Pharmacoresistant epilepsy: From pathogenesis to current and emerging therapies
ABSTRACTAlmost one-third of people with epilepsy continue to have seizures despite appropriate antiepileptic drug treatment, placing them at considerable risk of cognitive and psychosocial dysfunction and death. We recommend early referral to an epilepsy center when seizures are difficult to control.
KEY POINTS
- When seizures have failed to respond to two or three appropriate antiepileptic drugs, the chance of significant benefit from other drugs is 10% or less.
- The biologic basis of pharmacoresistance is multifactorial and varies from one patient to another.
- Social and lifestyle factors, including alcohol misuse and nonadherence to prescribed antiepileptic drugs, can contribute to or masquerade as pharmacoresistance.
- Current options for patients with pharmacoresistant epilepsy are surgery (the best option when feasible), vagus nerve stimulation, investigational drugs or devices, and aggressive combination treatment with available antiepileptic drugs.
Factors related to the disease (independent of the host)
These factors include etiology, epilepsy progression resulting in persistent changes of the epileptogenic network, and alterations of drug targets (ie, the “target” or pharmacodynamic hypothesis that reduced sensitivity to antiepileptic drugs is due to seizure-related alterations of specific drug targets25,26) or drug uptake into the brain27 (the “transporter” or pharmacokinetic hypothesis that the drugs are ineffective due to intrinsic or acquired overexpression of multidrug transporter proteins that hamper local drug delivery to target sites).28
Factors related to the drugs
Several drug-related factors have been implicated, such as the development of tolerance, lack of antiepileptogenic (disease-modifying) actions to interrupt the ongoing process of epileptogenesis rather than only suppressing seizures, and paucity of drugs with specific mechanisms of action tailored to difficult-tocontrol epilepsies.29
Patient characteristics
Variability in response (efficacy and adverse effects) to each antiepileptic drug can be due to interindividual differences in any of four interrelated fundamental factors: DNA, RNA, proteins, or metabolites. The field of study that aims to assess the effect of DNA variations (genotype) on a patient’s clinical response to a drug (phenotype) is known as pharmacogenetics. Age-related changes in pharmacokinetic and pharmacodynamic variables may contribute to age-dependent pharmacoresistance. Least studied are environmental factors that may play a role in the development or expression of pharmacoresistance.
NONPHARMACOLOGIC TREATMENTS
Ketogenic diet
The ketogenic diet, an important nonpharmacologic alternative, is usually reserved for young patients with difficult-to-control seizures. Originally developed almost a century ago, the diet mimics the biochemical changes associated with starvation. It is a strict regimen, high in fat and low in carbohydrate and protein (typically in a ratio of 4:1 or 3:1 in adolescents and very young children).
Such a strict regimen is difficult to implement and maintain and requires close supervision by a dietician and physician. In addition to the practical complexities, concerns also exist about the long-term effects of the diet on the child’s growth and overall health. For these reasons, the ketogenic diet is restricted to a small group of young patients with pharmacoresistant epilepsy and is not usually used long-term. There are few data indicating when it is appropriate to terminate the diet in patients who have a favorable response, but most clinicians wean the patient after 2 to 3 years.
Reports on the use of the ketogenic diet in adults are scarce, although benefit was seen in a small series.30 No long-term follow-up data exist for adults, especially regarding the risk of atherosclerosis.
Vagus nerve stimulation
Vagus nerve stimulation is a nonpharmacologic alternative for adults and for adolescents over age 12 years who have intractable focal seizures and who are not favorable surgical candidates. 31 Its effectiveness in younger patients and in those who have intractable generalized seizures is less clear, although published uncontrolled series have reported benefit (fewer seizures and better quality of life).32–34
A device consisting of a pulse generator is implanted subcutaneously in the precordium, and a lead wire is tunneled under the skin and attached to the left vagus nerve. The generator is programmed using a telemetry wand held over the device, with settings for current intensity (typically 1–2 mA), pulse width (250–300 μsec), frequency (30 Hz), and “duty cycle” (typically 30 seconds on stimulation, followed by 3 to 5 minutes off, cycling 24 hours/day). Hence, it provides “open-loop stimulation,” ie, continuous stimulation that is not modified in response to the patient’s EEG seizure activity. Patients or caregivers can also activate the device manually (“on demand”) at the first sign or warning of an impending seizure by swiping a handheld magnet.
Common side effects such as cough, voice alteration, and hoarseness are usually stimulation-dependent and tend to diminish with time. Notably, vagus nerve stimulation has none of the cognitive side effects often encountered with increasing doses of antiepileptic drugs. As with other implantable stimulators, some safety concerns exist in patients undergoing magnetic resonance imaging (MRI).
At least one-third of patients who receive this treatment show a sustained response, defined as a 50% or greater reduction in seizures. However, few achieve freedom from seizures, and therefore this therapy is considered palliative and is reserved for patients who are not candidates for surgery or for whom surgery has failed.
Unfortunately, it has not been possible to predict which patients will benefit from vagus nerve stimulation. The American Academy of Neurology recommends that this treatment be considered only after a thorough evaluation by a subspecialist to rule out nonepileptic conditions, false pharmacoresistance, and surgically treatable types of epilepsy.31
IS THE PATIENT A CANDIDATE FOR EPILEPSY SURGERY?
- Is the epilepsy diagnosis correct?
- Is the epilepsy focal? Have the following possibilities been excluded: generalized or multifocal epilepsy, situational or provoked seizures, or an epilepsy syndrome with spontaneous remission?
- Do seizures remain poorly controlled despite adequate pharmacologic trials?
- If so, do the seizures or medication side effects significantly affect the patient’s quality of life?
- Can an epileptogenic lesion be seen on MRI, and what is the suspected etiology?
- Is there converging evidence for a single epileptogenic focus?
- Are there abnormalities elsewhere in the brain?
- What are the chances of a good outcome in terms of seizure control and improvement in quality of life?
- What are the risks of surgery, and how do these compare with the risks of not having surgery?
- What are the patient’s perceptions and attitudes toward epilepsy surgery?
Surgical recommendations should be made after a thorough discussion of all preoperative data in a multidisciplinary patient management conference (Figure 1, Figure 2), in which epileptologists, neurosurgeons, neuroradiologists, neuropsychologists, and psychiatrists all actively participate.
Preoperative counseling is essential for the patient and his or her family, addressing the goals, risks, and benefits of the surgery. Treatment decisions should take into account the possible impact of surgery on the patient’s medical and psychosocial circumstances (risks of ongoing seizures vs surgical intervention; impact on the patient’s independence, employment status, emotional well-being, and psychiatric and other comorbidities).
