Study: Benign Rolandic Epilepsy and Generalized Paroxysms: An examination of 13 patients

Conclusions: [Researchers] found evidence that patients with benign rolandic epilepsy (BRE) may have generalized EEG discharges at onset as the sole manifestation lasting throughout the course of the syndrome. In some, focal paroxysms developed later. The course was benign. In our group of patients, clinical features and evolution were similar to those of typical cases of BRE. Response to valproic acid and levetiracetam was found to be particularly good.

Purpose: To present a retrospective study of 13 children with benign epilepsy with centrotemporal spikes (BECTS), also known as benign rolandic epilepsy (BRE), associated with generalized spikes and waves as the only EEG manifestation at onset.

Method: Charts of children with typical clinical criteria of BRE electroclinically followed-up between February 2000 and February 2015 were reviewed.

Results: Among 309 patients who met the electroclinical criteria of BRE, we identified 13 children who presented with the typical clinical manifestations but who, on the EEG, only had generalized paroxysms at onset that continued along the course of the syndrome. Generalized spike-and-wave discharges were observed in all patients when awake and during sleep (100%). During the evolution no particular electroclinical pattern was observed. The patients responded well to antiepileptic drugs, such as valproic acid and levetiracetam. Outcome was good in all patients.

Could one cause of epilepsy be a defective “cellular antenna”?

The motivation – The human genome includes many genes that encode proteins known as “kinases.” The functions of many kinases inside cells are known, for example, some are important for cell division and are involved in a wide spectrum of human diseases, including cancer. Researchers identified a category of kinases, termed CDKL, for which little biological information was known. Humans have five types of CDKL proteins, and what makes this family of kinases particularly interesting is that one of them, CDKL5, is associated with the genetic disorder “Rett syndrome.” This syndrome is characterized by several neurodevelopmental defects and includes epilepsy as one of its clinical manifestations.

The discovery – Leading an international team of researchers, Simon Fraser University’s Michel Leroux and his graduate student, Kwangjin Park, used the nematode C. elegans as a biological model to understand the function of CDKL proteins. C. elegans only has one CDKL protein, providing a simple system in which to reveal the biological functions of CDKL proteins. They found that the nematode CDKL protein localizes specifically to neuronal cilia, which are small hair-like cellular structures that act as “cellular antenna” and are essential for sensory physiology and development in humans. The nematode CDKL protein regulates the length of cilia. Notably, introducing any of three CDKL5 mutations found in humans into the nematode CDKL protein results in cilia length defects.

Its significance – The length of cilia is known to be important. The authors of this study propose that such length changes in nematode cilia may be relevant to the human disease. In collaboration with the Alex Bullock lab at the University of Oxford in the UK, they also uncovered for the first time the structures of human CDKL proteins. Now with knowledge of what these biomolecules look like, researchers can probe at the atomic level the functions of the CDKL proteins. Armed with this understanding, biomedical researchers will be in an excellent position to develop therapeutic molecules for the treatment of Rett syndrome, and potentially, other neurological disorders.

Birth of New Neurons in the Human Hippocampus Ends in Childhood: Study Including Data from Patients with Epilepsy

Adult ‘Neurogenesis’ is observed in other species, but appears not to occur in humans.

One of the liveliest debates in neuroscience over the past half century surrounds whether the human brain renews itself by producing new neurons throughout life, and whether it may be possible to rejuvenate the brain by boosting its innate regenerative capacity.

Now UC San Francisco scientists have shown that in the human hippocampus – a region essential for learning and memory and one of the key places where researchers have been seeking evidence that new neurons continue to be born throughout the lifespan – neurogenesis declines throughout childhood and is undetectable in adults.

The lab’s new research, based on careful analysis of 59 samples of human hippocampus from UCSF and collaborators around the world, suggests new neurons may not be born in the adult human brain at all. The findings present a challenge to a large body of research which has proposed that boosting the birth of new neurons could help to treat brain diseases such as Alzheimer’s disease and depression. But the authors said it also opens the door to exciting new questions about how the human brain learns and adapts without a supply of new neurons, as in seen in mice and other animals.

The researchers found plentiful evidence of neurogenesis in the dentate gyrus during prenatal brain development and in newborns, observing an average of 1,618 young neurons per square millimeter of brain tissue at the time of birth. But the number of newborn cells sharply declined in samples obtained during early infancy: dentate gyrus samples from year-old infants contained fivefold fewer new neurons than was seen in samples from newborn infants. The decline continued into childhood, with the number of new neurons declining by 23-fold between one and seven years of age, followed by a further fivefold decrease by 13 years, at which point neurons also appeared more mature than those seen in samples from younger brains. The authors observed only about 2.4 new cells per square millimeter of DG tissue in early adolescence, and found no evidence of newborn neurons in any of the 17 adult post-mortem DG samples or in surgically extracted tissue samples from 12 adult patients with epilepsy.

Biologists link protein, seizure suppression

Research shows that seizure suppression was associated with an increase in COX-2 expression in neurons.

James Hewett, associate professor of biology, and Yifan Gong, a Ph.D. candidate in biology and neuroscience, have co-authored an article in the journal Neuroscience (Elsevier, 2018) about a protein in the brain called T-cell intracellular antigen-1 (TIA-1).

“TIA-1 is known for its ability to regulate gene expression during cellular stress,” says Hewett, who studies the processes that suppress the severe electrical storms in the brain, leading to seizures. “We suspected that TIA-1 was involved with seizure suppression, but our findings suggested something else.”

He and Gong are interested in the function of an enzyme in the brain called cyclooxygenase-2 (COX-2). This enzyme makes prostaglandins — chemical messengers that aid in the performance of normal tasks, including learning and memory.

“Our findings raise the possibility that the level of neuronal COX-2 expression in the brain may be a determinant of the seizure threshold [a natural set-point for electrical activity, above which seizures occur]. This suggests that a better understanding of the regulation of COX-2 expression in the brain can provide new insights into molecular mechanisms that suppress seizure-induction,” adds Hewett, a pharmacologist by training.

Study: Age representation in antiepileptic drug trials: A systematic review and meta-analysis

Elderly patients are underrepresented in antiepileptic drug trials, according to an Epilepsy Research study.

OBJECTIVES: To analyze age representation trends over time in antiepileptic drug (AED) trials and to assess trial design elements as possible barriers to enrollment of elderly patients.

MATERIALS AND METHODS: We searched MEDLINE, EMBASE, and PsycINFO, and meta-analyzed demographic data of cohorts enrolled in randomized controlled trials (RCTs) of AEDs published since 1991. Data analysis included trends of age representation over time and trial design elements associated with average age of enrolled cohorts.

RESULTS: We identified 187 studies (n?=?48,077); 184 studies were included in the meta-analysis. The mean age of participants enrolled increased steadily from a mean age of 27.0 years (SD 5.7, range 21.0-38.4) in 1991-1992, to a mean age of 41.9 years (SD 11.4, range 28.8-71.4) in 2015-2016 (r?=?0.868, p?<?0.0001). Maximum age limit for inclusion of participants was present in 83 trials (44%). There was no significant decrease in the use of upper age limit over time (r?=?0.072, p?=?0.8161). Among the eligibility criteria assessed, only the exclusion of neurological conditions other than epilepsy was associated with a significant reduction of the average age of enrolled cohorts (-2.1 years, 95% CI -4.1 to -0.1).

CONCLUSIONS: Despite a progressive increase in the average age of participants enrolled in AED trials over time, elderly patients are still largely underrepresented. Successful strategies to increase representation of elderly patients in these trials will likely need to involve more than minimal protocol modifications of eligibility criteria.

Study: Extrahippocampal high-frequency oscillations during epileptogenesis

An Epilepsia study demonstrates an association between an increased rate of widespread high-frequency oscillations and the later development of epilepsy, suggesting the formation of large-scale distributed pathological networks during epileptogenesis.

Summary: The current study aimed to investigate the spatial and temporal patterns of high-frequency oscillations (HFOs) in the intra-/extrahippocampal areas during epileptogenesis. Local field potentials were bilaterally recorded from hippocampus (CA1), thalamus, motor cortex, and prefrontal cortex in 13 rats before and after intrahippocampal kainic acid (KA) lesions. HFOs in the ripple (100-200 Hz) and fast ripple (250-500 Hz) ranges were detected and their rates were computed during different time periods (1-5 weeks) after KA-induced status epilepticus (SE).

Recurrent spontaneous seizures were observed in 7 rats after SE, and the other 6 rats did not develop epilepsy. During the latent period, the rate of hippocampal HFOs increased at the ipsilateral site of the KA lesion in both groups, and the HFO rate was significantly higher in the animals that later developed epilepsy. Animals that later developed epilepsy also demonstrated widespread appearance of HFOs, in both the ripple and the fast ripple range, whereas animals that did not develop epilepsy only exhibited changes in the ipsilateral intrahippocampal HFO rate.

NYU Langone’s 2018 FACES Gala Raises $5.6 Million To Support Epilepsy Research, Education & Care

NYU Langone Health raised $5.6 million at its annual Finding A Cure for Epilepsy and Seizures (FACES) Gala to fund epilepsy research and the advancement of new therapies. Held on March 5, 2018, at Pier Sixty at Chelsea Piers, longtime FACES supporters Sukey and Mike Novogratz chaired this year’s gala. Mike Novogratz also serves as a trustee at NYU Langone.

Deborah and Bill Harlan were honored at the event for their contributions to epilepsy research over the past 15 years. “With the generous support of Deborah and Bill Harlan, FACES has contributed to hundreds of research initiatives that have led to important changes in the field,” said Orrin Devinsky, MD, professor of neurology, neurosurgery, and psychiatry, founder of FACES, and director of NYU Langone’s Comprehensive Epilepsy Center. “We are excited to honor and celebrate them tonight to show our appreciation for the time, energy, and philanthropic support they provide for our Comprehensive Epilepsy Center and FACES programs.”

A personal video message from actor Robert Redford was shown at the event, highlighting his commitment to the FACES mission and recognizing the Harlans. The evening also featured “Orange is the New Black” and “Unsolved” actor Michael Harney as the special guest speaker, sharing his firsthand experience working with Dr. Devinsky and unwavering support of the FACES programs.

Prof. Ley Sander Discusses Preventing SUDEP and How to Build Research Around SUDEP: Video from CURE Frontiers in Research Seminar Series

Video is available from the CURE Frontiers in Research Seminar Series talk given by Professor Ley Sander, discussing SUDEP prevention and research.

Talk summary: Individuals with epilepsy, particularly those with uncontrolled epilepsy, are at a much greater risk of premature death than those without. In fact, the standardized mortality ratio in those with epilepsy is between 2 and 3. In the UK, the most common cause of epilepsy-related death is due to Sudden Unexpected Death in Epilepsy (SUDEP), which accounts for up to one-fifth of deaths in some series. SUDEP is more common in those with frequent convulsive seizures (particularly nocturnal seizures) and in those with drug-resistant epilepsy. While the causes of SUDEP are unknown, the most commonly suggested underlying mechanisms are cardiac arrhythmias, respiratory depression and “cerebral shutdown.” Because no preventative measures currently exist, an understanding of SUDEP risk factors, potential mechanisms and the effectiveness of preventative measures is essential. To this end, there are a multitude of opportunities available in the field of SUDEP research and these opportunities will be interactively discussed during the presentation.

New Technology: Capturing Brain Signals With Soft Electronics

Klas Tybrandt, principal investigator at the Laboratory of Organic Electronics at Linköping University, has developed new technology for long-term stable neural recording. It is based on a novel elastic material composite, which is biocompatible and retains high electrical conductivity even when stretched to double its original length.

The result has been achieved in collaboration with colleagues in Zürich and New York. The breakthrough, which is crucial for many applications in biomedical engineering, is described in an article published in the prestigious scientific journal Advanced Materials.

The coupling between electronic components and nerve cells is crucial not only to collect information about cell signalling, but also to diagnose and treat neurological disorders and diseases, such as epilepsy.

It is very challenging to achieve long-term stable connections that do not damage neurons or tissue, since the two systems, the soft and elastic tissue of the body and the hard and rigid electronic components, have completely different mechanical properties.

“As human tissue is elastic and mobile, damage and inflammation arise at the interface with rigid electronic components. It not only causes damage to tissue; it also attenuates neural signals,” says Klas Tybrandt, leader of the Soft Electronics group at the Laboratory of Organic Electronics, Linkoping University, Campus Norrkoping.

Klas Tybrandt has developed a new conductive material that is as soft as human tissue and can be stretched to twice its length. The material consists of gold coated titanium dioxide nanowires, embedded into silicone rubber. The material is biocompatible – which means it can be in contact with the body without adverse effects – and its conductivity remains stable over time.

Study: Clinical and Electrographic Features of Sunflower Syndrome

CONCLUSIONS: Valproate monotherapy continues to be the most effective treatment for Sunflower Syndrome and should be considered early. For patients who cannot tolerate valproate, higher doses of lamotrigine or polypharmacy should be considered. Levetiracetam monotherapy, even at high doses, is unlikely to be effective.

BACKGROUND: Sunflower Syndrome describes reflex seizures – typically eyelid myoclonia with or without absence seizures – triggered when patients wave their hands in front of the sun. While valproate has been recognized as the best treatment for photosensitive epilepsy, many clinicians now initially treat with newer medications; the efficacy of these medications in Sunflower Syndrome has not been investigated. We reviewed all cases of Sunflower Syndrome seen at our institution over 15 years to describe the clinical course, electroencephalogram (EEG), and treatment response in these patients.

METHODS: Search of the electronic medical record and EEG database, as well as survey of epilepsy providers at our institution, yielded 13 cases of Sunflower Syndrome between 2002 and 2017. We reviewed the records and EEG tracings.

RESULTS: Patients were mostly young females, with an average age of onset of 5.5 years. Seven had intellectual, attentional or academic problems. Self-induced seizures were predominantly eyelid myoclonia?±?absences and 6 subjects also had spontaneous seizures. EEG demonstrated a normal background with 3-4?Hz spike waves?±?polyspike waves as well as a photoparoxysmal response. Based on both clinical and EEG response, valproate was the most effective treatment for reducing or eliminating seizures and improving the EEG; 9 patients tried valproate and 66% had significant improvement or resolution of seizures. None of the nine patients on levetiracetam or seven patients on lamotrigine monotherapy achieved seizure control, though three patients had improvement with polypharmacy.