**2. Background and definition of drug-resistant epilepsy (DRE)**

Patients with epilepsy whose seizures do not respond successfully to antiepileptic drug (AED) therapy are considered to have drug-resistant epilepsy (DRE). The prior equivalent term included medically intractable epilepsy or pharmaresistant epilepsy. This group of patient have the greatest burden of epilepsy related disabilities, and also added the significantly the healthcare resources expenses.

In 2010, a consensus proposal from task force of the International League Against Epilepsy (ILAE) commission on therapeutic strategies. A framework comprises two "hierarchical" levels is proposed for definition of drug-resistant epilepsy (DRE). Level 1 is categorization of outcome to a therapeutic intervention and level 2 is core definition of DRE based on how many "informative" trials of antiepileptic drugs (AEDs) resulted in a "treatment failure" outcome. The definition of DRE usually requires failure of two adequate trials of appropriately chosen and administered antiepileptic drugs (be it sequential monotherapy or combined polytherapy) [1]. It is also important to include the impact of seizure factors (frequency, severity, associated behavioural problem) on individual psychosocial wellbeing. Such impact will lead to the physicians' decision on drug options and the urgency of considering non-medical therapies.

Other important areas in the clinical assessment of DRE include the following.

#### **2.1 The epidemiology**

The prevalence of epilepsy patients aged 15 years or over in Chinese communities has been estimated at about 3–5.7 per 1000 [2], and about 40,000 Hong Kong people could be expected to have active epilepsy. The cumulative probability of a second attack at 1, 2, and 3 years was 30, 37 and 42% respectively. DRE comprised about one third of all epilepsy patients. A more recent study in 2008 showed the crude prevalence of active epilepsy and seizure disorder were estimated to be 3.94/1000. So the cases that should have under tertiary care for consideration of intensive work up will be around 1000 cases annually. There existed a treatment or referral gap of 20 years in the United States for this group of patient [3, 4]. It is foreseen that the local condition will be similar and an unmet need should call for more escalated awareness.

#### **2.2 The pathogenesis**

Prospective studies with chronic epilepsy patients suggested that 70–80% of patients retain their status as intractable versus in remission [5]. In other words, a minority, around 20% of initial intractable seizure cases will archive seizure freedom in long run and vice versa. Postulated mechanism leading to intractability includes glial proliferation and dendritic sprouting with synaptic recognition [6] in mesial temporal sclerosis. The concept of paroxysmal depolarization shift (PDS) is cellular events in which rapidly repetitive action potentials are not followed by the usual refractory period, thereby generating a prolonged membrane depolarization. Repetitive neuronal firing probably underlies the interictal and ictal unit and local field recording of high frequency oscillations (HFO).

Another compelling theory is the build-up of epileptic "neuronal network" (NN), via alternation in neuronal circuitry [7, 8]. A well-defined NN example is the limbic network with sequential propagation path via hippocampus, amygdala, lateral temporal neocortex and entorhinal cortex, medial thalamus and frontal inferior lobes. The interest on neuronal network analysis in epilepsy had gained strength with the use of high resolution recording techniques. Seizures start in a well-defined brain area and spread at great speed to connected brain area recruiting specific neuronal networks into typical oscillatory behaviour. Therefore, epilepsies should be considered as resulting from disturbed network interactions that implies "multi-targeted treatments" [9–13].
