Page 133 - ILAE_Lectures_2015

Monotherapy
Satisfactory seizure control with monotherapy is the desired aim in the treatment of the
epilepsies, and naturally IGE is not an exception. Any of the three first-line drugs can be
initiated and lack of effectiveness should not be assumed before ensuring that the maximum
tolerated dose has been achieved. If monotherapy with a particular agent finally fails, or
unacceptable adverse reactions appear, substitution with one of the other drugs is the next step.

Sodium valproate is the most effective drug in the treatment of all types of generalised seizures
with 75% of patients becoming seizure-free on monotherapy. It is used by most physicians not
only as first choice for monotherapy irrespective of absence syndrome, but also as a solid basis
for adjunctive therapy53,54 (Table 3). In addition, sodium valproate prevents the recurrence of
absence status55, is effective in myoclonic absences56, which are particularly difficult to treat,
and can abolish photosensitivity. There are anecdotal reports where children may not respond
to the syrup form, despite adequate levels, but do so with sodium valproate tablets. Common
adverse effects include nausea, vomiting, dyspepsia, gain in bodyweight, tremor, transient hair
loss and haematological abnormalities. The latter, even when highly clinically significant, can
be reversible following dosage reduction; discontinuation is rarely required57. Behavioural and
cognitive abnormalities, and acute liver necrosis58 and pancreatitis, that may be fatal and more
likely to occur in children on polypharmacy, are rare. However, the main factors that hamper
its use, mainly in women59, include an estimated risk of 1–2% for neural tube defects,
predominantly spina bifida aperta, in pregnancy (background population risk 0.2–0.5%),
which may increase when the drug is combined with benzodiazepines60, the as yet unresolved
question of polycystic ovarian syndrome61-63 and other endocrine side effects, and hair loss.
Occasional worsening of TA with sodium valproate has been reported64.

Ethosuximide is effective in TA, nearly as much as sodium valproate65, but does not protect
against GTCS and myoclonic seizures (Table 3). Therefore, while ethosuximide might be a
reasonable choice in a young child with CAE, it is not recommended as a first-line choice in an
older child with possible JAE (due to the much higher chance of developing CTCS), and in
JME. Common adverse effects are usually dose-related and include gastrointestinal
disturbances, anorexia, weight loss, drowsiness, photophobia and headache. Behaviour and
psychotic disturbances may occur. Aplastic anaemia, Stevens-Johnson syndrome, renal and
hepatic impairment are rare but life threatening.

Lamotrigine controls TA and GTCS66,67, but its effect on MS is unpredictable (Table 3), and
exacerbation of JME has been reported with lamotrigine68. Lamotrigine monotherapy may be
tried in women, particularly those that may be more vulnerable to side effects of sodium
valproate. Dose escalation should be gradual: in adults and children over 12 years initial dose is
25 mg daily for two weeks, followed by 50 mg daily for two weeks. Maintenance dose is 100–
200 mg/day in two divided doses, but can be increased to 400 mg per day in the absence of a
satisfactory response. In younger children, and in accordance with the recommendations
regarding add-on lamotrigine in this age group, the initial dose is 0.3 mg/kg bodyweight/day
daily for two weeks, followed by 0.6 mg/kg/day daily for two weeks. Maximum escalation
should not exceed 0.6 mg/kg every 1–2 weeks until optimal response. Maintenance dose usually
ranges between 2.5 and 7 mg/kg/day given in one or two divided doses, but can reach 10
mg/kg/day if lamotrigine is not combined with sodium valproate. This gradual initial dose
titration reduces the risk of allergic skin rash, which is higher when the drug is prescribed in
combination sodium valproate which inhibits lamotrigine metabolism. Skin rash occurs in
approximately 10% of patients, usually in the first eight weeks, and prompts discontinuation of
the drug. Serious rashes leading to hospitalisation, including Stevens-Johnson syndrome and
hypersensitivity syndrome, occur in approximately one in 300 adults and one in 100
children67,69. Other common side effects include headache, nausea, diplopia, dizziness, ataxia
and tremor.