Calcified Neurocysticercosis: Risk factors for calcification and associated factors for seizure relapse
Bustos, Javier A.
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Objective: Neurocysticerosis (NCC) is the leading cause of epilepsy in endemic areas. In the final stage of NCC, the viable intraparenchymal cysts die, either resolving completely or leaving calcified scars. In a proportion of patients they are accountable for the subsequent morbidity, mainly manifesting as epilepsy. These patients experience breakthrough seizures during their antiepileptic treatment and can later present with seizure relapse after their medication is withdrawn. This doctoral dissertation is intended to evaluate the proportion of calcification and its risk factors in patients with viable cysts who receive antiparasitic drugs (study 1) and the incidence and associated factors to seizure events in patients with already calcified NCC lesions during their antiepileptic treatment (study 2), and after the antiepileptic drug treatment is withdrawn (study 3). Methods: For the first study we evaluated the data of 220 adult patients with viable parenchymal NCC in a multilevel study from three previous clinical trials where patients received standard Albendazole (15 mg/kg/d), increased ABZ (22.5 mg/kg/d), or standard ABZ plus Praziquantel (PZQ, 50 mg/kg/d), and corticosteroids. Patients had MRI exams at baseline and at day 180 to assess cyst resolution and a CT scan at day 360 to assess calcification. For the second and third study we took advantage of a big cohort of patients with calcified NCC and neurological symptoms in Lima, Peru and developed a time-to-event study. For study two we selected patients with diagnoses of epilepsy who were under AED treatment (n=210) and for study three we included those patients from the cohort of 210 patient in whom their antiepileptic drug (AED) was withdrawn (n=62). In both studies we followed the participants for breakthrough seizure (study two) or seizure relapse (study three) from the time of enrollment until event, loss to follow-up, administrative censoring (36 months of follow-up or until November 2017) or withdrawal of AED (in case of study 2). During the follow-up in both studies, patients had a clinical evaluation every three months and were contacted by the study team by phone every two weeks. All seizure events were classified according the ILAE guideline. Results: The first study included 147 patients with a total of 497 cysts, with an overall percentage of calcification at one year after antiparasitic treatment of 37.8% (188/497). In the multilevel model, we found in seven predictors of calcification, two at cyst level: cysts larger than 14 mm and cysts with surrounding edema, and five at patient level: patients with more than 2 years of seizures, having mild antibody responses on EITB, an increased dose of ABZ alone, receiving low dose of dexamethasone, and no early re-treatment with antiparasitic drug. Study two involved 210 patients and 103 of those (49.1%) presented breakthrough seizure during the follow-up. In the time-to-event analysis the Kaplan-Meier method showed that only 36.0% remains free of epilepsy during the study time (36 months). The risk factors in the multivariate Cox analysis were having a seizure event in the year previous to the enrollment and a history of 10 or more seizure events. In the subsequent cohort (Study 3) 62 participants who withdrew AED were included, from them 17 (27.4%) presented with seizure relapses. The Kaplan-Meier estimator showed that the probability of being free of seizures after 3 years of AED withdrawal was 58.7%. The Cox model showed that the main risk factors were having seizures in the last two years before AED withdrawal which was observed in 31 participants; these participants had 9.2 times greater chances of having a seizure relapse. Because of that we perform a sub-analysis in this group and found that having a history of 10 or more seizures before AED withdrawal and a history of partial seizures with generalization or generalized seizures had a higher risk of having a seizure relapse, but without statistical significance. Conclusions: Residual calcified lesions after antiparasitic treatment in NCC represent less than half of cases and may be a preventable outcome. Some patients who present with remaining calcified scars developed breakthrough seizures under AED treatment and their management should be individualized. Finally, withdrawal of antiepileptic treatment should only be considered after at least two years since last seizure event.