Summary Purpose To examine patterns of use, efficacy and safety of intravenous ketamine for the treatment of refractory status epilepticus (RSE). Methods Multicenter retrospective review of medical records and EEG reports in ten academic medical centers in North America and Europe, including 58 subjects, representing 60 episodes of RSE were identified between 1999 and 2012. Seven episodes occurred after anoxic brain injury. Key findings Permanent control of RSE was achieved in 57% (34/60) of episodes. Ketamine was felt to have contributed to permanent control (“possible” or “likely” responses) in 32% (19/60) including seven (12%) in which ketamine was the last drug added (likely responses). Four of the seven likely responses, but none of the 12 possible ones, occurred in patients with post-anoxic brain injury. No likely responses were observed when infusion rates were lower than 0.9mg/kg/h; when ketamine was introduced at least eight days after SE onset; or after failure of seven or more drugs. Ketamine was discontinued due to possible adverse events in five patients. Complications were mostly attributed to concurrent drugs, especially other anesthetics. Mortality rate was 43% (26/60), but was lower when SE was controlled within 24h of ketamine initiation (16% vs. 56%, p=0.0047). Significance Ketamine appears to be a relatively effective and safe drug for the treatment of RSE. This retrospective series provides preliminary data on effective dose and appropriate time of intervention to aid in the design of a prospective trial to further define the role of ketamine in the treatment of RSE.

IMPORTANCE A major change has occurred in the evaluation of epilepsy with the availability of robotic stereoelectroencephalography (SEEG) for seizure localization. However, the comparative morbidity and outcomes of this minimally invasive procedure relative to traditional subdural electrode (SDE) implantation are unknown. OBJECTIVE To perform a comparative analysis of the relative efficacy, procedural morbidity, and epilepsy outcomes consequent to SEEG and SDE in similar patient populations and performed by a single surgeon at 1 center. DESIGN, SETTING, AND PARTICIPANTS Overall, 239 patients with medically intractable epilepsy underwent 260 consecutive intracranial electroencephalographic procedures to localize their epilepsy.

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Recent studies using diffusion tensor imaging (DTI) have advanced our knowledge of the organization of white matter subserving language function. It remains unclear, however, how DTI may be used to predict accurately a key feature of language organization: its asymmetric representation in one cerebral hemisphere. In this study of epilepsy patients with unambiguous lateralization on Wada testing (19 left and 4 right lateralized subjects; no bilateral subjects), the predictive value of DTI for classifying the dominant hemisphere for language was assessed relative to the existing standard - the intra-carotid Amytal (Wada) procedure. Our specific hypothesis is that language laterality in both unilateral left- and right-hemisphere language dominant subjects may be predicted by hemispheric asymmetry in the relative density of three white matter pathways terminating in the temporal lobe implicated in different aspects of language function: the arcuate (AF), uncinate (UF), and inferior longitudinal fasciculi (ILF). Laterality indices computed from asymmetry of high anisotropy AF pathways, but not the other pathways, classified the majority (19 of 23) of patients using the Wada results as the standard. A logistic regression model incorporating information from DTI of the AF, fMRI activity in Broca’s area, and handedness was able to classify 22 of 23 (95.6%) patients correctly according to their Wada score. We conclude that evaluation of highly anisotropic components of the AF alone has significant predictive power for determining language laterality, and that this markedly asymmetric distribution in the dominant hemisphere may reflect enhanced connectivity between frontal and temporal sites to support fluent language processes. Given the small sample reported in this preliminary study, future research should assess this method on a larger group of patients, including subjects with bihemispheric dominance.

Surgical treatment of focal epilepsy in the presence of periventricular nodular heterotopia (PVNH) poses a challenge, as the relative roles of the nodular tissue and the overlying cortex in the generation of seizures can be complex and variable. Here, we review the literature on chronic invasive EEG recordings in humans with this substrate and present two illustrative cases from our practice. We found that while inter-ictal spiking from nodules is common, clinical seizures rarely arise solely from nodular tissue. More typically, ictal onset is simultaneous with overlying neocortex or mesial temporal structures. Surgical outcome is more favorable in cases with unilateral (as opposed to bilateral) PVNH, and when a substantial or complete ablation of PVNH is performed. In rare cases, nodular ablation alone may be sufficient, as may be completed by MRI-guided laser interstitial thermal therapy. The mechanism(s) by which PNVH interacts with overlying cortex are not fully understood, but we suggest that PVNH either orchestrates or amplifies local network epileptogenicity. At present, invasive recordings with penetrating depth electrodes are required prior to surgical therapy, as illustrated in our cases.

We define a metric, mutual information in frequency (MI-in-frequency), to detect and quantify the statistical dependence between different frequency components in the data, referred to as cross-frequency coupling and apply it to electrophysiological recordings from the brain to infer crossfrequency coupling. The current metrics used to quantify the cross-frequency coupling in neuroscience cannot detect if two frequency components in non-Gaussian brain recordings are statistically independent or not. Our MI-in-frequency metric, based on Shannon's mutual information between the Cramér's representation of stochastic processes, overcomes this shortcoming and can detect statistical dependence in frequency between non-Gaussian signals. We then describe two data-driven estimators of MI-in-frequency: one based on kernel density estimation and the other based on the nearest neighbor algorithm and validate their performance on simulated data. We then use MI-in-frequency to estimate mutual information between two data streams that are dependent across time, without making any parametric model assumptions. Finally, we use the MI-infrequency metric to investigate the cross-frequency coupling in seizure onset zone from electrocorticographic recordings during seizures. The inferred cross-frequency coupling characteristics are essential to optimize the spatial and spectral parameters of electrical stimulation based treatments of epilepsy.

Summary: Purpose:We assessed neuroimaging lesion type and distribution in patients with periodic lateralized epileptiform discharges (PLEDs), with a view to identifying electrographic differences between PLEDs associated with differing lesion locations. Our observations led us to consider a conceptual synthesis between PLEDs and periodic complexes (PCs).Methods: Retrospective review of acute neuroimaging results (CT/MRI) on patients identified to have EEG PLEDs, for the period 1999-2003 (n = 106). Blinded classification of original EEG recordings.Results: Neuroimaging abnormalities were classified as acute or chronic cortical, or acute or chronic subcortical. Seven out of 106 scans were classified nonlesional. Overall ∼70% of scans had cortical abnormalities, whether acute or chronic; ∼23% had subcortical abnormalities. "Cortical" PLEDs were significantly longer in duration (p < 0.05) and more variable in morphology (p < 0.01) than "subcortical" PLEDs.Conclusions: Structural brain disease commonly, but not invariably, underlies PLEDs; lesion type is spatiotemporally variable. Cortical and subcortical PLEDs have distinct EEG signatures. There is evidence that these may relate to mechanisms for other pathological large-scale oscillatory brain synchronies (e.g., PCs). Key Words: PLED-EEG-Periodic complex-Basal ganglia-Thalamus.The term periodic lateralized epileptiform discharge (PLED) was first used in the seminal work by Chatrian et al., (1964), building on previous observations of this EEG phenomenon. PLEDs are a readily identified pattern, the acronym encapsulating their essential characteristics: widely distributed, polymorphic, repetitive complexes of approximate frequency 0.5-3 Hz, having one or more sharp components, present over one or other hemisphere. Variations on this theme are recognized: multiple independent PLED types in the same EEG (BiPLEDs [de la Paz and Brenner, 1981] widespread lesions are thought to lead to a marginal zone of cortical hyperexcitability that serves as the "pacemaker" for a spatially extended, synchronous EEG discharge. However, recent neuroimaging series (Garcia-Morales et al., 2002;Gurer et al., 2004) indicate that PLEDs may arise from a variety of structural substrates, including chronic and subcortical lesions. This raises the question of whether cortical and subcortical PLEDs are electrographically different, and what mechanisms fundamentally underscore PLED genesis, given the variety of underlying lesions.Our work began as a neuroimaging review of PLEDs, progressing to a comparative electrographic study. In particular, we asked whether duration of individual PLED complexes, repetition rate, stereotypy of discharge morphology, and the degree of inter-PLED slowing, had associations with lesion location. The observations led us to speculate on the electrogenesis of PLEDs in general, and their possible neurophysiological relationships to other forms of widespread periodic EEG phenomena. METHODSOver a 4-year period (1999)(2000)(2001)(2002)(2003), 121 instances of EEG PLEDs were...