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In patients with refractory epilepsy, potential efficacy in controlling seizures is not the only
consideration in choosing AEDs. In many cases, adverse effects from AEDs impair patients’
quality of life more than seizures themselves12. It is therefore important to discuss with
patients the most common, as well as most serious, adverse effects reported with any AED
before commencing treatment. In addition, many co-morbidities of epilepsy can be affected
by AEDs (e.g. cognition, mood, bone health), which will need to be taken into account when
deciding on an AED.

Many patients with refractory epilepsy will be on combinations of AEDs. There is little
empirical evidence to guide the choice of combination therapy. In the absence of evidence,
the notion of ‘rational polytherapy’ has gained currency13. This is based on the mechanism
of action (MoA) of AEDs (or more precisely their molecular pharmacological effects –
whether this is the same as the mechanism of anti-seizure activity in all cases is a moot point),
and involves combining drugs that have differing MoA, while avoiding those that have the
same or similar MoA. There is some evidence that this approach reduces the incidence of
neurotoxic side effects 14. The combination of valproate with lamotrigine can be synergistic,
which can translate into greater efficacy, as well as greater potential for adverse effects.
However, a number of other factors including patient preference may be more important than
molecular pharmacology in determining the efficacy of combinations. Clinical pragmatism
is likely to be a more successful basis for choosing AED combinations than the dogma of
mechanistic rationalism.

Non pharmacological treatments

All patients with refractory epilepsy should be reviewed in a specialist service to consider
suitability for non-pharmacological treatments, including epilepsy surgery. This cannot be
assessed without expert review of seizure semiology, epilepsy classification and imaging.
This is discussed in detail elsewhere in this textbook.

Neuromodulation is an option for patients with refractory epilepsy who are not candidates for
resective surgery. Vagal nerve stimulation remains the most widely used modality, and can
help reduce seizure frequency in a proportion of patients with refractory epilepsy. Deep brain
stimulation (targeting the anterior nucleus of the thalamus) has been licensed as a therapeutic
option for patients with epilepsy in the UK. Closed-loop responsive neurostimulation (RNS)
systems are also on the horizon15. There is likely to be further refinement in the techniques
of neurostimulation in the years ahead.

Address co-morbidities

Depression and anxiety
Depression is the most common co-morbidity of epilepsy, with a lifetime incidence of up to
35%. There is a growing body of evidence to suggest an organic link between temporal lobe
seizures and depression16. Patients with temporal lobe epilepsy are particularly at risk of
dysphoric disorders, including suicidality. Data from outcome studies also show worse
outcomes from medical and surgical treatment for epilepsy in patients with depression.
Depression significantly impairs patients’ quality of life, and is often untreated in patients
with epilepsy due to the erroneous belief among non-specialists that antidepressants of the
SSRI or TCA classes adversely affect seizure control17. Neurologists should take
responsibility for managing much of the psychiatric co-morbidity of epilepsy as the reality,
all too frequently, is that no one else will.

Cognition
Cognitive disorders frequently coexist with epilepsy, and can impair patients’ ability to
function normally, even when the seizure burden is reduced. These are frequently due to the