Several recent clinical and preclinical studies have suggested a potential role of immune response and neuroinflammation in the pathophysiology of epilepsy and epileptogenesis, including absence epilepsy [1,2,3,4]. Here we described 2 cases of CAE who showed epilepsy disappearance after occurrence of drug eruption, probably due to an immune response to ESM.
CAE, which is the most common form of epilepsy in children, depends on age and is one of the benign seizure disorders. VPA and ESM have been used as the ASMs for CAE [10, 11], but similar to the other ASMs, they have side effects, such as drug eruption. In general, occurrence of drug eruption in CAE patients would necessitate discontinuation of the offending ASM; however, in most cases, there is a risk of seizure recurrence. Interestingly, Kakisaka et al. reported resolution of seizures after a drug eruption episode due to lamotrigine (LTG) in a 57-year-old woman who had seizures after a cerebral infarction [8]. LTG administration was able to control her seizures, but she had a drug eruption after 35 days. The eruption was promptly improved after discontinuation of LTG, and her epileptic seizures were not observed thereafter. The clinical courses of our 2 cases were similar to this previously reported case.
The mechanism of epileptic seizure disappearance after a drug eruption is unclear. The immune modulation in drug allergies may be involved in seizure suppression. In this report, the case 1 was tested positive for DLST against ESM, and seemed to have drug eruption caused by type-4 allergy [12]. In general, the type-4 allergic reaction is involved in ASM-induced drug eruption. When the ASM antigen is recognized by and binds to the major histocompatibility antigen (MHC), the drug-specific CD4+ and CD8+ T cells are activated. As a result, the activated CD4+ and CD8+ T cells produce inflammatory cytokines such as interleukin-8 (IL-8), IL-2 and IFN-γ [5, 13]. Although the details of the mechanisms are unknown, immunomodulation, such as regulation of cytokine production, might contribute to the suppression of the epileptic seizure.
Immune response to viral infections is another possible mechanism. In fact, several cases of West syndrome have been reported to have seizure disappearance following acute viral infections, such as exanthema subitum, rotavirus colitis, measles, and mumps, so direct immune reactions in response to several viral infections might be involved in seizure disappearance [14, 15]. Inflammation as an immune response in viral infection may be associated with the disappearance of seizures.
Several other factors are also suspected to contribute to the seizure disappearance in our 2 cases. One is the antiepileptic and anti-inflammatory effects of prednisolone administration (case 1). However, it is unlikely that short-term administration of steroids, which is not a high-dose therapy, would result in the disappearance of seizures. The other is the anti-seizure effect of ESM and/or VPA itself. This possibility cannot be completely denied. However, even considering these factors, the strong coincidence of seizure disappearance with the appearance of drug eruption suggests that drug eruption is a trigger for epileptic seizure disappearance.
Our case report had some limitations. First, video EEG, which is useful for observing the obscure symptoms of CAE [16, 17], was not performed in our 2 cases, thus we could not confirm the detailed association between unclear symptoms and EEG. Second, several susceptibility genes for CAE have been reported [9, 18, 19]. It has also been reported that certain gene variants may be involved in the responsiveness to the treatment of CAE [20]. Several genetic factors may play a role in the disappearance of seizures after drug eruption. In future studies, a genetic test should be performed to identify any genetic factors that may be involved in the disappearance of seizures after drug eruption.
