Fact Sheet on Side Effects of AEDs

[Guest guest]

This is from the tuberous sclerosus association and has much good

information. The vitamin D deficiency is linked to low calcium levels

(hypocalcemia) which can lower seizure threshold and go on to cause

osteoporosis and osteomalacia (rickets in adults).

http://www.tuberous-sclerosis.org/publications/fs2antiepilepsy.pdf

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Anti-Epilepsy Drugs And

Their Adverse Effects

Introduction

About 70% of people with Tuberous Sclerosis will

have epilepsy. Epilepsy in Tuberous Sclerosis can

be very difficult to control and seizures can change

their nature with time. Many people will be on

permanent anti-epilepsy drugs and often take a

combination of drugs which control their seizures

either totally or in part. Many people with TS on

anti-epilepsy drugs will have learning difficulties

and so it is important that their parents and other

carers are aware of the unwanted effects that can

be produced by these long term drugs. Fortunately

the side-effects of the newer drugs, such as sodium

valproate and carbamazepine and lamotrigine

which many people take nowadays, are less than

the side-effects of the older drugs. Sometimes

behaviour can be affected by changing the

anti-epilepsy medicine. (See Fact Sheet No 13 by

Dr M Brodie).

Most doctors now feel that if possible one drug

only should be tried to control epileptic seizures.

When other drugs are added there is a tendency

for the drugs to interact which may make

management more difficult. In particular

phenytoin (Epanutin) has a very narrow range

between the `therapeutic' (effective) dose and the

higher `toxic' dose and therefore should be

monitored. In addition to blood level tests it is now

possible to test for levels of some drugs in the

saliva, and this may be preferable in a learning

disabled hyperactive child.

An adverse effect of the long-term use of these

drugs can be hypocalcaemia or even osteomalacia

(rickets) caused by Vitamin D deficiency. Children

with TS have been reported to be even more

vulnerable to these effects than other children with

epilepsy. In some cases, children fractured bones

easily when they fell or it became difficult for them

to walk because of weak bones. The drugs mainly

responsible for Vitamin D deficiency are phenobarbitone,

carbamazepine primidone (Mysoline),

and phenytoin. These drugs may also interact with

contraceptive pills, so pills with higher hormone

levels may be needed.

As a child grows seizures may change and it is

important not to continue treatment for one type

of seizure when the child may have outgrown them

and require a different form of medication. This is

important with infantile spasms. The drug of

choice nowadays is vigabatrin (Sabril), but because

of the associated risk of visual fixed defects it

should be removed once the risk of infantile

spasms has gone. Similarly, with infantile spasms

that may have been treated in infancy with

nitrazapam or clonazepam for many years beyond

the time when the spasms have ceased and

another form of myoclonic epilepsy is being

experienced. Benzodiazepines have sedative

properties and can produce fatigue, dizziness,

drowsiness and ataxia (unsteadiness of standing or

walking). Large doses may interfere with a child's

development and parents need to consider

whether total seizure control or a more aware child

is their most important aim.

The effect of drugs varies a great deal between

patients and there is no one drug that has been

found to be universally effective in children with

TS. Some are well controlled on a drug that has

caused great problems for another person or vice

versa. In reading the information about drugs

remember that most children do not develop

unwanted effects. Every person reacts differently

to a drug so it is a matter of keeping an eye open

in case problems arise. Try to establish a good

working relationship with your child's doctor.

Remember, you are your child's best advocate.

Drug treatment for epilepsy falls into two broad

areas: people with newly diagnosed epilepsy and

those who have failed to respond or developed

side effects to the initial drug treatment.

Before choosing or changing an anti-epileptic

drug, it is important to classify the type of seizure

disorder. Simplistically the types of epilepsy seen

Fact Sheet 2

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in Tuberous Sclerosis can be divided into two

types:

1. Symptomatic generalised epilepsies where the

seizures are a symptom of the underlying brain

disorder. When an EEG is done the abnormal

electrical activity begins all over the brain.

2. Localisation related epilepsy (focal, partial

epilepsy). The abnormal electrical activity

begins in one area of the brain and spreads.

Management of patients with

continuing seizures

If seizures are predictable then drugs such as

clobazam can be very useful, but if given daily,

tolerance develops. When used appropriately such

as for seizures that cluster around the time of

menstruation or when one seizure is followed by a

series either that day or the next, clobazam

tailored to the individual needs may greatly

improve seizure control.

As the response to an anti-epileptic drug is not

predictable in any individual it is best to make a

choice after weighing up the side effects.

Additional factors such as ease of use are

important, also drug interactions, (for example

with an oral contraceptive pill or other antiepileptic

drugs), pregnancy planning or any preexisting

diseases.

If it is necessary to add in a second drug, it is best

gradually to build up the dosage until either seizure

control is achieved or side effects develop. Once

the recommended dose is reached, if there is no

improvement within one to two months then the

new drug could be reduced and stopped and an

alternative tried.

Commonly used Anti-Epileptic

Drugs and their reported adverse

effects

Carbamazepine (Tegretol). This is used for

generalised tonic-clonic (grand mal) and all partial

seizures including temporal lobe seizures. It has

little or no beneficial effect on other types of

seizure and can make myoclonic seizures worse.

Doses should be gradually built up to avoid adverse

effects. These can include nausea, vomiting,

headaches, double vision, poor co-ordination and

drowsiness which may also occur at too high a

dosage. The commonest problem is a rash which

stops when the drug is withdrawn. More even

blood levels are produced by the slow release form

(Tegretol Retard). Oxcarabamazepine is related to

carbamazepine. Because it is metabolically

simpler, its use may have fewer complications.

Ethosuximide (Zarontin) This drug is used for

petit mal absences which are unlikely In TS.

Ethosuximide is a well tolerated drug. As well as

apathy and drowsiness, mild euphoria has been

reported as an adverse effect.

Phenytoin (Epanutin) Again this is a widely used

and effective drug. It may be called Dilantin

outside the UK. As mentioned before it should be

monitored when used with other drugs, as

excessive amounts can make seizures worse and

cause bizarre behaviour. Toxic signs to watch for

are nystagmus (involuntary eyeball jerking), double

vision and ataxia. Unwanted effects of phenytoin

include gum overgrowth and coarsening of facial

features. An excessive hairiness may also be

produced which may be unacceptable, particularly

in girls. Insomnia, nausea and a skin rash have also

been reported. At high doses there may be

behavioural disturbances and lack of drive. Vitamin

D deficiency may occur. It is teteragenic and a

higher dose oral contraceptive pill is needed.

Phenobarbitone This is one of the earliest drugs

and has been used for all forms of seizures. Babies

with TS may be given phenobarbitone if their first

seizures are not infantile spasms. In young children

it has the `paradoxical' effect of irritability,

aggressiveness and overactivity whereas adults

become sedated. In children it can also have a

dulling effect on attention and perception and

produce drowsiness, vertigo, headache and

nausea. Skin rashes can occur and Vitamin D

deficiency. In general, like phenytoin, phenobarbitone

has been largely replaced by sodium

valproate and carbamazepine.

Primidone (Mysoline) Primidone breaks down in

the body to phenobarbitone and therefore should

not be used in combination with that drug. Much

of what can be said about phenobarbitone also

applies to primidone. It has a higher incidence of

side effects compared to phenobarbitone.

Sodium Valproate (Epilim) This is widely used in

many forms of epilepsy and produces little or no

sedation taken alone. It is not recommended for

women of child-bearing age if they want a family.

Increased appetite can produce obesity. There

may be temporary hair loss when the drug is first

taken and rarely the hair regrows with curls or

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waves. Liver toxicity occurs in a small number of

cases (mainly developmentally delayed children

with metabolic disorders).

Gabapentin (Neurontin) is effective for partial

seizures and is one of the easiest of the new drugs

to use as it has few side effects and no interactions

with other anti-epileptic drugs. The main problem

are frequency of dosage (three times/day) and

if the person is in kidney failure a lower dose

has to be used. The commonest side effect

encountered is dizziness, which often begins on

initiating therapy and occasionally weight gain

Gabapentin does not interact with the oral

contraceptive pill.

Lamotrigine (Lamictal) is a first line drug for the

generalised epilepsies and a useful drug for partial

seizures. Its main problems are the interactions

with other anti-epileptic drugs (necessitating

different dosage schedules) and rash. However, it

appears to have some advantages in being a broad

spectrum anti-epileptic drug, effective in both

partial and generalised seizure disorders and with a

low side effect profile. Lamotrigine does not

interact with the oral contraceptive pill.

Vigabatrin (Sabril) is an effective anti-epileptic

drug and is the drug of choice for infantile spasms.

Interestingly, research in the USA shows that it is

rendered less effective if other anti-epileptic drugs

have already been tried (although if the first drug

has failed then the epilepsy is likely to be more

resistant anyway). However in adults it does have

high incidence of particularly psychiatric side

effects (anxiety, depression and psychosis).

Problems with vision have been reported recently.

These problems have limited its use, although

many patients have found it a very valuable antiepileptic

drug. If someone wants to continue

taking Vigabatrin it is recommended that they have

their visual fields checked every 6 months. This

may be difficult or impossible if the person has a

learning disability.

Topiramate (Topamax) is a very effective antiepileptic

drug but its usefulness is limited by its

side effects, particularly the problem of mental

slowing which may appear in up to 25% of people.

Weight loss can also be troublesome and there is

risk of kidney stones. It interacts with the oral

contraceptive pill.

Tiagabine (Gabitril) is a drug which appears

effective in people with partial seizures,

particularly those who have responded to

Vigabatrin. At present it appears from clinical

trials to have a lower side effect profile than

Vigabatrin and may provide a useful alternative to

Vigabatrin although no direct comparative studies

have been performed. The commonest side effect

encountered is dizziness. Dosage needs to be

adjusted in cases of impaired renal function.

Oxcarbazepine (Trileptal) is a recently licensed

anti-epileptic drug for partial seizures. Its main side

effects are rash and a low sodium in the blood. It

is structurally related to Carbamazepine but has

less side effects.

Levatiracetam (Keppra) is licensed as add on for

partial seizures. However it appears to be very

effective in the treatment of generalised epilepsies

particularly in those with learning disabilities. Its

main side effect is drowsiness but occasionally

behavioural problems are seen.

Cortiscosteroids (ACTH,Prednisone) These

drugs are mainly used for infantile spasms. They

can also be used for otherwise intractable seizures,

but in either case they are used under strict

medical supervision. Use is short-term because of

the risk of physical complications with long-term

use. Withdrawal from cortiscosteroids should be

gradual.

Benzodiazepines These drugs include clobazam

(Fristium), clonazepam (Rivotril), diazepam

(Valium), midazalam and nitrazepam (Mogadon).

Clobazam (Frisium) It is usually used in

combination with other anti-epilepsy drugs. As

mentioned above, clobazam tailored to the

individual needs may greatly improve seizure

control, but if used daily tolerance develops. It can

be very helpful when used intermittently.

Clonazepam (Rivotril) has been used for

various forms of epilepsy, particularly for infantile

spasms, myoclonic epilepsy and absence attacks

(petit mal). It can have a sedative effect in young

children which might be avoided by gradually

introducing the drug. It can also cause salivary and

bronchial hypersecretion (dribbling and

chestiness). Unwanted effects are ataxia and

fatigue and therefore a young child's development

may be delayed until the body gets used to the

drug. Extreme irritability, excitement, aggression

and hyperactivity have all been reported in

children with TS on clonazepam.

epam (Valium). This is a very useful drug

for prolonged seizures and many parents keep

" Stesolid " for rectal administration if their child is

liable to status epilepticus attacks. It is best

reserved for emergency situations. It can also be

used to treat non-convulsive status epilepticus.

Buccal Midazalam This is a useful alternative

to rectal diazapam for treating acute seizures or

status epilepticus. The medication is inserted in

the mouth, just under the cheek, so is more

socially acceptable than the rectal alternative. The

disadvantage is that it is unlicensed and has not

been properly evaluated in adults.

Nitrazepam (Mogadon). This is used to

promote sleep and as an anti-epilepsy drug for

infantile spasms. Adverse effects are similar to

clonazepam. Again addiction occurs readily and

great care must be taken when withdrawing from

the drug.

ANY CHANGES IN DRUGS SHOULD BE

MADE UNDER MEDICAL SUPERVISION

Surgery and other Non Drug

Therapy

It has been realised that some patients will never

become seizure free on currently available antiepileptic

drugs and surgery is an important

treatment option. In people with TS it may be

possible to remove a cortical tuber if it is acting as

a focus for epileptic seizures. However, the

assessment needed is complicated and requires a

multi-disciplinary team which is only available at a

few neuroscience centres in the United Kingdom.

Other rarer operations can occasionally be

beneficial in people with TS and severe epilepsy.

Other new therapies are now available eg vagal

nerve stimulation and other non-drug methods of

stopping seizures (such as utilising ways of

stopping seizure activity progressing in patients

who have prolonged auras and the ketogenic diet).

These are only of value for a small number of

patients and are still under evaluation.

Useful addresses:

British Epilepsy Association, New Anstey House,

Gate Way Drive, Yeadon, Leeds, LS19 7X.

Helpline: 0808 800 5050

National Society for Epilepsy,Chesham Lane,

Chalfont St , Gerrards Cross, Bucks, SL9

ORJ. Helpline: 01494 601 400

F.A.B.L.E. Charity, 9-13 Ashgate Road, Sheffield,

SL10 3BZ. Helpline: 0800 267 8894

Epilepsy Bereaved, P O Box 1777, Bournemouth,

Dorset, BH5 1YR.

Updated by

Professor Pamela M Crawford

MB, ChB, MD, FRCP, Consultant

Neurologist and Director of the

Special Centre for Epilepsy, York.

Further information on TS and the work of the TSA can be

obtained from: Mrs. Janet Medcalf, Head of Support Services,

PO Box 9644, Bromsgrove, B61 0FP.

Email: Support@...

Web: www.tuberous-sclerosis.org

Tuberous Sclerosis Association

The Tuberous Sclerosis Association is a Company Limited by Guarantee.

Registered in England No. 2900107. Registered Charity No. 1039549.

4 March 2002