Nonictal EEG biomarkers for diagnosis and treatment.

There are no reliable nonictal biomarkers for epilepsy, electroencephalography (EEG) or otherwise, but efforts to identify biomarkers that would predict the development of epilepsy after a potential epileptogenic insult, diagnose the existence of epilepsy, or assess the effects of antiseizure or antiepileptogenic interventions are relying heavily on electrophysiology. The most promising EEG biomarkers to date are pathologic high-frequency oscillations (pHFOs), brief EEG events in the range of 100 to 600 Hz, which are believed to reflect summated action potentials from synchronously bursting neurons. Studies of patients with epilepsy, and experimental animal models, have been based primarily on direct brain recording, which makes pHFOs potentially useful for localizing the epileptogenic zone for surgical resection, but application for other diagnostic and therapeutic purposes is limited. Consequently, recent efforts have involved identification of HFOs recorded with scalp electrodes, and with magnetoencephalography, which may reflect the same pathophysiologic mechanisms as pHFOs recorded directly from the brain. The search is also on for other EEG changes that might serve as epilepsy biomarkers, and candidates include arcuate rhythms, which may reflect repetitive pHFOs, reduction in theta rhythm, which correlates with epileptogenesis in several rodent models of epilepsy, and shortened sleep spindles that correlate with ictogenesis

Getting the best outcomes from epilepsy surgery.

Neurosurgery is an underutilized treatment that can potentially cure drug-refractory epilepsy. Careful, multidisciplinary presurgical evaluation is vital for selecting patients and to ensure optimal outcomes. Advances in neuroimaging have improved diagnosis and guided surgical intervention. Invasive electroencephalography allows the evaluation of complex patients who would otherwise not be candidates for neurosurgery. We review the current state of the assessment and selection of patients and consider established and novel surgical procedures and associated outcome data. We aim to dispel myths that may inhibit physicians from referring and patients from considering neurosurgical intervention for drug-refractory focal epilepsies. Ann Neurol 2018;83:676-690

Bimodal coupling of ripples and slower oscillations during sleep in patients with focal epilepsy.

OBJECTIVE: Differentiating pathologic and physiologic high-frequency oscillations (HFOs) is challenging. In patients with focal epilepsy, HFOs occur during the transitional periods between the up and down state of slow waves. The preferred phase angles of this form of phase-event amplitude coupling are bimodally distributed, and the ripples (80-150 Hz) that occur during the up-down transition more often occur in the seizure-onset zone (SOZ). We investigated if bimodal ripple coupling was also evident for faster sleep oscillations, and could identify the SOZ. METHODS: Using an automated ripple detector, we identified ripple events in 40-60 min intracranial electroencephalography (iEEG) recordings from 23 patients with medically refractory mesial temporal lobe or neocortical epilepsy. The detector quantified epochs of sleep oscillations and computed instantaneous phase. We utilized a ripple phasor transform, ripple-triggered averaging, and circular statistics to investigate phase event-amplitude coupling. RESULTS: We found that at some individual recording sites, ripple event amplitude was coupled with the sleep oscillatory phase and the preferred phase angles exhibited two distinct clusters (p \u3c 0.05). The distribution of the pooled mean preferred phase angle, defined by combining the means from each cluster at each individual recording site, also exhibited two distinct clusters (p \u3c 0.05). Based on the range of preferred phase angles defined by these two clusters, we partitioned each ripple event at each recording site into two groups: depth iEEG peak-trough and trough-peak. The mean ripple rates of the two groups in the SOZ and non-SOZ (NSOZ) were compared. We found that in the frontal (spindle, p = 0.009; theta, p = 0.006, slow, p = 0.004) and parietal lobe (theta, p = 0.007, delta, p = 0.002, slow, p = 0.001) the SOZ incidence rate for the ripples occurring during the trough-peak transition was significantly increased. SIGNIFICANCE: Phase-event amplitude coupling between ripples and sleep oscillations may be useful to distinguish pathologic and physiologic events in patients with frontal and parietal SOZ

Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction.

The neurochemical changes underlying human emotions and social behaviour are largely unknown. Here we report on the changes in the levels of two hypothalamic neuropeptides, hypocretin-1 and melanin-concentrating hormone, measured in the human amygdala. We show that hypocretin-1 levels are maximal during positive emotion, social interaction and anger, behaviours that induce cataplexy in human narcoleptics. In contrast, melanin-concentrating hormone levels are minimal during social interaction, but are increased after eating. Both peptides are at minimal levels during periods of postoperative pain despite high levels of arousal. Melanin-concentrating hormone levels increase at sleep onset, consistent with a role in sleep induction, whereas hypocretin-1 levels increase at wake onset, consistent with a role in wake induction. Levels of these two peptides in humans are not simply linked to arousal, but rather to specific emotions and state transitions. Other arousal systems may be similarly emotionally specialized

The role of high-frequency oscillations in epilepsy surgery planning.

BACKGROUND: Epilepsy is a serious brain disorder characterized by recurrent unprovoked seizures. Approximately two-thirds of seizures can be controlled with antiepileptic medications (Kwan 2000). For some of the others, surgery can completely eliminate or significantly reduce the occurrence of disabling seizures. Localization of epileptogenic areas for resective surgery is far from perfect, and new tools are being investigated to more accurately localize the epileptogenic zone (the zone of the brain where the seizures begin) and improve the likelihood of freedom from postsurgical seizures. Recordings of pathological high-frequency oscillations (HFOs) may be one such tool. OBJECTIVES: To assess the ability of HFOs to improve the outcomes of epilepsy surgery by helping to identify more accurately the epileptogenic areas of the brain. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (15 April 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 3), MEDLINE (Ovid) (1946 to 15 April 2013), CINAHL (EBSCOhost) (15 April 2013), Web of Knowledge (Thomson Reuters) (15 April 2013), www.clinicaltrials.gov (15 April 2013), and the World Health Organization International Clinical Trials Registry Platform (15 April 2013). SELECTION CRITERIA: We included studies that provided information on the outcomes of epilepsy surgery at at least six months and which used high-frequency oscillations in making decisions about epilepsy surgery. DATA COLLECTION AND ANALYSIS: The primary outcome of the review was the Engel Class Outcome System. Secondary outcomes were responder rate, International League Against Epilepsy (ILAE) epilepsy surgery outcome, frequency of adverse events from any source and quality of life outcomes. We intended to analyse outcomes via an aggregated data fixed-effect model meta-analysis. MAIN RESULTS: Two studies met the inclusion criteria. Both studies were small non-randomised trials, with no control group and no blinding. The quality of evidence for all outcomes was very low. The combination of these two studies resulted in 11 participants who prospectively used ictal HFOs for epilepsy surgery decision making. Results of the postsurgical seizure freedom Engel class I to IV outcome were determined over a period of 12 to 38 months (average 23.4 months) and indicated that six participants had an Engel class I outcome (seizure freedom), two had class II (rare disabling seizures), three had class III (worthwhile improvement). No adverse effects were reported. Neither study compared surgical results guided by HFOs versus surgical results guided without HFOs. AUTHORS CONCLUSIONS: No reliable conclusions can be drawn regarding the efficacy of using HFOs in epilepsy surgery decision making at present

Preface - Practical and theoretical considerations for performing a multi-center preclinical biomarker discovery study of post-traumatic epileptogenesis: lessons learned from the EpiBioS4Rx consortium.

The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) is a NINDS funded Center-Without-Walls international study aimed at preventing epileptogenesis after traumatic brain injury (TBI). One objective of EpiBioS4Rx relates to preclinical biomarker discovery for post-traumatic epilepsy. In order to perform a statistically appropriately powered biomarker discovery study, EpiBioS4Rx has made a rigorous attempt to harmonize the preclinical procedures performed at the three EpiBioS4Rx centers, located in Finland, Australia, and the USA. Moreover, we have also performed a rigorous interim analysis of the success of procedural harmonization, which is reported in this virtual special issue. The analysis included harmonization of the production of animal model, blood sampling, electroencephalogram analyses (seizures, high-frequency oscillations) and magnetic resonance imaging analysis. Based on lessons learned, we propose a 3-stage protocol to facilitate the success of preclinical multicenter studies: preparation ⇨ testing ⇨ multicenter study. The need of funding for preparation and testing phases, which precede the actual multicenter study and are necessary for its success, should be taken into account in the design of funding schemes

Neonatal umbilical cord blood transplantation halts skeletal disease progression in the murine model of MPS-I

Umbilical cord blood (UCB) is a promising source of stem cells to use in early haematopoietic stem cell transplantation (HSCT) approaches for several genetic diseases that can be diagnosed at birth. Mucopolysaccharidosis type I (MPS-I) is a progressive multi-system disorder caused by deficiency of lysosomal enzyme α-L-iduronidase, and patients treated with allogeneic HSCT at the onset have improved outcome, suggesting to administer such therapy as early as possible. Given that the best characterized MPS-I murine model is an immunocompetent mouse, we here developed a transplantation system based on murine UCB. With the final aim of testing the therapeutic efficacy of UCB in MPS-I mice transplanted at birth, we first defined the features of murine UCB cells and demonstrated that they are capable of multi-lineage haematopoietic repopulation of myeloablated adult mice similarly to bone marrow cells. We then assessed the effectiveness of murine UCB cells transplantation in busulfan-conditioned newborn MPS-I mice. Twenty weeks after treatment, iduronidase activity was increased in visceral organs of MPS-I animals, glycosaminoglycans storage was reduced, and skeletal phenotype was ameliorated. This study explores a potential therapy for MPS-I at a very early stage in life and represents a novel model to test UCB-based transplantation approaches for various diseases

Unbiased population-based statistics to obtain pathologic burden of injury after experimental TBI

Reproducibility of scientific data is a current concern throughout the neuroscience field. There are multiple on-going efforts to help resolve this problem. Within the preclinical neuroimaging field, the continued use of a region-of interest (ROI) type approaches combined with the well-known spatial heterogeneity of traumatic brain injury pathology is a barrier to the replicability and repeatability of data. Here we propose the conjoint use of an unbiased analysis of the whole brain after injury together with a population-based statistical analysis of sham-control brains as one approach that has been used in clinical research to help resolve this issue. The approach produces two volumes of pathology that are outside the normal range of sham brains, and can be interpreted as whole brain burden of injury. Using diffusion weighted imaging-derived scalars from a tensor analysis of data acquired from adult, male rats at 2, 9 days, 1 and 5 months after lateral fluid percussion injury (LFPI) and in shams (n = 73 and 12, respectively), we compared a data-driven, z-score mapping method to a whole brain and white matter-specific analysis, as well as an ROI-based analysis with brain regions preselected by virtue of their large group effect sizes. We show that the data-driven approach is statistically robust, providing the advantage of a large group effect size typical of a ROI analysis of mean scalar values derived from the tensor in regions of gross injury, but without the large multi-region statistical correction required for interrogating multiple brain areas, and without the potential bias inherent with using preselected ROIs. We show that the technique correctly captures the expected longitudinal time-course of the diffusion scalar volumes based on the spatial extent of the pathology and the known temporal changes in scalar values in the LFPI model

Spontaneous and visually driven high‐frequency oscillations in the occipital cortex: Intracranial recording in epileptic patients

High‐frequency oscillations (HFOs) at ≥80 Hz of nonepileptic nature spontaneously emerge from human cerebral cortex. In 10 patients with extraoccipital lobe epilepsy, we compared the spectral‐spatial characteristics of HFOs spontaneously arising from the nonepileptic occipital cortex with those of HFOs driven by a visual task as well as epileptogenic HFOs arising from the extraoccipital seizure focus. We identified spontaneous HFOs at ≥80 Hz with a mean duration of 330 ms intermittently emerging from the occipital cortex during interictal slow‐wave sleep. The spectral frequency band of spontaneous occipital HFOs was similar to that of visually driven HFOs. Spontaneous occipital HFOs were spatially sparse and confined to smaller areas, whereas visually driven HFOs involved the larger areas including the more rostral sites. Neither spectral frequency band nor amplitude of spontaneous occipital HFOs significantly differed from those of epileptogenic HFOs. Spontaneous occipital HFOs were strongly locked to the phase of delta activity, but the strength of δ‐phase coupling decayed from 1 to 3 Hz. Conversely, epileptogenic extraoccipital HFOs were locked to the phase of delta activity about equally in the range from 1 to 3 Hz. The occipital cortex spontaneously generates physiological HFOs which may stand out on electrocorticography traces as prominently as pathological HFOs arising from elsewhere; this observation should be taken into consideration during presurgical evaluation. Coupling of spontaneous delta and HFOs may increase the understanding of significance of δ‐oscillations during slow‐wave sleep. Further studies are warranted to determine whether δ‐phase coupling distinguishes physiological from pathological HFOs or simply differs across anatomical locations. Hum Brain Mapp , 2012. © 2011 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90310/1/21233_ftp.pd

Clinical manifestations and treatment of mucopolysaccharidosis type I patients in Latin America as compared with the rest of the world

Background Mucopolysaccharidosis I (MPS I) comprises a spectrum of clinical manifestations and is divided into three phenotypes reflecting clinical severity: Hurler, Hurler-Scheie, and Scheie syndromes. There may be important variations in clinical manifestations of this genetic disease in patients residing in different regions of the world.Methods Using data from the MPS I Registry (as of September 2009), we evaluated patients from Latin America (n=118) compared with patients from the rest of the world [ROW (n=727)].Results Phenotype distribution differed among patients in Latin America compared to ROW(Hurler 31 vs. 62%, Hurler-Scheie 36 vs. 21%, Scheie 10 vs. 11%, and unknown 22 vs. 6%). the frequency of certain symptoms, such as cardiac valve abnormalities, sleep impairment, and joint contractures, also differed between Latin America and ROW for some phenotypes. Median age at MPS I diagnosis was earlier in the ROW than Latin America for all phenotypes, and age at first treatment for Hurler and Hurler-Scheie patients was also earlier in the ROW. Hurler patients in Latin America showed a gap of 3.1 years between median ages of diagnosis and first treatment compared to only 0.5 years in the ROW. Treatment allocation in Latin America compared to ROW was as follows: enzyme replacement therapy (ERT) only, 80 vs. 45%; hematopoietic stem cell transplantation (HSCT) only, 0.9 vs. 27%; both ERT and HSCT, 0 vs. 16%; and neither treatment, 19 vs. 13%.Conclusion These data highlight important differences in MPS I patients between Latin America and ROW in terms of phenotypic distribution, clinical manifestations, and treatment practices.MPS I Registry team at Genzyme CorporationHosp Nacl Pediat JP Garrahan, Unidad Errores Congenitos Metab, Buenos Aires, DF, ArgentinaHosp Especialidades UMAE 25, Monterrey, MexicoGenzyme Corp, Latin Amer Grp, Registry Program, Rio de Janeiro, BrazilUniv Rosario, Fdn Univ Ciencias Salud, Bogota, ColombiaUniv Valparaiso, Fac Med, Neurol Infantil Programa Formac Neuropediat, Valparaiso, ChileUniv Chile, INTA, Lab Genet & Enfermedades Metab, Santiago, ChileUniversidade Federal de São Paulo, Ctr Referencia Erros Inatos Metab, São Paulo, BrazilGenzyme Corp, Latin Amer Grp, Compassionate Use Program, Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Ctr Referencia Erros Inatos Metab, São Paulo, BrazilWeb of Scienc