J R Soc Med 2004;97:15-19
doi:10.1258/jrsm.97.1.15
© 2004 Royal Society of Medicine
When is drug treatment not necessary in epilepsy? Factors that should influence the decision to prescribe
Richard W Newton MD
Department of Neurology, Manchester Children’s Hospitals, Royal
Manchester Children’s Hospital, Pendlebury, Manchester M27 4HA, UK
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INTRODUCTION
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Epilepsy is a common treatable disorder with an incidence in
the UK of
about 0.05% and a prevalence of
0.5%.
1 The average
secondary
school has about 6 children with the condition. A paediatrician
who
has diagnosed epilepsy will feel pressure to prescribe medication—as
indeed
will a clinician in adult practice. In view of the efficacy
of
anti-epileptic
drugs,
2 this is
understandable. The primary
aim of therapy is of course to prevent seizures,
but do anti-epileptic
drugs alter the natural history of the condition, either
in
the short term or by enhancing the chance of long-term remission?
Should
the benign epilepsies of childhood be treated differently?
How do medication
and everyday life issues interact? This paper
deals with the factors that
should influence the decision to
prescribe. The focus is on childhood and
adolescence, but much
of the published work relates to adults and many of the
points
are relevant to an adult population too.
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THE CONTEXT FOR THE DECISION TO TREAT
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The first, and crucial, issue in management of epilepsy is
diagnosis.
Although in most young people who are diagnosed as having
epilepsy
there will be supportive evidence from electroencephalograms
(usually
recorded interictally) there is no single diagnostic
test and the diagnosis
has often to be made on clinical grounds.
Classification of seizure type, the
definition of aetiology
and identification of the epilepsy syndrome are
integral to
this process. The reliance on clinical information offers ample
scope
both for under-diagnosis and for overdiagnosis, and even paediatric
neurologists
encounter difficulties with diagnosis. In the Dutch Study of
Epilepsy
in
Childhood
3 a panel
of three neurologists identified diagnostic
error in 4.6% of children with
recurrent paroxysmal events.
The diagnosis had to be deferred in 5.6% where
there had been
multiple events and in 7.4% following a single event. Overall,
one
in fifteen children with epilepsy were initially not recognized
to have
epilepsy.
Once sufficient diagnostic certainty is reached, the news should be given
to the family in a planned and structured way. Linked to the giving of that
news should be access to information, presented in a way that will be readily
understood. Information for the child will need to be geared to his or her age
and ability. Several studies indicate that at least a quarter of people
prescribed anti-epileptic drugs stop the therapy, either because of unwanted
effects or because it is perceived not to work; moreover, between 20% and 70%
deviate from the regimen suggested by their
doctors.4,5
What are the reasons for this poor adherence? One likely contender is lack of
understanding of the nature of the condition. Houston et
al.6 showed
that children with epilepsy had significantly less understanding of their
condition than did their counterparts with asthma and diabetes, even though
they had access to specialist nurses and the families had received written
information about the condition. Much of the information for children makes
use of analogy to help them understand, but a child of 8 or so tends to
interpret such material very literally. In my own department we think a simple
biological model potentially more useful than analogy in conveying the
necessary information, decreasing the child’s reluctance to disclose the
diagnosis to others and perhaps making him or her more inclined to accept the
treatment. A leaflet was written to meet the needs of 8–12-year-olds,
with particular attention to idioms and language, and was piloted with 240
children between school years 3 and 8. Even so, we found that several of the
central teaching points were being misunderstood. An essential part of medical
intervention is to develop age-appropriate information of this sort with
expert help. If children better understood the rationale of treatment,
adherence might well improve.
The decision to treat or not and the consultation process
Each consultation, as with any ‘contract’, consists of a
meeting of unlike minds. Parents and children have their own beliefs, hopes,
fears and expectations, and so do doctors (together, in their case, with an
evidence base). This issue was dealt with well by Haynes, Devereaux and
Gyatt,7 who made the
point that evidence does not make decisions; people do. If we hope to alter
people’s behaviour (by persuading them to take medication), the best
strategy is to influence their beliefs and accept their preferences.
Haynes’ term for this is not evidence-based medicine but
research-enhanced healthcare. Children should not be treated with drugs until
the family has a good understanding of the condition and the way treatment
might help. More effective ways of achieving this aim need to be defined. Drug
treatment, and the seizure suppression it brings, can be recommended on two
main grounds—that it may alter the natural history of the condition by
increasing the remission rate; and that it may enhance quality of life by
augmenting psychosocial opportunity and reducing risk of harm. The evidence
around these premises will be reviewed in the rest of this paper.
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NATURAL HISTORY AFTER A SINGLE SEIZURE
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An Italian hospital-based
study
8 of 397 adults
randomized to
treatment or no treatment found the 24-month recurrence rate
of
tonic–clonic seizures to be 26% in the treated group
and 51% in the
untreated group. In other words, without treatment
about half have another
episode within 2 years. Similar data
have been reported in children. For
example, of 186 children
with an initial afebrile unprovoked seizure 52% had a
recurrence,
and of those with a recurrence 79% had additional
seizures.
9
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SPONTANEOUS AND LONG-TERM REMISSION
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The National General Practice Study of
Epilepsy
10 looked
at
outcome 9 years from the index seizure. 275 general practitioners
participated
in the study and 1091 people with probable epilepsy were
identified.
Further assessment indicated that only 564 of these had definite
epilepsy.
At 9 years from the index seizure, 86% of those with definite
epilepsy
had achieved a 3-year remission, and 68% a 5-year remission.
The
detail in the paper does not allow us to draw conclusions
about the approach
to treatment, but the figure of 68% is remarkably
similar to that identified
in other studies (see below).
If it is possible for people with epilepsy to achieve spontaneous remission
without treatment, then prevalence rates in developing countries where
epilepsy is rarely treated should be very similar to those in the developed
world. The differences between countries would be accounted for either by
change in remission rate or by a change in death rate. A study from Ecuador
centred on a locality with a population of 75
000.11 7212 people
were screened with a cascaded questionnaire and 881 with epilepsy were
identified. This gave a prevalence rate of 0.67 (compared with the UK’s
0.5%); 15% of these were currently being treated. Only 29% had ever been
treated. 46% of the untreated appeared to be in long-term remission.
Osuntokun et
al.12 did a
population study of 18 954 people in Nigeria which revealed a 0.53% prevalence
of epilepsy with 4% treated. This was a town-based (Igbo-Ora) study, and it
was acknowledged that people in Aiyate rural community only 20 km away had
shown a much higher prevalence of 3.7%. The authors argued that the
town-dwellers had benefited from primary-care interventions to reduce the
incidence of common epileptogenic diseases such as central nervous system
infection. In rural
Ethiopia13 the
prevalence was 0.52% with only 1.6% of these ever treated.
In a Finnish community-based project Keranen and
Riekkinen14
identified 33 individuals whose epilepsy had not been treated. Of these, 42%
were epilepsy-free at 10 years and 52% at 20 years, though acquisition bias
cannot be discounted.
A different perspective is given on the figure from developing countries by
the remarkable work of Louise
Jilek-Aall.15 She
had established a rural community hospital and worked with people with
epilepsy from 1963 through to 1971. She then returned after 30 years and
obtained data on 164 of 200 people in the original group. She found that 60%
of the people had died and half of these had died from a cause related to
epilepsy, including prolonged status epilepticus, burns or drowning. Clearly,
therefore, in the developing world the reported prevalence rates in the
population may be lowered by the excess mortality in this group.
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NO DISADVANTAGE FROM DELAYING TREATMENT
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Experience in the developing world
On the matter of treatment timing, Feksi
et
al.
16 looked
at
a group of people in Kenya with chronic epilepsy. 249 of 302
completed the
study. 53% became seizure-free in the second six
months of therapy and 26% had
a more than 50% reduction in seizure
frequency. That is, almost 80% benefited.
These people had had
epilepsy for years before the onset of the study, which
suggests
that drug efficacy is not greatly influenced by treatment delay,
though
selection bias in this study cannot be excluded.
Experience in Europe
This finding is contradicted somewhat by the observations of
Reynolds.17 In data
from 241 adults and 167 children he showed that the number (rather than the
frequency) of seizures before starting treatment has a bearing on long-term
remission rates. People in the study were stratified according to the numbers
of seizures experienced in the year before study entry. The cohort was then
followed for 2 years. For those who had had two seizures before study entry,
remission at the endpoint was in excess of 80%; for those with twenty seizures
it was about 70%; whereas for those who had experienced fifty or more seizures
before study entry the remission rate was only 50%. Elwes, Johnson and
Reynolds18 looked
at intervals between untreated tonic–clonic seizures in adults. This was
a retrospective study of 183 adults with two to five seizures. At one month 56
had had a recurrence, at three months 93 and at 1 year 159. The median
interval between successive seizures fell steadily from 12 weeks (range
10–18) between seizures one and two, to 8 weeks (range 4–12)
between seizures two and three, to 4 weeks (range 2–2) between seizures
three and four, and finally to 3 weeks (range 1–4) between seizures four
and five. Their data, they suggested, were evidence for an accelerating
disease process.
This conclusion was not supported by the work of Van Donselaar et
al.19 In a
hospital-based study the Dutch group assessed the course of untreated
tonic–clonic seizures prospectively. 204 children aged one month to 16
years were recruited and followed until treatment needed to be started (78
children), or until they had had four seizures (41) or until 2 years had
passed (85). They looked for either an accelerating pattern or a decelerating
pattern. A decelerating pattern included children who became seizure free. 110
children were ‘unclassified’, usually because drug treatment was
started early (outside the protocol) after the first, second or third seizure.
3 of 41 children with more than four seizures showed a decelerating pattern, 8
of 41 an accelerating pattern. Overall, 47% showed a decelerating pattern.
Their conclusion was that the notion that epilepsy is a ‘progressive
disease’ could not be used to justify treatment with anti-epileptic
drugs.
Animal models
Advocates of early treatment have argued that over-stimulation of
excitotoxic cascades may lead to the influx of calcium ions, free radical
formation with enhanced proteolysis and triggering mechanisms and either
immediate cell necrosis or later programmed cell death. The
‘kindling’ animal model is often cited at this point—a
dynamic phenomenon whereby repeated initial subconvulsive stimuli lower
seizure threshold without producing spontaneous seizures. Koh and
Jensen,20 working
with rats, showed how anti-epileptic drugs may modulate the potential for
epileptogenesis when neurons are exposed to noxious stimuli. Topiramate
reversed the damaging effect of hypoxia on later-life seizure-induced neuronal
injury; carbamazepine and phenytoin prevented neuronal damage but did not
prevent kindled seizures. This knowledge, however, seems not to apply in man.
Anti-epileptic drug prophylaxis following head injury does not alter seizure
outcome.21 Indeed,
kindling has never been shown to happen in human beings. In many, as we have
seen, epilepsy is a non-progressive
condition.20
Mechanisms other than kindling may be important in some people. Seizures
may result from repeated seizure-induced neuronal loss and consequent changes
in neuronal circuitry: for example, repeated seizures arising from one
temporal lobe may be associated with the emergence of seizures in the other.
This ‘mirroring’ was demonstrated by
Hughes.22 Following
the initial appearance of a unilateral focus he showed that, in 1% of affected
people per annum, a bilateral focus appeared.
The MESS study
Results from the Multi-centre study of Early Epilepsy in Single Seizures
(MESS study), due to be published soon, offer new evidence that the timing of
treatment has negligible effect on remission
rates.23 1426
complete data sets are available involving 6976 patient years with 440
individuals aged between 0 and 19 years. Participants were randomized to start
treatment either early or after a delay. Preliminary data indicate that at 2
years the respective remission rates were 55% and 39% and at 5 years 68% in
both groups (almost identical to that in the National General Practice Study
of Epilepsy).10
Thus, a delay in treatment did not alter ultimate remission rates. We can
conclude that, if kindling or similar seizure-induced models of nerve-cell
injury do operate in human beings, the effects are small. Clinical and
experimental data do not support the view that anti-epileptic drugs alter the
underlying course of the condition.
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SHOULD THE BENIGN EPILEPSY SYNDROMES OF CHILDHOOD BE TREATED?
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In several epilepsy syndromes of childhood the outcome is nearly
always
favourable. These include benign neonatal convulsions,
benign occipital and
Rolandic epilepsy, benign myoclonic epilepsy
of infancy and specifically
activated seizure syndromes including
febrile seizures. In view of the good
outcome in a large majority
of children with these conditions, treatment is
not justifiable
on the argument it will enhance the likelihood of natural
remission.
The decision should centre on whether treatment will improve
the
person’s quality of life while the epilepsy is active.
For example, if
in benign epilepsy of childhood with centro-temporal
spikes (benign Rolandic
epilepsy) seizures are infrequent, short
and confined to sleep at night, it is
perfectly reasonable not
to use anti-epileptic drugs. If, however, a child
with the same
condition is having diurnal seizures with distressing sensations
of
the tongue and unilateral tonic–clonic movement, which
in turn are
attracting adverse comment from the child’s
peer group, then treatment
should be considered. Seizure frequency
alone is not an absolute determinant
of whether treatment should
be used or not. Some families will calmly
accommodate infrequent
seizures, while the very same frequency can leave other
families
in constant fearful anticipation of the next recurrence.
Consideration
of the psychosocial issues in each family may well lead to
different
decisions about similar patients.
The commonest of these conditions, febrile seizures, has been studied in
detail. In a meta-analysis of intervention studies with valproate and
phenobarbitone,
Newton24 showed
that, when the data were analysed by intention to treat, the administration of
anti-epileptic drugs did not alter seizure occurrence rates in this
condition.
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QUALITY OF LIFE
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The reported adverse outcomes in epilepsy include excess mortality,
sudden
unexpected death and intellectual deterioration or poor
academic performance
largely reflecting the degree of underlying
brain malfunction and the
biological substrate. It is not yet
proven whether medication, with optimum
treatment and assessment,
can reduce mortality rates. When deciding whether to
treat or
not the paediatrician needs to focus on the issues discussed
earlier
in this paper. The 5-year remission rate with use of
anti-epileptic drugs
seems to be about 68%, whether treatment
is started early or delayed. Early
treatment undoubtedly gives
earlier remission. If treatment is started after a
single seizure
the recurrence rate that at most is 50% without treatment,
means
two people are treated to save one person a recurrence. After
two
seizures most people have a recurrence and the decision
to treat is easier. At
this early stage, consideration must
be given to the family’s hopes,
fears and attitudes to
seizure recurrence on the one hand, and the unwanted
medication
effects on the other. We must bear in mind that even one or
two
seizures in a young person’s life can have serious
adverse psychosocial
consequences. This may lead to teasing
from an unkind peer group, altered
expectation on the part of
teachers and a resulting lack of self-esteem. All
these issues
must be weighed carefully before the contract between unlike
minds
is settled. Whether development of clinical
networks
25 will
improve
standards in the care of people with epilepsy remains to be
seen. In
about 20% of people on anti-epileptic drugs, unwanted
drug effects are
troublesome, though these can be mitigated
by slow progression to the target
doses. About 70% of those
treated with drugs will become seizure-free, with
obvious advantage
for other quality of life measures such as employment
prospects,
social adjustment and retaining a driving licence. In the MESS
study
23 preliminary
data point to a non-significant increase in self-esteem
in both treatment
groups (early and delayed), unrelated to seizure
or anti-epileptic drug
status. Individuals with no further seizures
had a higher sense of mastery
(control of their own destiny)
than those with recurrences.
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CONCLUSIONS
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Existing data indicate that long-term remission rates are not
altered by
the use of anti-epileptic drugs. A decision to treat
should therefore be based
on how the early achievement of remission
of seizures might improve quality of
life and avoid harm. After
two seizures most people will have a further
seizure and this
is probably the pivotal point at which the decision to treat
or
to delay treatment ought to be made.
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S. Kumar
When to start drug therapy in epilepsy
J R Soc Med,
April 1, 2004;
97(4):
208 - 208.
[Full Text]
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INTRODUCTION
THE CONTEXT FOR THE...
