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Chronic
side effects of antiepileptic drugs
In
general
Chronic effects on the brain
Behavioral disturbances
Involuntary movements
Effect on the nerves
Effect on the liver
Shrinking of tendons
Defense against infectious diseases
Malformations
In general
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Chronic side effects are continuing
adverse reactions to a drug. They may develop insidiously after
many years' treatment. Doctors are in many cases not particularly
aware of these symptoms, which can give much inconvenience to
the person who takes the medicine. The symptoms are overlooked,
or it is thought that they are due to something else. The person
involved may not realize that they have side effects as they first
appear after a long time of treatment. It is common that chronic
side effects are first noticed if treatment is stopped, or if
the medicine is changed.
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Top
Chronic effects
on the brain
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Phenytoin
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When phenytoin was first introduced
in 1938 as a remedy for epilepsy, it was claimed that this drug
made patients less lethargic than the older treatments. In fact
there is no proof of this. The reason that results seemed better
was that, at the same time, treatment with phenobarbital was stopped.
More recent psychological tests have clearly shown how phenobarbital
affects psychological functioning. In children the symptoms resemble
those in children with mild brain damage. They are restless, irritable
and have difficulty in concentrating on anything for more than a
few minutes. In trials performed using healthy adult "guinea pigs"
a connection has been found between high content of phenobarbital
and phenytoin in the blood, and an inability to carry out complicated
tasks that call for concentration. |
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Carbamazepine
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When treatment with carbamazepine
was started, a list of beneficial effects were described. They
were due to stopping taking phenytoin.
Treatment with phenytoin can be the
cause of a reduction in intellectual capacity and a gradual change
in personality. It may not be noticed by the person taking the
medicine, and their families may attribute these changes to epilepsy.
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| New
medicines |
New drugs, such as carbamazepine,
oxcarbazepine, valproate and vigabatrin affect the functioning of
the brain to a degree. It is just less pronounced than when phenobarbital
or phenytoin was used. |
Top
Behavioral
disturbances
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Hyperactivity
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This side effect is seen especially
in children. The child develops a restlessness which can assume
quite grotesque dimensions. The child cannot occupy itself for
more than a few minutes at a time, after which it demands attention
and new activities. It can in the long run become an unbearable
situation for parents to have to cope with.
Some antiepileptic medicines, which
can give lethargy in adults, can have the opposite effect on children.
Phenobarbital, primidone and clonazepam can have this effect.
Finally vigabatrin can also have this effect on both adults and
children, if given to persons whose epilepsy is the result of
brain damage.
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Top
Involuntary
movements
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Rare neurological symptoms, such
as involuntary movements, may also be seen. Phenytoin, primidone,
phenobarbital and carbamazepine can cause shaking of the arms,
with twitches when the hands are held out. Phenytoin, ethosuximide
and carbamazepine can cause involuntary twisting movements of
the arms and legs. Valproate and lamotrigine may cause tremor
of the hands. All these symptoms disappear when the dose is reduced.
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Top
Effect on the nerves
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Most of the old antiepileptic drugs
affect the nerves leading to the arms and legs so that the reflexes
disappear. When measured electrically, it can be seen that the
speed of the nerve impulses drops. Fortunately these changes in
the nerves seldom give symptoms.
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Top
Effect on the liver
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Enzyme induction
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Many antiepileptic drugs cause the
liver's enzymes to work at an increased speed, so-called enzyme
induction. The result is that many substances are broken down
too quickly, both things we eat and substances produced by the
body itself. The antiepileptic drugs which have this effect on
the liver are phenobarbital, primidone, phenytoin and, to a lesser
extent, carbamazepine. Vitamin D, vitamin K, the contraceptive
pill, the sex hormones and the adrenal cortex hormones are broken
down faster than is normal. Valproate, lamotrigine and levetiracetam
do not have this effect.
This rapid breaking down of K vitamin
can lead to bleeding in the newborn, if the mother and child are
not treated with K vitamin. Lack of vitamin D can lead to bone
fractures resulting from even slight knocks. If a shortage of
vitamin D arises, it is easily treated by giving extra vitamin
D in the food.
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| Failure
of the contraceptive pill |
In the case of the contraceptive
pill, the fast breaking down of their hormonal contents can lead
to failure. Pregnancy can occur, even though the pills have been
taken as they should.
The fast breaking down of the adrenal
cortical hormone can be important for a person who has had a transplantation
of a kidney, or another organ. After these operations treatment
is given with extra adrenal cortical hormone, to avoid rejection
of the organ. If one at the same time is taking antiepileptic
drugs, the dose of adrenal cortical hormone should be higher than
normal.
The changes that occur in the liver
are not lasting. If treatment with antiepileptic medicine is stopped,
enzyme induction stops in the course of a few weeks and the liver
functions as before.
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Top
Shrinking of tendons
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Dupuytren's contracture
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In the past many patients suffered
from shrinkage of the tendons of the hands and feet. There are several
causes of this condition (Dupuytren's contracture), one of the most
usual being lengthy treatment with phenobarbital. The changes occur
particularly in the tendons of the little finger, ring and middle
fingers. They eventually bend right down into the palm. They can
be straightened out surgically. |
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Defense against
infectious diseases
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Increased tendency to infection
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There are many specialized proteins,
antibodies, in the body which enable us to resist infectious diseases.
Phenytoin can prevent enough of these antibodies being produced,
particularly those present in saliva. This leads to more frequent
infections of the mouth and throat. Because there are too few antibodies,
the bacteria have free play. |
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Mouth infections
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The thickening of the gums,
gingival hyperplasia, seen in treatment with phenytoin, is in fact
a reaction to a chronic mouth infection. Thorough tooth brushing
can help stop this occurring. |
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Malformations
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Malformations are found more frequently
among the children of people with epilepsy than among the rest
of the population (about 5%). The reason for this is not known
with certainty. Heredity certainly plays a part, in that a child
whose father has epilepsy, but whose mother does not, also has
a higher chance of having malformations than other children do.
Medicine taken and seizures occurring during pregnancy have also
been under suspicion of causing malformations. Phenytoin, phenobarbital
and primidone have been particularly suspected.
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Harelip
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Malformations may take the form
of a harelip or cleft palate. These malformations can be corrected
surgically. In addition, malformations of the heart may be seen,
with the dividing walls between the ventricles missing. Malformations
which are less serious include the little finger being very small,
tiny fingernails on the little finger and toes, ears sitting too
low on the head, and the eyes being very far apart. |
| Spina
bifida |
Valproate and carbamazepine
have been suspected of causing malformations of the spinal cord,
spina bifida, which can cause paralysis of the child's legs and
lack of urinary control. An amniotic test can control if a fetus
has this serious malformation. If there is evidence of spina bifida,
an abortion will be advised. There is no actual proof as to whether
valproate or carbamazepine are to blame. Women who wish to have
children should, however, only be treated with valproate and carbamazepine
if there is no other effective alternative. |
| Change
of medicine during pregnancy |
In general it must be recommended
that treatment in pregnancy continues unchanged. Changes of treatment
increase the risk of seizures, which are damaging to the fetus.
If you plan to become pregnant, it is a good idea to consult your
doctor beforehand to be sure that treatment is adjusted as well
as possible.
All in all, it must be said that
fear of malformations has been exaggerated. There are only 5 children
out of 100 who will have malformations, and of these some can
be shown early in the pregnancy, or can be corrected relatively
easily.
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Case history
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A 67-year-old man came to the out-patients
clinic saying that he had heard that new drugs had been developed
to treat epilepsy, which did not slow the patient down as much
as the old drugs did. He had had convulsive seizures since his
youth. The seizures occurred most often at night or in the early
morning. The neurological examination revealed nothing abnormal.
EEG showed diffuse changes, such as could be expected in a case
of an idiopathic epilepsy. He was under treatment with phenytoin
and phenobarbital and had been free of seizures for four years.
His was put onto valproate, and first phenobarbital and then phenytoin
were gradually withdrawn. When next he came to the clinic, he
was in a raging temper: "I have had to go to bed all my working
life at half past seven, because I could not keep my eyes open!
I have never been able to go to the cinema or theater or to parties
at night! Now I am so wide awake I only need to go to bed at half
past eleven!" The reason for his anger was that he had missed
out on all the years when he might have lived a normal life. We
could only recommend him to try to catch up on all that he had
missed.
After several years he showed up
seizure free but very fat. He was changed to lamotrigine and quickly
lost weight. Now, however, he was awake until 01.30 in the morning.
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