Automating Interictal Spike Detection: Revisiting A Simple Threshold Rule.

Interictal spikes (IIS) are bursts of neuronal depolarization observed electrographically between periods of seizure activity in epilepsy patients. However, IISs are difficult to characterize morphologically and their effects on neurophysiology and cognitive function are poorly understood. Currently, IIS detection requires laborious manual assessment and marking of electroencephalography (EEG/iEEG) data. This practice is also subjective as the clinician has to select the mental threshold that EEG activity must exceed in order to be considered a spike. The work presented here details the development and implementation of a simple automated IIS detection algorithm. This preliminary study utilized intracranial EEG recordings collected from 7 epilepsy patients, and IISs were marked by a single physician for a total of 1339 IISs across 68 active electrodes. The proposed algorithm implements a simple threshold rule that scans through iEEG data and identifies IISs using various normalization techniques that eliminate the need for a more complex detector. The efficacy of the algorithm was determined by evaluating the sensitivity and specificity of the detector across a range of thresholds, and an approximate optimal threshold was determined using these results. With an average true positive rate of over 98% and a false positive rate of below 2%, the accuracy of this algorithm speaks to its use as a reliable diagnostic tool to detect IISs, which has direct applications in localizing where seizures start, detecting when seizures start, and in understanding cognitive impairment due to IISs. Furthermore, due to its speed and simplicity, this algorithm can be used for real-time detection of IIS that will ultimately allow physicians to study their clinical implications with high temporal resolution and individual adaptation.

Rufinamide for the treatment of epileptic spasms.

OBJECTIVE: The purpose of this study was to determine the safety and efficacy of rufinamide for treatment of epileptic spasms. METHODS: We retrospectively reviewed patients treated with rufinamide for epileptic spasms from January 2009 to March 2010. Age, presence of hypsarrhythmia, change in seizure frequency following rufinamide initiation, and side effects were assessed. Patients who had a ≥ 50% reduction in spasm frequency were considered responders. RESULTS: Of all 107 children treated with rufinamide during the study period, 38 (36%) had epileptic spasms. Median patient age was 7 years (range: 17 months to 23). One patient had hypsarrhythmia at the time of treatment with rufinamide, and 9 other patients had a history of hypsarrhythmia. Median starting dose of rufinamide was 9 mg/kg/day (range: 2-18) and median final treatment dose was 39 mg/kg/day (range: 8-92). All patients were receiving concurrent antiepileptic drug therapy, with the median number of antiepileptic drugs being 3 (range: 2-6). Median duration of follow-up since starting rufinamide was 171 days (range: 10-408). Responder rate was 53%. Median reduction in spasm frequency was 50% (interquartile range=-56 to 85%, P<0.05). Two patients (5%) achieved a >99% reduction in spasms. Rufinamide was discontinued in 7 of 38 patients (18%) because of lack of efficacy, worsening seizures, or other side effects. Minor side effects were reported in 14 of 38 patients (37%). CONCLUSIONS: Rufinamide appears to be a well-tolerated and efficacious adjunctive therapeutic option for children with epileptic spasms. A prospective study is warranted to validate our observations.

Circadian patterns of pediatric seizures.

OBJECTIVE: To evaluate the relationship of sleep/wake and day/night pattern to various seizure subtypes and epilepsy localizations. METHODS: Charts of 380 consecutive pediatric patients with epilepsy undergoing video-EEG (V-EEG) over 2 years were reviewed for seizure semiology, EEG localization, occurrence during the day (6 am-6 pm) or night, during wakefulness and sleep, 3-hour time blocks throughout 24 hours, and various epilepsy localizations, and etiology. RESULTS: A total of 1,008 seizures were analyzed in 225 children (mean age 8.5 ± 5.7 years). Sleep and wakefulness predicted seizure semiology and localization more reliably than daytime and nighttime. Auras, gelastic, dyscognitive, atonic, hypomotor, and myoclonic seizures, and epileptic spasms occurred more often in wakefulness, while tonic, tonic-clonic, automotor, and hypermotor seizures occurred more frequently in sleep (p < 0.05). Clonic, atonic, myoclonic, and hypomotor seizures occurred more frequently during daytime. Hypermotor and automotor seizures occurred more frequently at night (p < 0.05). Generalized seizures (6 am-12 pm), temporal lobe seizures (9 pm-9 am), frontal lobe seizures (12 am-6 am), parietal lobe seizures (6 am-9 am), and occipital lobe seizures (9 am-noon and 3-6 pm) revealed specific circadian patterns (p < 0.05). In addition, generalized and temporal lobe seizures occurred more frequently in wakefulness, while frontal and parietal seizures occurred more frequently in sleep, independent of day or night pattern (p < 0.05). CONCLUSION: Sleep and wakefulness, as well as time of day and night, are important considerations in proper characterization of seizure types and epilepsy localization. These findings may contribute to a better understanding of the mechanisms of nonrandom distribution of seizures, and may provide information for individualized treatment options.

Higher evening antiepileptic drug dose for nocturnal and early-morning seizures.

We describe 17 children with nocturnal or early-morning seizures who were switched to a proportionally higher evening dose of antiepileptic drugs and were retrospectively reviewed for seizure outcome and side effects. Of 10 children with unknown etiology, clinical presentation was consistent with nocturnal frontal lobe epilepsy (NFLE) in 5 and benign epilepsy with centrotemporal spikes (BECTS) in 3. After a mean follow-up of 5.3 months, 15 patients were classified as responders; 11 of these became seizure free (5 NFLE, 1 BECTS, 5 with structural lesions) and 4 (2 BECTS, 2 with structural lesions) experienced 75-90% reductions in seizures. Among two nonresponders, seizures in one had failed to resolve with epilepsy surgery. Nine subjects (53%) received monotherapy after dose modification, and none presented with worsening of seizures. Two complained of transient side effects (fatigue/somnolence). Differential dosing led to seizure freedom in 64.7% (11/17) of patients, and 88.2% (15/17) experienced ≥ 50% reductions in seizures.

Galantamine and nicotine have a synergistic effect on inhibition of microglial activation induced by HIV-1 gp120.

Chronic brain inflammation is the common final pathway in the majority of neurodegenerative diseases and central to this phenomenon is the immunological activation of brain mononuclear phagocyte cells, called microglia. This inflammatory mechanism is a central component of HIV-associated dementia (HAD). In the healthy state, there are endogenous signals from neurons and astrocytes, which limit excessive central nervous system (CNS) inflammation. However, the signals controlling this process have not been fully elucidated. Studies on the peripheral nervous system suggest that a cholinergic anti-inflammatory pathway regulates systemic inflammatory response by way of acetylcholine acting at the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) found on blood-borne macrophages. Recent data from our laboratory indicates that cultured microglial cells also express this same receptor and that microglial anti-inflammatory properties are mediated through it and the p44/42 mitogen-activated protein kinase (MAPK) system. Here we report for the first time the creation of an in vitro model of HAD composed of cultured microglial cells synergistically activated by the addition of IFN-gamma and the HIV-1 coat glycoprotein, gp120. Furthermore, this activation, as measured by TNF-alpha and nitric oxide (NO) release, is synergistically attenuated through the alpha7 nAChR and p44/42 MAPK system by pretreatment with nicotine, and the cholinesterase inhibitor, galantamine. Our findings suggest a novel therapeutic combination to treat or prevent the onset of HAD through this modulation of the microglia inflammatory mechanism.

Development of Real-Time RT-PCR Assay for Detection of Prunus necrotic ringspot virus in Fruit Trees.

A real-time fluorescent reverse-transcriptase polymerase chain reaction (RT-PCR) assay using a short fluorogenic 3' minor groove binder (MGB) DNA hydrolysis probe was developed for the detection of Prunus necrotic ringspot virus (PNRSV) in stone fruit trees. The covalent attachment of the minor groove binder moiety at the 3' end of the probe increased the probe target duplex stability and raised the melting temperature to a range suitable for real-time analysis. The real-time RT-PCR assay correlated well with conventional RT-PCR results for the detection of PNRSV. This assay reliably detects PNRSV in bark tissues of dormant cherry and plum trees. Furthermore, it is well adapted for the routine detection of PNRSV because it eliminates one risk of contamination by performing the whole test in a single closed tube. This system may replace the commonly used diagnostic techniques (e.g., woody indicators and immunological tests) to detect this virus.

Zymosan phagocytosis by mouse peritoneal macrophages is increased by apoHDL- and not by intact HDL-covered particles

The uptake of lipids and lipoprotein particles by macrophages undergoes phagocytic activation and the formation of foam cells are key events in atherosclerosis. In this study we determined how intact high density lipoproteins (HDL) and apolipoproteins-HDL (removal of the lipid component from HDL, i.e., apoHDL) influence the phagocytosis of zymosan by mouse peritoneal macrophages. Zymosan particles preincubated together with lipoproteins or alone (control) were incubated with the macrophages. Phagocytosis activity was reported as the percent of macrophages that internalized three or more zymosan particles. HDL co-incubated with zymosan did not influence the over-all uptake of zymosan particles compared to apoHDL, which greatly enhanced the ability of the particle to be phagocytized (P<0.001). Part of this effect might be related to a greater binding of apoHDL to the particles compared to that of HDL (P<0.05). We conclude that this can be a useful method to study the ability of lipoproteins, including modified lipoproteins obtained from subjects with genetic forms of hyperlipidemia, to opsonize particles such as red blood cells and thus to investigate the processes that control the formation of foam cells and the mechanisms of atherogenesis.