Introduction
Epilepsy is generally deemed intractable or refractory
to treatment if the use of two or more appropriately
chosen antiepileptic drugs (AEDs) fails to adequately
control seizures. The AEDs in question must be at the
maximum tolerated doses, at a sufficient therapeu-tic level and not be discontinued due to side effects.
A less commonly used definition of intractability
requires monthly seizures for a period of 18 months.1
Despite optimal medical management with appropri-ate AEDs, 20%–30% of adults and 10%–40% of chil-dren diagnosed with epilepsy continue to suffer from
seizures.
2–8
Furthermore, after the failure in efficacy
of two AEDs, the chance of achieving seizure free-dom by introducing subsequent drug regimens has
been shown to be less than 10%.
2,8–12
Intractable epilepsy is a significant problem for
the quality of life (QOL) of the individual patients.
Persistent seizures heavily impact on the patients’
behavior, cognitive ability and psychosocial
well- being. It has been shown that this condition
can lead to poor academic achievements, increased
probability of unemployment, low self-esteem, anxi-ety and depression, social isolation and ultimately to
decreased quality of life.
13,14
In addition, the unre-mitting seizures can pose a significant financial
burden, with patients suffering from poor seizure
control reported to represent approximately 25% of
epilepsy cases but accounting for greater than 85%
of epilepsy associated costs, mainly due to repeated
hospital admissions and extensive investigations.
15
Further to the financial burden, patients with refrac-tory seizures have higher mortality rate than patients
whose seizures are well-controlled, who have mor-tality rates comparable to the general population.
16
This is likely to be due to differences in the under-lying etiology rather than the effect of seizures “per
se”. Patients with refractory seizures have higher
rates of structural abnormalities or inborn errors of
metabolism (IEM). In addition, sudden unexpected
death in epilepsy (SUDEP) is forty times more com-mon in patients who continue to suffer from seizures
compared to patients who are seizure free.
17
The number of new AEDs has significantly
increased in the last 20 years, effectively doubling the
number of anticonvulsants available for physicians to
prescribe. Whilst the efficacy of new molecules in
controlling seizures has not dramatically increased,
safety and tolerability profiles are significantly better
than for the older AEDs. Many of the new drugs
have novel mechanisms of action and exhibit fewer
drug-interactions.
When considering the most appropriate choice
of treatment, it is essential to be confident about the
diagnosis and underlying etiology. This is of particu-lar importance in children with refractory epilepsy,
a large proportion of whom present specific age-dependent epilepsy syndromes. Accurate identifica-tion of the epilepsy syndrome is the foundation for the
choice of an appropriate treatment and increases the
likelihood of seizure remission.
18
In some instances,
identifying etiologies can radically alter the potential
treatment options, for example metabolic treatments
such as the ketogenic diet for epilepsies resulting
from IEM.
19
Surgery may be the most appropriate
treatment option in some cases, especially where
strong evidence exists for its efficacy, such as for the
anterior temporal lobectomy in drug-resistant tem-poral lobe epilepsy.
20
However, the most appropriate
timing for surgery remains debated. When surgery
is not a suitable treatment option, neurostimulation
therapies such as vagus nerve stimulation (VNS) may
be considered.
This review will outline the evidence for the use of
different treatment options for patients with intracta-ble seizures. Whilst the focus will be on the pharma-cological options, we will also review the extent and
quality of evidence supporting the efficacy of surgi-cal, metabolic, neurostimulatory and herbal interven-tions in the context of the associated side-effects,
safety and patient preferences. When appropriate, the
costs of the interventions will also be discussed.