Marian Todaro

MRI-identified pathology in adults with new-onset seizures

Objective: To determine the frequency and nature of potentially epileptogenic lesions on MRI in adults with new-onset seizures. Methods: We prospectively studied 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 10-year period. The MRI scans, performed clinically on 3- and 1.5-tesla scanners, were reviewed for their diagnostic yield, nature of abnormalities, and their association with abnormal electrical activity on EEG. Results: MRI scans were acquired in 764 patients (77%); potentially epileptogenic lesions were detected in 177 (23%). The frequency of potentially epileptogenic lesions was higher in patients who were diagnosed as having an epileptic seizure (28%) than in those with a nonepileptic event (8%) (p < 0.001), and highest in those who had focal-onset seizures (53%) (p < 0.001). The most common lesion type in patients with focal seizures was gliosis or encephalomalacia (49%). Other common lesion types were tumors (15%), cavernomas (9%), and mesial temporal sclerosis (9%). Abnormal MRI and EEG were concordant in 18% of patients, with EEG being normal in 55% of patients with epileptogenic lesions. Conclusions: MRI reveals potentially epileptogenic lesions in a minority of patients with 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 chance of having an abnormal EEG.

The pathophysiology of cardiac dysfunction in epilepsy

Alterations in cardiac electrophysiology are an established consequence of long-standing drug resistant epilepsy. Patients with chronic epilepsy display abnormalities in both sinoatrial node pacemaker current as well as ventricular repolarizing current that places them at a greater risk of developing life-threatening cardiac arrhythmias. The development of cardiac arrhythmias secondary to drug resistant epilepsy is believed to be a key mechanism underlying the phenomenon of Sudden Unexpected Death in EPilepsy (SUDEP). Though an increasing amount of studies examining both animal models and human patients have provided evidence that chronic epilepsy can detrimentally affect cardiac function, the underlying pathophysiology remains unclear. Recent work has shown the expression of several key cardiac ion channels to be altered in animal models of genetic and acquired epilepsies. This has led to the currently held paradigm that cardiac ion channel expression may be secondarily altered as a consequence of seizure activity-resulting in electrophysiological cardiac dysfunction. Furthermore, cortical autonomic dysfunction - resulting from seizure activity-has also been suggested to play a role, whereby seizure activity may indirectly influence cardiac function via altering centrally-mediated autonomic output to the heart. In this review, we discuss various cardiac dysrhythmias associated with seizure events-including tachycardia, bradycardia and QT prolongation, both ictally and inter-ictally, as well as the role of the autonomic nervous system. We further discuss key ion channels expressed in both the heart and the brain that have been shown to be altered in epilepsy and may be responsible for the development of cardiac dysrhythmias secondary to chronic epilepsy.

Disseminated Scedosporium prolificans infection in an ‘extensive metaboliser’: navigating the minefield of drug interactions and pharmacogenomics

We report a case of non‐fatal disseminated Scedosporium prolificans infection, including central nervous system disease and endophthalmitis, in a relapsed acute myeloid leukaemia patient with extensive CYP2C19 metabolism. Successful treatment required aggressive surgical debridement, three times daily voriconazole dosing and cimetidine CYP2C19 inhibition. In addition, the unique use of miltefosine was employed due to azole‐chemotherapeutic drug interactions. Prolonged survival following disseminated S. prolificans, adjunctive miltefosine and augmentation of voriconazole exposure with cimetidine CYP2C19 inhibition has not been reported.

The antiepileptic medications carbamazepine and phenytoin inhibit native sodium currents in murine osteoblasts.

Fracture risk is a serious comorbidity in epilepsy and may relate to the use of antiepileptic drugs (AEDs). Many AEDs inhibit ion channel function, and the expression of these channels in osteoblasts raises the question of whether altered bone signaling increases bone fragility. We aimed to confirm the expression of voltage‐gated sodium (NaV) channels in mouse osteoblasts, and to investigate the action of carbamazepine and phenytoin on NaV channels.

Association between CYP2C19 Polymorphisms and Outcomes in Cerebral Endovascular Therapy

BACKGROUND AND PURPOSE: Differing responses to clopidogrel following endovascular treatment of cerebrovascular diseases may increase the risk of vascular complications. CYP2C19 gene polymorphisms influence clopidogrel activity. We aimed to study the clinical impact of CYP2C19 gene polymorphisms in patients undergoing endovascular treatment. MATERIALS AND METHODS: This was a prospective, longitudinal, observational study. Information on demographics and cerebrovascular status was collected as baseline. Clopidogrel response was tested by the VerifyNow P2Y12 assay. CYP2C19 genotyping was undertaken by polymerase chain reaction–restriction fragment length polymorphism. Three-month follow-up data included vascular complications, mortality, and modified Rankin Scale score. Associations were investigated among CYP2C19 genotypes, clopidogrel responsiveness, and clinical outcomes. RESULTS: One hundred and eight participants were included. Median age was 56 years (interquartile range, 48.8–65.0 years), and 35 (32.4%) were male. Forty-four participants were classified into group 1 (homozygous CYP2C19*1/*1); 31, into group 2 (25 with CYP2C19*1/*2, two with CYP2C19*1/*3, three with CYP2C19*3/*3, one with CYP2C19*2/*3); 28, into group 3 (24 with CYP2C19*1/*17, four with CYP2C19*17/*17); and 5, into group 4 (CYP2C19*2/*17). A significantly higher proportion of participants in group 3 experienced ischemic events (9 of 28, 32.1%) compared with group 1 (5 of 44, 11.4%; P = .04; odds ratio, 3.7; 95% confidence interval, 1.1–12.6). There was no significant difference in clopidogrel response among the 4 genotype groups. CONCLUSIONS: Individuals with CYP2C19*17 may have increased risk of ischemic events following endovascular treatment, independent of clopidogrel responsiveness. Larger studies are required to confirm the influence of CYP2C19*17 on clinical outcomes and to understand the mechanisms for increased ischemic events.

An interdigitated electrode biosensor platform for rapid HLA-B*15: 02 genotyping for prevention of drug hypersensitivity

Prevention of life threatening hypersensitivity reactions to carbamazepine is possible through pre-treatment screening of the associated HLA-B*15:02 risk allele. However, clinical implementation of screening is hindered by the high cost and slow turnaround of conventional HLA typing methods. We have developed an interdigitated electrode (IDE) biosensor platform utilizing loop mediated isothermal amplification (LAMP) that can rapidly detect the HLA-B*15:02 allele. DNA amplification is followed by solid-phase hybridization of LAMP amplicons to a DNA probe immobilized on the IDE sensor surface, resulting in a change in sensor impedance. The testing platform does not require DNA extraction or post-amplification staining, achieving sample-to-answer in 1 h and 20 min. The platform was tested on 27 whole blood samples (14 HLA-B*15:02 positive and 13 negative) with sensitivity of 92.9% and specificity of 84.6% when applying a cutoff of impedance change. Based on these characters the LAMP-IDE platform has potential to be further developed into point-of-care use to help overcome barriers in HLA-B*15:02 screening.