What is the recommended workup and treatment plan for a patient with resistant epilepsy?

Workup for Resistant Epilepsy

Patients with drug-resistant epilepsy (defined as failure of two appropriately chosen antiseizure medications) should undergo comprehensive evaluation at a tertiary epilepsy center with video-EEG monitoring, high-resolution MRI with dedicated epilepsy protocol, and functional neuroimaging (FDG-PET and/or ictal SPECT) to determine surgical candidacy, as approximately 65% of appropriately selected patients achieve seizure freedom with surgery. 1

Definition and Initial Assessment

• Drug-resistant epilepsy is defined as persistence of disabling seizures despite appropriate trials of two antiseizure medications (ASMs), either alone or in combination 1, 2
• Approximately 30% of patients with epilepsy do not respond to two ASMs and are considered drug resistant, with focal epilepsies being the most common form 1, 3
• Children and adolescents show approximately 20% drug resistance with risk for poor long-term cognitive and psychosocial outcomes 1

Essential Diagnostic Workup

Structural Neuroimaging

• MRI with dedicated epilepsy protocol is the primary imaging investigation for all patients with drug-resistant focal epilepsy 1, 4
• The dedicated seizure protocol should include: 4
  • Coronal T1-weighted imaging
  • High-resolution 3D T1-weighted gradient echo sequences
  • Coronal T2-weighted sequences
  • Coronal and axial fluid-attenuated inversion recovery (FLAIR) sequences
• For refractory epilepsy, 3T MRI with dedicated epilepsy protocol demonstrates 84% sensitivity for detecting epileptogenic lesions 5
• MRI identifies structural etiologies including hippocampal sclerosis, tumors, focal cortical dysplasia (FCD), hemorrhage, and other structural lesions 1

Video-EEG Monitoring

• Scalp video-EEG telemetry is essential to confirm seizure type, localize seizure onset, and differentiate epileptic from non-epileptic events 1
• Prolonged monitoring captures both clinical and subclinical seizures to characterize the epileptogenic zone 4

Functional Neuroimaging

• Interictal [18F]FDG-PET is highly valuable for localizing the seizure onset zone, particularly in non-lesional epilepsy or patients with multifocal structural abnormalities 1
• Ictal perfusion SPECT or ictal subtraction SPECT (SISCOM - interictal SPECT fused, normalized, and subtracted from ictal SPECT) provides complementary localization information 1
• These functional imaging tools are especially useful in patients without visible brain lesions on MRI or those with hemispheric or multi-lobar cortical dysplasia, polymicrogyria, or localized stroke 1

Additional Evaluations

• Neuropsychological and neuropsychiatric assessment to evaluate cognitive function and identify eloquent cortex 1
• Functional MRI to map language and motor functions when resection near eloquent areas is considered 1
• Wada test for language and memory lateralization in selected cases 1

Invasive Monitoring Considerations

• Intracranial EEG electrodes (including stereoelectroencephalography) are indicated when non-invasive methods fail to adequately localize the epileptogenic zone in surgical candidates 1, 4
• Invasive monitoring is particularly valuable in patients with prior surgery and altered anatomy, where scalp EEG and non-invasive imaging have reduced sensitivity 4
• Precise localization is critical before surgical intervention to maximize seizure freedom rates while preserving eloquent cortex 4

Treatment Algorithm Following Workup

Surgical Candidacy Determination

• If the epileptogenic zone is correctly detected and located outside eloquent areas, surgical resection is safe, successful, and cost-effective, with approximately 65% of patients becoming seizure free 1, 4
• Surgery offers the best opportunity for complete freedom from seizures in pharmacoresistant patients 2, 6
• All patients with drug-resistant epilepsy should be evaluated at least once in a tertiary epilepsy center to discuss eligibility for surgical intervention 3

Non-Surgical Options for Ineligible Patients

• Vagus nerve stimulation (VNS) provides palliative seizure reduction for patients not suitable for resective surgery 7, 6, 3
• Responsive neurostimulation (RNS) and deep brain stimulation show efficacy in seizure control that increases over time 6, 3
• Ketogenic diet represents a therapeutic option for selected patients with drug-resistant epilepsy 7, 2

Continued Pharmacotherapy Optimization

• Pharmacological management may consist of ASM polytherapy, though quality of life considerations require balancing efficacy against drug-related adverse events 3
• Approximately 25% of patients with structural epilepsy require a second AED to control seizure activity 4

Critical Pitfalls to Avoid

• Apparent pharmacoresistance can result from noncompliance, non-epileptic seizures, misdiagnosis of seizure type or epilepsy syndrome, inappropriate medication use, or lifestyle issues—these must be excluded before labeling as truly drug-resistant 2, 8
• Only a small proportion of patients with refractory epilepsy are referred for expert evaluation and treatment, representing a major gap between evidence and practice 2, 6
• Delayed referral to comprehensive epilepsy centers results in years of uncontrolled disease and preventable morbidity 2, 8
• Failure to perform high-resolution MRI with dedicated epilepsy protocol may miss subtle structural lesions such as focal cortical dysplasia 5, 4