Lacosamide tolerability in adult patients with partial-onset seizures: Impact of planned reduction and mechanism of action of concomitant antiepileptic drugs.

OBJECTIVE: We evaluated the impact of planned dose reduction and mechanism of action of concomitant AEDs on tolerability in adults with partial-onset seizures undergoing lacosamide (LCM) titration. METHODS: Data were collected at baseline and 3-6 and 12-24 months post-LCM initiation. Subjects were categorized as having planned reduction of concomitant AEDs or not; AEDs were categorized as traditional sodium channel blockers (TSCB) or non-TSCB (NTSCB). Groups with/without planned reduction were compared on the presence and number of treatment-emergent adverse events (TEAEs) using chi-square tests or logistic regression and on time to LCM discontinuation with time-to-event methods controlling for standardized (STD) AED dose, a measure of concomitant AED load. Similar analyses were performed comparing subjects taking TSCB and NTSCB agents and used to identify relationships with ≥50% decreases in seizure frequency. RESULTS: One hundred six adults (mean age 41.4 ± 13.4; 50% male) underwent LCM titration from June 2009-2011 with complete data. Reduction of concomitant AEDs was planned at the time of LCM initiation in 59 (55.7%) subjects. Fewer subjects with planned reduction had TEAEs (49.2% vs. 68.1%; p=0.05), and these subjects had a lower risk of TEAEs (OR 0.36; p=0.019) after adjusting for STD AED dose. The hazard ratio (95% CI) for LCM discontinuation was 0.46 (0.23, 0.94) in subjects with planned reduction of concomitant AEDs vs. others (p=0.033) and 3.29 (1.01, 10.70) in subjects taking TSCB vs. NTSCB agents (p=0.048). Among all cases, those who ever had TEAEs had significantly higher STD dose at both follow-up visits (p=0.033 and p=0.023, respectively). Seizure outcomes were not significantly different between groups at the last follow-up assessment. SIGNIFICANCE: Planned reduction of concomitant AEDs during LCM initiation and the use of NTSCB agents only are associated with a reduced risk of TEAEs and LCM discontinuation in adults with partial-onset seizures. This study extends prior observations by considering total AED load in the assessment of tolerability and supports the benefits of early reduction of concomitant AEDs during LCM initiation.

Pathologic findings associated with invasive EEG monitoring for medically intractable epilepsy.

Invasive electroencephalography (EEG) monitoring is often needed for presurgical evaluation in patients with medically intractable epilepsy (MIE). This study retrospectively reviews the pathologic changes associated with EEG monitoring. Two hundred twenty-six patients who underwent invasive monitoring (53.5% males; mean age, 29.8 years) and 55 controls without EEG monitoring (52.7% males; mean age, 25.6 years) were evaluated. Median length of invasive EEG monitoring was 7.0 days. Compared with controls, patients who were monitored had more pathologic changes related to invasive EEG monitoring (n = 171 [75.7%] vs n = 12 [21.8%]; P < .0001) including meningeal or parenchymal chronic inflammation (n = 128 [56.4%] vs n = 11 [20.4%]; P < .0001) and acute contusion and/or acute/subacute infarct (n = 110 [48.5%] vs n = 0; P < .0001). Histologic evidence of pathologic changes typically associated with invasive monitoring and/or craniotomy occurred in 76% of our patients with invasive monitoring compared with 19% in patients without prior invasive EEG evaluation. The most common pathologic changes related to invasive monitoring were chronic inflammation and contusion/infarct.

Seizure outcome and its predictors after temporal lobe epilepsy surgery in patients with normal MRI.

PURPOSE: To characterize seizure outcomes following temporal lobe epilepsy (TLE) surgery in patients with normal preoperative brain magnetic resonance imaging (MRI). METHODS: We reviewed adult patients with pharmacoresistant epilepsy and normal MRI who underwent TLE surgery (1996-2009). Seizure outcomes were analyzed using survival and multivariate regression with Cox proportional hazard modeling. Two analyses were performed using two favorable outcome definitions: complete seizure freedom and Engel classification. KEY FINDINGS: Sixty-four patients were analyzed (mean follow-up 4.1 years; range 1-14.5 years). Most had a standard anterior temporal lobectomy (84%) and unremarkable pathology (45%). At 1 year, the chance of complete seizure freedom was 76% [95% confidence interval (CI) 71-81%] comparable to an 81% (95% CI 76-86%) chance of Engel score of 1. With longer follow-up, a progressively broadening significant discrepancy between the two outcome measures was observed. The chance of complete seizure freedom was 66% (95% CI 61-71%) at 2 years, and 47% (95% CI 40-54%) at 7 years and beyond, whereas the respective chances of achieving an Engel 1 classification were 76% (95% CI 70-82%), and 69% (95% CI 63-75%) at similar time points. Seizure outcome as defined by either measure was worse in patients with higher baseline seizure frequency (adjusted risk-ratio 2.7 when >12 seizures/month; p = 0.01) and with preoperative generalized tonic-clonic seizures (adjusted risk ratio 10.8; p = 0.0006). Memory measures declined with dominant hippocampus resections. SIGNIFICANCE: A normal MRI should not prevent presurgical evaluations in patients with suspected TLE, as favorable long-term postoperative seizure outcomes are possible. Proposed mechanisms of epileptogenicity and seizure recurrence in this group are discussed.

De novo sustained refractory status epilepticus and encephalopathy: a retrospective case series.

Refractory status epilepticus is a devastating persistent seizure state with a poor prognosis that requires emergency medical management. Recent studies have reported de novo, idiopathic refractory status epilepticus of unclear etiology in healthy young patients followed by severe neurologic sequelae. We present a series of 7 cases of de novo sustained refractory status epilepticus. We found that all patients were young and previously healthy and that, prior to the onset of refractory status epilepticus, all had prodromal viral-like symptoms. The onset of refractory status epilepticus was explosive and intractable, resulting in prolonged hospital stay and dependence on multiple antiepileptic medications. Clinical outcome was poor in all 7 patients. The laboratory findings suggest a possible immune activation that can have persisted in the nervous system after a nonspecific infection. We report on these patients so as to raise awareness of this unique entity to facilitate early diagnosis and treatment.

Neurodegeneration and neuroprotective agents in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune/ inflammatory disease of the central nervous system (CNS). MS affects more than two million people worldwide and has been recognized as the leading cause of neurological disability in young adults. MS has long been considered as a CNS disease of demyelination and inflammation. Axonal degeneration has however been increasingly accepted as a key pathogenetic element. Certain noninvasive tests such as optic coherence tomography (OCT), magnetization transfer imaging (MTI), and proton magnetic resonance spectroscopy (MRS) might be superior in early detection of axonal loss and neurodegeneration as compared to conventional neuroimaging studies. New therapeutic strategies targeting the neurodegenerative process in MS provide hope to the MS community. A number of phase II or III clinical trials that are designed to target such specific pathogenetic mechanisms include sodium channel blockers, matrix metalloproteinases (MMP) inhibitors, c-AMP selective phosphodiesterase inhibitors, NMDA receptor antagonists, amongst others. In the current review, we will discuss the current understanding of the mechanisms of neurodegeneration in MS, agents with neuroprotective properties, patents currently available and, their possible application in the treatment of MS.