Dang Khoa Nguyen

SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function

Several genes predisposing to autism spectrum disorders (ASDs) with or without epilepsy have been identified, many of which are implicated in synaptic function. Here we report a Q555X mutation in synapsin 1 (SYN1), an X-linked gene encoding for a neuron-specific phosphoprotein implicated in the regulation of neurotransmitter release and synaptogenesis. This nonsense mutation was found in all affected individuals from a large French-Canadian family segregating epilepsy and ASDs. Additional mutations in SYN1 (A51G, A550T and T567A) were found in 1.0 and 3.5% of French-Canadian individuals with autism and epilepsy, respectively. The majority of these SYN1 mutations were clustered in the proline-rich D-domain which is substrate of multiple protein kinases. When expressed in synapsin I (SynI) knockout (KO) neurons, all the D-domain mutants failed in rescuing the impairment in the size and trafficking of synaptic vesicle pools, whereas the wild-type human SynI fully reverted the KO phenotype. Moreover, the nonsense Q555X mutation had a dramatic impact on phosphorylation by MAPK/Erk and neurite outgrowth, whereas the missense A550T and T567A mutants displayed impaired targeting to nerve terminals. These results demonstrate that SYN1 is a novel predisposing gene to ASDs, in addition to epilepsy, and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies the pathogenesis of both diseases.

Revisiting the role of the insula in refractory partial epilepsy

Purpose:  Recent evidence suggesting that some epilepsy surgery failures could be related to unrecognized insular epilepsy have led us to lower our threshold to sample the insula with intracerebral electrodes. In this study, we report our experience resulting from this change in strategy.

Non-invasive pre-surgical investigation of a 10 year-old epileptic boy using simultaneous EEG–NIRS

Near-infrared spectroscopy (NIRS) is a novel imaging technique of potential value in the pre-surgical investigation of patients with refractory epilepsy. We recorded simultaneously electrophysiology (EEG; Compumedics, USA) and near-infrared spectroscopy (NIRS; ISS, USA) to examine the localization of the ictal onset zone and assess language lateralization in a young epileptic boy (L.H., 10 years) as part of his pre-surgical evaluation. L.H. underwent a prolonged EEG-NIRS recording while electro-clinical and electrical seizures were recorded. Results were compared to those obtained with other pre-surgical techniques (SPECT, FDG-PET, EEG-fMRI and EEG-MEG) and showed good concordance for ictal onset zone localization. A second NIRS session without EEG was carried out in order to investigate language lateralization. For this purpose, the patient performed a categorical verbal-fluency task during NIRS recordings. Results showed left-hemisphere dominance for language function in this young boy. This case report illustrates that multi-channel EEG-NIRS has the potential to contribute favourably to pre-surgical investigation in young patients.

Temporal Lobe Epilepsy Surgery Failures: A Review

Patients with temporal lobe epilepsy (TLE) are refractory to antiepileptic drugs in about 30% of cases. Surgical treatment has been shown to be beneficial for the selected patients but fails to provide a seizure-free outcome in 20–30% of TLE patients. Several reasons have been identified to explain these surgical failures. This paper will address the five most common causes of TLE surgery failure (a) insufficient resection of epileptogenic mesial temporal structures, (b) relapse on the contralateral mesial temporal lobe, (c) lateral temporal neocortical epilepsy, (d) coexistence of mesial temporal sclerosis and a neocortical lesion (dual pathology); and (e) extratemporal lobe epilepsy mimicking TLE or temporal plus epilepsy. Persistence of epileptogenic mesial structures in the posterior temporal region and failure to distinguish mesial and lateral temporal epilepsy are possible causes of seizure persistence after TLE surgery. In cases of dual pathology, failure to identify a subtle mesial temporal sclerosis or regions of cortical microdysgenesis is a likely explanation for some surgical failures. Extratemporal epilepsy syndromes masquerading as or coexistent with TLE result in incomplete resection of the epileptogenic zone and seizure relapse after surgery. In particular, the insula may be an important cause of surgical failure in patients with TLE.

Non-invasive continuous EEG-fNIRS recording of temporal lobe seizures

PURPOSE Functional near-infrared spectroscopy (fNIRS) is a technique that allows continuous non-invasive monitoring of tissue oxygenation and haemodynamics in the brain. By using combined EEG-fNIRS recordings, we sought to better understand the pathophysiology of temporal lobe seizures. RESULTS Nine patients (5 males; mean age 35 years; range 11-56 years) with refractory mesial temporal lobe epilepsy underwent combined EEG-fNIRS recordings. Eight complex partial seizures from 3 patients were successfully recorded. All seizures were associated with significant local and remote haemodynamic changes which outlasted the duration of seizures. Over the epileptogenic temporal lobe, increased oxygenation [increase in cerebral blood volume (CBV) and oxyhaemoglobin (HbO), decrease in deoxyhaemoglobin (HbR)] was followed by a deoxygenated state [increase in HbR]. A similar haemodynamic profile was seen over the contralateral temporal lobe (even without evidence of epileptic propagation) though variations generally had lower amplitudes. Heterogeneous haemodynamic changes in remote frontal and/or parietal areas were also noted early on when epileptic activity was limited to the temporal lobe. CONCLUSION EEG-fNIRS reveals complex local and remote oxygenation changes during temporal lobe seizures.

A Novel Low-Power-Implantable Epileptic Seizure-Onset Detector

A novel implantable low-power integrated circuit is proposed for real-time epileptic seizure detection. The presented chip is part of an epilepsy prosthesis device that triggers focal treatment to disrupt seizure progression. The proposed chip integrates a front-end preamplifier, voltage-level detectors, digital demodulators, and a high-frequency detector. The preamplifier uses a new chopper stabilizer topology that reduces instrumentation low-frequency and ripple noises by modulating the signal in the analog domain and demodulating it in the digital domain. Moreover, each voltage-level detector consists of an ultra-low-power comparator with an adjustable threshold voltage. The digitally integrated high-frequency detector is tunable to recognize the high-frequency activities for the unique detection of seizure patterns specific to each patient. The digitally controlled circuits perform accurate seizure detection. A mathematical model of the proposed seizure detection algorithm was validated in Matlab and circuits were implemented in a 2 mm2 chip using the CMOS 0.18- μm process. The proposed detector was tested by using intracerebral electroencephalography (icEEG) recordings from seven patients with drug-resistant epilepsy. The seizure signals were assessed by the proposed detector and the average seizure detection delay was 13.5 s, well before the onset of clinical manifestations. The measured total power consumption of the detector is 51 μW.

Action observation and execution: Intracranial recordings in a human subject

It is now well established that there exists a neuronal mechanism matching action perception and execution in the brain. Evidence for the existence of such a system comes primarily from studies in primates, where it has been shown that cells in premotor area F5 discharge when an individual performs a specific action and when it observes the same movement performed by others.1 In the human brain, evidence is indirect, and although no cortical recording studies have demonstrated the existence of these so-called “mirror neurons,”1 functional imaging studies have revealed activation of the likely homologue of monkey area F5 (Broca area) during action observation.2 Furthermore, magnetoencephalography3 and quantified EEG4 have shown activation of motor cortex during observation of finger movements. In this study, we report alpha rhythm patterns in functionally defined language and hand motor areas during execution and observation of simple finger movements in a patient with implanted subdural electrodes. The patient was a 19-year-old left-handed …

Expanding the Clinical Phenotype Associated With ELOVL4 Mutation: Study of a Large French-Canadian Family With Autosomal Dominant Spinocerebellar Ataxia and Erythrokeratodermia

IMPORTANCE The autosomal dominant spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative disorders with significant genetic heterogeneity. Despite the identification of 20 SCA genes, the cause of the disorder in a significant proportion of families with SCA remains unexplained. In 1972, a French-Canadian family segregating a combination of SCA and erythrokeratodermia variabilis (EKV) in an autosomal dominant fashion was described. OBJECTIVE To map and identify the causative gene in this large family with SCA and EKV using a combination of linkage analysis and whole-exome sequencing. DESIGN, SETTING, AND PARTICIPANTS A total of 32 individuals from the family have undergone complete neurologic and dermatologic examinations. MAIN OUTCOMES AND MEASURES Mutations in ELOVL4 have been reported in families with macular degeneration. Recently, homozygous mutations were found in patients with ichthyosis, spastic paraplegia, and severe neurodevelopmental defects. In the present study, we report on a heterozygote mutation in ELOVL4 in affected individuals from the family with SCA and EKV. The mutation segregates with a milder phenotype consisting of early-onset patches of erythema and hyperkeratosis, as well as SCA manifesting in the fourth or fifth decade of life. RESULTS We describe the mapping and the identification of a c.504G>C transversion in ELOVL4 resulting in the p.L168F substitution. We also provide clinical characterization of the phenotypes in 19 mutation carriers. CONCLUSIONS AND RELEVANCE We report, to our knowledge, the first mutation in ELOVL4 that is associated with SCA and EKV. This gene encodes a member of the elongase family, which is responsible for the elongation of very long-chain fatty acids (at least 26 carbons). These fatty acids participate in a wide variety of physiological functions, including skin barrier formation and peroxisome β-oxidation. Overall, these results provide additional insight into the pathogenesis of these complex neurodegenerative disorders.

The combination of subdural and depth electrodes for intracranial EEG investigation of suspected insular (perisylvian) epilepsy

Purpose:  We present two methods of implantation for the investigation of suspected insular and perisylvian epilepsy that combine depth and subdural electrodes to capitalize on the advantages of each technique.

The utility of magnetoencephalography in the presurgical evaluation of refractory insular epilepsy.

To study the utility of magnetoencephalography (MEG) in patients with refractory insular epilepsy. Covered by highly functional temporal, frontal, and parietal opercula, insular‐onset seizures can manifest a variety of ictal symptoms falsely leading to a diagnosis of temporal, frontal, or parietal lobe seizures. Lack of recognition of insular seizures may be responsible for some epilepsy surgery failures.