New antiepileptic drugs: focus on ezogabine, clobazam, and perampanel.

Ezogabine, clobazam, and perampanel are among the newest antiseizure drugs approved by the Food and Drug Administration between 2011 and 2012. Ezogabine and perampanel are approved for adjunctive treatment of partial epilepsy. Perampanel is also approved for adjunctive treatment of primary generalized tonic-clonic seizures. Ezogabine and perampanel have novel mechanisms of action. Ezogabine binds to voltage-gated potassium channels and increases the M-current thereby causing membrane hyperpolarization. Perampanel is a selective, non-competitive 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid receptor antagonist, which reduces neuronal excitation. Clobazam has been used worldwide since the 1970s and is approved for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. Clobazam is the only 1,5-benzodiazepine currently in clinical use, which is less sedating than the commonly used 1,4-benzodiazepines. Phase III multicenter, randomized, double-blind, placebo-controlled trials demonstrated efficacy and good tolerability of these 3 new antiepileptic drugs. These drugs represent a welcome addition to the armamentarium of practitioners, but it remains to be seen how they will affect the landscape of pharmacoresistant epilepsy.

New drug classes for the treatment of partial onset epilepsy: focus on perampanel.

Perampanel (2-[2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl] benzonitrile hydrate) is the latest in the line of new antiepileptic drugs with a novel mechanism of action. Perampanel inhibits α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-induced increases in intracellular Ca(2+) and selectively blocks AMPA receptor-mediated synaptic transmission, thus reducing neuronal excitation. Three Phase III multicenter, randomized, double-blind, placebo-controlled trials demonstrated the efficacy and good tolerability of perampanel as adjunctive treatment in patients with refractory partial-onset seizures. The drug is approved for use in the European Union and United States, with expected release onto the American market in June-September 2013, pending US Drug Enforcement Agency classification. The pharmacology of perampanel offers potential as more than just another new antiepileptic drug. This first-in-class drug will provide another option for practitioners of rational polytherapy. As an AMPA-receptor antagonist, perampanel may possess antiepileptogenic properties in addition to its demonstrated antiseizure properties.

Epilepsy and neuropsychological comorbidities.

PURPOSE OF REVIEW: Epilepsy is a chronic disorder with several associated comorbidities requiring timely recognition and treatment. This article discusses aspects of cognitive impairment; psychiatric disorders including depression, anxiety, and psychosis; and health-related quality-of-life issues pertaining to patients with epilepsy. RECENT FINDINGS: Cognitive problems in epilepsy may be present early in the disease course. Advances in imaging techniques are allowing correlation of structure and function as they relate to cognitive impairment in epilepsy. The relationship between epilepsy, depression, and anxiety is increasingly recognized, and these psychiatric comorbidities may affect suicide risk, patient-reported adverse antiepileptic drug effects, and quality of life. Psychiatric disorders are underrecognized and undertreated in patients with epilepsy. SUMMARY: Physicians who treat patients with epilepsy should be aware of the major impact that cognitive impairment and psychiatric comorbidities have on these patients. Identifying and treating these comorbidities in epilepsy patients is just as important as seizure treatment.

Electroencephalographic findings in acute subdural hematoma.

The aim was to determine the electroencephalographic (or electroencephalogram [EEG]) findings predictive of functional outcome in a subset of patients with acute subdural hematoma (SDH) with epileptiform activity on their EEG. Twenty-four patients who underwent evacuation for acute or acute-on-chronic SDH and with epileptiform activity on EEG were identified retrospectively. Their EEGs were reviewed and the findings categorized along with clinical information, the preoperative computed tomography (CT) scan, and functional outcome. Twenty-one patients (87%) had epileptiform discharges on EEG; 13 of them (62%) had midline epileptiform discharges and 9 of them (43%) had periodic lateralized epileptiform discharges (PLEDs). Both types of epileptiform discharges were significantly associated with the degree of midline shift on neuroimaging (P = 0.01, P = 0.04, respectively). Poor early outcomes were associated with the presence of bilateral (P = 0.03), midline (P = 0.04), and bilateral independent multifocal discharges (P = 0.09) on EEG. The EEG findings in this group of patients were complex. Epileptiform discharges were common, and specific types were associated with midline shift on neuroimaging and poor functional outcome at hospital discharge. Improvement in follow-up EEG examinations over time was predictive of good long-term functional outcome.

Extratemporal EEG and MRI findings in ANNA-1 (anti-Hu) encephalitis.

INTRODUCTION: Extratemporal involvement has been reported in ANNA-1 encephalitis, but the rate is unknown. EEG and MRI are used in the evaluation of these patients, but the relative value of each has not been determined. The study objectives were to measure the rate of extratemporal abnormalities, and to determine the relative value of MRI and EEG in an ANNA-1 encephalitis cohort. METHODS: We selected from the neuroimmunology laboratory database ANNA-1 seropositive patients who underwent: (1) neurological evaluation at Mayo Clinic Rochester between 1990 and 2010 (2) comprehensive autoimmune paraneoplastic serological evaluation and (3) at least one EEG and MRI. RESULTS: Of 28 identified patients, the EEG was abnormal in 24 (86%). Extratemporal abnormalities included slowing [12 (43%)], epileptiform discharges [eight (29%)], and epilepsia partialis continua [two (7%)]. In ten patients, only the MRI or EEG showed an abnormality but not both. Six patients had focal EEG abnormalities localized to regions other than those on MRI. In 13 patients with a negative MRI, the EEG showed a focal abnormality in seven (54%). CONCLUSION: Extratemporal EEG abnormalities are present in nearly half of ANNA-1 seropositive patients, suggesting that extratemporal involvement is common. EEG and MRI are often complementary in determining lesional distribution in ANNA-1 seropositive patients.

Seizures after evacuation of subdural hematomas: incidence, risk factors, and functional impact.

OBJECT: The purpose of this study was to evaluate the incidence of seizures or epileptiform abnormalities on electroencephalography (EEG) studies in patients undergoing surgical treatment for acute subdural hematoma (SDH). METHODS: This was a retrospective study of 134 consecutive patients with acute or acute-on-chronic SDH who underwent surgical treatment at the authors' institution between January 2004 and July 2008. Detailed information was collected regarding baseline clinical data (including preexistent functional impairment); Glasgow Coma Scale (GCS) sum scores before and 24 hours after surgery; presence of clinical seizures; EEG findings; and functional outcome on discharge and up to the 6-month follow-up. All brain CT scans were reviewed to calculate SDH volume and midline shift. The Glasgow Outcome Scale (GOS) score was used for functional assessment, and GOS scores of 1-3 were considered indicative of poor outcome. Univariate and multivariate logistic regression analyses were performed to identify statistical associations. RESULTS: Clinical seizures or epileptiform changes on EEG were observed during the acute postoperative period in 33 patients (25%). Preexistent functional impairment and seizures/epileptiform EEG findings after surgery were independently associated with poor functional outcome upon hospital discharge (p < 0.001 for both). Preexistent functional impairment (p < 0.001), lower GCS score before surgery (p = 0.04), and lower GCS score 24 hours after surgery (p = 0.007), but not seizures/epileptiform EEG findings, were independently associated with poor functional recovery at 1- to 6-month follow-up evaluations. Seizures/epileptiform EEG findings had a strong association with lower GCS scores after surgery (p = 0.01), and they were more common in patients who underwent evacuation by craniotomy (p = 0.02). CONCLUSIONS: Epileptic complications are common after acute SDH evacuation, and should be suspected in patients with an unanticipated depressed level of consciousness after surgery. Seizures worsen early functional outcome, but delayed favorable recovery is possible. Therefore, one should be cautious when discussing prognosis in the early postoperative period of patients with epileptic complications.

The classification of seizures and epilepsy syndromes.

This chapter focuses on the classification of seizures and epilepsy syndromes based on the International League Against Epilepsy's classification systems from 1981 and 1989, respectively, which are still used today in clinical practice and have formed the basis for a worldwide standardized approach to diagnosing, treating, and studying seizure disorders. This classification system is based on clinical seizure semiology and EEG correlation and makes a distinction between focal and generalized seizures. The clinical semiology and localization of simple partial, complex partial, and generalized seizures are discussed. Some common partial and generalized epilepsy syndromes are also highlighted.

Early onset familial Alzheimer Disease with spastic paraparesis, dysarthria, and seizures and N135S mutation in PSEN1.

OBJECTIVE: Early onset familial Alzheimer disease (EOFAD) can be caused by mutations in genes for amyloid precursor protein, presenilin 1 (PSEN1), or presenilin 2 (PSEN2). There is considerable phenotypic variability in EOFAD, including some patients with spastic paraparesis. The objective is to describe clinical and neuropathologic features of a family with a PSEN1 mutation that has been reported previously, without autopsy confirmation, in a single Greek family whose affected members presented with memory loss in their 30s, as well as variable limb spasticity and seizures. METHODS: We prospectively evaluated 2 children (son and daughter) with EOFAD and reviewed medical records on their mother. Archival material from the autopsy of the mother was reviewed and postmortem studies were performed on the brain of the daughter. RESULTS: All 3 individuals in this family had disease onset in their 30s, with cognitive deficits in multiple domains, including memory, language, and attention, as well as less common features such as spastic dysarthria, limb spasticity, and seizures. At autopsy both the mother and her daughter had pathologic findings of Alzheimer disease, and histologic evidence of corticospinal tract degeneration. Genetic studies revealed a mutation in PSEN1 leading to an asparagine to serine substitution at amino acid residue 135 (N135S) in presenilin 1. CONCLUSIONS: This is the first description of neuropathologic findings in EOFAD owing to N135S PSEN1 mutation. The clinical phenotype was remarkable for spastic dysarthria, limb spasticity, and seizures, in addition to more typical features of EOFAD.