Raymond A. Costa

MRI-guided stereotactic laser ablation (SLA) is at least as effective as and less harmful than typical surgical procedures for treating galactic seizures caused by hypothalamic hamartomas (HH), according to research

 Annual Meeting of the American Epilepsy Society (AES 2015).

“SLA seems minimally invasive and precise,” said Shawn Reddy, a medical student at Baylor University. “For our HH patients, SLA is an efficacious treatment for gelastic seizures.”

“Most patients,” he continued, “were minimal or no side effects from SLA.”

This study is particularly important because of the difficulty in surgically treating gelastic seizures due to HH.

For the study, the results of 37 SLA procedures performed at Texas Children’s Hospital were reviewed for efficacy and safety data. The patients were then split into 2 groups, those who previously had surgery (eg, gamma knife radiosurgery) and those who did not. “Twenty-nine of them [total patients] are currently seizure free at last clinical follow-up,” said Reddy. Additionally, of the 10 patients who previously had surgery, 8 were seizure free at last clinical follow-up.

Only one serious adverse event was noted by the researchers, and this patient had a temporal lobectomy less than 3 months before the SLA procedure.

“Finally,” Reddy concluded, “the majority of patients were discharged from the hospital the next morning.”

 at AES 2015 demonstrated that the use of whole-exome sequencing (WES) in initial diagnostic workup increases diagnostic yield in early onset epilepsy.

“We feel our study supports the clinical utility of using WES upfront for this cohort of patients based on diagnostic yield, the yield of those with specific treatment implications,” stated Michelle Demos, MD, of BC Children’s Hospital in Canada.

“Having a genetic diagnosis can have a significant clinical impact,” said Demos. “If you identify a disorder that has treatment implications, this is important.” However, access to genetic testing on a clinical basis is low.

The patient group for this study, done by Demos and colleagues, consisted of 50 children who had a diagnosis of epilepsy of unknown cause at 5 years old or younger. Depending on how old the diagnosis was at the time of the study, patients were either placed in a prospective (epilepsy < 6 months) or retrospective (epilepsy > 6 months) group.

Demos and colleagues made a definite or likely diagnosis in 32% of the patients and a potential or possible diagnosis in 22%. Further, 16% of the yields had treatment implications. Some of the identifications even occurred for patients who already underwent other genetic testing, such as chromosome microarray or specific gene testing.

This study also demonstrated that time to diagnosis from enrolling was quick. “It was under two months,” said Demos, “and obviously a lot faster when performed up front with their epilepsy diagnosis.”

“Having a genetic diagnosis does provide opportunity for the potential of a therapeutic indication, even if it’s not known, perhaps for the future,” she concluded.

Moving forward, this group will do an economic analysis of doing WES up front compared to other diagnostic testing.

The AES 2015 Annual Meeting was held December 4-8 in Philadelphia.

Session: Pediatric Epilepsy Highlights Section, Dec. 7, 2015.

1. Reddy S, et al. Safety and efficacy of stereotactic laser ablation of hypothalamic hamartomas. Abstract No 2.305, 2015. American Epilepsy Society Annual Meeting, 

2. Demos M, et al. Targeted analysis of whole exome sequencing in early onset epilepsy. Abstract No 1.311, 2015. American Epilepsy Society Annual Meeting, 

Articles

Highlights of recent pediatric epilepsy research include a minimally invasive surgical procedure and genetic testing.

Breakthrough Research in Pediatric Epilepsy

Early resective surgery should be considered in infants with epileptic encephalopathy (EE) due to malformation of cortical development for improvement of both seizure and developmental outcomes, according to research

The study, performed by Akio Takahashi, MD, of the National Center Hospital of Neurology and Psychiatry in Japan, and colleagues, was a retrospective analysis of 23 infants with EE who underwent epilepsy surgery between 2001 and 2012.

Most of the surgeries performed in this study were hemispherotomies but also included multi-lobar disconnection, lobar resection, lesionectomy, and callosotomy. Surgery outcomes were reported using the Engel Epilepsy Surgery Outcome Scale. Achieving a class I outcome indicates a seizure-free patient, and a class II outcome indicates rare disabling seizures.

Of the 21 children who underwent resective surgery, 14 achieved Engel class I outcomes and 1 achieved a class II outcome. Further, all 15 children with class I or II outcomes showed improvement in psychomotor retardation.

Other research presented at AES 2015 also demonstrated the efficacy of surgery in treating epilepsy. According to one study,

 not only is epilepsy surgery a useful treatment option in patients with refractory epilepsy, but a repeat surgery is a good option if the first surgery fails.

Refractory epilepsy, or drug-resistant epilepsy, according to the International League Against Epilepsy, is a significant cause of morbidity and mortality in pediatric neurology, stated the authors of the study, Anuj Jayakar, MD, and Jeffrey Bolton, MD.

Though surgeries have good success rates, sometimes patients need subsequent surgeries to become seizure free. The goal of this study, a retrospective analysis, was to characterize the patients undergoing repeat surgery and assess outcomes.

Jayakar and Bolton examined data for 25 children, between the ages of 4 months and 22 years, with refractory epilepsy who underwent repeat epilepsy surgery at Boston Children’s Hospital between 2005 and 2014. The initial surgeries were 16 resections, 3 hemispherectomies, and 6 Visualase® ablations.

Of the patients receiving resections, 13 required further resection and 3 required hemispherectomies as their second surgeries. All 3 patients who had hemispherectomies required a second surgery to complete the hemispherectomy. Of the 6 Visualase® ablation patients, 5 needed resection around the ablation and 1 needed a second ablation procedure.

Cortical dysplasia (n=14) and post-surgical scarring (n=12) were the most common etiologies in this study. Others included tumor, gliosis, hippocampal sclerosis, and neuronal heterotopias. 

Following the second surgery, 15 patients had Engel class I outcomes, and another 4 had Engel class II outcomes. Further, 13 of the patients were able to wean off of at least 1 antiepileptic drug.

“Despite failure of the first attempt, a repeat surgery should be considered to produce good seizure control,” concluded Jayakar and Bolton.

1. Takahashi A, et al. Epilepsy surgery for epileptic encephalopathy in infancy. Poster presented at: 69

 Annual Meeting of the American Epilepsy Society; December 2015; Philadelphia, PA. Abstract 2.309.

ILAE Commission Report. Proposal for a new classification of outcome with respect to epileptic seizures following epileptic surgery

3. Jayakar A, Bolton J. Clinical characteristics and outcomes in pediatric patients undergoing repeat epilepsy surgery. Poster presented at: 69

 Annual Meeting of the American Epilepsy Society; December 2015; Philadelphia, PA. Abstract 2.310.

Researchers demonstrated promising results in surgical treatment of epileptic encephalopathy and refractory epilepsy.

New Data for Surgical Epilepsy Treatment

An issue currently debated in the epilepsy community revolves around the treatment of spikes in electroencephalography (EEG). That is, what exactly should physicians do when presented with interictal epileptiform discharges (IEDs), or spikes? And how do they affect cognition, if at all?

Before the medical community can make any headway, some obstacles must be overcome. The first major hurdle is quantifying IEDs, which, as Ivan Sanchez Fernandez, MD, a researcher at Harvard University, tells us, we are not able to do yet. If there is no way to measure interictal epileptiform activity, then there is no way to correlate it with cognition.

One of the challenges of quantification is how resource intensive it is, requiring time and effort from EEG readers. Other challenges include differences in morphology, lateralization, and voltage across different EEGs.

One way to measure EEGs, the spike and wave index, was introduced

 in 2 studies on electrical status epilepticus during slow wave sleep (ESES), perhaps the most extreme form of interictal epileptiform activity. However, the clinical impact of this measurement remains unclear, said Sanchez Fernandez.

He went on to say that there is no consistent evidence that IEDs are related to impaired cognition, though they are correlated to abnormal neural networks in animal models, even in the absence of seizures.

Roberto Tuchman, MD, the Director of the Brain Development Network at Nicklaus Children’s Hospital, reiterated the point that there is no clear correlation with behavior and learning problems.

Though IEDs can cause short-term cognitive impairment, Tuchman said, little evidence of impairment over the long term exists.

Tuchman also highlighted the need for understanding social cognition as a process, as social cognitive dysfunction correlates with many developmental disorders.

He went on to ask, “does the epileptic activity itself contribute to severe neurological and cognitive impairments above and beyond what may be expected from the underlying pathology?”

In order to answer this question, he concluded, we need to develop standardized methodology for screening, measure and assess key developmental cognitive characteristics, and develop ways to think about EEG studies, as well as improve our understanding of the natural history of spikes.

Kevin Chapman, MD, of the University of Colorado, emphasized the need to establish a consistent spike and wave index and to read EEGs with more care and focus. This, he argued, can help establish whether or not there is a clinical impact of spikes on cognition.

Supposing there is a cognitive impact, can spikes even be treated?

Clinical data suggests anti-ictal capabilities of some therapies. One study mentioned by Chapman

 demonstrated a suppression of interictal epileptiform activity through the use of phenobarbital, carbamazepine, and valproic acid. Current research, however, is unclear on exactly which therapy is the most effective.

The final question centers around who should be treated. Chapman mentioned several factors for making that decision, including etiology, early development, regression, and spike index.

Even though the debate on IEDs is far from settled, researchers are certainly moving in the right direction.

Session:  Investigators' Workshop: Spikes and Cognition: Shoud We Treat Spikes? . Dec. 76, 2015.

Encephalopathy with electrical status epilepticus during slow sleep or ESES syndrome including the acquired aphasia

. Clin Neurophysiol. 2000;111(2)(suppl):94-102.

Levetiracetam efficacy in epileptic syndromes with continuous spikes and waves during slow sleep: experience in 12 cases

Do antiepileptic drugs differ in suppressing epileptiforms in children?

What exactly should physicians do when presented with interictal epileptiform discharges (IEDs), or spikes?

Unsettled Debate: Interictal Epileptiform Discharges

One of the Investigators’ Workshops at AES 2015 focused on hot topics and late-breaking research from 4 young investigators in the epilepsy community. According to moderator Michael Wong, MD, the goal of this workshop was to “feature and promote young investigators in epilepsy research.”

The first investigator, Maneesh Kumar, MD, PhD, of the University of Colorado, presented his research on metabolism in the zebrafish model of Dravet syndrome, a genetic epilepsy characterized by an early, febrile (typically) seizure that progresses into severe, recurring seizures. SCN1A-mutant zebrafish were used because they replicate the phenotype of Dravet syndrome.

The goal was to determine if there were any metabolic defects in Dravet syndrome and, if so, what could be causing them. Kumar first measured baseline glycolysis rates in SCN1A-mutant and wild type zebrafish, which he found to be lower in the mutants. He then treated both types with 4-aminopyridine (4AP), a potassium channel blocker. In the mutant fish he found a delayed, exaggerated response to the 4AP in glycolysis rate.

After testing to eliminate other explanations, Kumar concluded that glycolysis is the difference between the mutants and wild type. He purported that the mutation causing Dravet syndrome changes glycolytic genes, which then affect glycolysis and, in turn, metabolism.

Research presented by investigator Hongyu Sun, MD, PhD, of the University of Pennsylvania, aimed to determine if hippocampal neurons behave differently during seizures. Sun hypothesized that only a selective group of neurons are activated during seizures.

Using the transgenic mouse model, with a c-fos gene promoter, and Green Fluorescent Protein labeling, Sun found that pentylenetetrazol-induced seizures selectively activate a sub-group of neurons in the hippocampus. Further, these activated neurons show increased AMPA-receptor function in post-synaptic membrane.

Sun also determined that functional changes occur only in activated neurons and that the pre-seizure baseline features of the cell may predict susceptibility to a seizure.

With the goal of identifying targets that may be antiepileptogenic, Lauren Andresen, a graduate student at Tufts University, investigated methods of preventing the formation of hyper-excitable networks following injury.

Andresen hypothesized that, targeting thrombospondin increase in Î±2Î´-1, a calcium channel subunit, following freeze lesion injury may decrease maladaptive synaptogenesis and the formation of hyper-excitable networks.

She demonstrated that acute treatment with gabapentin, an antagonist for Î±2Î´-1, prevented synaptogenesis, and the gabapentin itself proved to be neuroprotective.

Further, Andresen explained, a genetic knockout also protected against synaptogenesis, decreasing the formation of a hyper-excitable network, though to a lesser extent than gabapentin.

Shennan Aibel Weiss, MD, PhD, of UCLA, presented his research on the mechanisms that drive seizure stage changes.

He found that the transition from the interictal stage to the preictal stage is not fully known. The transition from preictal to seizure onset “may involve pathological interconnected neuron clusters that coalesce and grow, reaching a critical mass, causing seizure promulgation.” Micro-seizures may facilitate the transition from onset to seizure spread.  Finally, the transition between spread and clonic bursting may involve an inhibitory rebound phenomenon.

Session: Investigators’ Workshop: Hot topics and late-breaking research from young investigators in the epilepsy community. Dec. 6, 2015.

Young epilepsy community members presented late-breaking research on Dravet syndrome, hippocampal neuron activity during seizure, and more at AES 2015.

Young Epilepsy Investigators’ Research

The use of telehealth to reach epilepsy patients was covered at AES 2015 by Rick Boyle, Special Projects Director at the Epilepsy Foundation Western/Central PA.

Telehealth, according to the federal Health Resources and Services Administration (HRSA), is “the use of electronic information and telecommunications technologies to support long-distance clinical health care, patient and professional health-related education, public health, and health administration.”

Boyle focused his discussion on the Pennsylvania pediatric epilepsy telemedicine pilot project. The goal, he said, “is to enhance coordination of care between primary and specialty care through telemedicine and other health education technology systems.” More specifically, the goal was to pilot, refine, evolve, and develop telemedicine visits, particularly in primary care settings.

This program, entitled State and Regional Approaches to Improving Access to Services for Children/Youth with Epilepsy, has been run with a major emphasis on the interprofessional collaborative process.

The project’s interprofessional implementation team includes partners from across health care, including the Children’s Hospital in Pittsburgh (CHP) and WellSpan Neurosciences, for neurology, and the PA Medical Home Initiative and the Keystone Rural Health Center, for medical home primary care practices.

With guidance from the Michigan Department of Community Health and tools and equipment from the telemedicine program at CHP, Boyle and colleagues developed a collaborative model.

The model calls for joint development of the protocol for identifying patients and scheduling telemedicine appointments, joint development of the workflow that outlines roles and responsibilities of partners, identification and ordering of telemedicine equipment, and joint development of process evaluation measures for children and parents, primary care physicians, and neurologists.

The creation of the workflow required that every partner identify and accept their roles throughout the process. Each partner has a role at specific junctures, which include day of appointment, patient arrival, patient visit, billing, and after visit procedure.

In 2 years, a total of 8 patients have been seen across 2 sites. Though the implementation of the project has been slow, Boyle says that “we are starting to pick up steam now.” The project is currently identifying more sites and patients.

A major part of the process is the data collection and sharing across sites for each visit. Feedback from the partners was also shared. It was then summarized and used for making changes for subsequent cycles of patient visits.

Boyle also identified that parent input in the form of surveys was “very empowering and helpful for the families.”

In regards to the impact on clinical care and practice, Boyle said, “access to the sub-specialty care has been critical for many new patients.” The appointments have been timelier, and families are experiencing significantly less travel, cost, and missed work time. In fact, all 8 families said it was easier to see the neurologist through this network.

Partners were also happy. Survey data indicated that care coordination, equipment, and communications were all helpful.

Boyle concluded that more adjustments on the model must be made moving forward to “help the primary care folks improve access for families.”

Session: Professionals in Epilepsy Care Symposium: Interprofessional Models and Collaborative Care. Dec. 5, 2015.

Is long-distance clinical health care and patient education a model that can work in the real world?

Telehealth: Treating Long-Distance Epilepsy Patients

Beginning a discussion on early life epilepsies (ELE) at AES 2015, Anne Berg, PhD, professor at Northwestern University, explained that ELE needs to be thought of differently than it traditionally has been. Simple classifications of epilepsies (ie, generalized or focal and symptomatic or idiopathic) no longer work. Since human genomes of patients with epilepsy have hit gene sequencers, researchers have learned that there are at least 1000 genes associated with epilepsy. Further, these genes are involved with almost every aspect of brain development, and not primarily ion channels, as previously thought.

“One of the paradigmatic shifts that has come along into the clinic is that most malformations of the brain are genetic in origin,” says Berg.

The advantage of the genetic origin is that instead of simply suppressing seizures, “we are getting upstream of the seizure, treating the disease process.”

The promise of such testing is high; however, there are two major challenges, the first being a poor perception of genetic testing, whether from insurance companies, physicians, or even patients. The other obstacle is the lack of a “research culture” that focuses on the clinical outcomes.

Berg, along with colleagues, started the Pediatric Epilepsy Research Consortium in response to these problems. One project of the consortium provided evidence that highlights the necessity for inclusion of genetic testing as part of early-life evaluations, as well as guidelines for genetic testing.

Alex Paciorkowski, MD, of the University of Rochester, provided insight to the importance of biological pathways of epilepsy.

According to Paciorkowski, “discovery of the large genetic heterogeneity of epilepsy is going to end up being the most important development in the understanding of the biology of epilepsy in the past decade.”

Given genetic heterogeneity, pathways may be more important than individual genes.

Putting complex biological systems in a data structure and using algorithms from graph theory, data from pathways could help us identify new epilepsy genes, correlate genes, identify diagnostic tests, and possibly develop a “common target for new therapies.”

Biological pathways reveal a multiplicity of the problem and indicate that epilepsy may more closely resemble a “sinking ship,” in that there may be multiple gene mutations in one pathway.

Ghayda Mirzaa, MD, a geneticist at Seattle Children’s Hospital, highlighted the mammalian target of rapamycin (mTOR) signaling pathway and provided some new research regarding genes associated with brain malformation-related epilepsy, such as PTEN, CCND2, and PIK3CA. One group of researchers

 found that a PIK3CA inhibitor dramatically reduced epileptic activity in mice that harbor PIK3CA mutations, despite presence of cortical dysplasia and brain overgrowth.

Mirzaa’s hope is that the “emerging correlation between molecular, genetic abnormality with pathway deregulation” will lead to clinically important new therapies.

Ann Poduri, MD, of Boston Children’s Hospital concluded the talk by urging those present to impart passion and new epilepsy knowledge on colleagues.  Further, Poduri says, “what we really need to do and we’ve begun to do in this community is to integrate the clinical, clinical research, and bench research.”

Session: Investigators’ Workshop 1: Genetics, Biology, and Treatment of the Early Life Epilepsies. Dec. 5, 2015.

Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy

Is it time to breathe new life into the traditional view of early life epilepsies?