Vigabatrin therapy implicates neocortical high frequency oscillations in an animal model of infantile spasms

Abstract

Abnormal high frequency oscillations (HFOs) in EEG recordings are thought to be reflections of mechanisms responsible for focal seizure generation in the temporal lobe and neocortex. HFOs have also been recorded in patients and animal models of infantile spasms. If HFOs are important contributors to infantile spasms then anticonvulsant drugs that suppress these seizures should decrease the occurrence of HFOs. In experiments reported here, we used long-term video/EEG recordings with digital sampling rates capable of capturing HFOs. We tested the effectiveness of vigabatrin (VGB) in the TTX animal model of infantile spasms. VGB was found to be quite effective in suppressing spasms. In 3 of 5 animals, spasms ceased after a daily two week treatment. In the other 2 rats, spasm frequency dramatically decreased but gradually increased following treatment cessation. In all animals, hypsarrhythmia was abolished by the last treatment day. As VGB suppressed the frequency of spasms, there was a decrease in the intensity of the behavioral spasms and the duration of the ictal EEG event. Analysis showed that there was a burst of high frequency activity at ictal onset, followed by a later burst of HFOs. VGB was found to selectively suppress the late HFOs of ictal complexes. VGB also suppressed abnormal HFOs recorded during the interictal periods. Thus VGB was found to be effective in suppressing both the generation of spasms and hypsarrhythmia in the TTX model. Vigabatrin also appears to preferentially suppress the generation of abnormal HFOs, thus implicating neocortical HFOs in the infantile spasms disease state.

Utilizing Animal Models of Infantile Spasms

“…Hypsarrhythmia generated in the TTX model includes high-frequency oscillations that occur most commonly contralateral to the site of TTX infusion (37, 38). The TTX model has been reported to respond to vigabatrin treatment (39), but no studies of ACTH treatment have been published.…”

Prevention of infantile spasms relapse: Zonisamide and topiramate provide no benefit

“…Short-term resolution of spasms and hypsarrhythmia is necessary, but clearly insufficient to guarantee an enduring response. Perhaps the key to sustained response without relapse is aggressive treatment beyond the resolution of spasms and hypsarrhythmia, with the goal of "correcting" a novel biomarker of epileptogenesis, such as the elimination of interictal HFOs, as suggested by a contemporary animal study 41 and a recent surgical series that included patients with infantile spasms. 39 A definitive evaluation of ZNS, TPM, or any other treatment for prevention of relapse is a challenging endeavor and will require a prospective, large-scale study with appropriate experimental controls.…”

HFO to Measure Seizure Propensity and Improve Prognostication in Patients With Epilepsy

“…Frost and coworkers used the tetanus toxin model for infantile spams and showed a reduction of HFO following vigabatrin therapy. 60 A mesiotemporal lobe epilepsy model showed a reduction of HFO following treatment with lacosamide and neurosteriods. 61 , 62 The same group showed that treatment with levetiracetam directly after status epilepticus could reduce the likelihood of spontaneous seizures and that this was reflected in reduced rates of HFO in the treatment group.…”