St. James’ College of Pharmaceutical Sciences, Thrissur, India.
Drug-resistant epilepsy (DRE) continues to pose significant therapeutic challenges, as nearly one-third of patients fail to achieve seizure control with antiepileptic medications. This review synthesizes current evidence on non-pharmacological management strategies, focusing on surgical interventions, neuromodulation, and dietary therapies. Respective surgery remains the most definitive treatment option for carefully selected patients, offering the potential for seizure freedom. However, for individuals in whom resection is not feasible, neuromodulation techniques such as vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS) provide effective alternatives, with long-term data supporting sustained seizure reduction and quality-of-life improvements. Non-invasive approaches, including transcranial magnetic stimulation and transcranial direct current stimulation, though still experimental, show potential as adjunctive strategies. Dietary therapies, particularly the ketogenic diet and its modified variants, offer metabolic modulation that reduces neuronal hyperexcitability, with favorable outcomes in both pediatric and adult populations. Collectively, these modalities represent a complementary, personalized approach to managing DRE, highlighting the importance of tailoring treatment strategies to individual patient profiles for optimal outcomes.
Epilepsy, a chronic neurological disorder characterized by recurrent unprovoked seizures. Seizures represent a transient occurrence of abnormal, excessive, or synchronous neuronal activity in the brain, manifesting with diverse clinical symptoms ranging from motor convulsions to subtle cognitive or sensory disturbances. It affects approximately 50 million individuals worldwide, imposing significant personal, social, and economic burdens.
While antiepileptic drugs remain the cornerstone of management, drug-resistant epilepsy (DRE) affects approximately one-third of patients with epilepsy, necessitating alternative approaches. Non-pharmacological interventions have therefore emerged as ideal alternatives in refractory cases. Surgical interventions provide the possibility of curative treatment through resection of epileptogenic foci. Neurostimulation techniques, including vagus nerve stimulation, deep brain stimulation, and responsive neurostimulation, aim to modulate epileptogenic networks. Dietary therapies, such as the ketogenic diet and its variants, exploit metabolic shifts to reduce neuronal hyperexcitability. Behavioral and psychological strategies, such as cognitive-behavioral therapy and biofeedback, further support seizure control and quality of life. Collectively, these non-pharmacological modalities expand the therapeutic landscape and clinical needs in epilepsy care.
SURGICAL TREATMENT
Epilepsy surgery is an evidence-based treatment choice for people with drug-resistant epilepsy. Epilepsy surgery is indicated in patients with seizure semiology indicating characteristic clinical localisations.
TYPES OF SURGERY
Epilepsy surgery is mainly divided into four types: respective, disconnective, ablative, and neuromodulatory procedures.
1.Resective surgeries, such as anterior temporal lobectomy and lesionectomy, aim on removing the area that causes seizures. These surgeries are impactful for patients with drug-resistant focal epilepsy.
2.Disconnective procedures, as well as corpus callosotomy, hemispherectomy, and multiple subpial transections, serve a palliative role by preventing the spread of seizures when surgery isn’t possible. Minimally invasive techniques, such as laser interstitial thermal therapy and radiosurgery, represent latest methods in targeted ablation.
3.Neuromodulatory methods, such as vagus nerve stimulation, responsive neurostimulation, and deep brain stimulation, provide alternatives for patients who cannot undergo curative surgery. This shift showcases a move towards personalized, network-based treatment for epilepsy.
NEUROMODULATION
Resective epilepsy surgery can achieve seizure freedom but is not feasible in many patients with multifocal, generalized, or eloquent cortex–involving epilepsies. Neuromodulation has therefore emerged as an important therapeutic option. Among available modalities, vagus nerve stimulation (VNS) is the most established, with more than three decades of clinical experience. Vagus nerve stimulation (VNS) was the first implantable neuromodulatory device approved for epilepsy (introduced in Europe in 1994 and approved by the U.S. FDA in 1997). Other techniques such as deep brain stimulation (DBS), responsive neurostimulation (RNS), and non-invasive options including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are expanding the armamentarium. This review summarizes the mechanisms, clinical efficacy, and safety of VNS with brief comparative insights into other neuromodulation strategies.
MECHANISM OF ACTION
VNS involves implantation of a programmable pulse generator connected to the left cervical vagus nerve, delivering intermittent electrical stimulation. The therapy modulates afferent vagal pathways projecting to the nucleus tractus solitarius and other brainstem nuclei, leading to reduced cortical hypersynchrony and enhanced parasympathetic tone. DBS and RNS act more focally by directly stimulating deep targets (e.g., anterior thalamus) or seizure foci; TMS / tDCS noninvasively modulate cortical excitability via magnetic or electrical fields.
CLINICAL EFFICACY OF VNS
Across multiple trials and meta-analyses, 45–65% of patients achieve ≥50% reduction in seizure frequency, with maximal benefit typically seen at 6–12 months post-implantation. Long-term data demonstrate durable effects, with many responders maintaining benefit for years. Pediatric series show particularly favorable outcomes, with responder rates up to 80% in drug-resistant absence epilepsy and some patients achieving seizure freedom. Beyond seizure control, VNS improves mood, alertness, and may reduce rates of status epilepticus and sudden unexplained death in epilepsy (SUDEP).
SAFETY AND TOLERABILITY
VNS is generally safe and well tolerated. Common stimulation-related adverse effects include transient hoarseness, cough, and throat discomfort, which often attenuate with parameter adjustment. Surgical risks include infection (<5%) and rare vocal cord paresis. Device revisions are required every 5–7 years due to battery depletion. Non-invasive variants (taVNS, nVNS) avoid surgical risks, though long-term data are still limited.
PREDICTORS OF RESPONSE
Early seizure reduction within the first month strongly predicts sustained benefit. Factors associated with improved response include earlier implantation, generalized or mixed seizure types, and optimized stimulation parameters. Conversely, 20–30% of patients exhibit limited or no benefit, underscoring the need for refined selection criteria and biomarker-guided programming.
COMPARISON WITH OTHER MODALITIES
While VNS is widely available and FDA-approved for patients ≥4 years of age, DBS and RNS offer alternative options for patients with focal DRE who are not surgical candidates. In the SANTE trial, anterior thalamic DBS achieved median seizure reductions of ~69% at five years, whereas RNS demonstrated 75% median reduction at nine years with gradual improvement over time. Both therapies require intracranial implantation but allow parameter adjustment and are reversible. TMS and tDCS remain experimental, with modest and transient seizure reductions reported in small trials.
|
Modality |
Invasiveness |
Responder Rate |
Key Target |
Notes |
|
VNS |
Implantable |
45–65% |
Left vagus nerve |
FDA-approved; widely used; mood benefits |
|
DBS |
Implantable |
~60–70% |
Anterior thalamic nucleus |
Strong evidence (SANTE trial) |
|
RNS |
Implantable |
~70–75% |
Seizure focus |
Closed-loop, personalized therapy |
|
TMS |
Non-invasive |
Variable, modest |
Cortical focus |
Experimental; transient effects |
|
tDCS |
Non-invasive |
Experimental |
Cortical focus |
Very safe; limited data |
KETOGENIC DIET
The Ketogenic diet has emerged as a non-pharmacological management for treatment resistant epilepsy.This diet includes,high fats and low carbohydrates; which can lead to production of ketone bodies, primarily beta -hydroxybutyrate, acetoacetate, acetone and can manage seizures. Keto diet is recommended for intractable childhood and adult epilepsy.
There are different types of ketogenic diet for epilepsy:
MECHANISM
Ketogenic diet exerts its therapeutic effects can be categorized as: mechanism reducing neuronal excitability, mechanism enhancing mitochondrial function,and the mechanisms related to modulation of sleep patterns and the gut microbiome.
CONCLUSION
A combination of advanced treatment methods, such as neuromodulation, dietary therapy, and surgery, can help people with drug-resistant epilepsy. Resective surgery is often the first choice for focal (single-area) seizures because it can be curative. When surgery isn't an option or doesn't provide a cure, neurostimulation methods can significantly reduce seizure frequency. Vagus nerve stimulation remains a cornerstone neuromodulation therapy for drug-resistant epilepsy, providing sustained seizure reduction, mood benefits, and a favorable safety profile. Vagus nerve stimulation, along with DBS and RNS, shows promise for reducing seizures and improving mood. The ketogenic diet is a successful non-drug option that uses the body's production of ketones to improve mitochondrial function, lower neuronal excitability, and control gut microbiota and sleep patterns. These methods work together to create a complete, personalized management plan that helps control seizures and greatly improves the quality of life for people with drug-resistant epilepsy.
REFERENCES
Angel Ajith*, Ann Maria John, Pooja Babu, Dr. Lincy George, Non-Pharmacological Strategies for Drug-Resistant Epilepsy: A Comparative Review of Neurostimulation, Diet and Surgery, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 12, 2279-2283 https://doi.org/10.5281/zenodo.17919968
10.5281/zenodo.17919968
