Two decades of research towards a potential first anti-epileptic drug.

The basic mechanisms by which brain insults, such as trauma, stroke or status epilepticus produce epilepsy are not completely understood, and effective preventive measures and treatment are still not available in the clinical setting. Over the last 2 decades we have conducted several studies with animal models of epilepsy (rodents and non-human primates) and demonstrated that drugs that modify neuronal plastic processes, such as anticholinergic agents (e.g., antimuscarinic compounds), if administered soon after brain injury and over a period of 10-20 days, have the potential to modify the natural course of post-traumatic epilepsy. To that end treatment with scopolamine showed promising results as a candidate agent in both the pilocarpine and kainate models. We then showed that biperiden, yet another cholinergic antagonist acting in the muscarinic receptor, that is widely used to treat Parkinson's disease, also decreased the incidence and intensity of spontaneous epileptic seizures, delaying their appearance in the pilocarpine model of epilepsy. In other words, biperiden showed to be a potential candidate to be further investigated as an antiepileptogenic agent. Accordingly, we tested the safety of biperiden in a small group of patients (as a small phase II safety assessment) and confirmed its safety in the context of traumatic brain injury (TBI). Now, we provide information on our ongoing project to evaluate the efficacy of biperiden in preventing the development of epilepsy in patients that suffered TBI, in a double blind, randomized, placebo-controlled trial.

Epilepsy in patients with angelman syndrome caused by deletion of the chromosome 15q11-13.

BACKGROUND: Angelman syndrome (AS) is a neurogenetic disorder characterized by severe mental retardation, speech disorder, stereotyped jerky movements, and a peculiar behavioral profile, with a happy disposition and outbursts of laughter. Most patients with AS present with epilepsy and suggestive electroencephalographic patterns, which may be used as diagnostic criteria. OBJECTIVE: To study epilepsy and response to treatment in a series of patients with AS determined by deletion. DESIGN: Parent and caregiver interview and medical record review. SETTING: Epilepsy Center at the University of São Paulo. PATIENTS: Nineteen patients with AS determined by deletion of chromosome 15q11-13. MAIN OUTCOME MEASURES: Epilepsy severity, epilepsy evolution, and response to antiepileptic drug treatment. RESULTS: All patients with AS in this group had generalized epilepsy, and 10 (53%) also had partial epilepsy. Main seizure types were atypical absences and myoclonic and tonic-clonic seizures. Mean age at onset was 1 year 1 month. Epilepsy aggravated by fever occurred in 10 patients (53%) and status epilepticus in 16 (84%). Eighteen patients (95%) had previous or current history of daily seizures, of which 14 (64%) had disabling seizures. Multiple seizure types were observed in 13 patients (53%). History of refractory epilepsy was reported in 16 patients (84%). Parents reported improvement, characterized by decrease in seizure frequency or seizure control, at the mean age of 5.3 years. Therefore, most of these patients had a period of refractory epilepsy; however, improvement occurred during late childhood and puberty. The best therapeutic response was obtained with valproic acid alone or in association with phenobarbital or clonazepam. Epilepsy was aggravated by carbamazepine, oxcarbazepine, and vigabatrin. CONCLUSIONS: Patients with AS with deletion have epilepsy with early onset and stereotyped electroclinical profile regarding seizure type, severity, and response to antiepileptic drug treatment. Another feature of AS is the age-related improvement, even in refractory cases, during late childhood and puberty. These characteristics are not specific to this syndrome but, when inserted in the proper clinical context, may anticipate diagnosis. We believe that AS should be considered a differential diagnosis in developmentally delayed infants with severe, generalized, cryptogenic epilepsy; however, a proper electroclinical delineation of each genetic group is mandatory.

Serial and prolonged EEG monitoring in anti-N-Methyl-d-Aspartate receptor encephalitis.

OBJECTIVE: To describe serial electroencephalographic (EEG) findings of three patients with anti-NMDAR encephalitis. METHODS: Three women (age 15-34years) with confirmed anti-NMDAR encephalitis underwent serial EEG recordings. Continuous EEG for 72h was performed in one case and 3-day video-EEG monitoring was obtained in two cases. RESULTS: Generalized rhythmic delta activity (GRDA) was found in all patients. GRDA persisted for hours, but was not continuous on a 24-h EEG recording, disclosed no frequency, voltage or field evolution, and was not seen on the first EEG of two patients. Extreme delta brush was noted in two patients who presented more severe disease. One patient presented seizures, which were electrographically and clinically different from the GRDA pattern and from dyskinetic movements. CONCLUSIONS: Serial or continuous EEG may be necessary to detect GRDA in anti-NMDAR patients. To avoid unnecessary treatment, this pattern should not be interpreted as indicative of ictal activity, unless there is evidence of its ictal nature. SIGNIFICANCE: Our findings may contribute to the diagnosis of anti-NMDAR encephalitis in cases with characteristic clinical picture.

Angelman syndrome caused by deletion: a genotype-phenotype correlation determined by breakpoint.

OBJECTIVES: Deletion of the chromosome 15q11-q13, the most common genetic mechanism associated with Angelman syndrome (AS), is highly associated with a severe phenotype. However, deletion is not a genetically homogeneous group as it is composed by two main groups: Class I with breakpoints at BP1 (proximal) and BP3 (distal) and Class II present breakpoints at BP2 (proximal) and BP3 (distal). In this study, we aimed to evaluate the impact of the breakpoint on the electroclinical profile. METHODS: We evaluated 16 patients with AS caused by 15q11-13 deletion (6 were Class I; 10 were Class II). We characterized epilepsy features by clinical history obtained from parents and caretakers with a pre-standard questionnaire. These data were corroborated by medical records, contact with previous physicians, and video-EEG monitoring. Suggestive EEG patterns for AS were classified according to the classical description of Boyd et al. (1988). RESULTS: AS patients with BP1-BP3 deletion had significantly more daily and disabling seizures than AS patients with BP1-BP2 deletion. They also presented a significant higher frequency of status epilepticus and epilepsy aggravated by fever. Need for polytherapy was significantly more frequent in BP1-BP3 patients. EEG features were similar in both groups. CONCLUSION: This study shows a significant correlation between the two deletion classes and AS clinical, but not the electrographic phenotype. Epilepsy is more severe and refractory to treatment in patients with larger deletions. Deletion is not a homogeneous group and knowledge on the breakpoint may have a clinical implication and represent an important factor in parental counseling.