Refractory focal epilepsy: Aetiology and immunological markers in adult patients

Abstract

Asianmukaisesta lääkityksestä huolimatta 25-30%:lla epilepsiapotilaista esiintyy kohtauksia, mikä aiheuttaa merkittävää inhimillistä kärsimystä ja taloudellisia menetyksiä. Vaikeahoitoista epilepsiaa sairastavien potilaiden epilepsioiden syistä on kuitenkin ollut vain vähän tutkimustietoa. Aikaisempien tutkimusten perusteella osalla epilepsiapotilaista on viitteitä elimistön immuunijärjestelmän aktivoitumisesta, mutta tietämys hyvin tutkituista vaikeahoitoista epilepsiaa sairastavista potilaista on ollut riittämätöntä. Väitöskirjatyön tavoitteena oli tutkia vaikeahoitoisen epilepsian kliinisiä piirteitä hyvin tutkituilla potilailla. Tarkoituksena oli arvioida vaikeahoitoisen epilepsian syyn vaikutusta ennusteeseen. Toisena keskeisenä tavoitteena oli tutkia vaikeahoitoisen epilepsian immunologisia merkkiaineita, joiden avulla voitaisiin löytää potilaat, joiden epilepsiassa immunologisilla tekijöillä saattaa olla kliinistä merkitystä.

Ensimmäisessä osatyössä tutkittiin vaikeahoitoisen paikallisalkuisen epilepsian syitä. Merkittävä osa vaikeahoitoista epilepsiaa sairastavista potilaista tuli seuranta-aikana kohtauksettomiksi. Kohtauksettomuuden saavuttaminen oli todennäköisempää potilailla, joiden epilepsian syy oli tuntematon (kryptogeeninen) verrattuna symptomaattista epilepsiaa sairastaviin potilaisiin. Osalla potilaista oli ollut kohtauksia hyvin pitkään ennen kohtauksettomuuden saavuttamista, mikä viittaisi siihen, että vaikeahoitoisen epilepsian ennuste ei ole yhtä huono kuin aikaisemmin on ajateltu. Jatkuvat lääkeponnistelut saattavat olla hyödyksi erityisesti kryptogeenistä epilepsiaa sairastavien potilaiden hoidossa.

Kolmessa muussa osatyössä tarkasteltiin vaikeahoitoisen epilepsian immunologisia merkkiaineita [fosfolipidi- ja tumavasta-aineet, interleukiini-(IL)-6, IL-1-reseptoriantagonisti, glutamaattidekarboksylaasi(GAD)-vasta-aineet]. IgG-luokan antikardiolipiinivasta-aineet olivat koholla osalla niistä potilaista, joilla on jatkuvasti kohtauksia verrattuna terveisiin kontrolleihin ja potilaisiin, joilla kohtauksia ei ole jatkuvasti. IL-6-pitoisuus oli koholla osalla temporaaliepilepsiaa sairastavista potilaista verrattuna muita epilepsiatyyppejä sairastaviin potilaisiin ja terveisiin kontrolleihin. Lähes 90%:llä niistä potilaista, joilla todettiin korkea GAD-vasta-ainetiitteri, oli temporaaliepilepsia. Niillä epilepsiapotilailla, joilla todettiin korkea GAD-vasta-ainetiitteri, todettiin myös runsaasti autovasta-aineita ja autoimmuunisairauksia, ja osalla havaittiin myös intratekaalista vasta-ainetuotantoa merkkinä epilepsian immuunivälitteisestä taustasta.

Tulosten perusteella immunologisia mittareita, kuten fosfolipidivasta-aineita, sytokiineja ja GAD-vasta-aineita, voitaisiin jatkossa käyttää vaikeahoitoisen epilepsian immunologisina biomarkkereina. Löydöksiä voitaisiin hyödyntää tunnistamalla ne epilepsiapotilaat, joille immunoterapeuttisista hoidoista saattaisi olla apua. Autovasta-aineiden ja sytokiinien patogeneettinen merkitys epilepsiassa on silti vielä avoin. Jatkossa on tarpeen kartoittaa immunologisten tekijöiden syy-seuraussuhteita erityisesti vastasairastuneilla epilepsiapotilailla.

In this dissertation, we studied the underlying causes of refractory focal epilepsy in terms of the possibility of seizure freedom. In the second section of the present dissertation, we studied immunological factors of refractory epilepsy. We measured antiphospholipid and antinuclear antibodies as well as cytokines in patients with refractory focal epilepsy to discover the effects of clinical determinants on the prevalence of these immunological markers. We measured serum levels of GADA in patients with controlled or refractory focal epilepsy, as well as in patients with primary generalised epilepsy. In the first part of the dissertation, we examined the aetiology of epilepsy in 119 patients with refractory focal epilepsy during a two-year follow-up. The aetiology was based on high-resolution brain MRI and patient history. A significant proportion of the patients attained remission during the follow-up. The chances of remission were significantly higher in patients with cryptogenic aetiology compared to patients with symptomatic aetiology. Some patients had attained remission after a long period of epilepsy. The present study demonstrates that aetiology is important in determining the prognosis of epilepsy. Furthermore, it shows that the prognosis of patients with refractory focal epilepsy might be better than previously reported. In the second part of the dissertation, we measured serum levels of anticardiolipin, anti-β2-glycoprotein I, and antinuclear antibodies in 95 patients with refractory focal epilepsy and in 10 patients with controlled focal epilepsy. Clinical determinants included the patient history, electro-clinical classification, and high-resolution brain MRI. Seventy healthy blood donors served as control subjects. Blood samples were drawn after the two-year follow-up. One sample was drawn from patients with no recent seizures, and two samples were drawn at a three-month interval from patients with recent seizures. The prevalence of IgG class anticardiolipin antibodies was increased in the patients with recurrent seizures compared to those with no recent seizures and the control subjects. The patients with recent seizures demonstrated an increased prevalence of moderate positive IgG class anticardiolipin antibodies compared to the control subjects and the patients with no recent sei! zures. No differences in the levels of IgM anticardiolipin or antinuclear antibodies were detected between patients and control subjects. All three patients with anti-β2-glycoprotein I antibodies had recurrent seizures. The prevalence of IgG class anticardiolipin antibodies was not associated with the epilepsy type, duration, or aetiology. These results suggest that the presence of antiphospholipid antibodies is associated with seizure frequency in refractory epilepsy. In the third study, we measured serum levels of IL-6 and IL-1RA in 86 well-evaluated patients with refractory focal epilepsy and in 5 patients with controlled focal epilepsy. Epilepsy was evaluated based on the patient history, electroclinical findings, and high-resolution brain MRI. Sixty-three healthy blood donors served as control subjects. Two blood samples obtained with a three-month interval were drawn similarly to that described for the antiphospholipid study. IL-6 concentrations were chronically increased in epilepsy patients compared with control subjects. All patients with increased levels of IL-6 had TLE. Furthermore, the mean and the median serum levels of IL-6 were higher in patients with TLE than in patients with extra-TLE. The concentrations of IL-1RA were not significantly different in patients compared with control subjects, although the patients with TLE tended to demonstrate smaller increases in the levels of IL-1RA. Age, sex, epilepsy surgery, and duratio! n of epilepsy were not associated with the level of IL-6. These findings demonstrate the importance of epilepsy type in determining the chronically increased levels of IL-6 in patients with refractory focal epilepsy. In the last part of the dissertation, we studied GADA with an RIA in the serum of 253 well-evaluated patients with refractory focal (184 patients), controlled focal (25), or primarily generalised epilepsy (44). The positive samples of patients were confirmed by IHC and WB in serum and CSF. The control samples for RIA were obtained from 200 non-diabetics without a history of epilepsy. In the patients with increased levels of GADA, serum was screened for polyendocrinopathies. Epilepsy was carefully classified based on patient histories, seizure semiology, and high-resolution brain MRI. A homogeneous subgroup of patients with increased levels of GADA was discovered. The majority of the patients with high levels of GADA had TLE, and all exhibited polyendocrinopathies, indicating an immune-mediated origin of epilepsy. IS in a few patients with high levels of GADA supports the CNS origin of GADA.

The aetiology of epilepsy is important for determining the prognosis of epilepsy. In patients with cryptogenic refractory epilepsy, continuous new drug trials are suggested because there are always patients who may benefit from them. The presence of IL-6 and a high level of GADA are increased in patients with TLE, but not in those with extra-TLE. In the GADA study, the polyendocrinopathies in patients with high levels of GADA, and IS of GADA in a few patients, strongly suggest an immunological background of epilepsy in these patients. IS of GADA might be a marker of an ongoing immunological process in the brain. These findings suggest that immunological mediators, such as antiphospholipid antibodies, cytokines, and GADA may serve as clinically significant inflammatory markers in refractory epilepsy. Measurements of IL-6 and GADA could be used to distinguish TLE from extra-TLE. In patients with epilepsy and specific autoantibodies or cytokines, alternative therapeutic interventions such as immunotherapy could be offered. Further studies are needed to determine the cause and effect relationship of seizures and immunological changes, as well as the effects of immunotherapeutic drugs, especially in patients with new-onset epilepsy.