Original Article

Etiology of Intractable Epilepsy in A Sample

of Egyptian Children
Shora Darwish, Nabil Hussien, Walid Foad, Mahmoud Monzer, Mohie El Din Tharwat
Department of Neurology, Al-Azhar University; Egypt

ABSTRACT
Background: Intractable epilepsy is one of the most complex problems in pediatric neurology and a health–threatening
condition, which has major medical, social and economic consequences. Objective: To study the etiological factors of
intractable epilepsy in a sample of Egyptian children. Methods: The children were divided into two main groups: Group I
(cases) included 42 epileptic children who fulfilling the criteria for intractability, they were 27 males and 15 females. Group
II (controls) included 40 epileptic children on AEDs with no seizures for more than 1 year, They were 24 males and 16
females. According to the age of included children: Group I (cases) was subdivided into: (a) Preschool children (from 2 to 6
years): included 19 children. (b) School children (above 6 to below 18 years): included 23 children. Group II (controls) was
subdivided also into: (a) Preschool children (from 2 to 6 years): included 25 children. (b) School children (above 6 to below
18 years): included 15 children. All patients (cases and controls) were subjected to: (I) Detailed medical and neurological
history. (II) Detailed history of epilepsy. (III) Full general and neurological examination. (IV) Neurophysiological assessment
by using conventional electro-encephalography (EEG). (V) Brain Magnetic Resonance Imaging (MRI) and/or CT Brain. (VI)
Neuropsychological assessment of Intelligence Quotient (IQ) to detect mental sub normality. (VII) Serum levels of
conventional antiepileptic drugs. (VIII) Routine blood investigations: Complete blood cell count and blood chemistry (Serum
calcium, magnesium and phosphorus). (IX) Selected laboratory assessment in blood was done: Metabolic testing when
needed as serum lactate and serum ammonia levels. Results: There was statistically significant difference between preschool
cases and controls as regards pregnancy health problems being higher in children with intractable epilepsy. 15.79% of preschool
cases were low birth weight and the result was statistically significant. Neonatal seizures were documented in (15.79%) of
preschool cases and 8.70% of school cases, this result was statistically significant in preschool cases. 68.42% of preschool cases
and 43.48% of school cases had motor developmental delay and this result was statistically significant in preschool children with
IE. In this study, 73.68% of preschool cases and 65.22% of school cases had abnormal neurological examination and this result
was statistically highly significant in preschool children with IE. All intractable epileptic children (preschool and school) had
various degrees of mental retardation, this result was statistically highly significant. Abnormal EEG was present in 94.74 % of
preschool cases and 100 % of school cases, this result was statistically highly significant in preschool cases and significant in
school cases. In this study, the most common aetiology of intractability was perinatal hypoxic ischemic encephalopathy in
35.71% of cases. Other less common aetiologies included were CNS infection in 11.90% of cases, mitochondrial disorder in
9.52% of cases, hyper-ammonemia (urea cycle disorder) in 7.14% of cases, tuberous sclerosis in 7.14% of cases and 4.76% had
corpus callosum agenesis. Conclusions: The most common etiological factors of intractability in preschool children are perinatal
hypoxic ischemic encephalopathy, hyperammonemia (inborn errors of metabolism), CNS infection, and corpus callosum
agenesis, while in school children are perinatal hypoxic ischemic encephalopathy, CNS infection, mitochondrial disorder, and
tuberous sclerosis. Recommendations: Early prediction of clinical risk factors of childhood intractable epilepsy is important to
minimize the complications of intractability. Providing proper perinatal care is the corner stone for reducing prevalence of
intractable epilepsy. [Int. J. Ch. Neuropsychiatry, 2018, 15(1 & 2): 1-9]

Key Words: Etiological Factors, Intractable Epilepsy, Sample, Egyptian Children.

INTRODUCTION whichever is longer2. 30% to 40% of patients with

epilepsy fail to respond to antiepileptic drugs or other
treatments. Refractory epilepsy may be progressive,
Intractable epilepsy is defined as a disorder in
carrying risks of structural damage to the brain and
patients having at least two seizures a month for over
nervous system, comorbidities (osteoporosis, fractures),
two years despite the administration of two first line
and increased mortality (from suicide, accidents, sudden
antiepileptic drugs1. The International League Against
unexpected death in epilepsy, pneumonia, vascular
Epilepsy (ILAE) defines drug resistant epilepsy as "a
disease), as well as psychological (depression, anxiety),
failure of adequate trials of two tolerated and
educational, social (stigma, driving), and vocational
appropriately chosen and used antiepileptic drug
consequences. (Kenneth D. Laxer, et al., 2014).
schedules (whether as monotherapies or in
combination) to achieve sustained seizure freedom".

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 Darwish, et al.: Etiology of Intractable Epilepsy in A Sample of Egyptian Children

Aim of the Work All patients (cases and controls) in this study were
To study the etiological factors of intractable subjected to the following procedures:
epilepsy in a sample of Egyptian children for early (I) Detailed medical and neurological history: The
prediction of these factors would help in planning history taking included:
early intervention. 1. Personal history.
2. Prenatal, natal and postnatal history to detect
any environmental hazards, other medical
SUBJECTS AND METHODS conditions and other system affection.
3. Family pedigree construction: This was
The epileptic children were selected from constructed to state consanguinity and
(Inpatient & outpatient), from the Paediatric similar condition in siblings or other
Neurology Unit. Neurology Department, Al-Azhar relatives and to detect any hereditary
University Hospitals. The children were divided into disorders.
two main groups, which included: Group I included 42 4. Developmental history.
epileptic children who fulfilling the criteria for (II) Detailed history of epilepsy: The history taking
intractability, they were 27 males (64.29%) and 15 included:
females (35.71%). Group II (controls) included 40 1. Age of onset of seizures: Under or above
epileptic children on AEDs with no seizures for more one year of age.
than 1 year, they were 24 males (60%) and 16 females 2. Neonatal seizures.
(40%). 3. Type of seizures.
4. Frequency of seizures:
According to the age of included children: a. Daily attacks.
Group I (cases) was subdivided into: b. More than one attack in a week.
(a) Preschool children (from 2 to 6 years): included c. One or more attack per month.
19 (45.24%) children. d. Less than one attack per month.
(b) School children (above 6 to below 18 years): 5. Previous status epilepticus.
included 23 (54.76%) children . 6. History suggestive of CNS infection
(meningitis–meningo-encephalitis).
Group II (controls) was subdivided into: 7. History of head trauma with
(a) Preschool children (from 2 to 6 years): included unconsciousness.
8. Seizure precipitant: Fever, sleep
25 (62.5%) children.
deprivation, dehydration, trauma, stress.
(b) School children (above 6 to below 18 years):
Presence of one, two or three seizure
included 15 (37.5%) children .
precipitants.
9. Febrile seizures.
Inclusion Criteria: 10. Details regarding antiepileptic drugs (AEDs)
1) Epileptic children with intractability (failure of 2 were recorded: Number of drugs Naming of
or more first line antiepileptic drugs to control drugs, Dosage, Duration of therapy.
seizures in children who experienced 1 or more (III) Full general and neurological examination.
seizures per month for 2 years)1. (IV) Neurophysiological assessment by using
2) Age from 2 to below 18 years. conventional electro-encephalography (EEG).
The United Nations Convention on the Rights of Electroencephalogram was performed according
Child (UNCRC) defined the child as every to the international 10 / 20 system. Chloral
human being below the age of 18 years7. hydrate 25 mg /kg as single dose was used
before tracing, when needed to do sleep EEG.
Exclusion Criteria: EEG interpretation:
Patients with pseudo-intractability were 1. Background activity (delta, theta, alpha and
excluded from the study which included epileptic beta).
children with: 2. Epileptiform discharges: sharp waves,
(a) Non – compliance. spikes, or polyspikes, spike and slow wave
(b) Non – therapeutic dose of antiepileptic drugs. complexes.
(c) Serum levels of conventional antiepileptic drugs 3. Conclusion: Focal epileptic activity, focal
under therapeutic ranges. epileptic activity with secondary
(d) Inappropriate selection of antiepileptic drugs. generalization, multifocal epileptic activity,
(e) Incorrect diagnosis. generalized epileptic activity, slowing and
hypsarrhythmia.

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 Darwish, et al.: Etiology of Intractable Epilepsy in A Sample of Egyptian Children
(V) Brain Magnetic Resonance Imaging (MRI)
and/or CT Brain: for detection of any structural
abnormalities such as: Hypoxic–ischemic
encephalopathy suggestive of perinatal asphyxia,
Hippocampal sclerosis, Mesial temporal
sclerosis, Neuronal migration defects, Tuberous
sclerosis, Hydrocephalus, Corpus callosum
agenesis, TORCH infection (Toxoplasmosis,
rubella, cytomegalovirus and herpes).
(VI) Neuropsychological assessment: Intelligence
Quotient (IQ) to detect mental subnormality (by
using Stanford Bennet test or even social
maturity by using Vineland test). Mental
subnormality below 90 and classified according
to Degree of mental retardation
(VII)Serum levels of conventional antiepileptic drugs:
Patients with low serum levels were excluded
from the study because of pseudo - intractability.
(VIII) Routine blood investigations: Complete blood
cell count and blood chemistry (Serum calcium,
magnesium and phosphorus).
(IX) Selected laboratory assessment in blood was
done: Metabolic testing when needed as serum
lactate level, serum ammonia level and even
screening for inborn errors of metabolism.
- Normal serum lactate level (up to 20 u/ml).
- Normal serum ammonia level (10-47 mg/ml).
(X) Statistics: Statistical analysis of the results was
conducted using statistical package for social
science (SPSS) version 17 to obtain mean,
standard error, student t- test to compare
between two groups in quantitative data, and
Chi-square to test significance for qualitative
data.
RESULTS
I- Demographic Data:
1. Age: The ages of intractable epileptic children
were ranged from 3 to 17 years, with a mean of
(8.16±4.47) years in group I and (6.57±3.49)
years in group II.
2. Sex:
- Preschool Children: Males in group I
(cases) were 11 (57.89%) and females were
8 (42.11%) with a male to female ratio of
1.4:1, while males in group II (controls)
were 15 (60%) and females were 10 (40%)
with a male to female ratio of 1.5:1.
- School Children: Males in group I (cases)
were 16 (69.57%) and females were 7
(30.43%) with a male to female ratio of
2.3:1, while males in group II (controls)
were 9 (60%) and females were 6 (40%)
with a male to female ratio of 1.5:1.
International J. Ch. Neuropsychiatry │ 2018 │ Vol. 15 │ Issue 1 & 2
3. Family history of seizures: In the present study,
4 (21.05%) of preschool IE cases had a family
history of epilepsy and 2 (8.70%) of school IE
cases had the same history. There was
statistically significant difference between
school cases and controls as regards family
history of seizures being more in controls
(P<0.05).
4. Consanguinity: In the present study, there was a
considerable consanguinity rate of (36.84%) in
preschool IE cases and (21.74%) in school cases.
There was no statistically significant difference
between preschool cases and controls as regards
consanguinity (P > 0.05). There was no
statistically significant difference between
school cases and controls as regards
consanguinity (P > 0.05). There was no
statistically significant difference between
preschool and school intractable epileptic
children as regards consanguinity (P>0.05).
II- Medical History of Study Groups:
1. Pregnancy: In the present study, maternal health
problems during pregnancy in preschool children
with IE were found in 3 (15.79%) cases;
included one mother had hypertension, one had
anemia and another had oligohydramnios. There
was statistically significant difference between
preschool cases and controls as regards
pregnancy problems.
2. Type of Delivery: There was statistically highly
significant difference between preschool cases
and controls as regards delivery problems
(P<0.01).
3. Birth Weight: In the present study, (15.79%) of
preschool cases were low birth weight. Low
birth weight was significantly higher in
preschool children with IE than their controlled
epileptic children (P<0.05). There was
statistically significant difference between
preschool and school intractable epileptic
children as regards low birth weight (P<0.05).
4. Type of Feeding: In the present study, there was
statistically significant difference between
preschool cases and controls as regards type of
feeding; artificial feeding was present only in
preschool cases.
III- Detailed History of Epilepsy:
1. Age of onset of seizures: There was significant
correlation between early onset seizures (below
1 year) and intractable epilepsy in preschool
children (P<0.05).
2. Neonatal Seizures: Neonatal seizures were
documented in (15.79%) of preschool cases and
(8.70%) of school cases There was statistically
3
 Darwish, et al.: Etiology of Intractable Epilepsy in A Sample of Egyptian Children
significant difference between preschool cases
and controls as regards neonatal seizures (P<
0.05).
3. Type of Seizures: Preschool Children: Multiple
seizure types were noted only in IE subjects and
documented in 5 (26.32%). This result was
statistically highly significant (P<0.01).
Myoclonic seizures were significant in IE group
(p < 0.05). Infantile spasm was significant in IE
group (p<0.05). School Children: Multiple
seizure types were noted only in IE subjects and
documented in 7 (30.43%). This result was
statistically highly significant (P<0.01). Partial
seizures were significant in IE group (P<0.05).
Myoclonic seizures were highly significant in IE
group (P < 0.01).
4. Frequency of Seizures: There was statistically
significant difference between preschool and
school intractable epileptic children as regards
frequency of seizures (P<0.05).
5. History of Previous Status Epilepticus of the
Study Groups: There was statistically highly
significant difference between preschool cases
and controls as regards history of SE (P<0.01).
IV- Pattern of Motor Development:
(68.42%) of preschool cases and (43.48%) of
school cases had motor developmental delay There
was statistically significant difference between
preschool cases and controls as regards pattern of
motor development being delayed higher in cases
group than control group (P<0.05). In this study,
(73.68%) of preschool cases and (65.22%) of school
cases had abnormal neurological examination and this
result was statistically highly significant in preschool
children with IE.
V- Intelligence Quotient (IQ) and
Electroencephalography (EEG) Findings of the
Study Groups:
All intractable epileptic children (preschool and
school) had various degrees of mental retardation and
this result was statistically highly significant.
Abnormal EEG was present in (94.74%) of preschool
cases and (100%) of school cases, this result was
statistically highly significant in preschool cases and
significant in school cases.
VI- Magnetic Resonance Imaging (MRI)
Findings of the Study Groups:
There was statistically significant difference
between preschool cases and controls as regards
structural MRI abnormalities which were higher in
children with intractable epilepsy than children with
well controlled epilepsy (P<0.05).
4 International J. Ch. Neuropsychiatry │ 2018 │ Vol. 15 │ Issue 1 & 2
VII- Etiological Factors of Intractable Epilepsy as
compared to well-Controlled Epilepsy:
Preschool Children:
As regard to IE group, no certain cause was
observed in 2 (10.53%), 6 (31.58%) had perinatal
hypoxic ischemic encephalopathy, 1 (5.26%) had
Tuberous sclerosis, 1 (5.26%) had mesial temporal
sclerosis, 2 (10.53%) had corpus callosum agenesis, 3
(15.79%) had hyper-ammonemia, 1 (5.26%) had
neonatal hyperbilirubinemia, 2 (10.53%) had CNS
infection and 1 (5.26%) had cerebrovascular ischemic
stroke.
As regard to controlled epileptic children, no
cause was observed in 15 (60%), 7 (28%) had
perinatal hypoxic ischemic encephalopathy, 2 (8%)
had CNS infection and 1 (4%) had toxoplasma
infection. There was statistically highly significant
difference between preschool cases and controls as
regards epilepsy aetiology and there was positive
correlation between intractability and remote
symptomatic aetiology of epilepsy (P<0.01).
School Children:
As regard to IE group, no certain cause was
observed in 3 (13.04%), 9 (39.13%) had perinatal
hypoxic ischemic encephalopathy, 2 (8.70%) had
Tuberous sclerosis, 4 (17.39%) had mitochondrial
disorder, 3 (13.04%) had CNS infection, 1 (4.35%)
had head trauma and 1 (2.38%) had down syndrome.
As regard to controlled epileptic children, no
cause was observed in 8 (53.33%), 3 (20%) had CNS
infection, 2 (13.33%) had perinatal hypoxic ischemic
encephalopathy, 1 (6.67%) had neonatal
hyperbilirubinemia, and 1 (6.67%) had post-surgical
operation hypoxic ischemic encephalopathy.
There was statistically highly significant
difference between school cases and controls as
regards epilepsy aetiology and there was positive
correlation between intractability and remote
symptomatic aetiology of epilepsy.
Preschool and school cases (intractable):
There was statistically significant difference
between preschool and school cases (intractable
epileptic children) as regards etiology of intractability
(P<0.05).
From the previous results we can conclude that:
The most common causes of intractable epilepsy
in our children (42) were:
(1) Perinatal hypoxic ischemic encephalopathy in 15
(35.71%) of cases.
(2) CNS infection in 5 (11.90%) of cases.
(3) Mitochondrial disorder in 4 (9.52%) of cases.
 Darwish, et al.: Etiology of Intractable Epilepsy in A Sample of Egyptian Children

(4) Inborn errors of metabolism (hyperammonemia) (3) CNS infection in 2 (10.53%) of cases.
in 3 (7.14%) of cases. (4) Corpus callosum agenesis in 2 (10.53%) of
(5) Tuberous Sclerosis in 3 (7.14%) of cases. cases.
(6) Corpus callosum agenesis in 2 (4.76%) of cases.
The most common causes of intractability in school
The most common causes of intractability in children were:
preschool children were: (1) Perinatal hypoxic ischemic encephalopathy in 9
(1) Perinatal hypoxic ischemic encephalopathy in 6 (39.13%) of cases.
(31.58%) of cases. (2) Mitochondrial disorder in 4 (17.39%) of cases.
(2) Inborn errors of metabolism (hyperammonemia) (3) CNS infection in 3 (13.04%) of cases.
in 3 (15.79%) of cases. (4) Tuberous Sclerosis in 2 (8.70%) of cases.

Table 1. Comparison of pregnancy problems between preschool and school children in cases and controls.
Group I Group II Chi-Square
Pregnancy
N % N % X2 P-value
Normal 16 84.21 25 100.00
Pre school Abnormal 3 15.79 0 0.00 5.330 0.021*
Total 19 100.00 25 100.00
Normal 20 86.96 15 100.00
School Abnormal 3 13.04 0 0.00 3.179 0.075
Total 23 100.00 15 100.00
X2 0.064
Chi-Square
P-value 0.801

Table 2. Comparison of birth between preschool and school children in cases and controls.
Group I Group II Chi-Square
Birth weight
N % N % X2 P-value
Normal 16 84.21 25 100.00
Pre school Low birth weight 3 15.79 0 0.00 5.330 0.021*
Total 19 100.00 25 100.00
Normal 23 100.00 15 100.00
School
Total 23 100.00 15 100.00
X2 5.041
Chi-Square
P-value 0.025*

Table 3. Comparison of age of onset of seizures between preschool and school children in cases and controls.

Group I Group II Chi-Square

Age of onset of seizures
N % N % X2 P-value
<1 y 10 52.63 4 16.00
Pre school >1 y 9 47.37 21 84.00 6.677 0.010*
Total 19 100.00 25 100.00
<1 y 7 30.43 3 20.00
School >1 y 16 69.57 12 80.00 0.522 0.470
Total 23 100.00 15 100.00
X2 2.128 0.103
Chi-Square
P-value 0.145 0.749

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 Darwish, et al.: Etiology of Intractable Epilepsy in A Sample of Egyptian Children

Table 4. Comparison of type of seizures & between preschool and school children in cases and controls.
Group I Group II Group I & Group II (P-value)
Type of seizures P-value P-value
Preschool School Preschool School Preschool School
Generalized N 11 12 14 11
0.477 0.225 0.573 0.168
seizures % 57.89 52.17 56.00 73.33
Partial N 8 15 10 4
0.118 0.307 0.566 0.022*
seizures % 42.11 65.22 40.00 26.67
Myoclomic N 7 10 2 0
0.453 0.385 0.024* 0.002**
seizures % 36.84 43.48 8.00 0.00
Infantile N 4 3 0 0
0.388 0.029* 0.210
Spasm % 21.05 13.04 0.00 0.00

Table 5. Comparison of EEG findings between preschool and school children in cases and controls.
Group I Group II Chi-Square
EEG findings
N % N % X2 P-value
Normal 1 5.26 10 40.00
Focal with secondary generalization 3 15.79 5 20.00
Pre school Generalized epileptogenic discharges 13 68.42 6 24.00 11.552 0.009**
Focal epileptogenic discharges 2 10.53 4 16.00
Total 19 100.00 25 100.00
Normal 0 0.00 4 26.67
Focal with secondary generalization 6 26.09 2 13.33
School Generalized epileptogenic discharges 12 52.17 7 46.67 8.601 0.035*
Focal epileptogenic discharges 5 21.74 2 13.33
Total 23 100.00 15 100.00
X2 3.392 2.215
Chi-Square
P-value 0.335 0.529

Table 6. Comparison of etiological factors of epilepsy between preschool and school children in cases and controls.
Group I Group II Chi-Square
Etiology of intractable epilepsy
N % N % X2 P-value
No certain cause 2 10.53 15 60.00
Perinatal hypoxic ischemic encephalopathy 6 31.58 7 28.00
Neurocutaneous disorder (Tuberous Sclerosis) 1 5.26 0 0.00
Mesial temporal sclerosis 1 5.26 0 0.00
Neonatal hyperbillirubinemia (kernicterus) 1 5.26 0 0.00
Pre
Corpus callosum agenesis 2 10.53 0 0.00 24.371 0.002**
school
Inborn error of metabolism (hyperammonemia) 3 15.79 0 0.00
CNS infection 2 10.53 2 8.00
Cerebrovascular ischemic stroke 1 5.26 0 0.00
Toxoplasma infection 0 0.00 1 4.00
Total 19 100.00 25 100.00
No certain cause 3 13.04 8 53.33
Perinatal hypoxic ischemic encephalopathy 9 39.13 2 13.33
Neurocutaneous disorder (Tuberous Sclerosis) 2 8.70 0 0.00
Mitochondrial disorder 4 17.39 0 0.00
Neonatal hyperbillirubinemia (kernicterus) 0 0.00 1 6.67
School 19.343 0.013**
CNS infection 3 13.04 3 20.00
Head trauma. 1 4.35 0 0.00
Chromosomal disorder (Down syndrome) 1 4.35 0 0.00
Post – Operation hypoxic ischemic encephalopathy 0 0.00 1 6.67
Total 23 100.00 15 100.00
Chi- X2 18.647 6.94
Square P-value 0.045* 0.225

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 Darwish, et al.: Etiology of Intractable Epilepsy in A Sample of Egyptian Children

DISCUSSION difference between preschool cases and controls as regards

neonatal seizures. In the study of Manoj et al. (2009),
neonatal seizures were documented in (21%) of IE cases.
Intractable Epilepsy (IE) is a burning concern for
Neonatal seizures can be associated with the strong
both patients and personnel dealing with epilepsy. IE
epileptic foci induced by neuronal damage during this
has an enormous impact on various components of an
period of rapid brain development; furthermore, most of
individual's life, including social, psychiatric,
these children demonstrate a history of prenatal asphyxia,
occupational, cognitive and sexual functioning3. The
congenital malformations and other factors that play an
goals in the assessment of a patient with presumed
important role in the development of intractable epilepsy
medically intractable epilepsy are to establish the
(5,6). In the present study partial seizures, myoclonic
diagnosis of a seizure disorder, to classify the type of
seizures and infantile spasms were more frequent in
seizures, to delineate the lesion responsible for the
children with IE and this agrees with the result of Joseph et
seizures and to explore the reasons for the
al. (2012)14. Eriksson and Koivikko (1997) stated that the
intractability4. Determination of risk factors for
presence of mixed seizure types, myoclonic seizures and
intractability may help us to understand aetiology and
infantile spasms may cause poor seizure control15. In the
aids in achieving optimum control of resistant
study of Chawla et al. (2002), there was association
epilepsy5. Early identification of intractability may be
between myoclonic seizures and intractability on
useful in designing alternative therapies such as anti-
multivariate analysis8.
inflammatory agents or surgical interventions. It
In the present study, mental retardation was
would also be essential in parental counselling and
highly significant in preschool and school children
individual support6.
with IE; motor developmental delay was significantly
In the present study, age of onset of seizures was
more noticed in preschool cases, this agrees with the
less than 1 year of age in 10 (52.63%) preschool
results of Wirrell et al. (2012); Yilmaz et al. (2013)16,6.
children with IE, as compared to only 4 (16%) with
The risk of associated mental retardation in patients
preschool well controlled epileptic children. There
with epilepsy is increased when there is associated
was significant correlation between early onset
motor impairments, when epilepsy begins at an early
seizures and childhood intractable epilepsy this agree
age, when the duration of epilepsy is prolonged, when
with Chawla et al. (2002), who found that 66% of IE
there are multiple seizure types – and when multiple
cases had onset of seizures below 1 year of age and
drugs in higher doses are required17.
Manoj et al. (2009), who found that (60%) of IE
In the present study, (94.74%) of preschool cases
children had onset of seizures early in infancy.
and (100%) of school cases had abnormal findings on
However, in some reports, no relation was found
EEG and these ranged from focal epileptic activity,
between age of onset of seizures and intractability5,8,9.
focal with secondary generalization to generalized
In the present study, maternal health problems
epileptic activity. This result was statistically highly
during pregnancy in preschool children with IE were
significant and higher than other previous studies of
found in 3 (15.79%) cases; included one mother had
Singhvi et al. (2000), who found abnormality in 69%
hypertension, one had anaemia and another had
cases, and Manoj et al. (2009), who found abnormality
oligohydramnios. There was statistically significant
in 84% cases19,5. Refractory epilepsy often has a
difference between preschool cases and controls as
severe general abnormal EEG20. In addition, some
regards pregnancy problems. In the study of Oskouit
studies describe the association between multifocal
al. (2005), maternal history of oligohydramnios or
spikes and intractability21. Focal EEG slowing, focal
polyhydramnios, intrauterine infections, teratogenic
and diffuse spike and wave, diffuse slowing and focal
drugs or abnormal foetal movements may suggest
spike and wave activity are predictors of unfavourable
neurological disorders in the foetus and structural
outcome22.
brain abnormalities10.
In this study, the most common aetiology of
Low birth weight new-borns are at higher risk
intractability was perinatal hypoxic ischemic
for brain injury leading to acute or remote
encephalopathy, 6 (31.58%) of preschool cases and
symptomatic seizures4. In the present study, 3
(39.13%) of school cases had perinatal asphyxia. In
(15.79%) of preschool children with IE were low birth
the study of Manoj et al., (2009); 71 % of intractable
weight. There was statistically highly significant
epileptic children had remote symptomatic aetiology,
difference between preschool cases and controls as
perinatal asphyxia constituted almost 50% children of
regards low birth weight. This agrees with the result of
intractable seizures and was an important predictor for
the study of Leuzzi (2002)11.
intractability5. In the study of Moinuddin et al. (2009);
In the present study, neonatal seizures were
hypoxic ischemic damage of the brain due to perinatal
documented in 3 (15.79%) preschool cases and 2
asphyxia and cerebral palsy were the main causes of
(8.70%) school cases. There was statistically significant

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 Darwish, et al.: Etiology of Intractable Epilepsy in A Sample of Egyptian Children
symptomatic epilepsy22. In this study, 2 (10.53%) of
preschool cases and 3 (13.04%) of school cases had
CNS infection. In the study of Trinka et al. (2002);
there was a small subgroup of patients with post
encephalitic unilateral temporal lobe epilepsy for
whom the outcome is favourable. The majority of
patients had multifocal seizure onset with bilateral
temporal lobe epilepsy and extra temporal multifocal
epilepsy and poor outcome after surgical treatment23.
In this study, 4 (17.39%) of school cases had
mitochondrial disorder. Seizures can be a presenting
feature of mitochondrial disease in children. When
present, seizures can be intractable and associated
with a poor prognosis24. In this study, 3 (15.79%) of
preschool cases had hyper-ammonemia due to urea
cycle disorder. Hyperammonemia secondary to an
underlying urea cycle defect can be associated with
intractable seizures25. In this study, 1 (5.26%) of
preschool cases and 2 (8.70%) of school cases had
tuberous sclerosis. Epilepsy is the most common
disorder in Tuberous Sclerosis Complex, frequently
associated with intractable and early onset seizures
and often as infantile spasms26. In this study, 2
(10.53%) of preschool cases had corpus callosum
agenesis. In some reports, development of infantile
spasms and subsequent intractable epilepsy was
observed in children with corpus callosum agenesis
and severe mental retardation27. In this study, 1
(5.26%) of preschool cases had mesial temporal
sclerosis. This agrees with results of Vincent (2011),
who reported that mesial temporal sclerosis is
associated with intractable complex partial seizures. In
this study, 1 (2.38%) of school cases had Down
syndrome28. It is currently known that there is a higher
incidence of seizures, particularly infantile spasms in
Down Syndrome (DS) compared to the general
population. Also, children with DS often have simple
or complex partial seizures as well as tonic – clonic
seizures29.
Conclusions
(1) The significant clinical risk factors of preschool
childhood intractable epilepsy are perinatal
health problems, low birth weight, neonatal
seizures, early onset seizures (below one year of
age), multiple seizure types, myoclonic seizures,
infantile spasm, status epilepticus, motor
developmental delay and abnormal neurological
examination.
(2) The significant clinical risk factors of school
childhood intractable epilepsy are multiple
seizure types, partial seizures and myoclonic
seizures.
(3) Mental retardation is highly significant co-
morbid condition associated with intractable
epilepsy in preschool and school children.
8 International J. Ch. Neuropsychiatry │ 2018 │ Vol. 15 │ Issue 1 & 2
(4) Abnormal EEG finding is a highly significant result
present in preschool cases and significant in school
cases. There is a positive correlation between
abnormal EEG findings and intractability.
(5) The most common etiological factors of
intractability in preschool children are perinatal
hypoxic ischemic encephalopathy,
hyperammonemia (inborn errors of metabolism),
CNS infection and corpus callosum agenesis,
while in school children are perinatal hypoxic
ischemic encephalopathy, mitochondrial
disorder, CNS infection and tuberous sclerosis.
Recommendations
(1) Early prediction of clinical risk factors of
childhood intractable epilepsy is important to
minimize the medical, social and economic
complications of intractability.
(2) Providing proper perinatal care is the corner
stone for reducing prevalence of intractable
epilepsy because of perinatal asphyxia is the
most common etiological factor of intractable
epilepsy in our children.
(3) Early and aggressive management of CNS
infection can help in reducing occurrence of
intractable epilepsy in affected children.
(4) Screening programs for mitochondrial disorder
and inborn errors of metabolism in suspected
cases should be done because of their positive
correlation with refractory seizures.
REFERENCES
1. Vajay G, Gupta D, Rajinder G. (2008): Intractable
epilepsy. JK. Practitioner; 12(2):105-107.
2. Engel J, McDermott M, Wiebe S, et al. (2012):
Early surgical therapy for drug – resistant temporal
lobe epilepsy: a randomized trial. JAMA;
307(9):922-930.
3. Kenneth D. Laxer, Eugen Trinka, Lawrence J.
Hirsch, Fernando Cendes, John Langfitt, Norman
Delanty, Trevor Resnick, Selim R. Benbadis, 2014:
The consequences of refractory epilepsy and its
treatment-Epilepsy & Behavior-37, 59-70.
4. Beyenburg S, Stavem K, Schmidt D. (2010):
Placebo-corrected efficacy of modern antiepileptic
drugs for refractory epilepsy: systemic review and
meta-analysis. Epilepsia; 51(1): 7-26.
5. Murthy J. (2009): Medically refractory epilepsy-
pre-surgical evaluation. Apicon.
6. Manoj G, Sushma M, Surekha J, et al. (2009):
Early predictors of intractable childhood epilepsy.
Bombay Hospital Journal; 51(1): 36-43.
7. Yilmaz B, Okuyaz C, Komur M. (2013): Predictors
of intractable childhood epilepsy. Pediatric
Neurology; 48 (1): 52-55.
 Darwish, et al.: Etiology of Intractable Epilepsy in A Sample of Egyptian Children
8. McMillan A and Simkiss D. (2009): The United
Nations Convention on the Rights of Child and
HIV/AIDS. Journal of Tropical Pediatrics;
55(2):71-72.
9. Chawla S, Aneja S, Kashyap R, et al. (2002):
Etiology and clinical predictors of intractable
epilepsy. Pediatric Neurology; 27:186-191.
10. Ohtsuka Y, Yoshinaga H, Kobayashi K, et al.
(2002): Predictors and underlying causes of
medically intractable localization – related epilepsy
in childhood. Pediatr Neurol; 24: 209-213.
11. Oskoui M, Webster R, Zhang X, et al. (2005):
Factors predictive of outcome in childhood
epilepsy. J Child Neurol; 20(11):898-904.
12. Leuzzi V. (2002): Inborn errors of creatine
metabolism and epilepsy: Clinical features,
diagnosis and treatment. J Child Neurology;
17(Suppl 3): 3S57-3S82; Discussion 3S 97.
13. Bertoli S, Cardinali S, Veggiotti P, et al. (2006):
Evaluation of nutritional status in children with
refractory epilepsy. Nutr J.; 5:14-20.
14. Callaghan B, Schlesinger M, Rodemer W. (2011):
Remission and relapse in a drug – resistant epilepsy
population followed prospectively. Epilepsia;
52:619.
15. Joseph I, Timothy A, Janet L. (2012): Evaluation
and management of drug – resistant epilepsy.
Wolsters Kluwer Health. http://www.uptodate.Com
16. Eriksson K and Koivikko M. (1997): Prevalence,
classification and severity of epilepsy and epileptic
syndromes in children. Epilepsia; 30: 389-399.
17. Wirrell E, Wong – Kisiel L, Mandrekar J, et al.
(2012): Predictors and course of medically
intractable epilepsy in young children presenting
before 36 months of age: A retrospective
population – based study. Epilepsia; 10: 1528.
18. Garbelli R, Frassoni C, Condorelli D. (2011):
Expression of connexin 43 in the human epileptic and
drug – resistant cerebral cortex. Neurology; 76: 895.
International J. Ch. Neuropsychiatry │ 2018 │ Vol. 15 │ Issue 1 & 2
19. Luoni C, Bisulli F, Canevini M. (2011):
Determinants of health – related quality of life in
intractable epilepsy: results from a large
multicenter study of consecutively enrolled patients
using validated quantitative assessments. Epilepsia;
52: 2181.
20. Singhvi J, Sawhney I, Lal V, et al. (2000): Profile
of intractable epilepsy in a tertiary referral center.
Neurology India; 48(4): 351-356.
21. Medical Research. (2012): Clinical features and
analysis for therapeutic effect of intractable
epilepsy. www.prm-taipeiplas.com.tw
22. Belaza P. (2009): Refractory epilepsy: A clinically
oriented review. Eur Neurol; 62:65-71.
23. Moinuddin A, Rahman M, Akhter S, et al. (2009):
Predictors of childhood intractable epilepsy-A
Retrospective study in a tertiary care hospital.
Bangladesh J Child Health; 33(1): 6-15.
24. Trinka E, Frederick A, Bastos A, et al. (2002):
Clinical findings and outcome in catastrophic post
– encephalitic epilepsy. John Libbey Eurotext; 2(3):
153-162.
25. Mattman A, Sirrs S, Mezei M, et al. (2011):
Mitochondrial manifestations: An overview. BC
Medical Journal; 53(4): 183-187.
26. Crisan E. (2012): Hyperammonemia clinical
manifestations.
http://emedicinemedscape.com/article.
27. Petrova L. (2011): Tuberous sclerosis and epilepsy.
Am J Electroneuro-diagnostic Technol; 51(1): 5-15.
28. Conti V, Marini C, Gana S, et al. (2011): Corpus
callosum agenesis and epilepsy. Am J Med Genet;
155A (4): 892-897.
29. Vincent R. (2011): Mesial temporal sclerosis in
epilepsy. CMAJ; 183(15): e1151.
30. Geerts A, Brouwer O, Stroink H, et al. (2012):
Onset of intractability and its course over time.
Epilepsia; 53(4): 741-751.
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