The subject with score 4 and 5 was grouped as

typicallateralization and score 1 , 2 and 3 was grouped as atypicallateralization.

Diffusion tensor imaging dataset was processed using DTI and Fiber Tools

software (Medical Physics, Dept. of Diagnostic Radiology, University Hospital

Freiburg, Freiburg, Germany). The diffusion tensors and their eigenvalues and

eigenvectors were calculated by the DTI processing unit of the software. DTI

based colour maps were generated. All the voxels of arcuate fasciculus was

manually selected and defined as region of interest on left and right side

separately. Mean FA values on each side were calculated. Laterality index of

mean FA value was calculated with formula of (Left FA- Right FA)/ (Left FA+

Right FA).


5. Statistical analysis

The patients demographic, clinical and EEG data was summarized as mean ±

SD for continuous variables and frequency and percentage for categorical

variables. The neuropsychological and language test results were expressed in

mean± SD. The assessment of the normality of data was done by Shapiro-Wilk

test. 2-tailed independent sample t-test was performed to compare the cases and

controls' neuropsychological and language score as the data was normally

distributed. The comparison of the scores of neuropsychological and language

tests with the clinical parameters were done using Spearman's rank correlation

coefficient or Mann-Whitney non-parametric test for independent samples

wherever appropriate.

The fMRI laterality was dichotomized into typical and atypical Jateralization.

Fisher's exact test was used to test the difference in the proportion between

cases and controls. Mann-Whitney U test! Fisher's exact test was applied to

study the difference in clinical characteristics of patients with atypical vs typical

lateralization.

p values of < 0.05 were considered as statistically significant. Statistical analysis

was performed with SPSS version 17.0 statistical software (SPSS Inc., Chicago,

IL).

RESULT

AND

ANALYSIS

29 RESULT AND ANALYSIS

RESULT AND ANALYSIS

A total of 15 patients were enrolled for the study from Epilepsy clinic of the

institute who fulfilled the inclusion criteria. There were 9 boys and 6 girls with

mean age of 11.8 years. Youngest and eldest child was 10 years and 15 years

respectively. The class of study ranged from 5th to gth standard. There were no

adverse perinatal events except prematurity in 1 child. One child had delayed

language development and required speech and language training. None of the

other children had any development delay, behavioral or medical co-morbidities.

Neurological examination was normal except for generalized hyperreflexia in one

and generalized hypotonia in another patient. The demographic profile is

summarized in Table 1.

Table 1: Demographic profile of the cases.

Age at the time of participation to study (In years) 11.8 ± 1.6 (10 -15) Mean ± SD (Range)

Boy to Girl ratio 3:2

Class of study; n (%)

Class V 3 (20%) Class VI 5 (33%) Class VII 3 (20%) Class VIII 3 (20%) Class IX 1 (7%) Adverse perinatal event (Prematurity) 1 (7%)

Delayed language development 1 (7%)


Seizure characteristics

All patients had either only nocturnal or predominantly nocturnal seizures. Only

27% (n = 4} children had additional daytime events also. Majority of parents

reported witnessing focal onset seizures predominantly involving face (27%),

face and upper limb (47%) and upper limb only (7%). Rest of the 3 parents

reported one side involvement but not sure of distribution. Left sided focal jerks

were reported in 4 (27%), right sided in 3 (20%) and 1 patient was reported to

have either side involvement on different occasions. Eight of the parents were

not certain about the side. Three (20%) patients had history of secondary

generalized seizures. None of the patients had prolonged seizures, history of

clustering or status epilepticus. The patients had relatively less frequent seizure

(1.7 events/patient/year), ranging from a total of 1 to 20 events. 40% of children

experienced a total of :S 5 events. More than 1 0 events occurred in one-third of

the patients. None of the child had history of febrile seizure. Family history of

febrile seizure was noted in 1 and one of the patient's father is diagnosed to have

idiopathic generalized epilepsy. None of the patient had family members affected

with learning difficulty or mental retardation.

Approximately three-forth of the patients had more than 1-year of seizure

freedom at the time of the study and mean seizure freedom was 32 months.

History of use of carbamazepine/ oxcarbamazepine was present in two-third (n =

1 0) patients. 1 patient had increased frequency of seizure with carbamazepine

and 3 (20%) of parents reported it as ineffective. Valporate was prescribed to 12


patients (80%). Only one patient received clobazam as add-on therapy. At the

time of enrollment to study, 1 patient was off medication, 11 patients were on

valporate monotherapy and 3 patients were on carbamazepine monotherapy.

The mean dose for valporate was 490 mg/day (200 mg - 800 mg) and for

carbamazepine was 460 mg (400 mg- 600 mg). The details of seizure and anti-

epileptic medications are summarized in table 2.

Table 2: Seizure characteristics and anti-epileptic medication

Age of first seizure (In years) 6.5 ± 1.7 (4 -10) Mean± SD (Range)

Total number of seizure 9 ± 5.8 (1 - 20) Mean± SD (Range)

Total number of seizures; n (%) 6 (40%) 1-5

6-10 4 (27%)

>10 5 (33%)

History of secondary generalized seizures; n (%) 3 (20%)

History of additional awake seizures; n (%) 4 (27%)

Duration of seizure freedom at the time of enrollment to

study (in months); Mean± SD (Range) 32.7 ± 29.4 (2- 96)

,,

Anti-epiletic medication used at any time course of disease Carbamazepine/ Oxcarbamazepine 10 (66%) Sodium Valporate 12 (80%) Clobazam 1 (7%) Anti-epilepic medication at time of enrollment to study Carbamazepine/ Oxcarbamazepine 03 (20%) Sodium Valporate 11 (73%) NoAED 01 (07%)

1-year seizure freedom at time of study; n (%) 11 (73%)

Family history of Febrile seizure 1 (7%)

Family history of idiopathic epilepsy 1 (7%}


EEG characteristics:

The patient was recruited for the study after reviewing the previous EEG(s). A

repeat EEG was done for study participants. 2 to 4 EEGs (Mean 2. 7 EEGs) per

patient were available for analysis. The most abnormal EEG and EEG at time of

enrollment were analyzed. Other EEGs were noted for any additional findings. A!l

EEG consisted of awake and sleep records. All patients had centro-temporal

spike in their most abnormal EEG both in awake and sleep. During awake, 5

patients had left CT spikes, 3 had right centro-temporal spikes and 8 had bilateral

independent spikes. All patients had increased activation during sleep. Additional

activation on contralateral side was noted in 4 patients during sleep. No

background slowing or atypical features were noted in any of the subjects.

A normal awake and sleep record was seen in 40% of the patients at the time of

inclusion to the study. Awake record of 8 patients were abnormal (Left - 1, Right

- 3 and bilateral - 5). 1 patient with normal awake record showed right CTS in

sleep. The hemispheric distribution of the centro-temporal spikes has been

shown in figure 1. A representative EEG example is shown in Figure 2.

The patients with normal EEG and those with abnormal EEG were compared for

difference in clinical variables. None of the patient with history of seizure in last 1

year had a normal EEG. Six out of 11 patients (54%) with 1-year seizure

remission had a normal EEG. The age of onset was similar but patients with

RESULT AND ANALYSIS 33

normal EEG was significantly younger (p = 0.26, Mann Whitney U test). The

comparison is summerised in table 3.

Figure 1: The hemispheric distribution of the centro-temporal spikes.

Awake Sleep Awake Sleep Most Abnormal EEG EEG at time of enrollment

Table 3: Comparison of clinical variables based of EEG at time of enrollment to the study

Clinical characteristics EEG at time of enrollment to the study

p value Clinical characteristics Normal EEG (n = 6) Abnormal EEG (n = 9) p value Age (In years) 12.711.9 11.2 ±1.1 0.27* Gender (Male) 5/6 4/9 0.29** Age at onset (In years) 5.3±1.3 7.3 11.9 0.03* Time of last seizure (Yrs) 4.3 ± 2.8 1.711.3 0.07* 1 -year seizure freedom 6/6 5/11 0.10** Current AED(Valporate/ carbamazepine)

3/5 8/9 0.50**

* Mann-Whitney U test (2 tailed) Fisher's exact test


^ I ^ - - ' V \ / A A ^ V V V ^ - ^ A V V V ^ ^ _ _ _ _ _

- y ^ — v — V W — " V ^ / ? -

Figure 2: EEG tracing of a patient showing right centro-temporal discharge in

awake and a normal background activity (A - Bipolar longitudinal montage, B -

Common average referential montage). Sleep tracings (B and D) shows marked

activation of independent bilateral centro-temporal discharges (Left > Right).

Frontal tangential dipole can be seen in common average referential montage

(D).


Neuropsychological and language assessment

The results of neuropsychological assessment in 15 cases and language

evaluation in 14 cases were compared to 30 healthy controls who were

administered same neuropsychological and language tests. The summary of the

scores is summarized in Table 3 and 4. The mean age of cases and controls

were i 1.8 and i 1.3 years respectively (p = 0.3). Both group consisted of 60%

boys and 40% girls.

The mean full scale intellectual quotient (FSIQ) other composite scores (VCI,

PRI, WMI and PSI) of Wechsler Intelligence Scale for Children- IV (WISC-IV)

was slightly lower in cases than in controls but the difference was not statistically

significance (Table 3). The trend towards poorer score in the processing speed

Index (PSI) was seen in the cases compared to the controls (73.8 vs 83.3; p =

0.08). The time taken to complete the trail making test- A, a test for processing

speed/ working memory was shorter in controls than cases (114.7 vs 86.5

seconds; p = 0.09). The performance of Trail making test part B and verbal

fluency was comparable between cases and control. The immediate and delayed

recall in visual reproduction was also similar. There was no significant difference

in the Rey Auditory Verbal learning Test (RAVAL T) 5 trials scores between cases

and controls. However, both immediate and delayed recall of the new learning in

cases had statistically significant lower scores than controls. The recognition


scores were similar but intrusions were significantly higher in the cases than

controls (p = 0.03). Table 4 summarizes the results of the neuropsychological

tests.

The language performance of the cases was inferior to the controls in all

language indices. The difference was highest for the working memory indices.

However, the difference did not reach statistical significance. The results are

tabulated in table 5.

Among the cases, various clinical and EEG variable was compared for their

correlation with neuropsychological and language test scores. There was no

correlation between various test performance and the age of onset, gender,

number of seizure, 1-seizure freedom or EEG abnormality at the time of

enrollment to the study.


Table 4: The neuropsychological test scores of the cases and the controls Neuropsychological tests

WISC IV composite score

Verbal comprehension Index (VCI) Perceptual reasoning Index (PRI) Working memory index (WMI) Processing speed Index (PSI) Full scale IQ (FSIQ} Trail Making test Part A

Time taken (seconds) Errors Trail Making test Part B

Time taken (seconds) Errors Visual reproduction

Immediate recall Delayed recall . Verbal fluency

Letter fluency Animal fluency Rey Auditory Verbal learning Test (RAVALT) Trial I Trial II Trial ill Trial IV Trial V Sum (1-V) Immediate recall Delayed recall Recognition- Total Recognition - Intrusions * 2-tarled rndependent sample t-test ** i patient was not willing for the test

Cases Controls p (n = 15) (n = 30) value*

76.1 ± 19.1 79.3 ± 12.8 0.51 73.7 ± 14.9 76.8 ± 13.8 0.48 83.3 ± 16.1 88.3 ± 14.2 0.29 73.8 ± 18.1 83.3 ± 14.2 0.08 71.3 ± 18.6 76.7 ± 14.0 0.35

114.7 ± 78.5 86.5 ±30.7 0.09 0.07 ± 0.26 0.10±0.55 0.19

275.1 ± 151.0 285.8 ± 138.2 0.81 8.0 ±7.8 4.5 ±6.0 0.10

26.3 ± 6.8 27.8 ± 5.3 0.44 19.5 ± 10.8 21.6±7.6 0.48

23.3 ± 10.9 24.3 ± 7.8 0.71 i4.8 ± 4.9 13.9 ± 3.8 0.52 n = 14**

6.4 ± 2.6 6.3 ±2.0 0.89 8.9 ± 2.3 9.4±2.1 0.42 11.0 ± 2.1 11.3 ± 2.2 0.64 11.6 ± 3.1 12.7 ± 2.2 0.20 12.4 ± 2.1 13.3 ± 1.8 0.13 50.3 ± 10.8 52.7 ± 8.8 0.44 9.6 ± 4.1 11.6 ± 2.2 0.04 9.6 ± 3.9 11.5 ± 2.3 0.05 14±1.4 14.4 ± 0.9 0.21 1.1 ± 2.5 0.1 ± 0.3 0.03


Table 5: The language performance of the cases and the controls

Language assessment Cases Controls P value (CELF IV) (n=,14) (n = 30) Core Language score 82.8 ± 21.4 87.47 ± 19.2 0.47

Receptive Language index 83.6 ± 17.7 87.2 ± 16.2 0.51

Expressive Language index 85.6 ± 19.8 93.5 ± 21.0 0.24

Language Content index 93.1 ± 22.0 98.3 ± 21.6 0.46

-Language Memory index 76.6 ± 16.8 81.1±18.8 0.45

Working Memory index 79.9 ± 15.3 88.6 ± 16.2 0.09


Imaging characteristics

A total of 10 patients and 4 controls MR imaging was performed. No structural

abnormality was found in any of the cases or controls.

language fMRI

The statistical parametric maps of the verb generation task for individual patient

were visualized. All cases and controls had activation of Broca's area (Inferior

frontal gyrus). Activation of Wernicke's area (Superior and middle temporal

gyrus) was inconsistent in the cases. Only 4 (40%) of the cases had activation of

Wernike's area compared to 75% (3/4) of the controls.

All controls had language lateralization to the left hemisphere. 40% (n = 4) of the

cases had either bilateral (n = 2) or right > left activation (n = 2). The patients with

left hemispheric lateralization of language were grouped as typical language

lateralization and those with bilateral or right sided activation was grouped as

atypical lateralization. There was no statistical significance difference between

neuropsychological performance scores and language score between patients

with typical verses atypical lateralization. The age of onset, total number of

seizure or EEG lateralization did not correlated with the laterality of language.

The representative examples of a control with typical language lateralization and


case with atypical language lateralization are shown in figure 3 and 4

respectively.

Diffusion tensor imaging

A total of 9 cases and 4 controls fractional anisotropy (FA) of right and left

arcuate fasciculus was computed by defining the region of interest manually. The

mean FA from right and left arcuate fasciculus was similar in cases and controls.

Fractional anisotropy on the left side was higher than the right in 78% (7/9) of

cases and 75% (3/4) of controls. Laterality index of mean FA of arcuate fasiculus

between cases and controls did not have statistically significant difference. The

result is tabulated in table 5. The representative case depicting asymmetrical

arcuate fasciculus is shown in figure 5.

Table 5: Mean fractional anisotropy of arcuate fasciculus

Cases (n = 9)

Left Arcuate fasciculus FA 0.540 ± 0.023

Right Arcuate fasciculus FA 0.523 ± 0.031

Laterality index (LI)** 0.015 ± 0.020

* Mann-Whitney U test (2 ta1led) ** Ll = (Left - Right)/ (Left + Right}

Controls (n = 4)

0.541 ± 0.022

0.524 ± 0.021

0.016 ± 0.019

p value*

0.94

0.88

0.76


Figure 3: fMRI activation co-registered of FLASH 3D during verb generation task

in a healthy control showing well lateralized language activation to left inferior

frontal gyrus in axial (a), sagittal (b) and coronal (c) sections. Surface render of

fMRI brain activation showing left (e) > right (d) Broca's area. SPM t = 2. Images

are displayed in neurological convention (Image left is subject's left)


Figure 4: fMRI activation co-registered of FLASH 3D during verb generation task

in a patient of BECTS showing language activation of bilateral inferior frontal

gyrus and right middle frontal gyrus in axial (a) and sagittal (b) sections. Surface

render of fMRI brain activation showing right (c) > right (d) Broca's area. Also

poorly localized activation can be noted. SPM t = 1.8. Images are displayed in

neurological convention (Image left is subject's left)


Figure 5: Diffusion tensor imaging tractography of the arcuate fasciculus of a

patient of BECTS reconstructed on the Neuro 3D application package (Leonardo,

Siemens, Erlangen, Germany) by employing a fractional anisotropy threshold of

0.2 and a processing angle above 30°. The tract reconstructed was coregistered

on subject's FLAIR images. (A) Right arcuate fasciculus, sagittal section. (B) Left

arcuate fasciculus, sagittal section. (C) Coronal section showing both arcuate

fasciculi. Leftward asymmetry of arcuate fasciculus can be noted.

DISCUSSION

i,.

44 DISCUSSION

Discussion

In the present study, the patients of SECTS were recruited using strict clinical

and electrographic criteria to exclude atypical forms of SECTS. Atypical seizure

semiology is associated with high incidence of language delay59 and educational

problems. 4 Specific atypical EEG patterns has been shown to be associated with

cognitive and behavioral problems.8,60

The age of onset, gender ratio, seizure frequency and seizure semiology was

comparable to those described in literature.1 None of the patient had isolated day

time event and 27% (4/15) had additional day time event. Two-third of patient

had a total of less than 1 0 seizures and 40% has seizure s 5, 3 out of 4 patients

had seizure freedom of > 1 year and electrographic remission was seen in 40% at

the time of study. This is with agreement with the natural history of typical

SECTS described in literature.1

Parental interview revealed poor scholastic performance in 8 out of 15 patients

and 1 of them required speech and language training. The observation is similar

to the previous reported frequency of educational problem from this institute.4

The mean full scale IQ (FSIQ) were lower for both cases and controls; possibly

because of population normative data was derived from different population and

this could lead to possible misclassification.61 The scores can be used for

45 DISCUSSION

comparative study but not for classification. FSIQ between cases and controls

did not have statistically significant difference. This is with agreement with the

studies by GOndOz et al.30 and Croona et al.29 The sub-scores of WISC-IV also

did not have statistically significant difference between cases and controls.

However, cases showed a trend towards lower processing speed index score (p

= 0.08). Trail making test (Part A) and CELF-IV working memory index, other

tests for domain of working memory/ speed of processing also showed similar

trend (p = 0.09). Despite showing a trend, none of these tests achieved

statistically significant difference. Previous studies have also found the domains

of working memory I speed of processing being unaffected.3• 29 Immediate and

delayed visual recall was similar in cases and control.

The Rey Auditory Verbal learning Test (RAVALT) performance by cases and

controls were similar over 5 trials. Both immediate and delayed recall of new

learning after the distracter list was poorer than controls. The patients with

SECTS also had higher errors (intrusions) on recognition testing than controls.

However, the recognition scores were similar. Impaired verbal learning has been

noted by earlier authors.3• 29 Giordani et. al in large series of 200 patients found

normal verbal learning as compared to normative data. No control group was

taken in this study. Verbal learning and recall of new learning is important

cognitive domain in school age children. This finding, especially with history of

poor academic performance in patients of BECTS can be clinically relevant.62

I

~. - "

46 DISCUSSION

Both cases and controls performance was similar for measures of executive

function, namely verbal fluency and trail making test Part B. Northcot et.al. has

also reported normal executive function in patients of BECTS33 but executive

dysfunction in SECTS children has been demonstrated by Croon a et. al. 29

The language function scores were slightly lower for all indices in cases but did

not achieve statistical significance. However, 3 out of 14 cases had significantly

lower scores ( < 5th percentile of normative data) in language scores and 1 among

them was under speech and language training. Small sample size could be a

possible reason for not achieving statistically significant difference. Language

deficits in SECTS have been observed by various authors. Staden et al have

found language dysfunction in 65% of their cohort.3 Similar finding is being

reported by Monjauze et al.31

in this study, most abnormal EEG showed bilateral centrotemporal spikes in

three-forth of the cases. The number of patients with unilateral discharges was

too small to be statistically analyzed. At the time of enrollment to the study, 40%

went into electrographic remission but their neuropsychological and language

performance did not defer from the patient with electrographic abnormality. This

may suggest persistence of neuropsychological abnormalities even after

subsidence of electrical activity. The reversibility of cognitive deficit was observed

47 DISCUSSION

after electrographic remission by few authors, 10 has led to the concept of

transient cognitive impairment in BECTS. On the other hand, persistence of

neuropsychological abnormality has also been reported in literature.32 With the

current evidence for both transient and chronic impact of electrical discharges, it

is possible that both mechanisms might be responsible.

Age of onset, total number of seizures and the duration of seizure freedom did

not correlated with the neuropsychological and language scores. Majority of our

cohort was on valporate monotherapy. Cognitive dysfunction due to valporate

exposure in childhood is shown to be minimal and non-significant.63

The language fMRI study using verb generation task showed consistent

activation of the Broca's area in controls that was more than Wernike's area. The

pattern of activation in controls was in agreement with the previous reports of

pattern of activation in healthy children.64 In comparison, cases showed less

frequent activation of Wernike's area. In anterior language area, 40% of cases

showed atypical activation, which is higher than our controls and reported

literature on healthy control. All the patients were right handed with scores of +90

or above on Edinburgh Handedness Inventory. Though, because of small

number of controls, statistical significance difference could not be demonstrated,

this seems to be a significant finding to suggest less lateralization of language

function in BECTS. Statistical significant difference between the clinical variables

48 DISCUSSION

(Age of onset, number of seizure, seizure freedom) and neuropsychological and

language scores in the groups with typical and atypical language lateralization

was not found, but a definite conclusion cannot be drawn due to small sample

size. Lillywhite et. al has reported subtle but significance difference in

lateralization in BECTS cases than controls in inferior frontal gyrus and found

correlation with specific language function, namely, sentence production.13

The DTI analysis showed higher mean fractional anisotropy in left arcuate

fasciculus in both cases and controls. No difference was observed between the

cases and controls in their FA values on either side of difference in mean FA

values between right and left. Fiber density analysis was not done as arcuate

fasciculus could not be constructed in all subjects using semi-automated method.

To best of our knowledge, no published literature on language white matter tracts

study is available in idiopathic focal epilepsy. A limited analysis in small number

of our patient showed similar DTI characteristics between cases and controls

despite higher frequency of atypical language lateralization in cases. A more

extensive analysis on larger sample size is required to explore the correlation

between asymmetry of white matter tracts and cognitive abilities in idiopathic

focal epilepsies. A relationship between structural white matter lateralization and

specific cognitive abilities in healthy children is reported by Lebel et. al.52

49 DISCUSSION

The major strength of the study is the strict inclusion criteria to include only

patients with typical BECTS. Inclusion of a matched control group in 1 :2 ratio,

use of comprehensive widely accepted neuropsychological and language test

battery and uniformity in handedness of subjects are other strength of the study.

Smaller sample size undergoing functional neuroimaging is major limitation.

The cognitive dysfunction and scholastic performance in epilepsy is multifactorial

that includes seizure burden, anatomical reasons in lesional epilepsy,

psychosocial factors, antiepileptic medications and genetic causes. In rolandic

epilepsy, with few nocturnal seizures and relatively low dose of AEDs, many of

the confounders can be minimized. The underlying functional neuroanatomical

derangement in BECTS children could be more likely either due to inherited

factor or electrical discharges or possibly combination of both.8• 9• 10• 11 Wide array

of specific cognitive and language disturbance reported by various authors could

possibly suggest that the underlying neurocognitive dysfunction may be patient

specific. The migratory nature of cortical hyperexitability may be postulated as

possible explanation for the same. Early recognition and neuropsychological

intervention of the underlying deficit needs to be emphasized as there is no

definite evidence for targeting· electrical discharges as therapeutic end point.65

CONCLUSION

' ..

'

; j

50 CONCLUSION

CONCLUSION

Our study of 15 patients of Benign Epilepsy of Childhood with Centrotemporal

Spikes (BECTS) revealed significant scholastic problems despite less frequent

seizures. Recall and recognition of new learning was the most affected domain,

though performance was slightly poorer in major language indices compared to

controls. Higher frequency of atypical language lateralization was noted in cases

than control but interpretation was limited due to small sample size. A limited DTI

analysis showed similar results in cases and controls.

The results highlight the importance of recognizing the scholastic performance in

this sub-group of epilepsy which in termed as "Benign" to prevent the long term

impact on child's psychosocial development.

Functional MRI has shown atypical lateralization in BECTS patients

substantiating the hypothesis of lack of cortical maturation of language function.

However, it requires cooperation of the patient and hence, use in younger

children in challenging. DTI of language network is an upcoming promising tool

and can be helpful in younger children. Further studies are required to study the

relationship of cognitive function and fMRI of language and other domain and

white matter tract imaging.

REFERENCES

51 REFERENCES

REFERENCES

1. Bouma PA, Bovenkerk AC, Westendorp RG, Brouwer OF. The course

of benign partial epilepsy of childhood with centrotemporal spikes: a

meta-analysis. Neurology 1997;48:430-7.

2. Beaussart M. Benign epilepsy of children with Rolandic (centro

temporal) paroxysmal foci. A clinical entity. Study ,of 221 cases.

Epilepsia 1972; 13: 795-811.

3. Staden U, Isaacs E, Boyd SG, Brandl U, Neville BG. Language

dysfunction in children with Rolandic epilepsy. Neuropediatrics

1998;29:242-8.

4. Vinayan KP, Biji V, Thomas SV. Educational problems with underlying

neuropsychological impairment are common in children with benign

epilepsy of childhood with centrotemporal spikes (BECTS). Seizure

2005;14:207-12.

5. Riva D, Vago C, Franceschetti S, Pantaleoni C, D'arrigo S, Granata T,

Bulgheroni S. Intellectual and language findings and their relationship

to EEG characteristics in benign childhood epilepsy with

centrotemporal spikes. Epilepsy Behav 2007;1 0:278-85.

6. Pinton F, Ducat B, Motte J, Arbues AS, Barondiot C, Barthez MA et al.

Cognitive functions in children with benign childhood epilepsy with

centrotemporal spikes (BECTS). Epileptic Disord 2006;8:11-23

52 REFERENCES

7. Piccirilli M, D'Aiessandro P, Sciarma T, Cantoni C, Dioguardi MS,

Giuglietti M, et al. Attention problems in epilepsy: possibile significance

of the epileptogenic focus. Epilepsia 1994;35: 1 091-6.

8. Massa R, de Saint-Martin A, Carcangiu R, Rudolf G, Seegmuller C,

Kleitz C, et al. EEG criteria predictive of complicated evolution in

idiopathic rolandic epilepsy. Neurology 2001 ;57:1 071-9.

9. Woolf M, Weiskopf N, Serra E, Preiss! H, Birbaumer N, Kraegeloh

Mann I. Benign partial epilepsy in childhood: selective cognitive deficits

are related to the location of focal spikes determined by combined

EEG/MEG. Epilepsia 2005;46:1661-7.

10. Yung AW, Park YO, Cohen MJ, Garrison TN. Cognitive and behavioral

problems in children with centrotemporal spikes. Pediatr Neural

2000;23:391-5.

11. Doose H, Neubauer BA, Peterson B. The concept of hereditary

impairment of brain maturation. Epileptics disorders 2000; 2(Suppl. 1 ),

845-849.

12. Adcock JE, Wise RG, Oxbury JM, Oxbury SM, Matthews PM.

Quantitative fMRI assessment of the differences in lateralization of

language-related brain activation in patients with temporal lobe

epilepsy. Neuroimage. 2003;18:423-38.

53 REFERENCES

13. Lillywhite LM, Saling MM, Harvey AS, Abbott OF, Archer JS, Vears OF,

et al. Neuropsychological and functional MRI studies provide

converging evidence of anterior language dysfunction in SECTS.

Epilepsia. 2009 ;50 :2276-84.

14. Vernooij MW, Smits M, Wielopolski PA, Houston GC, Krestin GP,

vander Lugt A. Fiber density asymmetry of the arcuate fasciculus in

relation to functional hemispheric language lateralization in both right

and left-handed healthy subjects: a combined fMRI and OTI study.

Neuroimage. 2007;35:1 064-76.

15. Richards T, Stevenson J, Crouch J, Johnson LC, Maravilla K, Stock P,

Abbott R, Berninger V. Tract-based spatial statistics of diffusion tensor

imaging in adults with dyslexia. Am. J. Neuroradiol 2007;29, 1134-9.

16. Engel J Jr. A proposed diagnostic scheme for people with epileptic

seizures and with epilepsy: Report of the ILAE Task Force on

Classification and Terminology. Epilepsia 200i ;42:796-803.

17. Loiseau P, Ouche 8, Loiseau J. Classification of epilepsies and

epileptic syndromes in two different samples of patients. Epilepsia

1991 ;32:303-9.

18. Cavazzuti GB. Epidemiology of different types of epilepsy in school

age children of Modena, Italy. Epilepsia i 980;21 :57-62.

19. Holmes GL. Benign focal epilepsies of childhood. Epilepsia

1993;34:S49-61.

54 REFERENCES

20. Cavazutti GB, Cappella L, Nalin A. Longitudinal study of epileptiform

EEG patterns in normal children. Epilepsia 1980;21 :43-55

21. Beaumanoir A, Sallis T, Varfis G, Ansari K. Benign epilepsy of

childhood with rolandic spikes: a clinical, electroencephalographic, and

teleencephalographic study. Epilepsia 1974;15: 301-5.

22. Heijbel J, Bohman M. Benign epilepsy in children with centrotemporal

EEG foci: intelligence, behavior, and school adjustment. Epilepsia

1975;i 6:679-87.

23. Loiseau P, Duche B, Cordova S, Dartigues JF, Cohadon S. Prognosis

of benign childhood epilepsy with centrotemporal spikes: a follow-up

study of 168 patients. Epilepsia i 988;29:229-35.

24. D'Aiessandro P, Piccirilli M, Tiacci C, lbba A, Maiotti M, Sciarma T, et

al. Neuropsychological features of benign partial epilepsy in children.

ltal J Neural Sci. 1990; 11 :265-9.

25. D'AIIessandro P, Piccirilli M, Sciarma T, Tiacci C. Cognition in benign

childhood epilepsy: a longitudinal study. Epilepsia 1995;36 (suppl 3):

8124.

26. Deanna TW, Roulet E, Fontan D, Marcoz JP. Speech and oromotor

deficits of epileptic origin in benign partial epilepsy of childhood with

rolandic spikes (BPERS). Relationship to the acquired aphasia

epilepsy syndrome. Neuropediatrics 1993;24:83-7.

55 REFERENCES

27. Wirrell EC, Camfield PR, Gordon KE, Dooley JM, Camfield CS. Benign

rolandic epilepsy: atypical features are very common. J Child Neurol.

1995;10:455-8.

28. Morooka K, Arimoto K, Takagi K, Hoshino K, Kanzaki M.

Developmental disabilities in benign childhood epilepsy with

centrotemporal spikes. Epilepsia 1995; 36 (suppl3): 8127.

29. Croona C, Kihlgren M, Lundberg S, Eeg-Oiofsson 0, Eeg-Oiofsson

KE. Neuropsychological findings in children with benign childhood

epilepsy with centrotemporal spikes. Dev Med Child Neurol.

1999;41 :813-8.

30. GOndOz E, Demirbilek V, Korkmaz B. Benign roiandic epilepsy:

neuropsychological findings. Seizure. i 999;8:246-9.

31. Monjauze C, Tuller L, Hommet C, Barthez MA, Khomsi A. Language in

benign childhood epilepsy with centro-temporal spikes abbreviated

form: rolandic epilepsy and language. Brain Lang. 2005;92:300-8.

32. Papavasiliou A, Mattheou D, Bazigou H, Kotsalis C, Paraskevoulakos

E. Written language skills in children with benign childhood epilepsy

with centrotemporal spikes. Epilepsy Behav. 2005;6:50-8.

33. Northcott E, Connolly AM, Berroya A, Sabaz M, Mcintyre J, Christie J,

et al. The neuropsychological and language profile of children with

benign rolandic epilepsy. Epilepsia 2005;46:924-30.

56 REFERENCES

34. Weglage J, Demsky A, Pietsch M, Kurlemann G. Neuropsychological,

intellectual, and behavioral findings in patients with centrotemporal

spikes with and without seizures. Dev Med Child Neurol. 1997;39:646-

51.

35. Metz-Lutz MN, Kleitz C, de Saint Martin A, Massa R, Hirsch E,

Marescaux C. Cognitive development in benign focal epilepsies of

childhood. Dev Neurosci. 1999;21 :i 82-90.

36. Lindgren S, Kihlgren M, Melin L, Croona C, Lundberg S, Eeg-Oiofsson

0. Development of cognitive functions in children with rolandic

epilepsy. Epilepsy Behav. 2004;5:903-10.

37. Hiscock M, Antoniuk D, Prisciak K, Von Hessen D. Generalized and

lateralized interference between concurrent tasks performed by

children: effects of age, sex, and skill. Dev Psychol1985;1 :29-48.

38. Ahmad Z, Balsamo LM, Sachs BC, Xu B, Gaillard WD. Auditory

comprehension of language in young children: neural networks

identified with fMRL Neurology 2003;60:1598-605.

39. Yuan W, Szaflarski JP, Schmithorst VJ, Schapiro M, Byars AW,

Strawsburg RH, Holland SK. fMRI shows atypical language

lateralization in pediatric epilepsy patients. Epilepsia. 2006;47:593-600.

40. Piccirilli M, D'Aiessandro P, Tiacci C, Ferroni A. Language

lateralization in children with benign partial epilepsy. Epilepsia.

1988;29:19-25.

57 REFERENCES

41. Ogawa S, Lee TM, Kay AR, Tank OW. Brain magnetic resonance

imaging with contrast dependent on blood oxygenation. Proc Natl Acad

Sci US A 1990;87:9868-72.

42. Woermann FG, Jokeit H, Luerding R, Freitag H, Schulz R, Guertler S,

et al. Language lateralization by Wada test and fMRI in 100 patients

with epilepsy. Neurology 2003; 61:699-701.

43. Arora J, Pugh K, Westerveld M, Spencer S, Spencer DO, Todd

Constable R. Language lateralization in epilepsy patients: fMRI

validated with the Wada procedure. Epilepsia 2009;50:2225-41.

44. Liegeois F, Connelly A, Salmond CH, Gadian DG, Vargha-Khadem F,

Baideweg T. A direct test for lateralization of language activation using

fMRI: comparison with invasive assessments in children with epilepsy.

Neuroimage. 2002;17:1861-7.

45. Geschwind N: The organization of language and the brain. Science

1970;170:940-4.

46. Turken AU, Whitfield-Gabrieli S, Bammer R, Baldo JV, Dronkers NF,

Gabrieli JD. Cognitive processing speed and the structure of white

matter pathways: Convergent evidence from normal variation and

lesion studies. Neuroimage 2008;42:1 032-44.

58 REFERENCES

47. Schmithorst VJ, Wilke M, Dardzinski BJ, Holland SK. Cognitive

functions correlate with white matter architecture in a normal pediatric

population: A diffusion tensor MRI study. Hum Brain Mapp

2005;26:139-47.

48. Beaulieu C. The basis of anisotropic water diffusion in the nervous

system-A technical review. NMR Biomed 2002;15:435-455.

49. Catani M, Howard RJ, Pajevic S, Jones DK. Virtual in vivo interactive

dissection of white matter fasciculi in the human brain. Neuroimage

2002; 17:77-94.

50. Nucifora PG, Verma R, Melhem ER, Gur RE, Gur RC. Leftward

asymmetry in relative fiber density of the arcuate fasciculus.

Neuroreport 2005;16:791-94.

51. Eluvathingal TJ, Hasan KM, Kramer L, Fletcher JM, Ewing-Cobbs L.

Quantitative diffusion tensor tractography of association and projection

fibers in normally developing children and adolescents. Cereb Cortex

2007;17:2760-8.

52. Lebel C, Beaulieu C. Lateralization of the arcuate fasciculus from

childhood to adulthood and its relation to cognitive abilities in children.

Hum. Brain Mapp. 2009;30:3563-73.

59 REFERENCES

53. Fletcher PT, Whitaker RT, Tao R, DuBray MB, Froehlich A,

Ravichandran C, et al. Microstructural connectivity of the arcuate

fasciculus in adolescents with high-functioning autism. Neuroimage.

2010;51 :1 i 17-25.

54. Oldfield, R. C. The assessment and analysis of handedness: The

Edinburgh inventory. Neuropsychololgia 1971; 9:97-113.

55. Gregory DL, Wong PK. Clinical relevance of dipole field in rolandic

spikes. Epilepsia 1992;33:36-44.

56. Wechsler D. Wechsler Intelligence Scale for Children 4. San Antonio,

TX: The Psychological Corporation; 2003. (WISC-IV)

57. Schmidt M. Rey auditory and verbal learning test. A handbook.

Western Psychological Services, Los Angeles; 1996

58. Semel E, Wiig EH, Secord WA. Clinical evaluation of language

fundamentals. 4th ed. The Psychological Corporation, Harcourt

Assessment Company, San Antonio, TX; 2003.

59. Verrotti A, Latini G, Trotta D, Giannuzzi R, Cutarella R, Morgese G,

Chiarelli F. Typical and atypical rolandic epilepsy in childhood: a follow

up study. Pediatr Neurol. 2002;26:26-9.

60. Saint-Martin AD, Seegmuller C, Carcangiu R, Kleitz C, Hirsch E,

Marescaux C, Metz-Lutz MN. Cognitive consequences of Rolandic

Epilepsy. Epileptic Disord. 2001 ;3 Spec No 2:SI59-65.

60 REFERENCES

61. Kamieniecki GW, Lynd-Stevenson RM. Is it appropriate to use United

States norms to assess the "intelligence" of Australian children? Aust J

Psychol2002;54:67-78.

62. Giordani 8, Caveney AF, Laughrin D, Huffman JL, Berent S, Sharma

U, et al. Cognition and behavior in children with benign epilepsy with

centrotemporal spikes (SECTS). Epilepsy Res. 2006;70:89-94.

63. Hessen E, Lossius Ml, Reinvang I, Gjerstad L. Influence of major

antiepileptic drugs on attention, reaction time, and speed of information

processing: results from a randomized, double-blind, placebo

controlled withdrawal study of seizure-free epilepsy patients receiving

monotherapy. Epilepsia. 2006;4 7:2038-45.

64. Wood AG, Harvey AS, Wellard RM, Abbott DF, Anderson V, Kean M,

Saling MM, Jackson GD. Language cortex activation in normal

children. Neurology 2004;63:1 035-44.

65. Nicolai J, Aldenkamp AP, Arends J, Weber JW, VIes JS. Cognitive and

behavioral effects of nocturnal epileptiform discharges in children with

benign childhood epilepsy with centrotemporal spikes. Epilepsy Behav.

2006;8:56-70.

STUDY PROFORMA

61 STUDY PROFORMA

STUDY PROFORMA fMRI characteristics of language dysfunction in Benign childhood Epilepsy with Centro

temporal Spikes (BECTS)

Participant's ID No -----

Age __ years (Date of Birth __/ _/_)

Female

Maternal age: Paternal age:

Consanguinity: Yes/No If yes, degree of consanguinity:

Antenatal history:

Regular ANC: Yes/ No

Diabetes D HypertensionD Seizureo Edempsiao

Any antenatal illness/ drugs/ irradiation/ trauma (Describe in details)

Birth history:

Order of birth: Term/ Preterm

Sex-Male/

Birth weight (in Kgs): __ Prolonged labour: Yes/ No

Normal delivery/ Forceps/ Vaccum /LSCS Perinatal asphaxia: Yes/No

Neonatal jaundice/ Kernicterus: Yes/No Neonatal sepsis: Yes/ No

Developmental history:

Gross motor:

Head control ____ _ Turning over-------

Sitting Standing Walking

language:

Monosyllables------ Bisyllables -----

Sentences-------

STUDY PROFORMA

Febrile seizure: Yes/ No

Age of onset of seizure:

Seizure type: Single/ Multiple

Semiology: Aura: None/ Somatosensory/ Others (Specify)

Speech Arrest

Feeling of suffocation

Hemifacial Seizures

Teeth Chattering

Other (Specify) -

Frequency:

Nocturnal: Daytime ratio

Last attack:

Clustering: Yes/ No

Precipitating factors:

Salivation

Hemiconvulsions

Guttoral Sounds

Contraction of Jaw

Paresthesias Over Tongue, lips

Brachiofacial Seizures

Tongue Trembling

Treatment history (Drugs/ Dosage/ Duration/ Response/ Side effects)

Current treatment:

History of reading difficulty: Yes/No

Learning difficulty or dyslexia: Yes/No

Attentional problems or ADHD: Yes/No

History of migraine headaches: Yes/No

History of sleep walking/night terrors: Yes/No

62

63 STUDY PROFORMA

Does anybody in your immediate family (parents, children, brothers or sisters) have or ever

had

Seizures or epilepsy: Yes/No

Migraine headaches: Yes/No

late speech development: Yes/No

learning difficulty or dyslexia: Yes/No

Attentional problems or ADHD: Yes/No

Fainting or blackout or syncope: Yes/No

SEEG (Date/EEG No/Mayo classification)-

1.

2.

Education:

Maternal education Paternal education

Class: Medium of teaching in school:

School performance: Excellent/ Above average/ Average/ Below average/ Poor

%age of marks in previous classes (All available records to be documented}:

Repetition of any class:

Parental assessment:

Any specific area of disability identified by teacher/ parents

Clinical examination:

Positive clinical finding including soft clinical signs, if any

64 STUDY PROFORMA

Edinburgh Handedness Inventory1

Where the preference is so strong that subject would never use the other hand, unless absolutely forced to, put two checks ( v' v').

If subject is indifferent, put one check in each column ( v' I v').

Some of the activities require both hands. In these cases, the part of the task or object for which hand preference is wanted is indicated in parentheses.

Task I Object Left Hand Right Hand

1. Writing

2. Drawing

3. Throwing

4. Scissors

5. Toothbrush

6. Knife (without fork)

?.Spoon

8. Broom (upper hand)

9. Striking a Match (match)

10. Opening a Box (lid)

Total checks: LH= RH=

Cumulative Total CT=LH+RH=

Difference D=RH-LH=

Result R = (D I CT) x I 00 = Interpretation:

(Left Handed: R < -40) (Ambidextrous: -40 :::;; R:::;; +40)

(Right Handed: R > +40)

1 Oldt1eld, R. C. (1971). The a'3Sessment and analysis of handedness: The Edinburgh inventory. Neuropsychololgia, 9, 97-113

neuropsychological and language evaluation in children...

Documents