Proof-of-concept of drug resistance hypotheses

As suggested by Sisodiya (2003), at least four criteria must be satisfied for a proposed drug-resistance mechanism of epilepsy to be accepted; the mechanism must 1) be detectable in epileptogenic brain tissue, 2) have appropriate functionality, 3) be active in drug resistance (and not be an epiphenomenon), and 4) drug resistance should be affected when the mechanism is overcome. These criteria are based on the famous Koch’s postulates, which were originally proposed by Robert Koch in 1890 to establish a causal relationship between a bacterium and a disease.

Drug-resistance hypothesis in epilepsyDetectable in brain (or peripheral) tissues of nonrespondersAppropriate functionalityActive in ASD resistanceResistance reversed when mechanism is overcome
Target hypothesis+ (rat)+ (rat)? (rat)? (rat)
+ (human)+ (human)? (human)? (human)
Transporter hypothesis+ (rat)+ (rat)+ (rat)+ (rat)
+ (human)+ (human)+ (human)? (human)
Pharmacokinetic hypothesis- (rat)- (rat)? (rat)? (rat)
+ (human)? (human)? (human)? (human)
Neural network hypothesis+ (rat)? (rat)? (rat)? (rat)
+ (human)? (human)? (human)+ (human)
Intrinsic severity hypothesis+ (rat)a? (rat)? (rat)? (rat)
+ (human)a? (human)? (human)? (human)
Gene variant hypothesis+ (rat)+ (rat)? (rat)? (rat)
+ (human)+ (human)+/? (human)+/? (human)
Epigenetic hypothesis+ (rat/mouse)+/? (rat/mouse)+/? (rat/mouse)+/? (rat/mouse)
+ (human)? (human)? (human)? (human)
Neuroinflammation/blood-brain barrier+ (rat, mouse)+ (rat)+ (rat)+ (rat)
+ (human)? (human)? (human)? (human)
  • a Increased seizure frequency/density compared with ASD responders.