Background: MLC601 is a possible modulator of amyloid precursor protein processing, and in a clinical trial study MLC601 showed some effectiveness in cognitive function in Alzheimer's disease (AD) patients. We aimed to evaluate the effectiveness and safety of MLC601 in the treatment of mild to moderate AD as compared to 3 approved cholinesterase inhibitors (ChEIs) including donepezil, rivastigmine and galantamine. Methods: In a multicenter, nonblinded, randomized controlled trial, 264 volunteers with AD were randomly divided into 4 groups of 66; groups 1, 2, 3 and 4 received donepezil, rivastigmine, MLC601 and galantamine, respectively. Subjects underwent a clinical diagnostic interview and a cognitive/functional battery including the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog). Patients were visited every 4 months, and the score of cognition was recorded by the neurologists. Results: There were no significant differences in age, sex, marital status and baseline score of cognition among the 4 groups. In total, 39 patients (14.7%) left the study. Trend of cognition changes based on the modifications over the time for MMSE and ADAS-cog scores did not differ significantly among groups (p = 0.92 for MMSE and p = 0.87 for ADAS-Cog). Conclusion: MLC601 showed a promising safety profile and also efficacy compared to 3 FDA-approved ChEIs.

Epilepsy is a common and debilitating neurological disease. When medication cannot control seizures in up to 40% of cases, surgical resection of epileptogenic tissue is a clinically and cost- effective therapy to achieve seizure freedom. To simultaneously resect minimal yet sufficient cortex, exquisite localization of the epileptogenic zone (EZ) is crucial. However, localization is not straightforward, given relative difficulty of capturing seizures, constraints of the inverse problem in source localization, and possible disparate locations of symptomatogenic vs. epileptogenic regions. Thus, attention has been paid to which state of vigilance best localizes the EZ, in the hopes that one or another sleep-wake state may hold the key to improved accuracy of localization. Studies investigating this topic have employed diverse methodologies and produced diverse results. Nonetheless, rapid eye movement sleep (REM) has emerged as a promising sleep-wake state, as epileptic phenomena captured in REM may spatially correspond more closely to the EZ. Cortical neuronal asynchrony in REM may spatially constrain epileptic phenomena to reduce propagation away from the source generator, rendering them of high localizing value. However, some recent work demonstrates best localization in sleep-wake states other than REM, and there are reports of REM providing clearly false localization. Moreover, synchronistic properties and basic mechanisms of human REM remain to be fully characterized. Amidst these uncertainties, there is an urgent need for recording and analytical techniques to improve accuracy of localization. Here we present a systematic review and quantitative analysis of pertinent literature on whether and how REM may help localize epileptogenic foci. To help streamline and accelerate future work on the intriguing anti-epileptic properties of REM, we also introduce a simple, conceptually clear set-theoretic framework to conveniently and rigorously describe the spatial properties of epileptic phenomena in the brain.

Study Objectives To compare estimated epileptic source localizations from 5 sleep-wake states (SWS): wakefulness (W), rapid eye movement sleep (REM), and non-REM 1-3. Methods Electrical source localization (sLORETA) of interictal spikes from different SWS on surface EEG from the epilepsy monitoring unit at spike peak and take-off, with results mapped to individual brain models for 75% of patients. Concordance was defined as source localization voxels shared between 2-5 SWS, and discordance as those unique to 1 SWS against 1-4 other SWS. Results 563 spikes from 16 prospectively recruited focal epilepsy patients across 161 day-nights. SWS exerted significant differences at spike peak but not take-off. Source localization size did not vary between SWS. REM localizations were smaller in multifocal than unifocal patients (28.8% vs. 54.4%, p=0.0091). All 5 SWS contributed about 45% of their localizations to converge onto 17.0±15.5% voxels. Against any one other SWS, REM was least concordant (54.4% vs. 66.9%, p=0.0006) and most discordant (39.3% vs. 29.6%, p=0.0008). REM also yielded the most unique localizations (20.0% vs. 8.6%, p=0.0059). Conclusions REM was best suited to identify candidate epileptic sources. sLORETA proposes a model in which an “omni-concordant core” of source localizations shared by all 5 SWS is surrounded by a “penumbra” of source localizations shared by some but not all SWS. Uniquely, REM spares this core to “move” source voxels from the penumbra to unique cortex not localized by other SWS. This may reflect differential intra-spike propagation in REM, which may account for its reported superior localizing abilities.

Drug-resistant epilepsy seems like a different disease compared with easy to control epilepsy, and new strategies are needed to help these patients. Vagus nerve stimulation (VNS) therapy is the most frequently used neurostimulation modality for patients with drug-resistant epilepsy who are not eligible for seizure surgery. In this study, we aimed to evaluate the efficacy and adverse effects of VNS in patients with drug-resistant epilepsy in an open-label, prospective, long-term study in Iran. We selected 48 patients with partial-onset drug-resistant epilepsy. Implantations were performed in the neurosurgery department of Loghman Hospital, Tehran, Iran. Follow-up visits were done on monthly bases for 5 years. Forty-four patients completed the study. Mean age of patients was 24.4 years. Mean years of epilepsy history was 14 years. The mean number of anti-epileptic drugs did not significantly change over five years (p = 0.15). There was no exacerbation of epilepsy; however, one patient discontinued his therapy due to unsatisfactory results. Five patient had more than 50 %, and 26 patients (59 %) had 25-49 % reduction in the frequency of monthly seizures persistently. Overall mean frequency of monthly seizures decreased by 57.8, 59.6, 65, 65.9, and 67 %, in 1st, 2nd, 3rd, 4th, and 5th years of follow-up, respectively. Most common side effects were as follows: hoarseness (25 %) and throat discomfort (10 %). We found VNS as a safe and effective therapy for drug-resistant epilepsy, with an approximate long-term decrease in mean seizure frequency of 57.8-67 %. Thus, VNS is recommended for suitable patients in developing countries.