20

COGNITIVE DETERIORATION IN
LENNOX-GASTAUT SYNDROME
AND DOOSE EPILEPSY

Virginie Kieffer-Renaux*, Anna Kaminska, and Olivier Dulac

Service de Neuropédiatrie
Hôpital Saint Vincent de Paul
82 Avenue Denfert Rochereau
75674 Paris Cedex 14, France

INTRODUCTION
Epilepsy in children comprises not only seizures, but also a risk for cognitive func-
tions and/or behavior that interfere with social integration and schooling. For no other
type of epilepsy is it more severe than for intractable generalized epilepsy, such as
Lennox-Gastaut syndrome (LGS) and Doose epilepsy. The incidence of these disorders
is low, in the range of 1%.20 However, since the epilepsy remains intractable for a number
of affected patients, the prevalence is in the range of 10%. Patients suffer from daily
seizures and major interictal paroxysmal activity. Several factors, including frequency and
severity of the seizures4 and major interictal EEG abnormalities seem to interfere with
the development of cognitive functions.
The distinction between these two conditions remains difficult, if not dis-
putable. Some authors consider that there is no clear boundary between them and
that they represent a continuum2 whereas others consider that both etiology and
outcome are clearly different.10 Neuropsychological characteristics are different,
however, and this approach may contribute to distinguish both conditions and their
etiologies.

* To whom correspondence should be addressed

Neuropsychology of Childhood Epilepsy, edited by Jambaqué et al.

Kluwer Academic / Plenum Publishers, New York, 2001. 185
186 V. Kieffer-Renaux et al.

1. DEFINITIONS
1.1. Lennox-Gastaut Syndrome
LGS was first identified based on the combination of several types of generalized
seizures, generalized slow spike-wave activity and deterioration of cognitive abilities,7 thus
constituting an epilepsy syndrome. The slow spike-wave (SSW) pattern was initially con-
sidered as a variant of “petit mal” and called “petit mal variant”. However, the SSW
pattern was clearly distinct from the 3 Hz tracing of absence seizures, the so-called “petit
mal”. It differs from the “petit mal” pattern since the spike-wave activity is slow, and
onset and end are not clear. Thus, it is often difficult to determine whether the patient is
in an interictal or an ictal condition, even with video-EEG recording. SSWs predominate
over the frontal lobes.2,13 This pattern is recorded in patients with a severe condition,
including drop attacks, tonic seizures and atypical absences during which there is pro-
gressive loss of antigravidic tone, and either the head or the whole body drops. Myoclonic
seizures are rare, if they occur at all, but focal seizures do occur.
LGS begins between 1 and 9 years, later in cryptogenic cases than in symptomatic
ones, particularly when it follows West syndrome.2,4,11,15,23 The disease is chronic with fre-
quent episodes of status epilepticus that do not seem to alter the outcome. It affects boys
more frequently than girls in a proportion of 1.5 to 1. In most cases, it is possible to iden-
tify some kind of non-progressive pre-existing brain damage. Forty percent of patients
previously had West syndrome, others partial epilepsy of various causes or either mental
retardation or behavior problems without epilepsy.3,9 It may be difficult to determine in
patients who display mental or behavior problems as the first sign whether these result
from prior brain dysfunction or represent the first manifestations of the epilepsy.25 Thus,
LGS is usually considered as a symptomatic condition. In the cases without any evidence
of brain damage, the condition is qualified as “cryptogenic”, which means that the cause,
likely brain damage, is “hidden”.

1.2. Doose Epilepsy

Doose was also faced with patients who suffered from drop attacks, several types
of generalized seizures and generalized spike waves, but in contrast to LGS cases, these
patients with high familial incidence of epilepsy exhibited myoclonus and 3 Hz SWs,
which he considered as signs of genetic predisposition.10 However, the course of the
disease in these patients was most variable, some of them being very similar to the groups
reported by Dravet as “benign” or “severe” myoclonic epilepsies of infancy,12 and
others having a later onset, between 2 and 5 years.7,13,22 Thus, this condition was not a
syndrome but an etiologic concept which Doose called “myoclonic-astatic epilepsy”, and
which is considered to be genetically determined, or cryptogenic but never due to brain
damage.
It is the tableau of a group of patients starting epilepsy after the age of one that
will be considered here and that, for practical purposes, we will call Doose syndrome
(DS) in the following sections.

1.3. Doose Syndrome

At the onset, patients have generalized tonic-clonic seizures which are soon followed
by myoclonic drop attacks whereas absences and tonic seizures are less frequent. DS has
Cognitive Deterioration in Lennox-Gastaut Syndrome and Doose Epilepsy 187

a high incidence of familial epilepsy, myoclonus and 3 Hz SW activity. The EEG shows
bursts of generalized SWs or polySWs. The outcome is variable. Some patients recover
after one to three years.14 Other patients have poor outcome because of the occurrence
of episodes of myoclonic status epilepticus during which the patient is drowsy and
exhibits erratic myoclonus of the face and upper limbs, lasting one to several weeks, inter-
mingled with vibratory tonic seizures at the end of night sleep. At this late stage, SSW
activity is frequent.17 Thus, it is only in the course of the disease that SSWs appear in
cases with unfavorable outcome. Mental deterioration seems to correlate with the occur-
rence of myoclonic status and tonic seizures. This group with unfavorable outcome has
long been considered as the “myoclonic variant of LGS”.1 However, multifactorial analy-
sis has shown that it is distinct from LGS from the very onset of the disease.17 While there
is growing evidence that LGS is affecting patients with previous brain damage, DS
appears to be genetically determined. Unfavorable cases of DS exhibit features of LGS
only later in the course of the disease. LGS is likely to combine neuropsychological fea-
tures related to the topography of the focus and to the frontally predominating SSW
activity. In contrast, DS produces myoclonus, and therefore mainly affects the rolandic
area. Later in the course of cases with unfavorable outcome, features due to rolandic
involvement are combined with features of frontal lobe involvement corresponding to
the SSWs occurring at that stage. Both conditions will now be compared.

2. INTELLECTUAL ABILITY
Intellectual ability deteriorates progressively. In a follow-up study of 7 years for
LGS and 5 years for DS, conducted by our team,19 a significant decrease in IQ was
observed in both conditions. The significance of this deterioration in IQ has been dis-
cussed. Most authors consider that a decrease in mental performance in children does
not reflect loss of abilities but merely an arrest of development compared to normal chil-
dren who continue to make acquisitions. In our series, it was possible to distinguish both
conditions: LGS patients clearly showed deterioration whereas DS patients displayed
stagnation. In a series of 37 patients, we found that although the mean age of onset was
earlier in DS (3 years) than in LGS (6 years), patients with DS exhibited deterioration
later in the course of the illness (between 8 and 10 years of age) than those with LGS
(between 6 and 8).
In LGS, intellectual deterioration has been found to be frequent12 and to occur
rapidly.3,16 It is more severe for symptomatic than for cryptogenic patients and for patients
with previous West syndrome than for those with later onset. Whether there is ongoing
deterioration is still a matter of debate. Ninety-five percent of the patients suffer from
mental retardation23 and 80% have an IQ under 50.6 In the series reported by Hirosaku
et al.,16 73% (53/72) of the patients demonstrated variable degrees of mental retardation
with an IQ under 70. In most instances, the average IQ of the symptomatic group was
significantly lower than that of the cryptogenic group (43% of cryptogenic patients had
an IQ below 35, compared to 76% of symptomatic patients): An IQ below 55 was
observed in 86% of cryptogenic and in 96% of the symptomatic cases.16
The outcome is more severe for cases following West syndrome than for
those without previous epilepsy, and therefore with a later onset.23 Thus, the outcome
depends on the age of onset of the seizure disorder, with the worst outcome for
those with earlier onset.6 A single series has shown similar outcome for cryptogenic and
symptomatic cases.4
188 V. Kieffer-Renaux et al.

In our series, we could not evaluate the difference between symptomatic and cryp-
togenic cases since we restricted our analysis to cryptogenic cases in order to concentrate
on the effect of epilepsy as opposed to the effect of pre-existing damage. In the previ-
ously mentioned series, we found a median IQ value of 61 from the first year of the
seizure disorder. For seventy of the patients, the IQ was below 75 three years after
onset,6,23 and below 45 seven years19 and 10 year16 after onset, respectively. In our series
of twenty-one cryptogenic cases, the children exhibited progressive intellectual slowing.4
Associated behavioral disturbances were present in all cases.
In DS, the outcome of intellectual abilities is more variable.10,19 Following cessation
of seizures, it may be favorable, with recovery of intellectual efficiency. Only a few seizure-
free patients are left with an IQ below 50.1,14 In a group of 14, we found a median IQ of
82 for patients who stopped having seizures one to three years following seizure onset.19
For patients with persisting and intractable seizures, the outcome is very poor. Some
become demented.10 In our series, the median IQ was 52, thus in the same range as that
of LGS patients.19 When following patients with unfavorable myoclonic-astatic epilepsy,
it appears that there is a time lag between the onset of epilepsy and mental deteriora-
tion, as opposed to LGS. In fact, the age of occurrence of deterioration, between 8 and
10 years of age, corresponds to the age of occurrence of repeated and long lasting
episodes of myoclonic status, thus two years later than for LGS patients.

3. SPECIFIC NEUROPSYCHOLOGICAL PATTERNS AT ONSET OF

THE DISORDER
During the first year of the seizure disorder, behavior problems are frequent, both
in LGS2,8 and DS.19 They consist of hyperkinesia3,8,13 with inability to pursue a given activ-
ity during more than a few minutes.13 Some patients exhibit also autistic or psychotic
traits. Patients of both groups have apraxia. They are unable to execute skillful tasks such
as puzzles and/or drawings on the Brunet-Lézine, Termann-Merrill or Wechsler scales.19
Only LGS patients show major slowing of intellectual functioning. They rapidly
develop impairment of motor speed, apathy, slowness and slow expression,3 which are
observable during clinical observation. These children need to be stimulated in order for
responses to be obtained.19 We found that they exhibited inattention, perseveration, insta-
bility and memory problems. Two children in our series had spatial disorientation and
were unable to perform everyday activities.19 In contrast, patients with DS suffer more
commonly than those with LGS from dysarthria that may result in mutism.14

4. LONG-TERM NEUROPSYCHOLOGICAL PROBLEMS

Long-term follow-up studies have revealed differences between favorable and unfa-
vorable cases of DS: Dysarthria was mainly observed in unfavorable cases with DS.19 The
latter and those with LGS showed important ideic slowing and praxic disorders. In the
series reported by Boniver et al.,4 patients with LGS were left with hyperkinetic behav-
ior on average 7 years after onset and with slowing of intellectual functioning.4 Perse-
verative behavior was observed in all three groups; however, we found that some patients
with either LGS or unfavorable DS were so slow and apathetic that any tendency to per-
severate would have been masked by the magnitude of the slowness.19
Cognitive Deterioration in Lennox-Gastaut Syndrome and Doose Epilepsy 189

5. CHARACTERISTICS
Only patients with unfavorable DS have dysarthria and ataxia.10 Both patients with
LGS and unfavorable DS exhibit mental deficiency, signs of frontal lobe involvement and
perseveration. Although slowness and decrease of IQ may result from intellectual dete-
rioration, the occurrence of a frontal lobe syndrome, evolving to dementia, also seems
to contribute to deterioration.

6. EFFECTS OF TREATMENT
Very few data are available regarding the effect of callosotomy or steroid treatment
on cognitive functioning in these cases. Some authors consider the effect of callosotomy
in LGS disputable.18 Others observed improvement of mental abilities, behavior19,26 and
memory21,24 when seizure frequency decreased.16,24

7. COMMENTS
DS differs from LGS with regard to the occurrence of articulation difficulties, sug-
gesting pre-rolandic involvement. Thus, neuropsychological findings are consistent with
the topography of the maximal spiking activity. In LGS, this activity affects most of the
brain from the beginning of the disorder, although it predominates over pre-frontal areas.
Global mental deterioration is indeed an early manifestation of this syndrome.
At the onset of DS, spike activity predominates over the rolandic areas. In fact, the
ictal manifestations mainly consist of myoclonus involving the motor strip. Dysarthria
and apraxia, two relatively specific symptoms in DS, involve areas of the brain that are
near the motor strip. In this disorder, SSWs occur later, if ever, and severe deterioration
is a relatively late manifestation of DS in cases with persistent intractable seizures.
DS also differs from LGS in the course of the disorder and the neuropsychologi-
cal pattern. DS has variable outcome with either a short or a long course of the disease.
Only the subgroup with persistent pharmacoresistant epilepsy is comparable to LGS, and
from the nosological point of view it has long been considered as indistinguishable from
LGS, therefore the name “the myoclonic variant of LGS”. However, this review demon-
strates that the neuropsychological profile is distinct in these two conditions and
therefore is likely to contribute to a differential diagnosis. Favorable cases of DS are
characterized by an IQ in the lower normal range, apraxia and perseveration. Although
the course is relatively short, a number of patients are affected in their cognitive abilities
and have major problems. The great number of convulsive seizures that occur in the short
course of the disease is likely to contribute to this deterioration. The persistent hyperki-
nesia requires specific rehabilitation. The effect of drug treatment with methylphenydate
has not been evaluated to our knowledge.
Patients with unfavorable DS exhibit an early course similar to those with favor-
able outcome. It is only after several months to a few years that cognitive functions are
affected. Within a few months to one or two years, deterioration is observed as the patient
exhibits long episodes of frequent seizures or even status epilepticus. The cognitive profile
is specific with apraxia and dysphasia as predominant features, although most functions
are affected with deterioration of the IQ. Deterioration of verbal functions is unusual in
the course of epilepsy.
190 V. Kieffer-Renaux et al.

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