An 86-year-old man named Mr. BM was prescribed carbamazepine 200 mg twice daily but took the doses only 4 hours apart which caused confusion and difficulty speaking in the afternoon. The doctor reiterates that prescriptions for twice daily medication should specify every 12 hours instead of BID to avoid this issue. Brand vs generic differences in anti-seizure medications can potentially cause problems if not the same formulation. Advice is offered on proper prescription writing including patient name, age, drug name, strength, directions, and refills.

1. Seizures- Convulsions- Epilepsy
Discussion by-
Shivankan Kakkar, MD

2.  Mr BM is an 86 year old man, started on
carbamazepine 200 mg PO BID four days
ago. In the early afternoon, his son visits and
finds him confused, with difficulty speaking.
What happened?
 The son finds out that his father had taken his
medicine twice daily (as prescribed) but the
first one at 8 in the morning and the second
one at 12 in the noon. (4 hour interval)
 It just reiterates the fact that instead of writing
twice daily (BID) in your prescriptions WRITE
every 12 hourly (q12h).
Shivankan Kakkar, MD
2

3. Name of patient, Date of birth or age,
weight
Rx: Name of drug, Strength of drug,
Amount of drug to be dispensed
Sig: Directions to the patient or parent on
how much drug to take and how frequently
Refills
Dispense as Written
Shivankan Kakkar, MD
3

4. •
•
•
•
•
•
Inactivates Na channels
Useful for partial and generalized seizures
Also: bipolar disorder, trigeminal neuralgia
Many, many side effects
Diplopia, ataxia
Low blood counts
• Agranulocytosis
• Aplastic anemia
Shivankan Kakkar, MD
4

5. • Bone marrow suppression
• Anemia, low WBC, low platelets
• Monitor CBC
Liver toxicity
• Monitor LFTs
SIADH (low Na level)
Stevens-Johnson syndrome
Drug blood levels monitored
•
•
•
•
Shivankan Kakkar, MD
5

6. •
•
•
•
•
Rare, life-threatening skin condition
Malaise and fever (URI Sx)
Extensive skin lesions
Skin necrosis and sloughing
Can be triggered by meds, often AEDs
•
•
•
•
Carbamazepine
Ethosuximide
Phenytoin
Lamotrigine
Shivankan Kakkar, MD
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7. Shivankan Kakkar, MD
7

8. • Sudden alteration in behavior
• Due to transient brain pathology
Shivankan Kakkar, MD
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9. • Partial – One discrete part of brain
• Simple partial – No alteration consciousness
• Complex partial – Alteration consciousness
Generalized – Entire brain effected
•
•
•
•
•
Tonic-clonic “Grand mal”
Myotonic
Atonic “Drop seizure”
Absence “Petit mal”
• Secondary generalized
Shivankan Kakkar, MD
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10. Shivankan Kakkar, MD
10

11. Shivankan Kakkar, MD
11

12. Shivankan Kakkar, MD
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13. Genetic: Juvenile myoclonic epilepsy
Metabolic: Hyponatremia, hypernatremia, hypoMg, hypoCa
Infection: Meningoencephalitis
Shivankan Kakkar, MD
13

14. •
•
•
•
•
•
Absence, myoclonic, and grand mal
Common in children
Absence seizures first (~5 years of age)
Myoclonic seizures later (~15 years)
Grand mal seizures soon after
Hallmark:
• Myoclonic jerks on awakening from sleep
• Shock-like, irregular movements of both arms
Shivankan Kakkar, MD
14

15. Shivankan Kakkar, MD
15

16. Shivankan Kakkar, MD
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17. Na Inactivators GABA Activators
•
•
•
•
Phenobarbitone
Tiagabine
Vigabatrin
•
•
•
•
Carbamazepine
Phenytoin
Lamotrigine
Valproic Acid Valproic Acid
Other Mechanisms
•
•
•
•
•
Gabapentin
Topiramate
Ethosuximide
Levetiracetam
Primidone
Shivankan Kakkar, MD
17

18. Shivankan Kakkar, MD
18
MoA

19. Shivankan Kakkar, MD
19

20. Shivankan Kakkar, MD
20

21. Shivankan Kakkar, MD
21

22. • First line treatment is benzodiazepines
• Rapid acting
Lorazepam drug of choice
Also often administer:
•
•
•
•
If
Phenytoin (PO) or fosphenytoin (IV)
Prevent recurrent seizures
still seizing after benzo/phenytoin -
•
•
phenobarbital
Often will then give general anesthesia and intubuate
Shivankan Kakkar, MD
22

23. • Status Epilepticus
• Benzodiazepines
• Absence seizures
• Ethosuximide
Shivankan Kakkar, MD
23

24. •
•
•
•
•
Pregnancy related condition
20weeks to 6weeks post-partum
Hypertension, proteinuria, edema = Preeclampsia
Eclampsia = preeclampsia + seizures
Treatment: MgSO4
Shivankan Kakkar, MD
24

25. • All AEDs carry risk if taken during pregnancy
• Valproic Acid carries the greatest risk
• Most teratogenic
• 1-3% chance of neural tube defects
Shivankan Kakkar, MD
25

26. •
•
•
•
•
Intracellular enzymes
Metabolize many drugs
If inhibited - drug levels rise
If induced - drug levels fall
AEDs that induce CYP450
•
•
•
Carbamazepine
Phenobarbital
Phenytoin
Shivankan Kakkar, MD
26

27. • Inhibitors are more dangerous
• Can cause drug levels to rise
• Cyclosporine, some macrolides, azole antifungals
Luckily, many P450 metabolized drugs rarely used
• Theophylline, Cisapride, Terfenadine
Some clinically relevant possibilities
• Some statins + Inhibitor - Rhabdo
• Warfarin
•
•
Shivankan Kakkar, MD
27

28. Some Examples
Inducers
Chronic Ethanol
Rifampin
Phenobarbitone
Carbamazepine
Griseofulvin
Phenytoin
Inhibitors
Isoniazid
Erythromycin
Cimetidine
Azoles
Grapefruit juice
Ritonavir (HIV)
•
•
•
•
•
•
•
•
•
•
•
•
Shivankan Kakkar, MD
28

29. •
•
•
•
•
•
•
•
•
Inactivates Na channels
Very useful tonic-clonic seizures
Gingival hyperplasia, hair growth
Rash
Folic acid depletion (supplement)
Decreased bone density
Gingival Hyperplasia
Long term use: nystagmus,
Teratogenic
Monitor blood levels
diplopia, ataxia
Shivankan Kakkar, MD
29

30. Shivankan Kakkar, MD
30

31. Shivankan Kakkar, MD
31

32. • Na and GABA effects
• ↑synthesis, ↓breakdown GABA
Also a mood stabilizer (bipolar
BAD for pregnancy
• Associated with spina bifida
Nausea / vomiting
Hepatotoxic – Check
LFTs Tremor, weight gain
•
•
disorder, acute mania)
•
•
•
Shivankan Kakkar, MD
32

33.  Day 1 Ms SB, a 21-year-old student who had recently moved away
from home town to college, was witnessed ‘having a fit’ by her
friends and was taken to the local hospital. The fit had stopped by
the time she arrived and Ms SB had no recollection of the event. She
was sent home from hospital with paracetamol for the resulting
headache, and referred to 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 college life quite
stressful. She admitted 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). Ms SB was prescribed lamotrigine 25 mg once
daily, increasing to 50 mg once daily after 14 days.
Shivankan Kakkar, MD
33

34. Q1 What is epilepsy?
Q2 Is the history of stress significant?
Q3 Do you agree with the choice of lamotrigine for Ms SB?
Q4 Is the dose of lamotrigine appropriate?
Q5 Outline a treatment care plan for Ms SB. What advice would you offer her if she asked about
contraception?
Month 3 Ms SB presented a prescription for lamotrigine. Her dose was now
50 mg in the morning and 50 mg at night. On receiving the prescription
Ms SB 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 a different brand.
Q6 Is there a significant difference between the different brands of antiepileptic drugs (AEDs)?
Month 4 Ms SB 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.
Detailed Discussion on the
Given Long Case
Shivankan Kakkar, MD
34

35. Q7 Is the choice of ciprofloxacin appropriate?
Month 5 The lamotrigine dose had been slowly titrated up to 150 mg twice daily but Ms SB 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.
Q8 What term is used to describe epilepsy that worsens around the time of menstruation, and how common is it?
Q9 What drug treatments are available for this form of epilepsy?
After discussion with Ms SB and her epilepsy, 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 increase the dose further 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.
Q10 Levetiracetam is not licensed as a monotherapy for generalised seizures. What is your opinion of the neurologist’s
choice?
Q11 Levetiracetam is one of the newer AEDs. What are the advantages of the newer drugs over the older ones?
Month 8 Unfortunately, Ms SB had had to withdraw from her college 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.
Q12 What advice can you offer about St John’s wort?
Q13 If indicated, what is the appropriate drug treatment for depression in people with epilepsy?
Month 10 Ms SB 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
than5 minutes.
Shivankan Kakkar, MD
35

36. Q14 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. Ms SB had started a career in banking. She and her husband had discussed
starting a family and wanted to know more about how Ms SB’s epilepsy would affect this.
Q15 What are the issues concerning pregnancy in women with epilepsy?
Q16 What drug should epileptic women who wish to become pregnant take, and at what dose?
Answers
A1
What is epilepsy?
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:
 Generalised seizures are a result of electrical activity spreading through the entire cerebral cortex.
They can be secondary to a partial seizure or a primary seizure type. 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).
Shivankan Kakkar, MD
36

37. 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. An accurate diagnosis is essential to ensure patients are offered the
correct drug treatment.
A2
A3
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 primary generalised epilepsy and is one of the
most common epilepsy syndromes. It is characterised by myoclonic jerks and, in many people,
generalised tonic– clonic seizures, often shortly after waking. Patients with JME may also experience
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?
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, pseudo- seizures, functional seizures or non-organic seizures, and although they can look
very much like epileptic seizures, during an attack an electro- encephalogram (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 to get an accurate diagnosis.
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 MsSB?
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:
Shivankan Kakkar, MD
37

38. (a) Teratogenicity: There is a high major congenital malformation rate in babies born to mothers treated
with sodium valproate during pregnancy. This risk is likely to be dose-related, increasing as the
exposure dose increases.
(b) 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 trial comparing the long-term outcomes
of the newer AEDs with 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 preventive 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. Ms SB’s history indicates she had already experienced absence and myoclonic
seizures prior to her presentation at the local hospital. 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 recommended 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 enzyme- inducing 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.
Shivankan Kakkar, MD
38

39. A 5
Outline a treatment plan for Ms SB. What advice would you offer her if she asked about contraception?
The plan should ensure that her treatment is prescribed at an appropriate dose, monitored
correctly, and that Ms SB receives all the information she needs about her treatment. Checks
should be made on whether Ms SB is taking any other medicines, particularly oral
contraception.
Before offering specific counselling to Ms SB it is important to check whether or not she is taking any other
medication. Concomitant therapy may affect the starting dose of lamotrigine.
(a) 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) Response to treatment: patients may keep a seizure diary.
(ii) For adverse effects, especially rash.
Women taking oral contraception should be advised to report any breakthrough vaginal bleeding,
as this suggests contraception is inadequate.
(b) Contraception. Although lamotrigine is not an enzyme-inducing drug, evidence suggests it can
reduce levels of levonorgestrel, although the effects on contraceptive efficacy are unknown. In
addition, combined oral contraceptives can reduce lamotrigine levels. There is general advice that
women’s contraceptive needs should be reviewed if lamotrigine is to be prescribed and combined
hormonal contraception may not be appropriate due to the issues of fluctuating lamotrigine levels.
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. Where other
contraceptive methods are not suitable the following recommendations are made for oral
contraception in women taking enzyme- inducing AEDs:
(i) Enzyme-inducing AEDs are likely to render progesterone-only contraceptives ineffective.
(ii) Women wishing to take combined oral contraceptives should start on a daily ethinylestradiol
dosage of at least 50 micro- grams.
Shivankan Kakkar, MD
39

40. (c) General counselling points that should be covered with Ms SB
include:
(ii)
(iii)
(iv)
(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.
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.
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 rare 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 potentialneutropenia).
Ms SB needs to ensure her medication does not run out and that doses are not missed, and needs
to know where to get further supplies. 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 postmortem. The exact cause
of SUDEP is not yet known.
A 6
Is there a significant difference between the different brands of antiepileptic drugs (AEDs)?
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. Ms SB should be informed of
the issues so that she can make an informed decision about whether she wishes to receive a
different brand of lamotrigine tablets.
In practice, consistent supply of a particular generic formulation can be difficult: brand prescribing is
often perceived as the best way to ensure consistent supply of AEDs.
Shivankan Kakkar, MD
40

41. Many of the older AEDs, such as carbamazepine and phenobarbital, have narrow therapeutic
indices. This means that small changes in drug levels resulting from changing to formulations with
differing bioavailabilities may result in side-effects or loss, or worsening, of seizure control.
The newer AEDs generally have more predictable pharmacokinetics and broader therapeutic
indices but still, small changes in drug levels may result in similar consequences.
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 ones: they represent the 90% confidence intervals when calculating the ratios of
pharmacokinetic parameters between the generic and the branded medicinal product.
A7
Is the choice of ciprofloxacin appropriate?
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-aminobutyric acid (GABA).
A macrolide antibiotic would be appropriate for Ms SB. 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.
A8
What term is used to describe epilepsy that worsens around the time of menstruation, and how common is it?
Catamenial epilepsy affects approximately 10% of women of childbearingage.
The definition of catamenial epilepsy is not an exact one, but around 10% of women with epilepsy
experience a worsening of seizures around the 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
Shivankan Kakkar, MD
41

42. A9
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?
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.
A 10
Levetiracetam is not licensed as a monotherapy for generalised seizures. What is your opinion of the
neurologist’s choice?
AEDs are sometimes prescribed as evidence-based treatments, and levetiracetam
monotherapy is a reasonable choice for Ms SB.
The use of levetiracetam as monotherapy is reasonable in this patient. Sodium valproate is not an ideal
therapeutic option because of its adverse effect profile and teratogenicity risk. Carbamazepine can
exacerbate myoclonic and absence seizures. Topiramate and zonisamide are other therapeutic options for
JME.
Levetiracetam is one of the newer AEDs. What are the advantages of the newer drugs over the older ones?
A 11 The newer AEDs include levetiracetam, oxcarbazepine, pregabalin, topiramate,
zonisamide,
lacosamide, rufinamide, eslicar- bazepine and retigabine. The properties of each drug should
be checked individually, but generally, the newer AEDs have advantages over the older AEDs,
including:
(a) Linear pharmacokinetics which provide a more predicable dose– responserelationship.
(b) Low protein binding, hence less potential to displace and be displaced by other drugs.
(c) Metabolism independent of the cytochrome P450 system, thus reducing drug
interactions, particularly with oral contra- ceptives.
Shivankan Kakkar, MD
42

43. (d) A wider therapeutic index.
(e) More acceptable side-effect profiles.
Newer AEDs are invariably more expensive than older agents but the decision when to start AED therapy
and which agent to use is an individual one, taking into account the age and sex of the patient, childbearing
potential, comorbidities and concomitant medication. These factors may outweigh the financial arguments
against newer AED use.
A12
What advice can you offer about St John’s wort?
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.
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 neurones. There are case reports of reduced efficacy when St John’s wort has
been added to AEDs not metabolised by cytochrome P450.
Ms SB should thus be advised to avoid it, even though there is no direct interaction between this
product and her prescribed therapy.
A13
If indicated, what is the appropriate drug treatment for depression in people with epilepsy?
The tricyclic and selective serotonin reuptake inhibitor (SSRI) antidepressants all have the
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, although there are recent concerns about its potential to cause QT
interval prolongation.
Shivankan Kakkar, MD
43

44. Recent evidence has shown a small increased risk of suicide with AEDs. Patients need to be aware of this
and know to seek medical advice if they develop mood changes or suicidal thoughts.
A14
What are the advantages and disadvantages of using buccal midazolam over rectal diazepam?
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. In NICE guidelines,
buccal midazolam is now the parenteral benzodiazepine of choice for the termination of
prolonged or repeated seizures in the community.
Midazolam is sufficiently lipophilic at physiological pH to cross the buccal mucosa rapidly.
Controlled trials, mainly in children and adolescents with severe epilepsy, have shown buccal
midazolam to be at least as effective as rectal diazepam in terminating epileptic seizures.
An important counselling point is to administer the drug buccally: oral administration would put a
fitting patient at risk of choking. 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. A written care plan is usually provided for the patient’s carers.
What are the issues concerning pregnancy in women with epilepsy?
There are several issues for women with epilepsy wishing to becomepregnant.
(a) 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.
(b) Teratogenicity of AEDs. In utero exposure to AEDs is associated with a higher risk of congenital
malformations.
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. In 2006 data were
published on pregnancy outcomes with in utero exposure to levetiracetam. Although no congenital
malformations were reported
A15
Shivankan Kakkar, MD
44

45. from monotherapy, it is too early to assess accurately the relative safety of levetiracetam in pregnancy.
(c) 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.
A16
What drug should epileptic women who wish to become pregnant take, and at what dose?
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 until at least the end of
the first trimester of 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.
MEMORIZE-RECALL-REINFORCE
Shivankan Kakkar, MD
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