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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 absolute

reduction (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 months

was 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 specific

medication 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 the

patients 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 occurred

and 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

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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).

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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

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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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