Seizure 21 (2012) 760763

Contents lists available at SciVerse ScienceDirect

Seizure
journal homepage: www.elsevier.com/locate/yseiz

LennoxGastaut syndrome in south Iran: Electro-clinical manifestations

Ali A. Asadi-Pooya a,b,c,*, Mohaddese Sharifzade a
a

Neurosciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Department of Neurology, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
c
Jefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas Jefferson University, Philadelphia, USA
b

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 16 July 2012
Received in revised form 31 July 2012
Accepted 9 August 2012

Purpose: LennoxGastaut syndrome (LGS) is an uncommon epileptic encephalopathy. In this study, we

tried to determine the clinical and EEG characteristics of patients with LGS in south Iran.
Methods: In this retrospective study, all patients with a clinical diagnosis of LGS were recruited at the
outpatient epilepsy clinic at Shiraz University of Medical Sciences from 2008 through 2012. Age, gender,
age at seizure onset, seizure type(s), epilepsy risk factors, EEG and imaging ndings of all patients were
registered routinely.
Results: During the study period, 2500 patients with epilepsy were registered at our epilepsy clinic. Onehundred and thirty-ve patients (5.4%) were diagnosed as having LGS. Age of onset (mean  standard
deviation) was 3.2  3.8 years. In 14 (10.4%) patients, age of onset was above 8 years. Eighty-three patients
(61.5%) were male and 52 (38.5%) were female. The most common seizure type was tonic, followed by
generalized tonicclonic and myoclonic seizures. The most common EEG nding was slow spike-wave
complexes. The most common abnormal MRI nding was brain atrophy.
Conclusion: LGS is an uncommon epileptic encephalopathy characterized by multiple seizure types, a
specic electroencephalographic pattern and psychomotor retardation, beginning in childhood.
However, variants of this classical triad including atypical EEG ndings, normal psychomotor function,
and late-onset disease could be seen in some patients. These atypical ndings in a patient with typical
history for LGS should not deter from the correct diagnosis. The mainstay for making a correct syndromic
diagnosis is a detailed clinical history.
2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Keywords:
LennoxGastaut syndrome
EEG
Seizure

1. Introduction
LennoxGastaut syndrome (LGS) is a relatively uncommon
epileptic encephalopathy. LGS is characterized by intractable,
multiple seizure types and an interictal electroencephalogram
(EEG) showing bursts of slow spike-and-wave complexes (SSW),
generalized paroxysmal fast activity (GPFA), and a slow background. All patients have lifelong epilepsy.1 It has been thought
that mental retardation (MR) is seen in all patients and it was
suggested that it should be a part of the diagnostic criteria.
However, there are reports on patients with LGS and without MR.2
Onset of LGS is usually before the age of 8 years. Occurrence rates
peak between 3 and 5 years of age, although late-onset cases have
been reported.3
LGS, which accounts for approximately 110% of all childhood
epilepsies, is notoriously resistant to medical and even surgical
treatments.13 When these patients become adults, most continue

* Corresponding author at: Neurosciences Research Center, Shiraz University of

Medical Sciences, Shiraz, Iran. Tel.: +98 9352274990.
E-mail address: aliasadipooya@yahoo.com (A.A. Asadi-Pooya).

to experience seizures as well as cognitive, psychiatric, and

behavioral problems.4 Therefore, it is not surprising that the
disorder has a devastating impact on patients quality of life and
imposes a considerable burden on their families.5 Misdiagnosis
and consequently mistreatment of this syndrome is common.1
In the current study, we tried to determine the clinical and
electroencephalographic manifestations of patients with LGS in
south Iran.
2. Methods and material
In this cross-sectional retrospective chart review study, all
patients with a clinical diagnosis of LGS were recruited at the
outpatient epilepsy clinic at Shiraz University of Medical Sciences,
which is the only epilepsy clinic in south Iran, from September
2008 through May 2012. The diagnosis of LGS was made based on
the clinical and electroencephalographic grounds1 and all patients
had to be under the care of the epileptologist at our institution.
Out-patient EEG (either awake or sleep) was performed in all
patients at the time of referral. Study time for EEG was 10 min and
we performed intermittent photic stimulation in all patients.
Hyperventilation was typically performed in children above ve

1059-1311/$ see front matter 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.seizure.2012.08.003

A.A. Asadi-Pooya, M. Sharifzade / Seizure 21 (2012) 760763

years of age, if they were cooperative. The high frequency lter was
set to 70 Hz and the low lter was at 0.16 Hz. Brain imaging study
[magnetic resonance imaging (MRI)] was performed, when
possible. Other tests (e.g., blood tests) were requested based upon
the clinical judgment.
We studied the demographic, clinical, EEG and imaging
ndings. Age, gender, age at seizure onset, seizure type(s), epilepsy
risk factors (including history of pregnancy complications or
signicant head trauma, positive family history of epilepsy and
parental consanguinity), EEG and imaging ndings of all patients
were registered routinely. Demographic variables and relevant
clinical variables were summarized descriptively to characterize
the study population. This study was conducted with approval of
the Shiraz University of Medical Sciences Review Board.
3. Results
During the study period, 2500 patients with epilepsy were
registered at our epilepsy clinic. One-hundred and thirty-ve
patients (5.4%) were diagnosed as having LGS. Age of onset
(mean  standard deviation) was 3.2  3.8 years. Minimum age of
onset was the neonatal period and maximum age was 17 years
(Fig. 1). In 14 (10.4%) patients, age of onset was above 8 years. Eightythree patients were male (61.5%) and 52 (38.5%) were female. The age
of the patients at referral was 12.4  8.8 years. The minimum age at
referral was seven months and the maximum age was 43 years.
Fifty-eight patients (43%) reported having two seizure types
and 77 (57%) had three or more seizure types. Tonic seizures were
reported in 90 (66.7%); generalized tonicclonic seizures in 83
patients (61.5%); myoclonic seizures in 79 (58.5%); atypical
absences in 66 (49%); atonic seizures in 27 (20%); astatic (drop
attacks) in 14 (10%); and complex partial seizures in 12 (9%).
Thirty-ve (26%) patients had history of episodes of status
epilepticus.
Epilepsy risk factors were reported to be as follows: perinatal
complications in 34 patients (25%) (including, hypoxic-ischemic
insults in 28 and sepsis, low-birth-weight and hyperbilirubinemia
in others); CNS infections in 5 (3.7%); family history of epilepsy in
33 (24.4%); parental consanguinity in 67 (49.6%); and history of
signicant head trauma in one patient.

[(Fig._1)TD$IG]

761

Table 1
EEG ndings in patients with LennoxGastaut syndrome.
EEG nding

Number

Percent

Background abnormality
Slow spike-wave complexes
GPFA
Polyspikes
Multifocal spikes
Slow spike-wave complexes + GPFA
Neither slow spike-wave complexes nor GPFA

132
117
61
33
13
50
7

97.8
86.7
45.2
24.4
9.6
37
5.2

GPFA: generalized paroxysmal fast activity.

Three patients were not mentally retarded and the rest had
mild to severe cognitive impairment. One patient was a university
student in electrical engineering at a local university, one had high
school diploma and another one nished his 9th grade. Many
patients had medical or neurological comorbidities. These included: cerebral palsy in 45 (33%); attention-decit hyperactivity
disorder in 11 (8%); hypothyroidism 4 (3%); congenital heart
disease in 3 (2%); cancer in 2 (1.5%); and tuberous sclerosis,
diabetes mellitus, hypopituitarism, renal failure, and hearing loss,
each in one patient.
We requested EEG for all patients at the time of referral
(Table 1). Brain imaging studies were done in 102 patients; 33
patients could not afford these tests. The results are summarized in
Table 2. Blood tests were not performed in the majority of patients
(81 patients; 60%). When it was performed, it was not conclusive in
most cases. Blood tests were normal in 48 patients (35.6%), but
showed lactic acidosis in two, anemia and vitamin B-12 deciency
in one, hypothyroidism in one, hypercholesterolemia in one, and
hypocalcemia in another patient.
4. Discussion
LennoxGastaut syndrome (LGS) is a relatively uncommon
epileptic encephalopathy. LGS is often characterized by a triad of
multiple seizure types, a specic interictal EEG showing bursts of
slow spike-wave complexes and/or generalized paroxysmal fast
activity, and mental retardation In the current study, 5.4% of all
patients with epilepsy (children and adults) had LGS, which is
slightly higher than the rates reported in some previous
studies.1,6,7 The prevalence has been estimated at 12% of all
patients with epilepsy, although gures as high as 10% have been
reported.7 In a previous study from the USA, LGS accounted for 4%
of all childhood epilepsies.6 The probable reason for this
discrepancy will be discussed later.
Clinical manifestations of LGS are more or less similar in various
studies. The sex ratio (male to female) and age of onset of LGS in
our study were similar to previous reports.1,6,8 Males outnumber
females in LGS (male to female ratio in our study = 1.6:1). Age of
onset is often below eight years; however in about 10% of our
patients the syndrome started after 8 years of age. Late-onset LGS
has been reported in the literature before. In a previous study, 15%
Table 2
Brain imaging abnormalities in patients with LennoxGastaut syndrome.

Fig. 1. Age of onset (mean  standard deviation) in patients with LennoxGastaut

syndrome was 3.2  3.8 years. Minimum age of onset was the neonatal period and
maximum age was 17 years.

Brain MRI nding

Number

Percent

Normal
Brain atrophy
Hypoxic-ischemic changes
Neuronal migrational disorders
Leukodystrophy or leukoencephalopathy
Periventricular calcication
Canavan disease
Ventricular cyst
Not performed

54
17
11
9
8
1
1
1
33

52
17
11
9
8
1
1
1

762

A.A. Asadi-Pooya, M. Sharifzade / Seizure 21 (2012) 760763

of the patients with LGS had late-onset disease.8 It is advised to

consider and investigate for genetic disorders, particularly
chromosomal abnormalities, in patients with late-onset LGS.911
The clinical hallmark of LGS is having multiple seizure types. In
our study, two-fths of the patients had two seizure types and
three-fths had three or more seizure types. Tonic seizure was the
most common seizure type, followed by generalized tonicclonic,
myoclonic and atypical absence seizures. This is very similar to
previous reports.1,8 However, to correctly diagnose the seizure
types and consequently the syndrome itself needs a standardized
approach, particularly with regards to taking a detailed clinical
history. The routine use of a standard proforma minimizes the risk
of missing clinical ndings, including seizure types, and most of the
time leads to a correct diagnosis.12 An incorrect diagnosis may
indeed have many negative consequences; one is taking suboptimal antiepileptic drugs. Misinterpretation of tonic and myoclonic
seizures as complex partial seizures and subsequently, mistreatment of the syndrome has been reported in a previous study.13
Mental retardation has been considered as a criterion of the
classic triad seen in patients with LGS; however, some patients
have normal or near-normal cognitive prole.14 There are authors
who have chosen not to include mental retardation as a
requirement for dening LGS in their studies.8 In our study,
2.2% of patients had normal cognitive function and achieved some
education. In a previous study from the same region (i.e., the
Middle East), 4% of the patients did not have mental retardation.15
Epilepsy risk factors, particularly perinatal complications, and
also comorbid neurological and medical conditions observed in our
patients were more or less similar to previous studies.6,8 However,
rate of parental consanguinity (about 50%) was high in our study.
Similarly, the rate of family history of epilepsy (24%) observed
among our patients was high. In a previous Western study, the
latest gure was only 13%,8 however, in a previous report from the
Middle East, positive consanguinity was observed in 30% and
positive family history of epilepsy was found in 22% of the
patients.15 High consanguinity rate was previously reported in
patients with epilepsy from the same region (Shiraz, Iran).16 In that
study, it was observed that the percentage of consanguinity in
parents of the patients with epilepsy was signicantly higher
compared to a sample of the general population (Odds Ratio = 2.6;
95%-Condence Interval: 1.9293.536; P < 0.0001). This high rate
of familial marriage might result in more prevalent genetic
disorders (e.g., neuronal migrational disorders, metabolic disorders such as mitochondrial respiratory chain defects, etc.), which
could present as LGS, clinically.17 Maybe, one reason for observing
high rate of family history of epilepsy among our patients (24%)
compared to a previous study (13%)8 is this high rate of parental
consanguinity. Likewise, it is probable that higher percentage of
LGS among all epilepsies observed in our study compared to some
previous reports7 is related to the high rate of familial marriage in
our region, at least to some extent. This nding needs further
exploration in future investigations.
The hallmark electroencephalographic feature in LGS is slow
(<2.5 Hz) spike-wave bursts with abnormal background activity.1
Similar results were observed in our study (Table 1). However, not
all patients with LGS have slow spike-waves (SSW) in their EEGs. In
our study, about 13% of patients did not have SSW. Bursts of
generalized paroxysmal fast activity (1020 Hz) (GPFA), particularly during sleep, also dene the EEG prole of the LGS.1 However,
in our experience, there are patients with LGS (about 5%) who
neither have SSW nor show GPFA in their EEG (particularly, if we
do not record sleep EEG or have a suboptimal EEG). If other clinical
manifestations (i.e., multiple seizure types, particularly tonic
seizures, and cognitive impairment) of LGS are present and EEG
shows background abnormality and a diffuse (e.g., polyspikes) or
multifocal epileptiform abnormality and you cannot make a better

syndromic diagnosis, we suggest considering LGS, despite not

seeing either SSW or GPFA in EEG. The EEG background probably is
never normal in LGS and shows a diffuse slowing and absent
normal rhythms.1 In our study, three patients had normal
background activity in their EEG. This was probably due to
technical problems, most importantly short recording time, in our
EEG lab.
Brain MRI is probably the most important diagnostic tool to
help identify the etiology of LGS. The spectrum of brain MRI
abnormalities in our patients with LGS was similar to a previous
study.18 However, in our study, brain imaging was normal in more
than half of the patients that is much higher than the rate observed
in that previous study (22%).18 In another study from the Middle
East, in 36% of the patients who had brain MRI, the results were
normal and in most of those with abnormal MRI, brain atrophy was
reported.15 These discrepancies are probably related to technical
problems (e.g., most of our pediatric patients had performed 0.5 T
MRI). Modern 3 T MRI scanners and sequences can be used to
identify subtle abnormalities in patients with refractory epilepsy
and previously unremarkable or inconclusive brain MRI scans.19
Other laboratory studies (which were very limited) were often
normal or non-specic in our study; however in a minority of
patients metabolic disorders could be detected. It has been advised
that patients with no identiable etiology or those with normal or
non-specic brain imaging should receive evaluations for inborn
errors of metabolism.7
5. Conclusion
LennoxGastaut syndrome is an uncommon epileptic encephalopathy characterized by multiple seizure types, a specic
electroencephalographic pattern (slow spike-waves or generalized
paroxysmal fast activity) and psychomotor retardation, beginning
in childhood. However, variants of this classical triad including
atypical EEG ndings, normal psychomotor function, and lateonset disease could be seen in some patients. These atypical
ndings in a patient with typical history for LGS should not deter
from the correct diagnosis. The mainstay for making a correct
syndromic diagnosis is a detailed clinical history.
6. Limitations of the study
This was a clinic-based series and may not represent the full
spectrum of patients with LennoxGastaut syndrome; because the
mildest disease varieties may not be referred to a university clinic
and therefore, the possibility of selection bias remains in place.
Another limitation of our study is that, in some patients we did
not record sleep EEG and EEG time in the out-patient setting was
too short to record deep sleep in most cases. Besides, we did not
have access to high quality imaging studies (e.g., 3 T MRI) and
sophisticated genetic and metabolic studies. As a matter of fact, in a
large number of the patients even a simple imaging study such as
CT scan was not available; therefore, we could not identify the
etiology with certainty and we did not try to enter into the etiologic
classication of LGS in this paper.
Conict of interest
The authors have no conict of interest.
Acknowledgment
We would like to appreciate the Neurosciences Research
Center, Shiraz University of Medical Sciences, for supporting this
study.

A.A. Asadi-Pooya, M. Sharifzade / Seizure 21 (2012) 760763

References
1. Cameld PR. Denition and natural history of LennoxGastaut syndrome.
Epilepsia 2011;52(Suppl. 5):39.
2. Shyu HY, Lin JH, Chen C, Kwan SY, Yiu CH. An atypical case of LennoxGastaut
syndrome not associated with mental retardation: a nosological issue. Seizure
2011;20(10):8203.
3. Arzimanoglou A, French J, Blume WT, Cross JH, Ernst JP, Feucht M, et al. Lennox
Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. Lancet Neurology 2009;8:8293.
4. Cameld C, Cameld P. Twenty years after childhood-onset symptomatic
generalized epilepsy the social outcome is usually dependency or death: a
population-based study. Developmental Medicine and Child Neurology 2008;50:
85963.
5. Douglass LM, Conclusions:. Long-term management of LennoxGastaut syndrome: future directions. Epilepsia 2011;52(Suppl. 5):28.
6. Trevathan E, Murphy CC, Yeargin-Allsopp M. Prevalence and descriptive epidemiology of LennoxGastaut syndrome among Atlanta children. Epilepsia
1997;38:12838.
7. Crumrine PK. LennoxGastaut syndrome. Journal of Child Neurology 2002;17:
S705.
8. Goldsmith IL, Zupanc ML, Buchhalter JR. Long-term seizure outcome in 74
patients with LennoxGastaut syndrome: effects of incorporating MRI head
imaging in dening the cryptogenic subgroup. Epilepsia 2000;41(4):3959.
9. Orrico A, Zollino M, Galli L, Buoni S, Marangi G, Sorrentino V. Late-onset
LennoxGastaut syndrome in a patient with 15q11.2-q13.1 duplication. American Journal of Medical Genetics Part A 2009;149A(5):10335.

763

10. Ferlazzo E, Adjien CK, Guerrini R, Calarese T, Crespel A, Elia M, et al. Lennox
Gastaut syndrome with late-onset and prominent reex seizures in trisomy 21
patients. Epilepsia 2009;50(6):158795.
11. Rocha J, Guerra C, Oliveira R, Doria S, Rego R, Rosas MJ. Late-onset Lennox
Gastaut syndrome as a phenotype of 15q11.1q13.3 duplication. Epileptic Disorders 2012;14(2):15962.
12. Asadi-Pooya AA, Emami M, Sperling MR. Age of onset in idiopathic (genetic)
generalized epilepsies: clinical and EEG ndings in various age groups. Seizure
2012;21(6):41721.
13. Lo WD, Donat JF, Wright FS. Tonic and myoclonic seizures in LennoxGastaut
syndrome mistaken as complex partial seizures. Journal of Epilepsy 1991;4:
2115.
14. Chevrie JJ, Aicardi J. Childhood epileptic encephalopathy with slow spike-wave.
A statistical study of 80 cases. Epilepsia 1972;13:25971.
15. Habib HS. Clinical characteristics and responsiveness to treatment in Lennox
Gastaut syndrome. A retrospective hospital audit. Neurosciences (Riyadh)
2006;11(1):247.
16. Asadi-Pooya AA. Epilepsy and consanguinity in Shiraz, Iran. European Journal of
Paediatric Neurology 2005;9:3836.
17. Lee YM, Kang HC, Lee JS, Kim SH, Kim EY, Lee SK, et al. Mitochondrial respiratory
chain defects: underlying etiology in various epileptic conditions. Epilepsia
2008;49(4):68590.
18. Liu SY, An N, Fang X, Singh P, Oommen J, Yin Q, et al. Surgical treatment of
patients with LennoxGastaut syndrome phenotype. ScienticWorldJournal
2012;2012:614263.
19. Craven I, Grifths PD, Hoggard N. Magnetic resonance imaging of epilepsy at 3
Tesla. Clinical Radiology 2011;66(3):27886.