Medicine (RMH) - Theses
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ItemIdentification of predictors of epilepsy outcomes( 2013)BACKGROUND: Epilepsy is a group of complex conditions characterized by the occurrence of recurrent spontaneous seizures, associated with high risk of brain abnormalities, co-morbid disorders and premature mortality. These issues in patients with new onset-seizures have not been well characterized. Furthermore, the first anti-epileptic drug (AED) treatment will fail in more than 50% of patients because of inadequate seizure control or intolerable adverse effects. Substitution to a newer AED may result in better outcomes. AIMS: (1) To determine the frequency and type of potentially epileptogenic abnormalities identified on MRI, in patients presenting with a possible new-onset seizure disorder, and their association with abnormal electrical activity on electroencephalogram (EEG), the frequency of co-morbidities and injuries, and the incidence of mortality (2) To examine whether patients who fail their first AED will have better neuropsychiatric, neurocognitive, quality of life (QOL), bone density and content, body composition and metabolism outcomes if substituted to monotherapy treatment with a newer-generation AED, levetiracetam, compared with another older-generation AED, valproate or carbamazepine. METHODS: (1) A consecutive series of 993 patients (597 males [61%], mean (SD) age: 42.2 (18.8) years, range: 14.3-94.3 years) who presented to an adult First Seizure Clinic over a ten year period were studied. The MRI scans were acquired using a dedicated epilepsy protocol or other specific protocols depending on clinical indication on either a 1.5T or 3.0T scanners. The co-morbidities and injuries were obtained from two state-wide administrative datasets, the Victorian Admitted Episodes Dataset (VAED) and the Victorian Emergency Minimum Dataset (VEMD), for the period from June 18, 1999 to June 30, 2010. Mortality data were collated from the National Death Index (NDI) developed by the Australian Institute of Health and Welfare (AIHW). (2) A randomized comparative trial was undertaken. Participants with focal epilepsy who had failed monotherapy with phenytoin sodium, carbamazepine, or valproate sodium were randomized to substitution monotherapy with levetiracetam (n= 51) or a different older AED (n= 48). Assessments were performed at baseline, 3 months, and 12 months using questionnaires measuring neuropsychiatric, QOL, seizure control, AED adverse effects, and neurocognitive outcomes. Assessments of bone density and content, body composition and metabolism were performed at 3- and 15 months after randomization. The assessments included: areal bone mineral density (aBMD) at lumbar spine, total hip, forearm, and femoral neck and total body bone mineral content [dual energy x-ray absorptiometry (DXA); Hologic QDR® 4500A densitometer], body composition [Hologic Software Version 5.73], peripheral quantitative computed tomography at non-dominant radius and tibia [pQCT; Stratec XCT 3000], serum markers of bone turnover, sex and metabolism hormones, questionnaires for bone health and lifestyle, blood pressure and anthropometry. RESULTS: (1) Potentially-epileptogenic lesions were detected in 177 (23%) of the patients in the First Seizure Clinic Cohort. Their frequency was higher in patients who had focal-onset seizures (53%). MRI and EEG were concordant in terms of the presence or absence of epilepsy associated abnormality in 62%, with 18% having an abnormality on both utilities. Almost 65% of patients with epilepsy had, at least, one co-morbid disorder as defined by an epilepsy-specific co-morbidity index, and 32% presented to Emergency Departments after sustaining an injury. Those patients were more likely to be males, have lesional focal epilepsy, frequent seizures and be diagnosed with epilepsy at 65+ years of age. The overall case mortality was 8.3% (82 cases) in the cohort. Standardized mortality ratio (SMR) for patients with new-onset seizures was 2.2 (95% CI 1.73-2.80); p< 0.001. The highest excess mortality was seen in younger patients (< 60 years). Proportionate mortality ratio (PMR) was highest for deaths from cerebrovascular diseases (16%) and malignant neoplasms (16%). Epilepsy was listed as the leading cause of death in 10%. (2) In the RCT, there were no differences in depression scores at 3 months between the treatment groups (improvement in 39.5% of the levetiracetam group vs. 34.1% of the older AED group; p= 0.60), but a greater proportion of the older AED group improved on the 89-item Quality of Life in Epilepsy Inventory (QOLIE-89) compared with the levetiracetam group (71.1% vs. 48.8% respectively; p= 0.04). The QOL, anxiety, and AED adverse effects scores were improved in both groups at 3 and 12 months after randomization. There were significant decreases in both treatment groups in aBMD at the lumbar spine (-9.0%; p< 0.001 in the levetiracetam group and -9.8%; p <0.001 in the older AED group), forearm (-1.46%; p< 0.001 and -0.96%; p< 0.001 respectively) and femoral neck (-0.47%; p= 0.026 and -1.45%; p< 0.001 respectively) on DXA scanning. The total hip aBMD significantly decreased in the older AED group (-0.84%; p< 0.001). The treatment groups did differ only in the change in femoral neck aBMD (p= 0.005). The serum levels of C-terminal telopeptides of type I collagen (βCTX), a marker of bone resorption, decreased in both groups (-16.1%; p= 0.021and -15.2%; p= 0.028 respectively) while procollagen 1 N-terminal peptide (P1NP), a marker of bone formation, significantly decreased in the older AED group (-27.3%; p= 0.008). There was no significant change in percentage abdominal fat in either treatment group. CONCLUSIONS: (1) MRI reveals potentially-epileptogenic lesions in a minority of patients who present following a newly-diagnosed seizure disorder. Lesions are most common in patients who have experienced focal seizures. The presence of a potentially-epileptogenic MRI lesion did not influence the likelihood of having an abnormal EEG. The majority of patients with new-onset seizures who consult a specialized First Seizure Clinic suffer from somatic or psychiatric co-morbid disorders. This finding should provide useful implications in the diagnosis and management of epilepsy and co-existing conditions, as well as in health care provision. Patients with new-onset seizures have a two-fold increased mortality compared with the general population. Cerebrovascular disease, and neoplasms, but not epilepsy, were the leading causes of death in epilepsy. (2) Substitution monotherapy in a patient who is experiencing ongoing seizures or tolerability issues is associated with sustained improvements in measures of QOL, psychiatric and adverse events outcomes. The significant bone loss at the lumbar spine, forearm, and femoral neck seen in both treatment groups and the modest reduction in bone turnover indicates that the adverse effects on bone health of chronic AEDs is likely occur with the newer-generation AEDs as well the older-generation AEDs.