Epilepsy in cerebral palsy. Comprehensi e questionnaire research

Praca O R Y G I N A L N A / original article
N E U rologia dziecięca
Epilepsy in cerebral palsy.��������������������������������������
Comprehensive
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questionnaire research
performed in three different provinces in Poland
Padaczka w mózgowym porażeniu dziecięcym. Badania populacyjne na podstawie wyników
z trzech województw
Maria Mazurkiewicz-Bełdzińska, 1Marta Szmuda, 1Agnieszka Matheisel, 2Janusz Wendorff,
3
Anna Gniadkowska-Nowakowska
1
Departament of Developmental Neurology, Chair of Neurology, Medical University of Gdańsk, Poland
Department of Pediatric Neurology, Polish Mother’s Memorial Hospital Research Institute, Łodź
3
County of Kielce Children’s Epilepsy Outpatient Centre
1
2
ABSTRACT
Introduction: Children with cerebral palsy (CP) often suffer from
associated neurological problems and the association between
CP and epilepsy is considered to be an important issue. In last
years advantages in epilepsy treatment have been made (several new antiepileptic drugs have been introduced). Aim of
study: Determination of the prevalence of CP among children
with epilepsy in the group of patients embraced by the care of
developmental neurology out-patient clinic in three provinces in
Poland as well as determination of major types of antiepileptic
treatment. Materials and Methods: The study group consisted
of 1115 consecutive patients presented in outpatients’ childneurology clinics in three province-cities in Poland (Gdansk,
Lodz and Kielce). We isolated the group of patients with CP and
analysed their type of epilepsy and type of received treatment
as well as overall response rate for treatment comparing those
results with non-CP epilepsy group. Results: Among 1115
patients with epilepsy – 178 had CP (16%). Children with CP
had mostly secondarily generalized seizures (62%), tonic seizures (22%), complex partial seizures (20%), myoclonic seizures
(10%), atypical absence seizures (8%). Majority of CP children
were treated with valproic acid (74%), than carbamazepine
(41%). Interestingly statistically significant more children
with CP than with “pure” epilepsy were treated with benzodiazepines. The success rate (more than 75% of seizure reduction) was 54.6% (89% on monotherapy), this was significantly
less that in isolated epilepsy group. Conclusions: Epilepsy is
a serious co-morbidity in children with CP. There are several
factors which need to be considered when starting treatment,
especially that the effectiveness of AEDs treatment seems to
be less effective in children with CP.
Key words: epilepsy, cerebral palsy, antiepileptic treatment,
children
Vol . 1 6 /20 0 7 , n r 32
STRESZCZENIE
Wprowadzenie. Współwystępowanie mózgowego porażenia
dziecięcego (MPD) i padaczki jest częstym zjawiskiem i wymaga
szczególnej uwagi ze strony neurologów dziecięcych. W ostatnich latach dokonał się znaczny postęp w leczeniu padaczki oraz
zwiększyła się znacznie liczba dostępnych na rynku leków przeciwpadaczkowych, co pozwoliło na dobór optymalnej metody
leczenia u pacjentów z MPD. Cel pracy. Określenie częstości
występowania padaczki oraz sposobu jej leczenia u pacjentów z
MPD w trzech regionach Polski. Materiał i metody. Badaniem
objęto 1115 dzieci z rozpoznaną padaczką i współistniejącym
MPD pozostających pod opieką trzech poradni neurologicznych
dla dzieci (w Gdańsku, Łodzi i Kielcach). Rodzaj padaczki, a
także metody i skuteczność jej leczenia zostały poddane analizie. Grupę kontrolną stanowiły dzieci z izolowaną padaczką.
Wyniki. Padaczka występowała u 178 (16%) pacjentów z
MPD. W tej grupie przeważały napady częściowe złożone wtórnie uogólnione (62%), ponadto występowały napady toniczne
(22%), częściowe złożone (20%), miokloniczne (10%), atypowe
napady nieświadomości (8%). Większość dzieci z MPD była
leczona kwasem walproinowym (74%) i karbamazepiną (41%).
Benzodiazepiny stosowano statystycznie częściej u dzieci z
padaczką i współistniejącym MPD niż w grupie z izolowaną
padaczką. Sukces terapeutyczny (zmniejszenie liczby napadów
o co najmniej 75%) osiągnięto u 54,6% pacjentów (z tego u 89%
stosowano monoterapię) – odsetek ten był znacząco niższy
niż w grupie dzieci z izolowaną padaczką. Wnioski. Padaczka
często występuje u dzieci z MPD. Skuteczność leczenia przeciwpadaczkowego w tej grupie jest niższa niż w grupie dzieci z
izolowaną padaczką.
Słowa kluczowe: padaczka, porażenie mózgowe, leczenie
padaczki, dzieci
35
Praca O R Y G I N A L N A / original article
Cerebral palsy (CP) is a non-progressive disorder, caused by
permanent brain damage at early stage of development. Patients
with CP present a variety of symptoms and abnormalities, that
creates all together characteristic neurological syndromes of heterogeneous ���������������������������������
etiology�������������������������
. Movement disorders are often
������������������
accompanied
by decrease in cognitive functions, sight or hearing impairment
and speech delay. Clinical picture is frequently associated with
presence of epilepsy. According to the world-wide literature, epilepsy exists in about 15 to 60 [1] or even 90% [2] patients with
diagnosed CP. That patients constitutes about 0.5–1% of general
population. The frequency of epilepsy varies among different
types of CP – higher in spastic quadriplegia and the lowest in
spastic diplegia and dystonic CP [3, 4]. According to Gururaj [1],
CP epilepsy constitutes about 10–20% of all epilepsies. However,
there is still not enough epidemiological data to confirm that percentage.
Correct diagnosis confirming coexistence of both neurological conditions in children is particularly valuable, as ipso facto
provides a possibility of prompt pharmacological or neurosurgical
treatment implementation. It is highly significant in patients, who
not only suffer from physical and mental impairment connected
with the presence of CP, but also are at risk of escalated course
of epilepsy. Moreover, the age of seizure onset is considerably
lower in comparison to children with isolated epilepsy, as well as
the monotherapy is commonly found to be ineffective [5].
The aim of this study was� to
����������
verify the
���������������
prevalence of
������
CP
among children with epilepsy in the group of patients embraced
by the care of developmental neurology out-patient clinic in three
provinces in Poland as well as determine major types of antiepileptic treatment.
Majority of the scientific research are conducted on numerically low groups of patients and they do not define unequivocally
the incidence, the course and prognosis of epilepsy in children
with CP. There are also not enough data determining appropriate
treating procedures in these patients.
For this reason, the following study was performed to characterize the population of children with concurrent CP and epilepsy with a regard to applied treatment (group 1). Control group
consisted of children with isolated epilepsy (group 2). A special
attention was paid to seizure onset, neonatal seizures, frequency
of particular seizures types, methods of treatment, as well as presence of mental retardation.
We believe that our analysis, conducted on the numerically
large group of patients, represents reliable characteristics of CP
children with coexisting epilepsy and also constitutes an objective review of actually applied methods of treatment in Poland.
We believe that this study will contribute to standardization of
antiepileptic therapy in the nearest future and will allow to obtain
credible epidemiological data that will enable early diagnosis of
epilepsy in children with CP.
Material and methods
There were totally 1115 cases included in the study. All of the
patients were attending to the outpatients’ developmental neurology clinics in one of the 3 clinical sites: in Gdańsk, Łódź or
Kielce. Every patient suffered from epilepsy and visited pediatric
neurologist from 1st January to 31st December 2005. Among the
group of epileptic patients we identified the study group (group
1) and the control group (group 2). The study group consisted
36
M. Mazurkiewicz-Bełdzińska, M. Szmuda, A. Matheisel et al.
of 178 patients with concurrent CP and epilepsy. The control
group comprised of 937 children suffering from epilepsy without
any other neurological deficits. The age of patients ranged from
9 months to 18 years. The data were collected on the basis of
questionnaires, completed by patients, parents or legal representatives and pediatric neurologists during the control visits from
January to December 2005. The queries in the questionnaires
referred to family history, main diseases, results of neurological
examination, methods and outcome of applied antiepileptic treatment. Selected details, that were statistically analyzed, referred to
age, gender, neonatal convulsions, seizure onset, type of epileptic seizures, antiepileptic therapy, outcome of applied treatment,
classification of the CP, mental retardation.
Obtained results were statistically analyzed and compared.
Then, the principal differences between group 1 and group 2
were isolated. A special attention was paid to seizure type, seizure onset, methods and effects of applied treatment.
Definition of neonatal convulsions describes the convulsions
during the first 30 days of life.
Types of epileptic seizures were defined according to the
International League Against Epilepsy revised classification
from 1989 year. Epileptic seizures in patients with CP can take
many forms. Due to the fact that they may be difficult to distinguish from involuntary or stereotypic movements, breath-holding
spells, swallowing abnormalities, vasovagal syncopes and other
non-epileptic paroxysmal disorders coexisting with CP [20]. Epileptic seizure was recognized only in conditions that were unambiguous and did not arouse a suspicion of non-epileptic nature.
Good seizure control was defined by 75% or more reduction
in number of seizures in a period of 3 months. Seizure-free period
of 3 months was another parameter measured in both groups of
patients.
Classification of CP included: spastic quadriplegia (spasticity
involving all four limbs with involvement of the arms being more
marked than or equal to that of the legs), spastic diplegia (spasticity of the lower extremities with a variable but lesser involvement
of the upper limbs), spastic hemiplegia (spasticity of the arm and
leg on one side), extrapyramidal, ataxic and mixed type (including spastic and extrapyramidal manifestations) [6, 7].
Presence of mental retardation was stated on the basis of psychological or pedagogical diagnosis.
The objectives of the study were explained to the parents or
legal representatives of children when possible and also an informed
consent was obtained. Statistical analysis using Chi-square analysis, student t-test and Mann-Whitney test was performed. The level
p<0.05 was considered as the cut-off value for significance.
Results
A total of the 1115 patients were included in the study. There were
178 (16%) children with CP and concurrent epilepsy (group 1),
and 937 (84%) children with isolated epilepsy (group 2). Gender
proportion of girls to boys in the whole studied population was
520:595 (0.87), respectively, in the group 1 it was 81:97 (0,83)
and in the group 2 the proportion was 439:498 (0.88). The age of
patients in group 1 ranged from 10 months to 17 years (mean: 6.7
years) and in the group 2 ranged from 9 months to 18 years (mean
age: 5.4 years).
Occurrence of particular types of CP in the study group is
presented in table I.
Neurologia D ziecięca
Padaczka w mózgowym porażeniu dziecięcym. Badania populacyjne na podstawie wyników z trzech województw
Table I. Incidence of CP types in children from the study group
CP classification
Spastic quadriplegia
Spastic diplegia
Spastic hemiplegia
Extrapyramidal type
Ataxic type
Mixed type
Incidence (%)
41
39
15
2
1
2
Neonatal convulsions were observed in 20 (11%) patients in
group 1 and 49 (5.2%) patients in group 2. Although the percentage was two times higher in children with CP and epilepsy than
in the controls, it proved to be statistically not significant.
Mental retardation occurred more frequent in the study group
1. It was estimated at 80% (144 patients) versus 24% (225 patients)
in the group 2. This proportion was assessed as statistically significant (p<0.05). Similar results are confirmed in the literature [7, 8].
There was a strong correlation between early seizure onset
and coexistence of epilepsy and CP (p<0.05). The mean age was
evaluated at 1.2 year of life. Seizure onset in epileptic children
without neurological deficits was estimated at 4.2 years.
Table II. Profile of patients with isolated epilepsy and concurrent CP
Number of patients
Girls/Boys ratio
Mean age
Neonatal convulsions
Mental retardation
Age of onset of epilepsy
Group 1
178 (16%)
81/97 (0.83)
6.7
20 (11%)
144 (80%) *
1.2
Group 2
937 (84%)
439/498 (0.88)
5.4
49 (5.2%)
225 (24%)
4.2
* p<0.05
The highest incidence of epilepsy was observed among
patients who presented spastic quadriplegia (41%), and the
lowest was present in ataxic CP (8%). However, there was no
straight statistical correlation between the concrete type of CP
and the epilepsy. The specific information on incidence of epilepsy among different types of CP is demonstrated below.
Table III. Incidence of epilepsy among different types of CP
Type of CP
Spastic quadriplegia
Spastic diplegia
Spastic hemiplegia
Extrapyramidal
Ataxic
Mixed
Incidence of epilepsy (%)
73 (41%)
30 (17%)
23 (13%)
16 (9%)
14 (8%)
22 (12%)
Primarily generalized tonic-clonic seizures were seen among
161 patients (14.4%) from the total studied cohort. Respectively,
there were also observed tonic seizures in 198 patients (17.8%),
atonic or astatic seizures in 24 patients (2.2%), myoclonic seizures in 55 patients (4.9%), typical absence seizures in 71 patients
(6.3%), atypical absence seizures in 42 patients (3.8%), simple
partial seizures in 58 patients, (5.2%), complex partial seizures
in 232 patients (20.8%) and secondarily generalized tonic-clonic
seizures in 347 patients (31.1%).
Vol . 1 6 /20 0 7 , n r 32
It was proved that secondarily generalized tonic-clonic seizures were observed more frequent among children with CP in
comparison to control group and this difference was statistically
significant (110 patients; 62% in the group 1 vs. 237 patients;
25% in the group 2). The type of seizure that was the most rarely
observed in the study population referred to the primarily generalized tonic-clonic seizure (2 patients; 1%; p<0.05).
Frequency of particular seizure types in both groups of
patients is presented in the table IV.
Table IV. Incidence of different seizures types in group 1 and group 2
Type of seizures
Secondarily generalized tonicclonic seizures
Tonic seizures
Complex partial seizures
Myoclonic seizures
Atypical ����������������
absence seizures
Typical�����������������
absence seizures
simple partial seizures
Atonic / astatic
Primarily generalized tonicclonic seizures
Group 1
110 (62%)*
Group 2
237 (25%)
39 (22%)
35 (20%)
18 (10%)
14 (8%)
2 (1%)
2 (1%)
6 (3%)
2 (1%)*
159 (17%)
197 (21%)
37 (4%)
28 (3%)
69 (7%)
56 (6%)
18 (2%)
159 (17%)
* p<0.05
All of the patients were receiving antiepileptic drugs (AEDs)
through the whole period of the study. 682 of all children (61.3%)
were treated by means of monotherapy but still polytherapy
proved to be necessary in 433 patients (38.9%). It has been
investigated that application of antiepileptic monotherapy among
children with CP was significantly smaller than in children with
isolated epilepsy (36% vs. 66%). On the other hand, polytherapy
composed of two AEDs was the most frequent decision in the
group of children with CP (40% in group 1 vs. 22% in group2,
p<0.05). 3 AEDs were applied in 28 patients (16%) from group
1 and 56 patients (6%) from the group 2. More than 3 AEDs were
administered to 15 (6%) and 56 (6%) patients group 1 and 2,
respectively. These relations are presented at the figure 1.
Good seizure control was obtained in 54% of patients with
CP and 87% of patients from control group. Seizure-free
��������������������
period
of 3 months was observed in 38% of patients from the 1 group
and even 78% of the 2 group
Figure 1. Number of applied AEDs in children with and without CP
It has been proved that among a variety of available AEDs,
valproic acid and clonazepam were the most commonly admin37
Praca O R Y G I N A L N A / original article
M. Mazurkiewicz-Bełdzińska, M. Szmuda, A. Matheisel et al.
istered in children with CP. These results occurred to be statistically significant (p<0.05). Valproic acid was also applied very
often in children with isolated epilepsy (59% in group 2 vs. 74%
in group 1), however, it was not statistically relevant. There was
no correlation between the usage of other AEDs and CP (table
VI).
Table VI. Treatment of epilepsy according to the presence of CP
AEDs
Valproic acid
Carbamazepine
Clonazepam
Topiramate
Lamotrigine
Oxcarbazepine
Vigabatrin
Group 1
131 (74%)*
73 (41%)
69 (39%)*
46 (26%)
26 (15%)
10 (6%)
8 (4%)
Group 2
534 (59%)
365 (39%)
37 (4%)
196 (21%)
178 (19%)
84 (9%)
25 (3%)
*p<0.05
Discussion
Incidence of epilepsy connected with CP was estimated on 16%
among all epilepsies in studied population. Above investigation
was performed on large numerically group of 1115 patients and
this aspect amplify the reliability of our findings. Especially as the
number of patients in other studies rarely exceeds 100 [1, 10].
Moreover, we also proved as the other authors that spastic
quadriplegia and spastic diplegia are the most frequent types of
CP associated with epilepsy occurrence [1, 3, 4, 10] and this fact
undoubtedly depends on an extension of brain damage.
Epilepsy onset strongly correlated with neurological deficits.
The age of first seizures in children with CP was significantly
lower than in children with isolated epilepsy. In the group 1 seizure onset was estimated on slightly over the first year of life.
Early epilepsy onset up to 12 months in CP is widely confirmed
in the literature [10–14]. Seizure onset between the first and the
second year of life were also observed by Paucic-Kirincic in 2005
[9] and Singhi in 2003 [15].
Some of the studies consider a relationship between the
neonatal convulsions and future presence of epilepsy and other
neurological deficits [16, 17]. We also observed this association.
There was a twice higher percentage of neonatal convulsions in
anamnesis in the studied group with CP.
In our research, children with CP presented different types
of epileptic seizures. Obtainable scientific data do not describe
a direct correlation between classification of CP and characteristic type of epileptic seizures. Due to not unified conditions of
the studies (different numerical force of the population or time
38
of observation, etc.), the frequency of particular epileptic seizures vary from 12.9% [19] to 50% [9] for secondarily generalized
tonic-clonic seizures or from 44% [19] to even 85% [20] for primarily generalized tonic-clonic seizures. Our findings in group 1
indicate that secondarily generalized tonic-clonic seizures were
observed the most frequently. On the contrary, primarily generalized tonic-clonic seizures occurred very rarely in comparison
with children from group 2. Definitely, the discrepancies referring to the incidence of different epileptic seizures in CP patients
need further investigation.
Majority of patients from the study group were treated with
2 AEDs simultaneously and the improvement was present. Over
a half of the patients experienced a 75% reduction in a number
of seizures and 38% of patients were seizure-free for at least 3
months. However, these proportions were incomparably higher
among children with isolated epilepsy. There were over a half
more children with 75% reduction in seizures and almost two
times more of seizure-free children for at least 3 months. The
number of patients on monotherapy was also significantly higher
in children with isolated epilepsy. Although the therapy of epilepsy in CP patients included commonly 2 AEDs, the seizure
control in this group was insufficient. It is still a matter of discussion if there is a real demand on switching from monotherapy to
2 AEDs in children with CP or the decision on polytherapy is
useless due to the extent brain damage and poor outcome. Assuming all above facts, we can say that necessity of polytherapy in
children with concurrent CP and epilepsy has still been unconfirmed. Valproic acid was the most frequently applied antiepileptic
specimen in both groups. The percentage of valproic acid administration among children with CP was 15% higher and this proportion occurred to be statistically significant. Subsequent AEDs
commonly prescribed in the study group was clonazepam. These
decisions were the most likely made due to the extensive range of
action of both AEDs.
We also proved that that mental retardation accompanies
CP and epilepsy particularly often. It occurred to be three times
higher than in the control group.
This study clearly indicates that epilepsy in patients with CP
is associated with presence of neonatal convulsions. Moreover,
these patients present worse seizure control, even though polytherapy was applied. Mental retardation as well as coexistence of
physical handicap and epileptic seizures with potential adverse
events of applied AEDs are additional factors, that significantly
lower quality of life in patients with CP. Entirety of various conditions and aspects of CP complicated by the epilepsy leads to the
general conclusion that it is essential to improve methods of treatment as well as accurate and certain diagnosis, including genetic
and prenatal factors determining occurrence of CP in children.
Neurologia D ziecięca
Padaczka w mózgowym porażeniu dziecięcym. Badania populacyjne na podstawie wyników z trzech województw
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Adres do korespondencji:
Department of Developmental Neurology, Chair of Neurology
Medical University of Grańsk, Dębinki 7 St. 80-952 Gdańsk, Poland
e-mail: [email protected]
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39