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ARTICLE IN PRESS
E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y 1 1 ( 2 0 0 7 ) 1 0 – 1 6
1090-3798/$ - see frodoi:10.1016/j.ejpn.20
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Official Journal of the European Paediatric Neurology Society
Original Article
Treatment of epilepsy in Rett syndrome
Peter Huppkea,�, Karola Kohlerb, Knut Brockmanna, Georg M. Stettnera, Jutta Gartnera
aDepartment of Pediatrics and Pediatric Neurology, Georg August University, Robert-Koch-Strasse 40, D-37075 Gottingen, GermanybDepartment of Genetic Epidemiology, Georg August University, Robert-Koch-Strasse 40, D-37075 Gottingen, Germany
a r t i c l e i n f o
Article history:
Received 19 August 2006
Received in revised form
13 September 2006
Accepted 13 September 2006
Keywords:
Rett syndrome
Epilepsy
Treatment
nt matter & 2006 Europe06.09.003
hor. Tel.: +49 551 39 6210;huppke@med.uni-goetti
A B S T R A C T
Introduction: Epilepsy is very frequent in Rett syndrome (RTT) patients and often difficult
to treat. Because most cases of RTT are caused by mutations in the MECP2 gene it is
reasonable to assume that convulsions are based on common pathogenetic mechanisms
and thus should have a similar response to antiepileptic drugs. Purpose: To find the optimal
treatment for epilepsy in RTT.
Methods: We performed a retrospective study on 110 female patients with confirmed
MECP2 mutations.
Results: The median age was 10 years, 58% had a history of epilepsy and 55% received
antiepileptic drugs (AEDs). Only sulthiame, carbamazepine and valproate were adminis-
tered in an adequate frequency to allow statistical analysis. The best anticonvulsive results
were seen in the RTT group that was treated with carbamazepine. Sulthiame was slightly
less effective while valproate was significantly less effective. The rate of side effects was
equivalent in all groups. In conclusion, carbamazepine should be recommended as first
choice AED in RTT. If carbamazepine is not effective or not well tolerated sulthiame ought
to be taken as second choice AED.
& 2006 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1. Introduction
Rett syndrome (RTT[MIM 312750]) is one of the most common
causes of mental retardation in females.1 In classical RTT the
disease is characterized by four clinical stages2: In stage one,
with an onset at 6–18 months of age, an initial normal or near
normal period of development is followed by a period of
stagnation lasting weeks to months. In stage two, acquired
skills, especially hand function and speech are lost also over a
period of weeks to months. In stage three, the condition
stabilizes for years or decades and in many cases the residual
functions even improve. In stage four, also spanning decades,
many individuals with RTT show a slow decline in motor
functions especially ambulation, however the mental residual
an Paediatric Neurology
fax: +49 551 39 6252.ngen.de (P. Huppke).
functions are spared. In 1999 the first mutations in the MECP2
gene causing RTT were described.3 The detection rate for
these mutations varies between 60% and 80%.4
The EEG abnormalities in RTT are well documented.5–16
During stage one the EEG is usually normal but in some
children epileptiform activity occurs during sleep. In stage
two, a slowing of the background activity is noted and
frequently central or centrotemporal spikes are recorded.
Stage three is characterized by a further slowing of the
background activity and multifocal sharp wave discharges. In
stage four, the epileptiform activity becomes even more
frequent especially during sleep in most RTT patients but in
some it also normalizes. The background activity is even
slower in stage four than in stage three.
Society. Published by Elsevier Ltd. All rights reserved.
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E UR O P EA N J O UR NA L O F PA ED I ATR I C N E U RO L O G Y 11 (2007) 10 – 16 11
Epilepsy is very frequent in RTT. In Steffenburg and
colleagues study 53 RTT female aged 5–55 years, more than
90% had a history of epilepsy.17 The seizures had a median
age of onset at four years (range 0.2–27.6 years). The most
common seizure types were partial complex, tonic-clonic,
tonic and myoclonic seizures. Partial seizures occurred in 62%
and generalized seizures also in 62%. In 54% the epilepsy was
intractable. They also found that the severity of the epilepsy
tended to decrease after 20 years of age. Recently, it has been
found that mutations in the cyclin-dependent kinase-like
gene CDKL5 are responsible for a RTT like phenotype in
females with an onset of seizures in the first 3 months of
life.18,19
Regarding optimal treatment strategies for epilepsy in RTT
there are currently only very limited data available. In the
study of Steffenburg and colleagues most reported RTT
patients received carbamazepine, lamotrigine or valproate.17
The effectiveness of the treatment was, however, not
described. Two studies have been performed on patients
treated with lamotrigine.20,21 Uldall and colleagues report on
four RTT patients, three of whom had concomitant medica-
tion. All of them had a seizure reduction of at least 50% but
none were seizure free. Stenbom and colleagues treated 12
girls with RTT. Only five had epilepsy while the others were
treated to evaluate the effect on motor function. Two of these
five, of whom one received a monotherapy and the other
concomitant medication, responded well to the treatment
and had a seizure reduction of 59% and 48%, respectively.
Goyal and colleagues treated eight RTT patients with topir-
amate, two of them as a monotherapy; they describe
improved seizure control in all of them.22 Finally, there are
two reports of ketogenic diet treatment in RTT both with
favourable results.23,24
So far no clinical studies have been reported that compare
the efficiency of various antiepileptic drugs (AEDs) in RTT
patients with epilepsy. Since most cases of RTT are caused by
MECP2 mutations with comparable functional consequences
it is reasonable to assume that convulsions are based on
common pathogenetic mechanisms and thus respond simi-
larly to antiepileptic drugs. In order to test this hypothesis
and establish treatment recommendations for epilepsy in
RTT we performed a retrospective study on 110 patients.
2. Materials and methods
2.1. Subjects
Gottingen has a long history of research on RTT and the
neuropediatric department is closely connected to the Parent
Support Group for Children with RTT. As most patients in our
study live scattered throughout Germany the epilepsy treat-
ment is predominantly provided by neurologists in the local
area. However, most were seen at least once in Gottingen. To
provide a study group large enough for statistical analysis not
only girls treated in Gottingen but also those treated else-
where were included. A questionnaire was developed and
sent to the families to be filled in together with the
neurologist in charge of the patient. The data were comple-
mented by hospital notes and seizure diaries. In order to have
a homogenous group of RTT patients, only females with
confirmed mutation in the MECP2 gene were included. The
Ethics Committee of the Georg August University Gottingen
approved the study.
2.2. Assessment of outcome
The effects of the first and second treatment with an AED as a
monotherapy were analysed separately as were the effects of
a polytherapy. The adverse effects were analysed combined
for the first and second monotherapy AED. The adverse
effects of the polytherapy were not included. Five variables
were determined to assess the outcome of the AED treatment:
(1)
Reduction of seizure frequency: We analysed the absolutereduction (reduction) and the number of patients with a
reduction of more than 50% (reduction 450%).
(2)
Seizure free time span: The absolute time span in monthswas analysed (seizure free) and the number of patients
that were seizure free for more than 6 months (seizure
free X6 m).
(3)
Effect of the medication: To determine the effect of a specificmedication in a broader way we asked if the seizures were
shorter, milder or less frequent and defined this as a
positive effect (positive effect). If they were longer, more
severe, more frequent or unchanged we defined this as
negative effect.
(4)
Duration of treatment: The time length during which thepatients continued the medication without being with-
drawn because of lack of seizure control or adverse effects
(duration).
(5)
Adverse effects: We asked if any adverse effects occurredand whether these were the reason for medication with-
drawl.
2.3. Statistical inference
The three drugs, sulthiame, carbamazepine, and valproate,
which were given frequently enough as first AED monother-
apy for statistical analysis were tested for significant differ-
ences in the outcome variables. The dichotomous variables
(reduction 450%, seizure free X6 m, positive effect) were
analysed by the Chi-square test (global comparison of all
three drugs) and the Fisher’s Exact (pairwise). The metric
variables (duration, reduction, seizure free) were analysed
nonparametrically using the Kruskal–Wallis test (global) and
the Wilcoxen–Mann–Whitney test (pairwise).
3. Results
Female patients (110) with a confirmed clinical and molecular
diagnosis of RTT entered the study. All patients were in stage
three or early stage four of RTT. The median age was 10 years
(range 3–48 years). Of all 64 (58%) had a history of epilepsy and
61 of them had received AEDs. In all patients serial EEG
studies were performed, however the results were not
included in this study because in many patients it was not
possible to obtain the original recordings. The total number of
ARTICLE IN PRESS
Table 1 – Results of 1st AED monotherapy in 58 RTT patients
AED (n) Reduction (%)median
Reduction450% n (%)
Seizure free(m) min/median/max
Seizure free46 m n (%)
Positive effectn (%)
Duration (m)min/median/max
STM (15) 87 9/14 (64%) 0/3/90 6/15 (40%) 8/15 (53%) 1/36/96
CBZ (16) 98 10/14 (71%) 0/7/180 9/16 (56%) 13/15 (87%) 3/102/330
VPA (16) 30 5/13 (38%) 0/0/24 1/15 (6%) 8/16 (50%) 5/29/100
LTG (3) 64 1/2 0/0/0 0/3 1/3 6/–/132
PHT (1) 0/1 0/1 120
TPM (0)
LEV (1) 0/1 1/1 4
VGB (2) 30 1/2 0/1/2 2/2 3/–/4
PB (2) 0/1 1/1 0/1 12
PRM (4) 60 2/4 0/5/36 1/1 3/4 1/–/36
OXC (0)
CLB (1) 1/1 10
Total (59) 28/51 (54%) 19/53 (36%) 36/58 (62%)
AED ¼ antiepileptic drug, STM ¼ sulthiame, CBZ ¼ carbamazepine, VPA ¼ valproate, LTG ¼ lamotrigine, PHT ¼ phenytoin, TPM ¼ topiramate,
LEV ¼ levetirazetam, VGB ¼ vigabatrin, PB ¼ phenobarbital, PRM ¼ primidone, OXC ¼ oxcarbazepine, CLB ¼ clobazam.
Table 2 – Results of 2nd AED monotherapy in 25 RTTpatients
AED (n) Reduction450% n
Seizurefree 46 mn
Positiveeffect n
STM (4) 0/3 0/3 3/4
CBZ (7) 3/7 1/6 3/7
VPA (9) 4/8 2/8 4/9
LTG (9) 0/1 1/1 0/1
PHT (1)
TPM (1) 1/1 0/1 0/1
LEV (0)
VGB (0)
PB (1) 0/1 0/1
PRM (1) 0/1 0/1
OXC (1) 0/1 1/1 1/1
CLB (1)
Total (25) 8/21 (38%) 5/22 (23%) 11/25 (44%)
Abbreviations see Table 1.
E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y 1 1 ( 2 0 0 7 ) 1 0 – 1 612
patients in each different category varies as some informa-
tion could not be reliably obtained particularly in the older
patients. Three patients were excluded from the study
because the data was insufficient. In 58 patients data was
available on the first AED, 25 were treated with a second AED
and 19 received at least one polytherapy. The onset of
epilepsy ranged between 10 months and 28 years (median
age 4 1/3 years), the duration of the seizures was from 0.5 to
30 min (median duration 1.5 min). Twelve different AEDs were
used to treat the epilepsy namely carbamazepine, clobazam,
lamotrigine, levetirazetam, oxcarbazepine, phenobarbital,
phenytoin, primidone, sulthiame, topiramate, valproate,
and vigabatrin. The results of the assessment are shown in
Tables 1–4.
Overall the first AED monotherapy had a positive effect on
the epilepsy in 62% of RTT patients. Fifty four percent had a
reduction in seizure frequency of more than 50%, 36%
remained seizure free for at least 6 months (Table 1). A
second AED monotherapy led to a seizure reduction of more
than 50% in only 38% of RTT patients, a positive effect was
seen in 44% and a seizure free period of more than 6 months
could only be achieved in 23% patients (Table 2). The AED
polytherapy following an ineffective monotherapy resulted in
a 50% reduction of seizure frequency in 42% of RTT patients,
the overall positive effect was 47% and a seizure-free interval
of more than 6 months was seen in 40% (Table 3).
Three drugs, sulthiame, carbamazepine, and valproate,
were given frequently enough as first AED monotherapy to
allow statistical analysis (Table 1 and Table 5, Figs. 1 and 2).
Fifteen patients received sulthiame as the first AED. It led to a
seizure reduction of greater than 50% in 64% of patients, 40%
were seizure free for more than 6 months and the effect was
positive in 53%. Carbamazepine was also given in 15 cases. It
led to reduction of seizures in 71%, a seizure-free period
longer than 6 months in 56% and a positive effect in 87%.
Sixteen RTT patients received valproate as the first AED, 38%
of them showed a reduction of seizures of more than 50%, 6%
were seizure-free for more than 6 months and the effect was
positive in 50%. The median duration of treatment was 36
months for sulthiame, 102 months for carbamazepine and 29
months for valproate.
The global test comparing all three drugs revealed a
statistically significant difference in the seizure-free time
span measure in month (seizure free, p ¼ 0.0251) as well as
dichotomized (seizure free 46 m, p ¼ 0.0202). The pair wise
comparisons showed that patients receiving carbamazepine
had a significantly longer seizure free time span in months
than those receiving valproate (p ¼ 0.0076) and were signifi-
cantly more likely to have a seizure-free period longer than 6
months (p ¼ 0.0142). Furthermore, a global difference in the
duration of the treatment could be detected (p ¼ 0.0359).
ARTICLE IN PRESS
Table 3 – Results of the AED polytherapy in 19 patients
AED Polytherapy with Reduction 450% n (%) Seizure free 46 m n (%) Positive effect n (%)
STM (1) 2,3,4,11,13 5/7 (71%) 2/5 (40%) 5/7 (71%)
CBZ (2) 1,3,4 3/3 (100%) 1/3 (33%) 3/3 (100%)
VPA (3) 1,2,4,6,7,8,9,10,11,12 5/12 (41%) 4/10 (40%) 5/12 (41%)
LTG (4) 1,2,3,6 2/7 (28%) 2/7 (28%) 2/7 (28%)
PHT (5) 6,8 0/2
TPM (6) 3,5 1/2 2/3 2/3
LEV (7) 3 0/1 0/1
VGB (8) 3,5,10,13 0/3 0/1 2/4
PB (9) 3 1/1 1/1 0/1
PRM (10) 3 0/2 0/1 1/2
OXC (11) 1,3 1/2 0/1 1/2
CLB (12) 1,3,8 0/2 1/3
Total 18/42 (43%) 12/32 (37%) 22/47 (47%)
Several patients received more that one polytherapy. Abbreviations see Table 1.
Table 4 – Adverse effects of the AEDs used as 1st or 2ndmonotherapy
AED Adverseeffects n (%)
Discontinueddue to adverseeffects n (%)
STM 7/18 (39%) 0/18 (0%)
CBZ 9/22 (41%) 3/22 (14%)
VPA 10/25 (40%) 2/25 (8%)
LTG 2/4 1/4
PHT 1/1 1/1
TPM 1/1 0/1
LEV 0/1 0/1
VGB 1/2 1/2
PB 1/2 0/2
PRM 3/4 2/4
OXC 1/1 1/1
CLB 1/1 0/1
Total 37/82 (45%) 11/82 (13%)
In one patient no data was available on adverse effects. Abbrevia-
tions see Table 1.
E UR O P EA N J O UR NA L O F PA ED I ATR I C N E U RO L O G Y 11 (2007) 10 – 16 13
The duration that patients received carbamazepine was
significantly longer than in those patients treated with
sulthiame (p ¼ 0.0295) or valproate (p ¼ 0.0271). No global
statistical differences could be detected in the reduction of
seizure frequency or in the effect of medication. The
summary statistics, however, (Table 1) show a trend that
carbamazepine is more effective than valproate.
Adverse effects of AEDs are with a total of 45% frequently
seen in our study (Table 4). The spectrum and rate of side
effects observed in this study is comparable to that seen in
other patients with epilepsy (data not shown). However, only
in 13% of our RTT patients did the side effects result in a
discontinuation of the medication. Within the group of
commonly administered AEDs the frequency of side effects
was similar.
In this study 61 RTT patients with epilepsy were treated
with AED. In addition, nine females received AED without a
history of seizures (sulthiame n ¼ 2, carbamazepine n ¼ 2,
valproate n ¼ 5), seven of them on the basis of a pathological
EEG, two because of non-seizure events such as episodes of
hyperventilation. In none of these nine patients did the
clinical status improve under AED.
4. Discussion
In an attempt to clarify the overall effect of antiepileptic
treatment on epilepsy in RTT we performed a retrospective
study in 110 patients with clinical and molecular confirmed
RTT. So far, the choice of an AED is based on the preference
and individual experience of the physician in charge of the
patient. To establish optimal treatment recommendations for
a certain disease an aged matched prospective study is
recommended. For RTT this is almost not feasible due to the
low prevalence of disease and thus the long duration of such
a study to achieve statistically valid results. Therefore, we
performed a retrospective study based on the work and
experience of many physicians treating single RTT patients.
The frequency of epilepsy in our group was 58% and thus
lower than in the study by Steffenburg and colleagues with
almost 90%. This is most likely due to the lower median age of
our group.17 However, the median age of epilepsy onset was
comparable; 4 years and 4 months and 4 years, respectively.
Around 54% of the females showed a reduction of seizure
frequency of more than 50% after taking the first AED and 36%
were seizure free for at least six months. This number is
lower than reported in unselected groups of patients with
epilepsy, underlining that the epilepsy in RTT has a relatively
severe course.25 The second AED monotherapy after discon-
tinuing the first AED lead overall to a seizure reduction of
more than 50% in only 38% of the patients and a seizure-free
period of 6 months or longer in 22%. An AED polytherapy was
slightly better than the second AED monotherapy and
resulted in a 50% reduction of seizure frequency in 43% and
ARTICLE IN PRESS
0102030405060708090
100
STM CBZ VPA
Sei
zure
red
uctio
n (%
)
Fig. 1 – Effect of sulthiame (STM), carbamazepine (CBZ) and
valproate (VPA) on seizure reduction in 41 RTT patients.
Seizure reduction in % frequency during AED treatment.
Each ~ represents one patient.
0
2
4
6
8
10
12
14
16
Pat
ient
s (n
)
STM CBZ VPA
Fig. 2 – Effect of sulthiame (STM), carbamazepine (CBZ) and
valproate (VPA) on the likelihood of a seizure free period of
more than 6 months in 46 RTT patients. Number of patients
who were seizure free for more than 6 months (grey bars) in
comparison with the number of patients who failed to be
seizure free for more than 6 months (white bars).
Table 5 – Statistical analysis comparing the efficacy of the treatment with sulthiame (STM), carbamazepine (CBZ) andvalproate (VPA)
STM,CBZ,VPA STM vs CBZ STM vs VPA CBZ vs VPA
Test Chi-square Fisher’s exact
Reduction 450% 0.1913 1 0.2568 0.1283
Seizure free 46 month 0.0202 0.7152 0.0801 0.0142
Positive effect 0.0683 0.1086 1 0.0538
Kruskal–Wallis Wilcoxon–Mann–Whitney
Reduction 0.065 0.9612 0.0711 0.03
Seizure free 0.0251 0.3828 0,0811 0.0076
Duration 0.0359 0.0295 0.625 0.0271
E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y 1 1 ( 2 0 0 7 ) 1 0 – 1 614
a seizure-free interval of more than 6 months in 37% of
patients. These numbers reveal that there is a large group of
RTT patients with intractable seizures regardless of the AED
used.
Three drugs, namely sulthiame, carbamazepine, and
valproate, were used in a frequency high enough to allow
statistical analysis on efficacy. However, it has to be kept in
mind that the total number of patients is small due to the low
prevalence of RTT. Around 71% of patients showed a seizure
reduction of 50% or more when carbamazepine was used as
the first AED, 56% were seizure free for more than 6 months.
In contrast, treatment with valproate resulted in a seizure
reduction of more than 50% in only 38% of patients and a
seizure-free period of longer than 6 months was only seen in
6%, the latter difference being statistically significant
(p ¼ 0.014). This difference in efficacy is also reflected by the
length of time that a RTT patient took the medication without
being withdrawn because of lack of seizure control or adverse
effects. The median time for carbamazepine was 102 months
where as it was only 29 months for valproate (p ¼ 0.027).
Sulthiame turned out to be slightly less efficient than
carbamazepine. Treatment with sulthiame gave a seizure
reduction frequency of more than 50% in 64% of patients and
a seizure-free period of longer than 6 months for 40% of
patients. However, the length of time on sulthiame was with
36 months significantly shorter than that for carbamazepine
(p ¼ 0.029).
Side effects of these AEDs appeared with a frequency of
40%. The spectrum of effects is comparable to that seen in
other epilepsy groups. Because many physicians were part of
this study it was not possible to analyse the severity of the
side effects. Nevertheless, only in a few cases did the side
effects result in a discontinuation of the medication.
The low efficacy of valproate may relate to the pathophy-
siology of RTT. The mutated MECP2 gene encodes a defective
methyl-CpG-binding protein 2 (MeCP2). MeCP2 binds to
methylated CpGs in the DNA and offers itself binding sites
for a co-repressor complex that includes histondeacetylases.
The deacetylation of core histones leads to a conformational
change of the chromatin which in turn leads to transcrip-
tional silencing of genes. Studies have shown hyperacetyla-
tion of histones as a result of the mutations in MECP2.26,27
Recently it has also been shown that valproate is a potent
inhibitor of histondeacetylases and causes hyperacetylation
of histones.28 The effects of MECP2 mutations and valproate
therapy therefore act synergistically on the histone acetyla-
tion status and consequently valproate might aggravate the
status of disease. The overall low efficiency of a polytherapy
in RTT might also be due to the fact that it was often
combined with valproate.
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E UR O P EA N J O UR NA L O F PA ED I ATR I C N E U RO L O G Y 11 (2007) 10 – 16 15
Besides sulthiame, carbamazepine and valproate, well-
known AEDs like lamotrigine, topiramate and others were
not taken frequently enough to allow statistical analysis on
the effect. Lamotrigine, which was found to be effective in
other studies, was given in eleven patients either in combina-
tion (n ¼ 7) or as monotherapy (n ¼ 4) in our study. A positive
effect was seen only in one out of four patients under
monotherapy and in two out of seven when given in
combination with other AEDs. Therefore, the effect of
lamotrigine in our study does not seem to be as favourable
as described by others.
Nine female RTT patients received AEDs although no
seizures had occurred so far, seven because of pathological
EEGs and two for the treatment of other non-seizure episodes.
In none of them AEDs improved the clinical status. This is in
concordance with the personal experience of the authors.
Therefore, there seems to be no indication so far to treat RTT
patients with an AED in the absence of seizures.
4.1. What is the optimal and recommended treatment forepilepsy in RTT?
In our study carbamazepine was found to be the most
effective AED among the AEDs possible to study in this series
and appears to be the treatment of first choice for epilepsy in
RTT patients. Sulthiame was found to be slightly less effective
than carbamazepine. The rate of side effects is comparable in
both of them. Sulthiame seems to be a reasonable second
choice AED in cases where carbamazepine has led to
intolerable side effects or is not effective. Valproate was
found to be significantly less effective than carbamazepine
and sulthiame. Because of its most likely inhibitory effect on
histondeacetylases it should not be one of the first choice
AEDs for epilepsy in RTT patients. Although in our study
group only sulthiame, carbamazepine and valproate were
administered frequently enough to allow statistical conclu-
sions, single data analysis on the other AEDs including
lamotrigine did not indicate that one of them is notably
superior to carbamazepine or also sulthiame.
Acknowledgements
The authors thank all families who participated in our study.
We also acknowledge the help of the Elternhilfe fur Kinder
mit Rett-Syndrom (Parent Support Group for Children with
RTT) and the physicians who completed questionnaires so
thoroughly.
Grand sponsor: The German Research Foundation; Grant
number: HU 941/2-1.
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