October 2024

NEUROSCIENCES

UPDATES IN NEUROLOGY: DRUG-RESISTANT EPILEPSY

Drug-resistant epilepsy (DRE) occurs when two appropriate antiepileptic drug trials fail to achieve sustained seizure freedom. 
 
A better understanding of the predictors and mechanisms of drug resistance is essential to guide management and the development of new therapeutics.

Key Updates
​
  • The prevalence of intractable, drug-resistant epilepsy varies depending on the setting, but it can be as high as one-third of patients in epilepsy centers.
    • Despite many new anti-seizure medications over the last four decades, drug resistance has not significantly changed.
    • Only 11% of patients who failed the first anti-seizure medication (ASM) due to lack of efficacy respond to subsequent treatments.
  • ​Early referral to an epilepsy center for patients who do not respond to initial treatments is crucial to avoid “pseudoresistance” due to wrong diagnosis, drug selection or dosing.
  • Experts recommend that a referral for a diagnostic or surgical evaluation should be offered to every patient with epilepsy (up to 70 years of age) as soon as drug resistance is ascertained.
  • Epilepsy care has evolved tremendously over the last decade and state-of-the-art epilepsy centers offer etiology-directed medical and surgical interventions and comprehensive treatment of comorbidities and special populations.

​Predictors of Drug-Resistant Epilepsy

  • ​Clinical
    • Younger age at onset​
    • Short latency (for example, after a stroke)
    • Neurodevelopmental abnormalities
    •  Neuropsychiatric comorbidities
    • Recreational drug use
    • Related comorbidities (such as a migraine)
    • Poor response to first ASM
    • Number of previous ASMs
    • Number of seizures before starting ASMs
    • Ethnicity, socioeconomic factors
    • History of catamenial epilepsy (JME, GGE)
    • ​Family history of epilepsy
    • Focal, infantile spams, initial myoclonic seizures
    • Focal or mixed type (vs. generalized)
    • Multiple seizure types
    • Status epilepticus at onset
    • Status epilepticus
    • Photoparoxysmal response
    • Seizure clusters
    • History of CAE progressing to JME
  • Epilepsy etiology
    • Metabolic
    • Infectious
    • ​Structural
  • Genetic
    • ​Gene variants associated with DREs (multiple, such as SCN1A variants)
  • Seizure related:
    • ​Gene variants associated with drug resistance
  • ​EEG/electrophysiologic:
    • Slow background
    • Multifocal epileptiform discharges
    • Epileptiform EEG​
    • Epileptiform focality (JME)
    •  Abnormal EEG
    •  MRI imaging
    • MRI brain abnormalities
    • Biomarkers (protein, miRNAs)
    • Plasma, serum, CSF​

Referral to Epilepsy Center

​Consider referring patients to a subspecialty program like those listed below for targeted treatment based on etiology:
  • Genetic program
  • Autoimmune epilepsy clinic
  • Tumor-related epilepsy program
  • Functional neurological disorders program
  • First seizure clinic
  • Acute symptomatic seizure follow-up clinic

Comprehensive treatment choices for select populations include:
  • Women with epilepsy
  • Ketogenic diet
  • Epilepsy in older adults
  • Neuromodulation clinic
  • Neuropsychiatric treatment of comorbidities  ​

When to make surgical referrals:
  • Diagnostic or surgical referral for epilepsy evaluation should be offered to every patient with epilepsy (up to 70 years of age) as soon as drug resistance is ascertained.
  • Consider a direct surgical referral for patients who have a brain lesion in non-eloquent cortex, even if they are seizure-free on one or two ASMs.
Stephen Schuele, MD, MPH, chief of Epilepsy/Clinical Neurophysiology in the Ken and Ruth Davee Department of Neurology and professor of Epilepsy/Clinical Neurophysiology and of Physical Medicine and Rehabilitation at Northwestern Medicine.

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