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.
Local drug delivery
Direct delivery of drugs into the epileptogenic brain tissue holds promise, particularly for patients whose foci cannot be surgically removed. By bypassing the systemic circulation, this approach has the potential to avoid systemic and even whole-brain side effects.
However, only a few proof-of-principle experiments have been conducted in animals, and to date no clinical study has explored the utility of intraparenchymal or intraventricular antiepileptic drug delivery in humans.
Cell and gene therapies
The emerging field of experimental cell- and gene-based neuropharmacology holds promise for location-specific therapeutic strategies. In ex vivo gene therapy, bioengineered cells capable of delivering anticonvulsant compounds might be transplanted into specific areas of the brain. On the other hand, in vivo gene therapy would involve delivering genes by viral vectors to induce the localized production of antiepileptic compounds in situ.
Endogenous anticonvulsants such as gamma-aminobutyric acid (GABA) and adenosine have been tried in various animal experiments. 49 Before they can be applied clinically, significant questions need to be addressed, including the potential for toxicity or maladaptive plasticity and long-term therapeutic safety and efficacy.
Cell transplantation is aimed at restoring the physiologic balance of neurotransmitters, and is currently being investigated for the treatment of several neurologic disorders such as Parkinson disease and Huntington disease.50 Unlike delivery of exogenous compounds, cell transplantation (heterologous fetal cell grafts or embryonic or adult stem cells) has the potential to form restorative synaptic connections and assimilate within existing cells and networks in the host tissue. An essential limitation to xenotransplantation in humans is the risk of immunologic rejection.
The future
We hope that continued progress in genomics will lead to targeted development of disease-modifying drugs that can impede or reverse the process of epileptogenesis. Advances in informatics and genetics may be harnessed to predict which patients are likely to develop pharmacoresistance, to cure certain genetic epilepsies, and to individualize antiepileptic drug selection on the basis of each person’s genetic profile.
