Person:

Pearl, Phillip

Crucial to the success of epilepsy surgery is the availability of a robust biomarker that identifies the Epileptogenic Zone (EZ). High Frequency Oscillations (HFOs) have emerged as potential presurgical biomarkers for the identification of the EZ in addition to Interictal Epileptiform Discharges (IEDs) and ictal activity. Although they are promising to localize the EZ, they are not yet suited for the diagnosis or monitoring of epilepsy in clinical practice. Primary barriers remain: the lack of a formal and global definition for HFOs; the consequent heterogeneity of methodological approaches used for their study; and the practical difficulties to detect and localize them noninvasively from scalp recordings. Here, we present a methodology for the recording, detection, and localization of interictal HFOs from pediatric patients with refractory epilepsy. We report representative data of HFOs detected noninvasively from interictal scalp EEG and MEG from two children undergoing surgery. The underlying generators of HFOs were localized by solving the inverse problem and their localization was compared to the Seizure Onset Zone (SOZ) as this was defined by the epileptologists. For both patients, Interictal Epileptogenic Discharges (IEDs) and HFOs were localized with source imaging at concordant locations. For one patient, intracranial EEG (iEEG) data were also available. For this patient, we found that the HFOs localization was concordant between noninvasive and invasive methods. The comparison of iEEG with the results from scalp recordings served to validate these findings. To our best knowledge, this is the first study that presents the source localization of scalp HFOs from simultaneous EEG and MEG recordings comparing the results with invasive recordings. These findings suggest that HFOs can be reliably detected and localized noninvasively with scalp EEG and MEG. We conclude that the noninvasive localization of interictal HFOs could significantly improve the presurgical evaluation for pediatric patients with epilepsy.

Aromatic L-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurometabolic disorder that leads to a severe combined deficiency of serotonin, dopamine, norepinephrine and epinephrine. Onset is early in life, and key clinical symptoms are hypotonia, movement disorders (oculogyric crisis, dystonia, and hypokinesia), developmental delay, and autonomic symptoms. In this consensus guideline, representatives of the International Working Group on Neurotransmitter Related Disorders (iNTD) and patient representatives evaluated all available evidence for diagnosis and treatment of AADCD and made recommendations using SIGN and GRADE methodology. In the face of limited definitive evidence, we constructed practical recommendations on clinical diagnosis, laboratory diagnosis, imaging and electroencephalograpy, medical treatments and non-medical treatments. Furthermore, we identified topics for further research. We believe this guideline will improve the care for AADCD patients around the world whilst promoting general awareness of this rare disease. Electronic supplementary material The online version of this article (doi:10.1186/s13023-016-0522-z) contains supplementary material, which is available to authorized users.

Up to one-third of patients with epilepsy are medically intractable and need resective surgery. To be successful, epilepsy surgery requires a comprehensive preoperative evaluation to define the epileptogenic zone (EZ), the brain area that should be resected to achieve seizure freedom. Due to lack of tools and methods that measure the EZ directly, this area is defined indirectly based on concordant data from a multitude of presurgical non-invasive tests and intracranial recordings. However, the results of these tests are often insufficiently concordant or inconclusive. Thus, the presurgical evaluation of surgical candidates is frequently challenging or unsuccessful. To improve the efficacy of the surgical treatment, there is an overriding need for reliable biomarkers that can delineate the EZ. High-frequency oscillations (HFOs) have emerged over the last decade as new potential biomarkers for the delineation of the EZ. Multiple studies have shown that HFOs are spatially associated with the EZ. Despite the encouraging findings, there are still significant challenges for the translation of HFOs as epileptogenic biomarkers to the clinical practice. One of the major barriers is the difficulty to detect and localize them with non-invasive techniques, such as magnetoencephalography (MEG) or scalp electroencephalography (EEG). Although most literature has studied HFOs using invasive recordings, recent studies have reported the detection and localization of HFOs using MEG or scalp EEG. MEG seems to be particularly advantageous compared to scalp EEG due to its inherent advantages of being less affected by skull conductivity and less susceptible to contamination from muscular activity. The detection and localization of HFOs with MEG would largely expand the clinical utility of these new promising biomarkers to an earlier stage in the diagnostic process and to a wider range of patients with epilepsy. Here, we conduct a thorough critical review of the recent MEG literature that investigates HFOs in patients with epilepsy, summarizing the different methodological approaches and the main findings. Our goal is to highlight the emerging potential of MEG in the non-invasive detection and localization of HFOs for the presurgical evaluation of patients with medically refractory epilepsy (MRE).

Background and Objectives

Inherited disorders of GABA metabolism include SSADH and GABA-transaminase deficiencies. The clinical features, pathophysiology, diagnosis, and management of both are discussed, including an updated list of ALDH5A1 mutations causing SSADH deficiency.

Methods

Our SSADH patient database was analyzed and murine and translational studies leading to clinical trials are reviewed.

Results

The database containing 112 SSADH-deficient patients (71 pediatric and adolescent subjects, 41 adults) indicates that developmental delay and hypotonia are the most common presenting symptoms. Epilepsy is present in 2/3 of patients by adulthood. Murine genetic model, and human studies using flumazenil-PET and transcranial magnetic stimulation, have led to therapeutic trials and identified additional metabolic disruptions. Suggestions for new therapies have arisen from findings of GABAergic effects on autophagy with enhanced activation of the mTor pathway. A total of 45 pathogenic mutations have been reported in SSADH deficiency including the discovery of three previously unreported.

Conclusions

Investigations into the disorders of GABA metabolism provide fundamental insights into mechanisms underlying epilepsy and support the development of biomarkers and clinical trials. Comprehensive definition of the phenotypes of both SSADH and GABA-T deficiencies may increase our knowledge of the neurophysiological consequences of a hyperGABAergic state.