Focal refractory epilepsy

What is focal refractory epilepsy?

Focal epilepsy describes a group of disorders in which patients experience seizures that arise from a specific part of the brain1. Refractory epilepsy occurs when seizures persist despite trials of at least two tolerated and appropriately chosen antiseizure medicines2.

Focal refractory epilepsy: a vast unmet need

Epilepsy is one of the most common neurological diseases, affecting over 50 million people worldwide, according to the World Health Organization3. Approximately one in five patients with epilepsy has focal refractory epilepsy (FRE). Currently, it is estimated that there are around 2 million prevalent patients with FRE in the United States, the United Kingdom and the European Union, combined4.

Refractory epilepsy is a devastating condition. The mortality in people with refractory epilepsy is four times higher than in the general population5. In the United Kingdom alone, approximately 1,000 epilepsy-related deaths are recorded each year6. The hallmark symptom of FRE is recurrent and unpredictable seizures, which can cause injury and become life-threatening. People with epilepsy often struggle with anxiety, depression, and the social stigma associated with their disease7, and their professional life is severely restricted.

Unsatisfactory treatment options

Antiseizure medicines

Despite the availability of many antiseizure medications, with over 30 medicines approved to date, there is still a very large number of patients who have refractory epilepsy. The proportion of patients with refractory epilepsy has barely changed over the past 3 decades, and still represents about one third of the overall population with epilepsy8,9.

Among patients who have failed to respond satisfactorily to two anti-seizure medicines, the probability of achieving seizure freedom after one year with the addition of further medicines is less than 1010.

Furthermore, the chronic use of multiple antiseizure medicines is associated with significant safety and tolerability issues, including, but not limited to: sedation, rash, coordination disturbances, psychiatric symptoms including depression, reduced bone density, weight gain/loss, pregnancy risks (including birth defects, neurodevelopmental disorders and major congenital malformations), and drug-drug interaction issues11.

Surgical treatment options

According to the International League Against Epilepsy (ILAE), patients with FRE should be considered for surgery if they have failed two antiseizure medications. The two main surgical treatment options with the highest probability of achieving seizure freedom are resective surgery and laser ablation (or laser interstitial thermal therapy or LITT), with a probability of achieving seizure freedom at 50-76%12 and 58%13, respectively, at one year. However, both resective surgery and laser ablation involve the permanent destruction of cerebral tissue with a risk of long-term consequences including visual field defect, cognitive impairment and personality change, as well as acute risks of haemorrhage and infection14. Owing to patients’ aversion to the loss of cerebral tissue and surgical risks, epilepsy surgery has been significantly under-utilized in patients with FRE to date.

References

  1. Nascimento et al (2023): https://doi.org/10.1002/epd2.20045
  2. Kwan et al (2010): https://doi.org/10.1111/j.1528-1167.2009.02397.x
  3. https://www.who.int/news-room/fact-sheets/detail/epilepsy
  4. Sources for prevalence estimates: CDC; Epilepsy Society; Vaughan et al (2019): https://thejns.org/doi/abs/10.3171/2018.3.JNS171722; Beghi (2020): https://doi.org/10.1159/000503831; Lopez-Rivera et al (2022): https://doi.org/10.1016/j.ebr.2022.100527
  5. Shankar et al (2024): https://doi.org/10.1007/s00415-023-12165-4
  6. Epilepsy Action: www.epilepsy.org.uk
  7. Scott et al (2017): https://doi.org/10.1111/epi.13769
  8. Chen et al (2018): https://doi.org/10.1001/jamaneurol.2017.3949
  9. Perucca et al (2023): https://doi.org/10.1016/S1474-4422(23)00151-5
  10. Wiebe et al (2001): https://doi.org/10.1056/NEJM200108023450501; Engel et al (2012): https://doi.org/doi:10.1001/jama.2012.220; Halford et al (2020): https://doi.org/10.1111/ane.13257
  11. Perucca et al (2012): https://doi.org/10.1016/S1474-4422(12)70153-9
  12. Lamberink et al (2020): https://doi.org/10.1016/S1474-4422(20)30220-9
  13. Chen et al (2023): https://doi.org/10.1111/epi.17560
  14. Hader et al (2013): https://doi.org/10.1111/epi.12161; Baxendale et al (2018): https://doi.org/10.1016/j.yebeh.2017.08.003; Bjellvi et al (2021): https://doi.org/10.1111/epi.17040

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