Advancing Care: Surgery and Specialized Treatments

When standard anti-seizure medications fail to provide control, the focus of care for Familial Focal Epilepsy with Variable Foci 1 (FFEVF1) shifts to more advanced interventions. In the epilepsy community, the “rule of two” is a critical milestone: if a person has tried two appropriately chosen medications and still has seizures, they should be referred to a Level 4 Comprehensive Epilepsy Center for a surgical evaluation ^[1]. This evaluation typically includes a review of seizure videos, prolonged video-EEG, neuropsychological testing, and a detailed discussion with a multidisciplinary team.

Debunking the Surgery Myth

A common misconception is that because FFEVF1 is a “genetic” condition, surgery will not work. This is incorrect. While the pathogenic DEPDC5 variant is present in every cell, the seizures themselves often start from one specific, localized patch of abnormal tissue (like Focal Cortical Dysplasia) ^[2][3].

If doctors can find this specific “focus,” surgery can be successful. Recent research has shown:

• High Success Rates: In a systematic review of 44 selected patients with DEPDC5 mutations who underwent focal surgery, approximately 78% achieved Engel Class I outcomes, meaning they became completely free of disabling seizures ^[4].
• Significant Improvement: Over 90% of these patients saw a meaningful reduction in how often their seizures occurred ^[4].

Individual prognosis depends on whether the seizure focus can be safely removed without risking memory, language, or vision.

Finding the “Invisible” Target

The biggest challenge in FFEVF1 surgery is that the seizure focus is often invisible on a standard MRI ^[5][3]. If your initial MRI was normal, specialized centers use a multi-step “presurgical workup” to map the brain’s activity:

1. Advanced Imaging: Tools like PET scans (which look at brain metabolism) or MEG (which maps magnetic activity) can pinpoint a focus that structural scans miss ^[6][7].
2. Image Post-Processing: Software like MAP-ping can analyze existing MRI data to find subtle areas of blurred “gray-white matter” boundaries that suggest dysplasia ^[8].
3. SEEG (Stereoelectroencephalography): If non-invasive tests aren’t clear, doctors may place tiny electrodes directly into the brain (Phase 2 monitoring) to precisely record the beginning of a seizure ^[9][10]. This is an invasive procedure with risks, done only after careful team review.

The Ketogenic Diet

For those who are not candidates for surgery, or as an additional treatment, the medical ketogenic diet is an established option for some drug-resistant epilepsies. This strict high-fat, low-carbohydrate medical diet changes how the brain uses energy ^[11].

• DEPDC5 Response: In a small study of children with drug-resistant DEPDC5 epilepsy, 75% achieved seizure freedom initially on the diet ^[11]. However, it is not guaranteed that this result persists long-term.
• Medical Supervision: The diet requires rigorous supervision by a specialist medical team due to nutritional, metabolic, and medication interaction risks. Some families report secondary improvements in behavior while on the diet, though evidence is limited ^[11].

Neuromodulation: Electronic “Brakes”

If a single seizure focus cannot be found, or if it is located in a “high-priority” area of the brain, neuromodulation may be a palliative option. These devices act like “electronic brakes” to interrupt seizure activity, usually reducing rather than eliminating seizures:

• VNS (Vagus Nerve Stimulator): A small device implanted in the chest that sends regular pulses to the brain via the vagus nerve ^[12].
• RNS (Responsive Neurostimulation): A “smart” device that monitors brainwaves and sends a pulse only when it detects the beginning of a seizure. RNS generally requires one or two identifiable seizure-onset zones to be effective ^[13].
• DBS (Deep Brain Stimulation): A device that sends continuous electrical signals to specific deep structures in the brain to reduce overall excitability ^[14].

These devices have different age and regulatory indications that vary by country, and they require a specialist’s evaluation ^[14][15].