Drug-Resistant Temporal Lobe Epilepsy with Hippocampal Sclerosis: Implications of Gluten-Associated Immunity and Interleukin-6

More than 30% of patients with epilepsy have inadequate seizure control despite the availability of more than 20 anti-seizure medications. Temporal lobe epilepsy (TLE) is the most common form of focal drug-resistant epilepsy (DRE), and hippocampal sclerosis (HS) is the most common aetiology of TLE. Inflammatory mechanisms and neurodegeneration significantly contribute to the development of TLE. Moreover, recent studies highlight the role of the gut in controlling autoimmune inflammation within the brain and suggest an increased prevalence of coeliac disease (CD) in patients with epilepsy. Several investigations have reported the associations of the proinflammatory cytokine interleukin 6 (IL-6) with other inflammatory markers in patients with TLE. Finally, increasing data support the clinical importance of anti-glutamic acid decarboxylase antibodies (GADAs) as an autoimmune aetiology of epilepsy. In gluten ataxia, a link to GADAs has also been suggested.

This dissertation studied whether two types of gluten immunity, i) CD-type immunity (diagnosis of CD or CD-specific TG2/EmA antibodies) or ii) AGA-type immunity (subjects with anti-gliadin antibodies (AGAs) but without CD), are associated with DRE and, if so, whether it is dependent on the epilepsy type and aetiology. Second, this study evaluated the plasma concentrations of the cytokines IL-6 and IL-10 and their ratios in patients with DRE, especially TLE with HS (TLE+HS). Third, the associations between plasma concentrations of the cytokines IL-6 and IL-10 and their ratios with GADAs were investigated.

Study I was a pilot study and included 48 adult patients with focal DRE and 71 consecutive healthy blood donors who served as controls for antibody measurements. In addition to CD-associated serology for different antibodies, genotyping and small bowel biopsy were performed. Studies II–IV were cross- sectional studies and included 265 consecutive adult patients with epilepsy. Blood samples were used for all four studies. MRI examination was performed for most of the patients in all the studies.

In Study I, seven patients with focal DRE had CD-type immunity. All these patients had TLE + HS. None of the patients with TLE without HS (TLE–HS) or extratemporal epilepsy had CD-type immunity (p= 0.0002). Four patients with CD-type immunity had evidence of dual pathology, whereas none of the other patients did (p= 0.0002).

In Study II, of 253 patients, 34 had TLE+HS, 97 had TLE-HS, 88 had other focal epilepsies, and 34 had generalised epilepsies. Overall, 22 patients had CD-type immunity, and another 29 had AGA-type immunity. TLE+HS was more common in patients with CD-type immunity than in patients with AGA-type immunity (31.8% versus 11.9%, P = 0.019). In addition, transglutaminase 6 antibodies were measured from the patients and the results showed no significant difference in the transglutaminase 6 seropositivity among patients with CD-type immunity, AGA- type immunity, or those without gluten immunity.

Study III demonstrated that the median levels of IL-6 did not differ between the epilepsy types, whereas the IL-6/IL-10 ratio was greater in TLE+HS patients than in TLE-HS patients (3.1 vs. 1.6, p = 0.042). This study included 20 TLE patients with right-sided HS lateralisation, 13 patients with left-sided HS, and one patient with bilateral HS. Within the TLE+HS population, the median IL-6 level was greater in patients with right-sided HS than in patients with left-sided HS (1.7 vs. 0.8 pg/mL, p = 0.043), but the IL-6/IL-10 ratio did not differ between the right and left lateralisations (p = 0.832).

Study IV included 247 patients whose GADA titres had been measured previously. The median IL-6 concentration was significantly greater in patients with high GADA titres (2.86 pg/mL) than in GADA-negative patients (1.18 pg/mL) (p= 0.039). Similarly, IL-10 concentrations were also higher in patients with high GADA titres (1.45 pg/mL) than in GADA-negative patients (0.50 pg/mL), but the difference was not significant. Neither the IL-6 nor the IL-10 concentrations were significantly different between the groups on the basis of GADA positivity.

The most significant finding of the present study was a previously unrecognised link between CD-type immunity and TLE +HS. In patients with TLE+HS, CD-type autoimmune responses against dietary gluten may modify disease processes, leading to intractable epilepsy and HS. An increased understanding of immunological factors may contribute to the development of immunomodulatory treatments both in refractory epilepsy and in cases of gluten-related pathology, offering a potential dietary intervention to prevent the development of refractory epilepsy. Based on the study findings, screening for CD in DRE is recommended, although there are still insufficient data on the effects of a gluten-free diet on seizures. However, screening can identify patients with an atypical or asymptomatic form of CD, which is estimated to be 5–6 times more common than patients with symptomatic CD and whose treatment is a lifelong gluten-free diet. Second, systemic upregulation of IL-6 was associated with the presence of HS, revealing increased concentrations in TLE patients with right-sided HS. Third, similarly increased IL-6 activation was observed in TLE patients with autoimmune GADA, demonstrating that multiple mechanisms may lead to systemic immune activation. In addition, on the basis of the present results, GAD autoimmunity is a separate and specific entity from gluten-related immunity-associated TLE.