Medical Update: A treatment for drug-resistant epilepsy
Drug therapy is ineffective in 30% epilepsy patients, who should be referred to specialised centres to evaluate available therapeutic alternatives.
One third of epilepsy patients do not respond to drug therapy
Epilepsy is a brain disease where nerve cells don’t signal properly, which causes seizures. Seizures occur due to abnormal synchronous neuronal activity in the brain, causing transient clinical symptoms. Epilepsy is a common neurological disease with a global incidence of 7.6 per 1000 people, affecting approximately 50 million people worldwide.
The treatment of epilepsy is mainly based on anti-seizure drugs, with about two-thirds of patients achieving seizure freedom. The remaining third of patients are considered to have drug-resistant epilepsy (DRE) and are eligible for alternative treatments, such as epilepsy surgery and non-pharmacological therapies.
Surgical treatments for DRE
Surgical intervention remains a cornerstone in the management of epilepsy for carefully selected patients, particularly those with focal epilepsy. Lobar resection is the most established surgical method and is often performed in mesial temporal lobe epilepsy. Patients with well-defined seizure foci on imaging and EEG studies tend to have the best outcomes. Another surgical approach is callosotomy, which is primarily recommended for patients with severe drop seizures, such as atonic or tonic seizures, that result in significant morbidity. By severing the corpus callosum, this procedure prevents seizure propagation between hemispheres, effectively reducing the overall burden of seizures.
A minimally invasive alternative to open resection is laser interstitial thermal therapy (LITT), which uses laser-generated heat to ablate epileptogenic foci. This technique is particularly beneficial for deep-seated lesions and offers a lower risk of cognitive side effects compared to traditional surgical resections. In carefully selected cases, these surgical interventions can significantly improve seizure control and quality of life, often leading to reduced dependence on antiepileptic drugs.
Neuromodulation: expanding options for non-resective candidates
For patients who are not candidates for resective epilepsy surgery, neuromodulation provides an effective palliative strategy. Vagus nerve stimulation (VNS) is a well-established technique that involves the implantation of a device under the skin of the chest, which delivers intermittent electrical pulses to the vagus nerve. Over time, this stimulation has been shown to reduce seizure frequency and improve patient outcomes.
Deep brain stimulation (DBS) offers another option, particularly for focal epilepsies that do not have a single well-defined seizure focus. By targeting the anterior nucleus of the thalamus, DBS modulates seizure activity and has demonstrated efficacy in reducing seizure burden. Another advanced neuromodulation technique is responsive neurostimulation (RNS), a closed-loop system that continuously monitors electrocorticographic activity and delivers targeted stimulation when seizure patterns are detected. Unlike traditional neuromodulation systems, RNS provides chronic intracranial EEG monitoring, allowing for personalized treatment adjustments based on the patient’s evolving condition.
Focused Ultrasound (FUS): a promising non-invasive therapy
A novel and rapidly evolving technique in epilepsy treatment is FUS. This non-invasive modality utilizes high-intensity ultrasound beams to selectively target and ablate epileptogenic tissue without requiring surgical incisions. Early studies have highlighted its potential both in preclinical models and in initial clinical applications.
One of the primary advantages of FUS is its minimally invasive nature. Unlike traditional surgical approaches, it does not require incisions, thereby reducing the risk of infection, postoperative complications, and prolonged recovery times. Clinical trials have demonstrated that FUS can effectively reduce seizure frequency in patients with drug-resistant epilepsy, particularly when applied to well-localized seizure foci.
Another significant benefit is the potential for cognitive preservation. Unlike some surgical interventions that may carry the risk of cognitive impairment, FUS has been shown to have minimal impact on cognitive function, making it a suitable option for patients with epileptogenic foci near eloquent brain regions.
Beyond its ablative capabilities, FUS is also being explored for neuromodulation. Researchers are investigating its potential for altering neuronal excitability and interrupting seizure propagation pathways using low-intensity ultrasound pulses. Additionally, FUS enables the temporary and safe opening of the blood-brain barrier (BBB), which could enhance the targeted delivery of therapeutics to epileptogenic regions.
While early results are promising, further research and larger clinical trials are needed to establish standardized treatment protocols and confirm the long-term safety and efficacy of this technique.
Future perspectives in DRE treatment
Management of drug-resistant epilepsy has evolved significantly, offering an increasing number of therapeutic options beyond pharmacological treatment. Epilepsy surgery remains a highly effective intervention for carefully selected patients, with research confirming its superior outcomes in achieving seizure freedom compared to medical therapy alone. Despite this, surgical options are often underutilized due to barriers in patient selection and access to specialized centers.
Neuromodulation therapies such as VNS, DBS, and RNS have expanded the landscape of treatment possibilities, particularly for individuals who are not candidates for resective surgery. These modalities have shown considerable efficacy in reducing seizure burden while maintaining cognitive function. Additionally, advancements in non-invasive techniques, particularly FUS, represent a promising frontier. The ability of focused ultrasound to perform precise tissue ablation and modulate neuronal activity without requiring open surgery offers a potential paradigm shift in epilepsy management.
Current research underscores the importance of a multidisciplinary approach, where individualized treatment plans are developed within comprehensive epilepsy centers. Future efforts should focus on optimizing patient selection criteria, refining therapeutic protocols, and expanding access to emerging technologies.
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