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.
EPILEPSY SURGERY: CURATIVE OR PALLIATIVE
Epilepsy surgery can be classified as curative or palliative, depending on the goal.
Curative procedures
Curative procedures include lobectomy, lesionectomy, and multilobar or hemispheric surgery (hemispherectomy).
Anterior temporal lobectomy and hippocampectomy are used for temporal lobe epilepsy and have several variations.
“Mesial temporal lobe epilepsy associated with hippocampal sclerosis,” a recognizable syndrome with complex partial seizures, stereotyped electroclinical features, and fairly typical natural history, is the most common of the focal epilepsies in adults.36 Its prognosis is poor when treated medically, but it responds well to surgery.37,38 In a landmark prospective trial, 58% of 40 patients randomized to surgical treatment were free of disabling seizures after 1 year, compared with only 8% of 40 patients treated medically.39
Lesionectomy and lobectomy are resective approaches targeting seizure foci outside the temporal lobe (most often in the frontal lobe, less commonly in the parietal or occipital lobes) or within the temporal lobe but outside the hippocampus (neocortical temporal lobe epilepsies).
The nature of the underlying substrate plays a significant role in determining the natural history,40 surgical strategy, and prognosis for freedom from seizures postoperatively. Patients with seizures due to structural lesions that are visible on MRI (“lesional epilepsies,” eg, cavernous angiomas or circumscribed lowgrade tumors) may become seizure-free after limited resections targeting the lesion itself (lesionectomy) or extending to involve part of a lobe or an entire lobe (lobectomy).
A favorable surgical outcome is much more likely if the lesion can be completely removed.41 At times, however, the lesion cannot be resected in its entirety, for example if it is located within inaccessible or essential (eloquent) cortex.
On the other hand, identifying the epileptogenic focus in patients with no visible structural abnormality on MRI (“nonlesional epilepsies”) can be challenging and usually requires intracranial investigations. In this instance, the aim of surgery is to resect regions that are electrographically abnormal. In general, the postoperative outcome is less favorable in nonlesional focal epilepsies than in lesional epilepsies.42
Multilobar resections and hemispherectomy are indicated when seizures arise from extensive, diffuse, or multiple regions of a single hemisphere.
If the neurologic function supported by the abnormal hemisphere is intact, a tailored multilobar resection aims at eliminating the epileptogenic focus without creating new deficits.
If, however, the underlying hemispheric abnormality is associated with significant contralateral hemiparesis, hemiplegia, or visual field deficits, the need to preserve function does not limit surgery, and hemispherectomy can be considered. Hemispherectomy can be the procedure of choice for selected infants and young children with catastrophic epilepsies and unilateral brain damage.43,44 The goal is to control seizures by completely disconnecting the abnormal epileptogenic hemisphere from the opposite, “good” hemisphere. A second major goal is to improve psychosocial and cognitive development by eliminating the child’s uncontrolled seizures.
Palliative procedures
Palliative procedures, in contrast to curative ones, rarely eliminate seizures entirely. It is important to determine that patients are not candidates for a more definitive, potentially curative resective procedure before considering palliative surgical options such as corpus callosotomy, multiple subpial transections, or vagus nerve stimulation.
Corpus callosotomy (transection of the corpus callosum) is performed in a small number of patients, ie, those who have disabling seizures that rapidly become generalized or injurious drop attacks and are not candidates for focal resection. By disconnecting the two hemispheres, this procedure aims to hinder the fast interhemispheric spread of seizure discharges.
Callosotomy may be complete or involve only a portion of the corpus callosum. The extent of resection has been correlated with favorable outcome.45
Some investigators report a 50% or greater reduction in seizure frequency, with drop attacks and generalized tonic-clonic seizures showing the most consistent improvement. In addition, behavior and quality of life may also improve.46
Multiple subpial transections are reserved for seizures arising from eloquent cortex (ie, from areas that cannot be removed without incurring unacceptable neurologic deficits). Therefore, the surgeon only transects the epileptogenic cortex in a vertical manner, so as to interrupt the horizontal cortical connections without resection. This approach is thought to disrupt the synchrony of seizure propagation while preserving physiologic function.
A meta-analysis of small case series suggests some decrease in seizure frequency with no or minimal neurologic compromise in up to 60% of patients.47
COMPLICATIONS OF EPILEPSY SURGERY
Resective surgery is not without risk, but often the risk is much less than that posed by uncontrolled epilepsy in the long term. Operative mortality rates vary from almost zero for temporal lobe surgery to 2.5% for hemispherectomy. The reported risk of permanent surgical morbidity varies by type of surgery from 1.1% for temporal lobe resection to about 5% for frontal lobe resection.4
NOVEL EPILEPSY THERAPIES
The failure of available antiepileptic drugs to control seizures in a substantial number of patients underscores the need to develop novel therapies such as electrical stimulation, local drug delivery, cell transplantation, and genebased therapies.48 Future targeted therapies could be coupled to seizure-forecasting systems to create “smart” implantable devices that predict, detect, and preemptively treat the seizures in a “closed-loop” fashion.
Targeted electrical stimulation
To modulate abnormal cortical hyperexcitability, electrical stimulation can be applied to the peripheral nervous system (eg, vagus nerve stimulation) or central nervous system. Central nervous system stimulation can be broadly divided into two approaches:
Direct stimulation targets presumed epileptogenic brain tissue such as the neocortex or hippocampus.
Indirect stimulation targets presumed seizure-gating networks such as in the cerebellum and various deep brain nuclei in the basal ganglia or thalamus (deep brain stimulation), which are believed to play a central role in modulating the synchronization and propagation of seizure activity.
Systematic, well-designed studies are currently under way. The budding field of electrical stimulation faces a number of challenges, which include optimizing stimulation variables and target sites, selecting favorable candidates, validating long-term safety and efficacy, evaluating long-term effects on tissue reorganization, plasticity, and epileptogenicity, and developing reliable algorithms for seizure detection and prediction.
