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
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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
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
REVIEW OF LITERATURE 13
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
REVIEW OF LITERATURE 14
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
REVIEW OF LITERATURE 15
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
REVIEW OF LITERATURE 16
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
REVIEW OF LITERATURE 17
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
MATERIALS AND METHODS 20
• 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
MATERIALS AND METHODS 21
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.
MATERIALS AND METHODS 22
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
MATERIALS AND METHODS 23
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.
MATERIALS AND METHODS 24
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
MATERIALS AND METHODS 25
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
MATERIALS AND METHODS 26
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
were visually inspected to determine laterality of language activation.
MATERIALS AND METHODS 27
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).
MATERIALS AND METHODS 28
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%)
30 RESULT AND ANALYSIS
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
31 RESULT AND ANALYSIS
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%}
32 RESULT AND ANALYSIS
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
RESULT AND ANALYSIS 34
^ 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).
35 RESULT AND ANALYSIS
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
36 RESULT AND ANALYSIS
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.
37 RESULT AND ANALYSIS
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
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