Ebook Drugs in use (4E): Part 2

18
Epilepsy
Ben Dorward

Case study and questions

Day 1 Miss SL, a 19-year-old student who had recently moved away from
home to university, was witnessed ‘having a fit’ by her friends and was
taken to the local A&E department. The fit had stopped by the time she
arrived and Miss SL had no recollection of the event. She was sent home
from hospital with paracetamol for the resulting headache, and referred
to a ‘faints and fits’ clinic at the local neurology department.
At the neurology clinic she commented that she had been experiencing jerking movements for several years, most notably in the morning, and that these had occasionally led to her dropping her breakfast.
Her friends had also commented to her that she was prone to daydreaming. On questioning she stated that initially she had found the transition
to university life quite stressful. She admitted to taking full advantage of
the social opportunities, and to feeling very tired due to having to get up
early for lectures after late nights out.
The neurologist made a diagnosis of juvenile myoclonic epilepsy
(JME). Miss SL was prescribed lamotrigine 25 mg once daily, increasing to
50 mg once daily after 14 days, and was referred to an epilepsy nurse
specialist.
Q1
Q2
Q3
Q4
Q5
Q6

What is epilepsy?
Is the history of stress significant?
Do you agree with the choice of lamotrigine for Miss SL?

Is the dose of lamotrigine appropriate?
Outline a pharmaceutical care plan for Miss SL. What advice would you
offer her if she asked about contraception?
What is the role of the epilepsy nurse specialist?

Month 3 Miss SL presented a prescription for lamotrigine. Her dose was
now 50 mg in the morning and 50 mg at night. On receiving the


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prescription Miss SL commented that the tablets did not look the same as
those she was given at the hospital. On further questioning you realise
she was previously dispensed a generic brand of lamotrigine and the
general practitioner (GP) has prescribed the Lamictal brand.
Q7

Is there a significant difference between the different brands of
antiepileptic drugs (AEDs)?

Month 4 Miss SL developed a bad chest infection. As she was known to
be allergic to penicillin (previous urticarial rash to amoxicillin) the GP
prescribed ciprofloxacin 500 mg twice daily for 7 days.
Q8

Is the choice of ciprofloxacin appropriate?

Month 5 The lamotrigine dose had been slowly titrated up to 150 mg

twice daily but Miss SL was not responding to treatment, and now constantly felt quite tired. The myoclonic jerks continued and she had had
several further tonic–clonic seizures. The frequency of seizures was
increasing, and this was particularly noticeable in the 2–3 days before her
period.
Q9

What term is used to describe epilepsy that worsens around the time of
menstruation, and how common is it?
Q10 What drug treatments are available for this form of epilepsy?

After discussion with Miss SL and her epilepsy nurse specialist, the neurologist decided to change the lamotrigine to levetiracetam. She was prescribed 250 mg twice daily and instructed to increase the dose to 500 mg
twice daily in 2 weeks’ time. If she did not experience a reduction in
seizure frequency after 2 weeks at 500 mg twice daily, then she was to
further increase the dose to 750 mg twice daily. At the same time she was
instructed to reduce the morning and evening doses of lamotrigine by
50 mg every 2 weeks.
Q11 Levetiracetam is not licensed as a monotherapy for generalised seizures.
What is your opinion of the neurologist’s choice?
Q12 Levetiracetam is one of the newer AEDs. What are the advantages of the
newer drugs over the older ones?

Month 8 Unfortunately, Miss SL had had to withdraw from her university studies. She had become very low in mood but was not keen to take
‘antidepressants’. She had read that St John’s wort can be effective for low
mood and came to seek your advice.
Q13 What advice can you offer about St John’s wort?


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Q14 If indicated, what is the appropriate drug treatment for depression in
people with epilepsy?

Month 10 Miss SL experienced a particularly bad cluster of seizures and
injured herself on falling. She was admitted to a neurological ward for
observation and assessment. The consultant neurologist prescribed 10 mg
of buccal midazolam to be used when required to terminate tonic–clonic
seizures lasting longer than 5 minutes.
Q15 What are the advantages and disadvantages of using buccal midazolam
over rectal diazepam?

Month 22 Levetiracetam had been gradually titrated upwards to a dose of
1500 mg twice daily and her seizures had become well controlled. Miss SL
had started a career in accounting and met a partner. They had discussed
starting a family and wanted to know more about how Miss SL’s epilepsy
would affect this.
Q16 What are the issues concerning pregnancy in women with epilepsy?
Q17 What drug should epileptic women who wish to become pregnant take,
and at what dose?

Answers
What is epilepsy?

A1

Epilepsy is a neurological disorder characterised by a tendency
towards epileptic seizures. An epileptic seizure is the result of
abnormal electrical activity in the brain. The manifestation of an
epileptic seizure depends on the area of the brain affected by the

abnormal electrical activity.

There are two main seizure types:
(a)

(b)

Generalised seizures are a result of electrical activity spreading
through the entire cerebral cortex. They can be secondary to a focal
seizure or idiopathic (see below). Absence, myoclonic and tonic–
clonic (grand mal) seizures are forms of generalised seizure.
Partial (focal) seizures are a result of a localised electrical disturbance
and are often the result of functional changes caused by brain
tumours or congenital structural abnormalities such as focal cortical
dysplasia. Partial seizures can be further subdivided into simple–
partial and complex–partial, based on whether there is an impairment of consciousness (complex–partial) or not (simple–partial).


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There are a large number of epilepsy syndromes that can be characterised by the pattern of seizure type, age of onset and response to drug
treatment. Many of the generalised epilepsy syndromes have a genetic
basis. The diagnosis of epilepsy is largely a clinical one. An accurate
eyewitness account of the seizures is one of the most useful pieces of
information in making a diagnosis.
JME is a form of idiopathic generalised epilepsy and is one of the
most common epilepsy syndromes. It is characterised by myoclonic
jerks and generalised tonic–clonic seizures, often shortly after waking.

Many patients also have absence seizures. People with JME can be photosensitive, i.e. myoclonic and tonic–clonic seizures can be precipitated by
flashing or flickering light.
Is the history of stress significant?

A2

Tiredness and a lack of sleep can increase the number of seizures,
particularly myoclonic seizures in JME.

Also, a significant number of people presenting to a neurology clinic with
possible epilepsy will be diagnosed with non-epileptic attack disorder
(NEAD). Such seizures can be called non-epileptic seizures, pseudoseizures, functional seizures, or non-organic seizures, and although they
can look very much like epileptic seizures, during an attack an electroencephalogram (EEG) will show no abnormal electrical brain activity.
This is one of the reasons why it is very important that a person with
suspected epilepsy should be referred to a suitably trained neurologist.
NEAD can often be a reaction to stress. To complicate matters further, some patients with epilepsy may have non-epileptic as well as
epileptic seizures. There is no specific drug treatment for NEAD.
Do you agree with the choice of lamotrigine for Miss SL?

A3

(a)

(b)

Sodium valproate and lamotrigine are considered first-line
treatments for JME; however, sodium valproate is no longer
recommended as a first-line treatment in women of childbearing
potential, for a number of reasons:
Teratogenicity. There is a 2–3% incidence of fetal abnormalities

among the general population. The UK Epilepsy and Pregnancy
Register (see A16b) records a major malformation rate of 5.9% for
babies born to mothers treated with sodium valproate during
pregnancy.
Side-effects can include weight gain, hair loss and menstrual disturbances, all of which are particularly undesirable in young women.

The SANAD trial was a large-scale practice-based randomised controlled


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trial comparing the long-term outcomes of the newer antiepileptic drugs
(AEDs) against the older ones. One arm of the study compared valproate
to lamotrigine in the treatment of generalised epilepsy syndromes and
concluded that sodium valproate was more effective but lamotrigine was
better tolerated. Overall, sodium valproate was the most cost-effective
treatment for generalised epilepsy.
It is generally recommended that preventative drug treatment for
epilepsy should only be considered after a person experiences a second
seizure, but in certain epilepsy syndromes treatment may be warranted
before a second seizure occurs. Miss SL’s history indicates she had already
experienced absence and myoclonic seizures prior to her presentation
at A&E. Many people diagnosed with JME will require lifelong drug
treatment.
Is the dose of lamotrigine appropriate?

A4

Yes. It is very important to adhere to the recommending starting
regimen for lamotrigine, which depends on whether it is prescribed as monotherapy or in combination with other antiepileptics. Rapid dose escalation is associated with the
development of rash, including cases of toxic epidermal necrolysis and Stevens–Johnson syndrome, which are severe, potentially
fatal hypersensitivity reactions. For this reason, people started on
lamotrigine should be counselled to seek medical attention
immediately if they develop a rash.

Lamotrigine is metabolised hepatically by glucuronidation. The enzymeinducing AEDs, which include carbamazepine and phenytoin, can
accelerate the metabolism of lamotrigine, whereas sodium valproate
inhibits lamotrigine glucuronidation. It is therefore very important to
check the patient’s concomitant medication to ensure the dose is appropriate, as the starting dose and titration regimen are dependent on
whether lamotrigine is prescribed as monotherapy, in combination with
sodium valproate, or in combination with enzyme-inducing AEDs.
Outline a pharmaceutical care plan for Miss SL. What advice would you
offer her if she asked about contraception?

A5

The pharmaceutical care plan should ensure that her treatment is
prescribed at an appropriate dose, monitored correctly, and that
Miss SL receives all the information she needs about her treatment. Checks should be made on whether Miss SL is taking any
other medicines, particularly oral contraception.

Before offering specific counselling to Miss SL it is important to check
whether or not she is taking any other medication. Concomitant therapy
may affect the starting dose of lamotrigine (see A4 and below).


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Monitoring. It is not necessary to monitor serum levels of lamotrigine, and therapeutic dose monitoring generally has limited
applications in monitoring AED therapy. Other monitoring
includes:
i(i)
(ii)

(b)

Response to treatment: patients may keep a seizure diary.
For adverse effects, especially rash.

Women taking oral contraception should be advised to report any
breakthrough vaginal bleeding, as this suggests contraception is
inadequate.
Contraception. Although lamotrigine is not an enzyme-inducing
drug, recent evidence suggests it can reduce levels of progestogens
and women taking lamotrigine need to be aware that oral contraceptives may not be fully effective. In addition, combined oral
contraceptives can reduce lamotrigine levels. Starting or stopping an
oral contraceptive may thus require adjustment of the lamotrigine
dose. The Summary of Product Characteristics recommends that
women’s contraceptive needs should be reviewed if lamotrigine is to
be prescribed, and they should be advised to use effective alternative
non-hormonal contraception.
The efficacy of oral contraceptives is also reduced in women
taking the enzyme-inducing antiepileptics phenytoin, carbamazepine, oxcarbazepine, phenobarbital, primidone and topiramate, all of which enhance metabolism of the female sex hormones.
The following recommendations are made for oral contraception in

women taking enzyme-inducing AEDs:
ii(i) Enzyme-inducing AEDs are likely to render progesterone-only
contraceptives ineffective.
i(ii) Women wishing to take combined oral contraceptives should
start on a daily ethinylestradiol dosage of at least 50 micrograms. In practice this can be achieved by doubling the dose of
preparations containing 30 micrograms of ethinylestradiol
(iii) If breakthrough bleeding occurs then the daily ethinylestradiol
dose can be further increased to 75 or 100 micrograms. An
alternative option is to consider taking three consecutive pill
packets without a break, followed by a 4-day break, rather
than the usual 7 (‘tri-cycling’). Non-hormonal methods of
contraception may also be considered.

(c)

General counselling points that should be covered with Miss SL
include:


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iii(i) Explaining the name of the drug and the aim of treatment, i.e.
to prevent and hopefully stop further seizures. The drug may
not have an instant effect, and the dose will be gradually
increased to minimise the risk of side-effects.
ii(ii) Lamotrigine needs to be taken regularly at the same time of
the day and evenly spaced out during the day, i.e. take each
dose approximately 12 hours apart for a twice-daily regimen.

Written information is also beneficial for people with complicated treatment regimens, and for those with epilepsy who
have learning difficulties.
i(iii) The potential side-effects of lamotrigine should be explained,
including the importance of reporting any new rash.
Gastrointestinal side-effects such as nausea can occur, as well
as tiredness and headache. As with many AEDs, particularly
the older drugs, lamotrigine is associated with a risk of haematological toxicity and patients should be advised to seek medical advice if they develop symptoms suggestive of anaemia
(fatigue, breathlessness etc); low platelets (bruising or bleeding); or infection (because of potential neutropenia).
i(iv) Miss SL needs to ensure her medication does not run out and
that doses are not missed, and needs to know where to get
further supplies. In some parts of the UK shared care protocols
for epilepsy exist where hospitals are responsible for supplying
newly prescribed medication until the patient is stabilised on
the new treatment. Omission of doses or sudden discontinuation of AEDs can lead to worsening seizures, possibly status
epilepticus, and are thought to be a factor associated with
sudden unexplained death in epilepsy (SUDEP). This term is
used when people with epilepsy die suddenly and no obvious
cause is found at post mortem. The exact cause of SUDEP is not
yet known.
ii(v) Depending on where they live, people with epilepsy may be
entitled to claim exemption from prescription charges.
i(vi) If Miss SL has a driving licence then she must be advised that
she should contact the Driver & Vehicle Licensing Authority
(DVLA). Current UK regulations state that a person can apply
for a driving licence when they have been completely free of
seizures for 1 year, or have had a pattern of sleep seizures only
for 3 years.
(vii) Miss SL could be advised of local and national support groups
for patients with epilepsy.

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In developed countries with ready access to AEDs the overall prognosis for people with epilepsy is good: up to 70% will have their
seizures controlled with drug treatment.
What is the role of the epilepsy nurse specialist?

A6

Epilepsy clinical nurse specialists perform a vital role in providing
practical and emotional support to people with epilepsy and their
carers. They may be based in hospital or primary care settings,
and can be very useful contacts for patient-specific medication
enquiries.
Is there a significant difference between the different brands of AEDs?

A7

Generic versions of medicines are often significantly cheaper than
branded ones. Although the prescribing of generic medicines is
recommended to reduce drug costs, this practice is somewhat
controversial in relation to the prescribing of AEDs; however, Miss
SL can be reassured if the neurologist and GP feel it is acceptable
to switch brands, her response to lamotrigine therapy should not
be affected.

The pharmacist has an important role in listening to patients’ concerns
about the appearance of their tablets and providing reassurance when

appropriate.
Many of the older AEDs, such as carbamazepine and phenobarbital,
have narrow therapeutic indices. In the case of phenytoin, its metabolism
is saturable. This means that small dose increases, such as those caused by
a switch to a slightly more bioavailable formulation, may produce a disproportionate increase in the serum concentration of drug and result in
toxicity. There are published case reports and series describing loss of, or
worsening, seizure control or side-effects after switching to an alternative
brand of AED.
The newer AEDs generally have more predictable pharmacokinetics
and broader therapeutic indices. In the case of generic lamotrigine the UK
Department of Health has advised that there is no compelling evidence
to suggest that swapping to a generic alternative will have an adverse clinical outcome. More research is required into brand switching of AEDs to
identify patient groups who may be at risk.
In testing generic medicines, the European Agency for the
Evaluation of Medicinal Products (EMEA) stipulates that to prove bioequivalence between a generic and branded medicinal product, the
bioavailability must be within 80% and 125%. The pharmacokinetic
parameters used for comparison include the maximal concentration
(Cmax) and area under the curve (AUC). A potential variation of up to
25% may seem significant, but the limits of 80% and 125% are statistical


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ones: they represent the 90% confidence intervals when calculating the
ratios of pharmacokinetic parameters between the generic and the
branded medicinal product. There are some limitations of bioequivalence
studies:
(a)

(b)

Bioequivalence studies are usually performed in young healthy
volunteers who are taking no other, potentially interacting, drugs.
Extrapolating results from studies in healthy volunteers to an
elderly population with comorbidities and concomitant drug
therapy, or to paediatric populations, may not be accurate.
The studies compare generic medicines to their branded equivalent
but not against other generic brands.

One AED commonly associated with prescribing and administration
errors is modified-release carbamazepine, which is often prescribed for
epilepsy and has several advantages over the standard tablet formulations, such as less fluctuation in plasma levels, thereby reducing sideeffects and improving seizure control; and twice-daily administration,
which may encourage patient adherence. Pharmacists should actively
clarify prescriptions for twice-daily regimens of carbamazepine if the
modified-release formulation is not prescribed. Occasionally, however, in
patients exquisitely sensitive to carbamazepine, the modified-release
tablets are prescribed three times a day.
Is the choice of ciprofloxacin appropriate?

A8

No. Ciprofloxacin is a quinolone antibiotic associated with an
approximately 1% risk of seizures. Quinolone antibiotics are
thought to inhibit membrane receptor binding of the inhibitory
neurotransmitter gamma-amino butyric acid (GABA).

A macrolide antibiotic such as erythromycin would be appropriate for
Miss SL. However, it is important to remember that erythromycin is a

strong inhibitor of the cytochrome P450 3A4 isoenzyme and can interact
with a number of the older, hepatically metabolised AEDs, notably
carbamazepine. Concomitant erythromycin therapy can increase
carbamazepine levels resulting in intoxication.
What term is used to describe epilepsy that worsens around the time of
menstruation, and how common is it?

A9

Catamenial epilepsy affects approximately 10% of women of
childbearing age.

The definition of catamenial epilepsy is not an exact one, but around 10%
of women with epilepsy experience a worsening of seizures around the


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time of menstruation. Seizures may also worsen mid-cycle, around the
time of ovulation. Catamenial seizures are thought to result from the
changing levels of sex hormones that occur throughout the menstrual
cycle, in particular the reduction of serum progesterone prior to the onset
of menstruation.
What drug treatments are available for this form of epilepsy?

A10

Clobazam, a benzodiazepine, is often prescribed in short courses

for catamenial epilepsy.

Clobazam at a dose between 5 and 30 mg/day (sometimes higher in
refractory cases) may be prescribed to be taken on the days it is anticipated that seizures will be worse. Clobazam is prescribed in addition to
the patient’s regular AEDs.
Acetazolamide has also been used intermittently for catamenial
epilepsy. This is a relatively fast-acting antiepileptic that can be initiated
at a therapeutic dose. Its use is based on expert opinion.
Levetiracetam is not licensed as a monotherapy for generalised seizures.
What is your opinion of the neurologist’s choice?

A11

AEDs are sometimes prescribed outside of their licence indications, and levetiracetam monotherapy is a reasonable choice for
Miss SL.

The use of leveiracetam as monotherapy is reasonable in this patient.
Sodium valproate is not an ideal therapeutic option because of its adverse
effect profile and teratogenicity risk. Carbamazapine can exacerbate
myoclonic and absence seizures. Topiramate and zomisamide are other
therapeutic options for JME.
There are a number of reasons for prescribing outside licensed
indications. These include:
(a)

(b)

Exceeding the maximum dose recommended in the Summary of
Product Characteristics. The general principle when prescribing
AEDs is to start at a low dose to minimise adverse effects and then

increase the dose until seizures are controlled or side-effects become
unacceptable. For many AEDs central nervous system (CNS) sideeffects such as drowsiness and somnolence are dose related and
become the limiting factor in dose escalation. Many of the more
severe side-effects of hepatic and haematological toxicity are
idiosyncratic reactions, and the incidence is not related to the drug
dose; rash from lamotrigine is an exception to this.
Prescribing for an indication not listed in the Summary of Product
Characteristics, e.g. for use as monotherapy when it is licensed as an
adjunctive therapy only. Most of the newer AEDs gained marketing


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authorisation as adjunctive therapy in epilepsy. These authorisations were granted based on the results of trials using the drug as
adjunctive therapy in refractory epilepsy. It would be ethically very
difficult to justify a drug trial in epilepsy where a patient would be
given a placebo monotherapy, i.e. no treatment. Given the heterogeneity of epilepsy and the often tight inclusion and exclusion criteria of drug trials, applying results from these trials to every day
practice can have limitations.
Specialist epilepsy centres may occasionally use AEDs unlicensed in the
UK for refractory cases. One example is felbamate, a drug associated with
a risk of hepatic failure and aplastic anaemia. People prescribed felbamate
require close monitoring of liver function and full blood count (FBC).
Levetiracetam is one of the newer antiepileptic drugs. What are their
advantages over the older drugs?

A12

The newer AEDs include gabapentin, levetiracetam, oxcarbazepine, pregabalin, topiramate and zonisamide. The properties of

each drug should be checked individually, but generally speaking
the newer AEDs have advantages over the older AEDs, including:
(a)
(b)
(c)
(d)
(e)

Linear pharmacokinetics which provide a more predicable
dose–response relationship.
Low protein binding, hence less potential to displace and be
displaced by other drugs.
Metabolism independent of the cytochrome P450 system,
thus reducing drug interactions, particularly with oral contraceptives.
A wider therapeutic index.
More acceptable side-effect profiles.

Newer AEDs are invariably more expensive than older agents. In the UK
newer AEDs can be used in people who have not responded to, or are
intolerant of, the older agents, or in those for whom the use of older
agents is unsuitable. In women of childbearing potential the older AEDs
are usually considered unsuitable because of their teratogenic risk and
potential interactions with oral contraceptives.
When taking into account the factors above, and individual patient
factors, newer AEDs are sometimes used as first-line therapy.
What advice can you offer about St John’s wort?

A13

In the UK St John’s wort is not recommended to be used concomitantly with any AEDs.

St John’s wort is derived from the plant Hypericum perforatum and has
antidepressant actions that are not fully understood but which may be
exerted through the inhibition of neurotransmitter reuptake.


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St John’s wort has been shown to induce metabolism of cytochrome
P450, notably the 3A4 isoenzyme, and thus has the potential to interact
with drugs metabolised by this pathway and reduce their effectiveness.
Carbamazepine is metabolised by CYP 3A4.
St John’s wort can also induce p-glycoprotein, a transport protein
implicated in drug resistance in epilepsy by the mechanism of actively
expelling drugs from neurons. There are case reports of reduced efficacy
when St John’s wort has been added to AEDs not metabolised by
cytochrome P450. Miss SL should thus be advised to avoid it, even
though there is no direct interaction between this product and her
prescribed therapy.
If indicated, what is the appropriate drug treatment for depression in
people with epilepsy?

A14

The tricyclic and selective serotonin reuptake inhibitor (SSRI)
antidepressants all have potential to lower the seizure threshold
and their use in epilepsy is cautioned against. If depression in a
person with epilepsy becomes severe enough to warrant drug

therapy then the decision to treat with antidepressants is a clinical one, weighing up the risks and benefits of treatment.

SSRI antidepressants are considered first-line treatment for depression in
the general population. Citalopram has been advocated as an appropriate
drug to use in people with epilepsy as it is thought to confer a lower risk
of inducing seizures.
Recent evidence has shown a small increased risk of suicide with the
AEDs. Patients need to be aware of this and know to seek medical advice
if they develop mood changes or suicidal thoughts.
What are the advantages and disadvantages of using buccal midazolam
over rectal diazepam?

A15

A number of benzodiazepines are used to terminate epileptic
seizures. Rectal diazepam (as a solution, not suppositories) has
historically been used, but its use is associated with the stigma
and inconvenience of having to remove clothing to enable
administration.

The use of buccal midazolam as an alternative to rectal diazepam is
becoming more widespread. Midazolam is sufficiently lipophilic at physiological pH to rapidly cross the buccal mucosa. Controlled trials, mainly
in children and adolescents with severe epilepsy, have shown buccal
midazolam to be as least as effective as rectal diazepam in terminating
epileptic seizures.


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Buccal administration represents an unlicensed route of midazolam
administration. The injection formulation can be administered buccally
or a 10 mg/mL buccal formulation (made as a pharmaceutical special in
the UK) can be used. An important counselling point is to administer the
drug buccally: oral administration would put a fitting patient at risk of
choking. The drug should be given using an oral syringe positioned
between the gum and the cheek and by splitting the dose between both
sides of the mouth. A usual adult dose would be 5–10 mg, which is
0.5–1 mL of a 10 mg/mL formulation. With such a small volume the risk
of accidental swallowing is low.
There are concerns over the risk of respiratory depression when
using benzodiazepines outside a hospital setting, but they are relatively
safe in carefully selected patients when carers are properly trained in how
to administer and when to use them and, importantly, are clear on when
to get further help.
What are the issues concerning pregnancy in women with epilepsy?

A16
(a)

(b)

(c)

There are several issues for women with epilepsy wishing to
become pregnant.
Fertility. Fertility rates are reduced in women with epilepsy
compared to age-matched controls. The possible causes of this are
multiple and probably not just purely biological.

Teratogenicity of AEDs. In utero exposure to AEDs is associated with
a higher risk of congenital malformations. Accurately assessing the
risk of individual drugs is difficult because women are not always
treated with monotherapy; however, sodium valproate is associated
with the highest risk of congenital malformations. The teratogenic
risk of AEDs has to be balanced against the risk to mother and baby
from uncontrolled seizures.
The UK Epilepsy and Pregnancy Register was created in 1996
with the aim of collecting data on pregnancy outcomes from
women with epilepsy taking AEDs, particularly the newer agents. In
2006 data were published on pregnancy outcomes with in utero
exposure to levetiracetam. Although no congenital malformations
were reported from monotherapy, it is too early to assess accurately
the relative safety of levetiracetam in pregnancy.
Altered pharmacokinetics of AEDs in pregnancy. In the third
trimester the serum levels of a number of AEDs, including lamotrigine, phenytoin, carbamazepine and sodium valproate, can reduce as
a result of a variety of pharmacokinetic mechanisms. Regular
monitoring of drug levels may be required to guide clinical care.


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What drug should women with epilepsy who wish to become pregnant
take, and at what dose?

A17

Ideally pregnancy should be planned and drug therapy reviewed
to optimise treatment at the lowest possible doses. Folic acid

should be prescribed at a dose of 5 mg/day for women with
epilepsy who wish to become pregnant, and should be continued
throughout pregnancy.

Folic acid supplementation has been shown to reduce neural tube defects
in the general population. Women with epilepsy may be deficient in folic
acid owing to the effects of drug therapy, and so should be prescribed a
higher dose than the general population. There are anecdotal reports of
folic acid exacerbating seizures, but the benefits of therapy outweigh the
risk.
Acknowledgement
The author would like to thank Dr Stephen Howell (Consultant
Neurologist, Sheffield Teaching Hospitals NHS Foundation Trust) for
reviewing and commenting on this chapter.

Further reading
Crawford P. Best Practice Guidelines for the Management of Women with
Epilepsy. Epilepsia 2005; 46: 117–124.
Crawford P, Feely M, Guberman A, Kramer G. Are there potential problems
with generic substitution of antiepileptic drugs? A review of issues.
Seizure 2006; 15: 165–176.
Duncan JS, Sander JW, Sisodiya SM, Walker MC. Adult epilepsy. Lancet 2006;
367: 1087–1100.
Hunt S, Craig J, Russell A et al. Levetiracetam in pregnancy: preliminary
experience from the UK Epilepsy and Pregnancy Register. Neurology
2006; 67: 1876–1880.
Mack CJ, Kuc S, Grünewald RA. Errors in prescribing, dispensing and administration of carbamazepine: a case report and analysis. Pharm J 2000;
265: 756–760.
Marson AG, Al-Kharusi AM, Alwaidh M et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or
topiramate for treatment of partial epilepsy: an unblinded randomised

controlled trial. Lancet 2007; 369: 1000–1015.
Marson AG, Al-Kharusi AM, Alwaidh M et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and
unclassifiable epilepsy: an unblinded randomised controlled trial.
Lancet 2007; 369: 1016–1026.


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MHRA. St John’s wort: interactions with all antiepileptics. Drug Safety Update
2007; 4: 7.
National Institute for Health and Clinical Excellence. TA76. Newer Drugs for
Epilepsy in Adults. NICE, London, 2004.
National Institute for Health and Clinical Excellence. TA79. Newer Drugs for
Epilepsy in Children. NICE, London, 2004.
National Institute for Health and Clinical Excellence. CG20. The Epilepsies:
The Diagnosis and Management of the Epilepsies in Adults and Children in
Primary and Secondary Care. NICE, London, 2004.
Perucca E. Role of therapeutic drug monitoring in epilepsy. Hosp Pharm Eur
2002 (Winter): 37–39.
Shorovan SD. Handbook of Epilepsy Treatment, 2nd edn. Blackwell, Oxford,
2005.
Wiznitzer W. Buccal midazolam for seizures. Lancet 2005; 366: 182–183.


19
Parkinson’s disease
Stuart Richardson

Case study and questions

Day 1 Mr LN, a 67-year-old retired bookmaker, was admitted to the
neurology ward. His presenting complaints included difficulty in getting
up from chairs and initiating walking.
Eighteen months earlier he had noticed that his self-winding watch,
which he wore on his right wrist, was consistently losing time. When
moved to his left wrist, the watch kept perfect time. Friends had pointed
out that he had developed a limp, dragging his right foot. These symptoms had worsened over the previous 18 months, and he had also developed a resting tremor in his right hand and leg. He had noticed changes
in his bowel habits many years previously.
His general practitioner (GP) suspected Parkinson’s disease and
referred Mr LN to a neurologist for confirmation of the diagnosis.
Q1
Q2
Q3
Q4
Q5

What are the main symptoms of Parkinson’s disease?
Is it possible to make a definitive diagnosis of IPD?
What biochemical defects are thought to be present in a patient such as
Mr LN?
Outline a pharmaceutical care plan for Mr LN.
Which drugs are usually considered for the initial treatment of patients
with IPD and what are their modes of action?

Day 2 Mr LN was started on ropinirole.
Q6
Q7

Do you agree with this choice?
How should Mr LN’s ropinirole therapy be adjusted to optimise his
response?

Day 13 Mr LN was discharged on ropinirole 500 micrograms three times
daily and instructed to titrate the dose as directed. Mr LN’s GP was sent a


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365

letter describing his recent admission and advice on how to further titrate
the dose of ropinirole.
Month 18 Mr LN was admitted for reassessment. Despite never completely abating, Mr LN’s symptoms of bradykinesia and rigidity had
temporarily improved following initiation and up-titration of ropinirole;
however, recently Mr LN had experienced a worsening of these symptoms, and his wife reported that he had become rather obsessive about
cleaning out the garden shed, performing this task on an almost daily
basis. On admission he was taking ropinirole 6 mg three times daily.
Q8

What recommendations would you make with regard to Mr LN’s drug
therapy?

It was decided to start Mr LN on Sinemet Plus 125 mg three times daily
and to simultaneously reduce the dose of his dopamine agonist.
Q9

How can the adverse effects of levodopa be minimised?

Month 18, Day 8 Mr LN was discharged. He was now stabilised on
Sinemet Plus, two tablets three times daily, and ropinirole 4 mg three
times daily and had experienced a significant improvement in his motor
function.
Month 66 Mr LN was again admitted for reassessment. His therapy and
symptoms had remained stable on the Sinemet and ropinirole until
recently, when he had started to notice his arms shaking about 1 hour
after each dose of Sinemet Plus. This lasted for about 45 minutes before
stopping. Mr LN also complained of painful dystonic cramps at night,
which caused him to wake early most mornings. He had attempted to
counter this by taking an extra Sinemet Plus tablet shortly before going
to bed, which sometimes helped. His wife added that he was becoming
profoundly immobile up to 2 hours before his Sinemet doses were due
during the day.
On examination he was found to have a mask-like face and a resting tremor in both hands and legs. ‘Cog-wheel’ rigidity was found in all
four limbs. He had difficulty initiating speech and his voice was very
quiet. He struggled to rise from his chair, and had a characteristic ‘parkinsonian shuffle’ when walking. When his shoulders were pulled forward
from standing he staggered forward and had to be supported to stop him
falling.


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D r ug s i n U s e

Mr LN complained of occasional falls and was not confident to leave
the house. He relied on his wife to do everything for him. He admitted to
being depressed about his condition.
There was no other medical history of note. All routine laboratory
tests were within normal ranges. His drug therapy was ropinirole 4 mg

three times daily plus two Sinemet Plus tablets at 8 am, 2 pm and 7 pm
and, occasionally, one Sinemet Plus tablet at 11 pm.
Q10 Which of the long-term complications of levodopa therapy is Mr LN
suffering from?
Q11 What alterations to Mr LN’s drug therapy would you recommend in order
to try to minimise these effects?
Q12 How could you monitor and assess Mr LN’s response to these changes?
Q13 Can you suggest any non-drug management that might benefit Mr LN?

Mr LN’s drug therapy was changed to one Madopar dispersible 62.5 mg
tablet on waking around 7 am, and one Sinemet Plus tablet at 10 am,
1 pm, 4 pm and 7 pm. In addition, he was prescribed one Sinemet CR
tablet at 10 pm. The nursing staff were asked to complete an hourly
‘on–off’ chart. Parts of the chart for days 1 and 5 are shown in Table 19.1.
Table 19.1
Time

Day 1

Day 5

7 am
8 am
9 am
10 am
11 am
12 noon
1 pm
2 pm
3 pm

off
off (dose)
on (dyskinesia)
on (dyskinesia)
on
off
off
off (dose)
on (dyskinesia)

off (dose)
on (dyskinesia)
on
off (dose)
on (dyskinesia)
on
on (dose)
on (dyskinesia)
on

Month 66, Day 6 Mr LN’s mobility and dyskinesias were improved;
however, he remained depressed about his condition.
Q14 Would Mr LN benefit from an antidepressant?
Q15 If so, which would you choose?

Month 66, Day 8 Mr LN had noticed a significant reduction in the shaking of his arms following his recent regimen change; however, he was still
becoming considerably immobile about 1 hour before his dose of

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367

Sinemet. His sleep had improved so that he was getting at least 6 continuous hours’ sleep and no longer woke in pain from cramps.
The consultant neurologist recommended commencing entacapone.
Q16 Why has the consultant neurologist recommended entacapone, and does
this necessitate the adjustment of Mr LN’s other IPD therapy?
Q17 What counselling points would you highlight to a patient commencing
entacapone?

Month 66, Day 11 During the ward round, you noted that Mr LN’s morning medication was still on his bedside table. His medication now
comprised one Madopar dispersible 62.5 mg tablet on waking around
7 am, one Sinemet Plus tablet at 10 am, 1 pm, 4 pm and 7 pm, and a
Sinemet CR tablet at 10 pm. In addition, he was taking one entacapone
tablet alongside each dose of Sinemet Plus and 3 mg ropinirole three
times a day (made up of a 1 mg and a 2 mg tablet for each dose). His
regimen thus comprised a total of 16 tablets per day.
On questioning, Mr LN informed you that although he was feeling
better, he was concerned at the number of tablets he was taking and
feared that he would have problems remembering to take them all when
he returned home. He also found the new tablet quite hard to swallow
because of its size.
Q18 In view of MR LN’s concerns, what options are there for rationalising his
medications?

Month 75 Mr LN was admitted as an emergency by his GP, having developed visual and auditory hallucinations over the previous week. He was
hearing voices talking about him, threatening to kill him. He was also
seeing insects crawling up the walls and burrowing into his skin. On
examination he was clearly distressed and very frightened. His medication on admission was one Madopar dispersible tablet on waking, one

Stalevo 100/25/200 tablet four times daily, one Sinemet CR tablet at night
and one ropinirole XL tablet 8 mg daily.
Q19 Which drugs might have contributed to Mr LN’s symptoms?
Q20 What adjustments would you recommend be made to Mr LN’s
medication?

Month 75, Day 7 The recommendations had been carried out. Mr LN’s
visual hallucinations had improved, but he was still experiencing distressing auditory hallucinations and the control of his symptoms had
deteriorated, such that he was experiencing frequent ‘off’ periods.


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Q21 What course of action would you suggest to improve Mr LN’s symptoms?

Mr LN was started on rivastigmine 1.5 mg twice daily. The dose was
increased over the next 10 days to 4.5 mg twice daily. His dopaminergic
therapy was adjusted to one Stalevo 100/25/200 tablet five times daily,
one Sinemet CR tablet at night and one Madopar 62.5 mg dispersible
tablet upon waking. His ropinirole XL therapy was discontinued. His
hallucinations resolved and acceptable control of his Parkinson’s
symptoms was achieved. He was discharged on this regimen.
Q22 What is the long-term outlook for Mr LN?

Answers
What are the main symptoms of Parkinson’s disease?

A1

The main symptoms in patients with Parkinson’s disease are
tremor, rigidity, bradykinesia (slowness of movement), akinesia
(loss of movement) and postural abnormalities.

The onset of Parkinson’s disease is usually insidious and progression slow.
Many patients first notice a resting tremor. This usually initially affects
the hands and may be unilateral. The tremor disappears on movement
and during sleep, and may be worse under stress. The patient is usually
over 50 years old on presentation.
Rigidity manifests as an increased resistance to passive movement
and is classically termed ‘cog-wheel’ rigidity, with a ratchet-like phenomenon felt at the wrist on passive movement of the hand.
Bradykinesia manifests as a general slowness in movement. Together
with the rigidity, it is responsible for the typical abnormalities of gait: difficulty in starting and finishing steps, resulting in shuffling; a stooped
head; flexed neck, upper extremities and knees; and a lack of normal arm
swing.
A wide range of non-motor symptoms (NMS) have also been
described in Parkinson’s disease, all of which can have a significant
impact on quality of life. These include bowel and bladder problems,
fatigue, pain, sleep disorders and autonomic dysfunction, in addition to
difficulty in swallowing and speech alteration, drooling of saliva and
olfactory disturbance. Loss of postural reflexes leads to postural imbalance and sometimes to frequent falls. NMS are common and can occur
at all stages of Parkinson’s disease, including long before diagnosis.
Symptoms increase in number and severity as the disease progresses.


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369

Until recently, there has been a tendency for healthcare professionals to
overlook these features in favour of the more apparent motor symptoms.
Is it possible to make a definitive diagnosis of idiopathic Parkinson’s
disease (IPD)?

A2

At present the only way of making a definite diagnosis of IPD is
by postmortem study of the brain.

IPD is the most common cause of parkinsonism, accounting for approximately 75% of cases presenting to neurologists. Other causes include
other neurodegenerative diseases such as progressive supranuclear palsy
(PSP) and multiple system atrophy (MSA), intoxication with heavy
metals, treatment with therapeutic drugs (neuroleptics, metoclopramide),
and chronic cerebrovascular disease.
The definitive diagnosis of Parkinson’s disease is based on characteristic neuropathological findings of Lewy bodies and neuronal loss in the
substantia nigra and other brainstem nuclei. Studies have shown that
only 65–75% of patients diagnosed as having early Parkinson’s disease
had the characteristic findings at postmortem.
Current opinion and guidelines recommend that all patients with
a ‘suspected’ diagnosis of IPD must be referred untreated to a specialist
who can reliably differentiate between IPD and other parkinsonian
syndromes.
Previously the response to a ‘challenge’ of levodopa or dopaminergic agents has been used for diagnostic purposes; however the NICE
guidance for Parkinson’s disease does not advocate that this be performed
routinely, although guidelines vary worldwide.
The use of imaging techniques is increasing in this field. Single
photon emission computed tomography (SPECT) with DatSCAN, a radiolabelled cocaine derivative, can be used to measure the amount of
dopamine-releasing neurons in the brain. This type of imaging can aid
differentiation between parkinsonian and non-parkinsonian syndromes,

but it is unable to distinguish between IPD, MSA and PSP.
What biochemical defects are thought to be present in a patient such as
Mr LN?

A3

Several biochemical defects are thought to be present in patients
with Parkinson’s disease.

A combination of cholinergic (excitatory) and dopaminergic (inhibitory)
mechanisms acting in the striatal tracts of the basal ganglia of the brain
are thought to be responsible for the smooth control of voluntary movements. Imbalances in the neurotransmitters lead to movement disorders.


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In patients with Parkinson’s disease, dopamine concentrations in the
three major parts of the basal ganglia are reduced to a fraction of normal.
Compensatory mechanisms operate and symptoms are not noted until a
severe loss (80%) of dopaminergic neurons has occurred. The severity of
some symptoms, such as bradykinesia, has been found to correlate with
striatal dopamine levels; however, abnormalities of other neurotransmitters, including norepinephrine (noradrenaline), 5-hydroxytryptamine
(serotonin) and gamma-aminobutyric acid, have also been reported. The
full relevance of these changes is unclear.
Outline a pharmaceutical care plan for Mr LN.

A4

The goals of symptomatic drug treatment are to help the patient
function independently for as long as possible, and to achieve
this with the minimum of adverse effects.

Patients with Parkinson’s disease have a chronic deteriorating condition
which will result in lifelong drug therapy of increasing complexity.
A long-term pharmaceutical care plan would include:
(a)
(b)
(c)
(d)
(e)

(f)

(g)

(h)

Involving Mr LN in the choice of appropriate initial therapy.
Ensuring the development of appropriate treatment outcome
measures and a suitable treatment monitoring programme.
Ensuring that the patient understands the role of drugs in the symptomatic treatment of the disease and their possible adverse effects.
Ensuring that the patient and carers understand the importance of
adherence and timing of drug doses.
Anticipating problems such as the potential for nausea and vomiting with levodopa preparations, and offering appropriate advice on
their prevention.
Counselling the patient and carers about drugs that should be
avoided in Parkinson’s disease. These include medicines which act
as dopamine antagonists, such as metoclopramide and the older

antipsychotics (e.g. chlorpromazine, haloperidol).
As the disease progresses and more drugs are added to the regimen,
medicine taking may become problematic and advice on methods
for improving and maintaining adequate adherence should be given.
As most patients with IPD will be elderly, the general considerations
given to elderly patients should also be applied.

As treatment may continue for many years and become increasingly complex, continuity of pharmaceutical care is an issue and consideration
should be given to a personal, individualised patient record that can be
used by pharmacists at various stages of the disease.


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The Parkinson’s Disease Society (www.parkinsons.org.uk) publishes
a helpful booklet on drug use in IPD which is of value to patients and
carers and can be used as a counselling aid. Patients with IPD now have a
life expectancy near to normal, so treatment, help and support may be
necessary for over 20 years. Non-pharmacological considerations include
education on the disease itself, advice on diet, exercise programmes, and
other areas such as driving, alcohol intake and recreational activities.
Which drugs are usually considered for the initial treatment of patients
with IPD and what are their modes of action?

A5

Initial drug therapy as recommended by NICE guidelines for both
early- and late-onset IPD will usually be chosen from the following: levodopa preparations; a dopamine agonist; or a monoamine

oxidase B inhibitor (MAOBI).

There is still considerable debate about the best initial choice of therapy
for patients with IPD, and also when to start symptomatic treatment.
Most experts now advocate early treatment to provide patients with maximal clinical benefit at the start of their illness. Most Parkinson’s disease
specialists start treatment when a patient’s symptoms begin to interfere
with their lifestyle. What constitutes this will vary from patient to
patient, but may include impairment of activities of daily living, threatened loss of employment, or gait disturbance with a risk of falling.
When a decision is made to initiate treatment the age of the patient,
the degree and type of symptoms and the patient’s expectations will
influence drug choice. Patients should be made aware that drug treatment
can provide symptomatic relief, but that there is at present no way of
halting the progression of the disease. Levodopa is the most effective drug
in the symptomatic management of Parkinson’s disease, and virtually all
patients will experience meaningful benefit; however, it can cause significant short- and long-term adverse effects, and there is a growing body of
evidence and opinion among experts that most patients should initially
be started on a dopamine agonist instead.
The rationale for early use of dopamine agonists is that they provide
similar benefits to levodopa in early disease, but are significantly less
likely to lead to the development of motor complications, particularly
dyskinesias. Studies directly comparing levodopa with the dopamine
agonists ropinirole, pramipexole and cabergoline as initial therapy for
Parkinson’s disease have been published and appear to confirm this
theory. It is thus generally recommended to begin therapy with a
dopamine agonist in patients who require this but who still have relatively mild symptoms. Patients with more severe symptoms, and those


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over 70 (in whom the development of motor complications is less likely),
should probably be started on a levodopa preparation.
Anticholinergic drugs are now rarely used for the treatment of
Parkinson’s disease. They provide some relief of tremor but are of little
value in the treatment of other features, such as rigidity and bradykinesia.
In addition, adverse effects are common. These include peripheral effects
such as dry mouth, blurred vision and constipation, as well as potentially
serious central effects including confusion and hallucinations. Their use
is best reserved for younger patients (under 60), in whom resting tremor
is the predominant feature. Anticholinergic drugs are thought to act
by correcting the relative central cholinergic excess brought about by
dopamine deficiency.
The MAOBIs selegiline and rasagiline selectively inhibit monoamine
oxidase B, one of the enzyme systems which break down dopamine. The
action of endogenous dopamine is thus augmented. Selegiline has a mild
anti-parkinsonian effect and is sometimes used either alone in early
disease, or later to potentiate the action of levodopa preparations. It is
widely believed to possess neuroprotective properties in early disease, but
this has yet to be proved. Selegiline is metabolised to amphetamine
derivatives, so it may have an alerting effect, especially at night, when it
can cause insomnia, vivid dreams and nightmares. Rasagiline, although
very similar in chemical structure, is not metabolised to amphetamine
derivatives and so is potentially free of alerting side-effects.
Dopamine deficiency cannot be rectified by the administration of
dopamine, because dopamine does not cross the blood–brain barrier.
Levodopa does cross the blood–brain barrier and is converted to dopamine in the basal ganglia. Levodopa is thus thought to act primarily by
increasing brain dopamine concentrations. If levodopa is administered
alone, over 95% of a dose is decarboxylated to dopamine peripherally,
which results in reduced amounts being available to cross the blood–

brain barrier and problematic peripheral side-effects such as nausea,
vomiting, and postural hypotension. Levodopa is therefore now almost
always administered with a dopa-decarboxylase inhibitor, either carbidopa
or benserazide. These dopa-decarboxylase inhibitors do not cross the
blood–brain barrier and so smaller daily doses of levodopa can be administered, thereby reducing the incidence of peripheral side-effects.
Levodopa therapy is particularly helpful in controlling symptoms of
bradykinesia or akinesia.


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Do you agree with this choice?

A6

Yes. The choice of initial therapy is based on many different factors that will vary from patient to patient. The use of a dopamine
agonist is indeed appropriate in this situation, as would be the
use of levodopa.

The dopamine agonists can be split into two different categories: ergot
and non-ergot. Ergot-derived dopamine agonists include the older generation products bromocriptine, lisuride, pergolide and cabergoline. Nonergot-derived agonists include the newer agents pramipexole, ropinirole,
and rotigotine.
Use of the ergot-derived agonists has declined considerably over the
last few years as a result of increased concerns about long-term sideeffects, specifically cardiac fibrosis. There are clear monitoring guidelines
for patients who remain on these agents.
Critical appraisal of the literature evaluating the two non-ergotderived oral agonists provides no evidence to prefer one over the other.
Rotigotine, the transdermal patch formulation, although considered less
potent than the other non-ergot-derived dopamine agonists, provides

continuous dopaminergic stimulation (CDS) over a 24-hour period.
Although it is suggested that 24-hour continuous drug release more
closely resembles endogenous dopamine release and may reduce the risk
of motor fluctuations and dyskinesias developing, there are at present no
firm clinical data to support this. Ropinirole XL is also available as a oncedaily preparation, but requires patients to be previously stablised on the
three times a day preparation before switching.
How should Mr LN’s ropinirole therapy be adjusted to optimise his
response?

A7

Like any dopaminergic therapy, ropinirole must be started at a
low dose and increased gradually in order to reduce the incidence
of side-effects and to establish the lowest effective dose.

In order to facilitate gradual up-titration, ropinirole is available as a
‘starter pack’ that contains all the medication required for a stepwise dose
titration over a 4-week period. A ‘follow-on’ pack allows further stepwise
titration over a similar period to a therapeutic dose. This dose can then be
further increased as required and tolerated by the patient.
Rotigotine patches are also available in a starter pack format.
Pramipexole doses are often referred to in both the salt and the base form.
It is important to be aware of this when referring to doses with patients
and other healthcare professionals; however, there are a number of
information materials available to aid patients and reduce confusion.