Luca de Palma

PCDH19-related epilepsy in two mosaic male patients

PCDH19 gene mutations have been recently associated with an epileptic syndrome characterized by focal and generalized seizures. The PCDH19 gene (Xq22.1) has an unusual X‐linked inheritance with a selective involvement for female subjects. A cellular interference mechanism has been hypothesized and male patients can manifest epilepsy only in the case of a mosaicism. So far about 100 female patients, and only one symptomatic male have been described. Using targeted next generation sequencing (NGS) approach we found a PCDH19 point mutation in two male patients with a clinical picture suggestive of PCDH19‐related epilepsy. The system allowed us to verify that the two c.1352 C>T; p.(Pro451Leu) and c.918C>G; p.(Tyr306*) variants occurred in mosaic status. Mutations were confirmed by Sanger sequencing and quantified by real‐time polymerase chain reaction (PCR). Up to now, the traditional molecular screening for PCDH19‐related epilepsy has been targeted to all females with early onset epilepsy with or without cognitive impairment. Male patients were generally excluded. We describe for the first time two mosaic PCDH19 point mutations in two male patients with a clinical picture suggestive of PCDH19‐related epilepsy. This finding opens new opportunities for the molecular diagnoses in patients with a peculiar type of epilepsy that remains undiagnosed in male patients.

PCDH19-related epilepsy and Dravet Syndrome: Face-off between two early-onset epilepsies with fever sensitivity.

Aim of this study is to compare PCDH19-related epilepsy and Dravet Syndrome (DS) in order to find out differences between these two infantile epilepsies with fever sensitivity. We retrospectively reviewed the medical records of 15 patients with PCDH19-related epilepsy and 19 with DS. Comparisons were performed with Fishers exact test or Students t-test. Females prevailed in PCDH19-related epilepsy. Epilepsy onset was earlier in DS (5.0+2.1 vs 11.2+7.0months; p<0.05). The second seizure/cluster occurred after a longer latency in PCDH19-related epilepsy rather than in DS (10.1±13.6 vs 2.2±2.1months; p<0.05). Seizures were mainly single and prolonged seizures in DS, and brief and clustered in PCDH19-related epilepsy. Myoclonic and clonic seizures have been found only in DS. Other types of seizures were found in both epilepsies with a prevalence of GTCS and atypical absences in DS, and focal motor and hypomotor seizures in PCDH19-related epilepsy. Seizures with affective symptoms have been confirmed to be typical of PCDH19-related epilepsy. Status Epilepticus equally occurred in both groups. Photosensitivity was detected only in DS. No differences were found about the presence of intellectual disabilities and behavioral disturbances. We were able to find out some distinctive features, which could address the diagnosis towards DS or PCDH19-related epilepsy, since first manifestation. These considerations suggest to definitively considering PCDH19 gene as cause of a proper epileptic phenotype.

Photosensitivity is an early marker of neuronal ceroid lipofuscinosis type 2 disease

This study aimed to identify early clinical, magnetic resonance imaging (MRI), and electroencephalographic (EEG) characteristics of neuronal ceroid lipofuscinosis type 2 (CLN2) disease to enable early diagnosis, thus providing the key to early treatment, and optimized care and outcomes.

Acute intralesional recording in hypothalamic hamartoma: description of 4 cases

Hypothalamic hamartomas (HHs) are intrinsically epileptogenic lesions associated to medically intractable focal epilepsy mainly characterized by gelastic and focal seizures. Intralesional recording with deep electrodes has documented the presence of ictal discharge arising from inside the lesion. Nevertheless interictal and ictal scalp EEG is poorly informative and non-localizing in a great deal of cases. HH disconnection leads to seizure remission in most cases. To describe the intralesional EEG recordings and to compare them with concomitant scalp EEG and with previous cases reported in literature. We reviewed the medical records of 17 children affected by drug-resistant focal epilepsy associated to HH. We recorded intralesional electrical activity during stereo-endoscopic disconnection in three cases and during deep brain stimulation implantation in one. We also correlated it with the simultaneous scalp-EEG recording. Acute intralesional recordings in our cases confirmed the presence of epileptiform abnormalities intermingled with low-voltage activity, mostly on the same side of the HH attachment. Paroxysmal activity recorded inside the HH was always evident. Mapping of HH epileptogenic activity could be useful to confirm the usefulness of disconnection procedure. This should consider on-site recording from the HH and if abnormalities are detected safely proceed to disconnection of the HH.

Increasing volume and complexity of pediatric epilepsy surgery with stable seizure outcome between 2008 and 2014: A nationwide multicenter study

OBJECTIVE The objective of the study was to assess common practice in pediatric epilepsy surgery in Italy between 2008 and 2014. METHODS A survey was conducted among nine Italian epilepsy surgery centers to collect information on presurgical and postsurgical evaluation protocols, volumes and types of surgical interventions, and etiologies and seizure outcomes in pediatric epilepsy surgery between 2008 and 2014. RESULTS Retrospective data on 527 surgical procedures were collected. The most frequent surgical approaches were temporal lobe resections and disconnections (133, 25.2%) and extratemporal lesionectomies (128, 24.3%); the most frequent etiologies were FCD II (107, 20.3%) and glioneuronal tumors (105, 19.9%). Volumes of surgeries increased over time independently from the age at surgery and the epilepsy surgery center. Engel class I was achieved in 73.6% of patients (range: 54.8 to 91.7%), with no significant changes between 2008 and 2014. Univariate analyses showed a decrease in the proportion of temporal resections and tumors and an increase in the proportion of FCDII, while multivariate analyses revealed an increase in the proportion of extratemporal surgeries over time. A higher proportion of temporal surgeries and tumors and a lower proportion of extratemporal and multilobar surgeries and of FCD were observed in low (<50surgeries/year) versus high-volume centers. There was a high variability across centers concerning pre- and postsurgical evaluation protocols, depending on local expertise and facilities. SIGNIFICANCE This survey reveals an increase in volume and complexity of pediatric epilepsy surgery in Italy between 2008 and 2014, associated with a stable seizure outcome.

Radiofrequency thermocoagulation of the seizure-onset zone during stereoelectroencephalography

To assess long‐term outcome and identify prognostic factors of radiofrequency thermocoagulation (RFTC) following stereoelectroencephalography (SEEG) explorations in particularly complex cases of focal epilepsy.

Epilepsy surgery of “low grade epilepsy associated neuroepithelial tumors”: A retrospective nationwide Italian study

To analyze the attitude and results of Italian epilepsy surgery centers in the surgical management of “low grade epilepsy associated neuroepithelial tumors” (LEATs).

EPINETLAB: a software for seizure-onset zone identification from intracranial EEG signal in epilepsy

The pre-operative workup of patients with drug-resistant epilepsy requires in some candidates the identification from intracranial EEG (iEEG) of the seizure-onset zone (SOZ), defined as the area responsible of the generation of the seizure and therefore candidate for resection. High-frequency oscillations (HFOs) contained in the iEEG signal have been proposed as biomarker of the SOZ. Their visual identification is a very onerous process and an automated detection tool could be an extremely valuable aid for clinicians, reducing operator-dependent bias, and computational time. In this manuscript, we present the EPINETLAB software, developed as a collection of routines integrated in the EEGLAB framework that aim to provide clinicians with a structured analysis pipeline for HFOs detection and SOZ identification. The tool implements an analysis strategy developed by our group and underwent a preliminary clinical validation that identifies the HFOs area by extracting the statistical properties of HFOs signal and that provides useful information for a topographic characterization of the relationship between clinically defined SOZ and HFO area. Additional functionalities such as inspection of spectral properties of ictal iEEG data and import and analysis of source-space magnetoencephalographic (MEG) data were also included. EPINETLAB was developed with user-friendliness in mind to support clinicians in the identification and quantitative assessment of HFOs in iEEG and source space MEG data and aid the evaluation of the SOZ for pre-surgical assessment.

Vigabatrin efficacy in GPR56-associated polymicrogyria: The role of GABAA receptor pathway

To the Editors: G protein–coupled receptor 56 (GPR56) gene mutations are responsible for the syndromic condition known as bilateral frontal and frontoparietal cortical malformation (BFPP). The main clinical features of BFPP include severe mental retardation, developmental delay, and epilepsy, often presenting as Lennox-Gastaut syndrome. Although there is some evidence of the pathogenesis of BFPP, the pathophysiology of the resulting epilepsy is poorly understood. Localized freezing in neonatal mice brain is currently used as an experimental model mimicking the histologic characteristics of a human four-layered polymicrogyria. This model documented a widespread functional disruption of c-aminobutyric acid A receptors (GABAARs) revealing a downregulation of GABAAR sub-units. 6 We observed four female patients from two families with consanguineous parents. All of them presented with BFPP due to GPR56 mutations. Mutations in 16q12.2–21 were identified [C.1453C>T and C.1693C>T]. All patients presented with tonic and secondarily generalized seizures. Epileptic spasms occurred in half of them. All patients had drugresistant epilepsy, gait impairment, and intellectual disability. All treatments were ineffective, including benzodiazepines and barbiturates. Vigabatrin was introduced at a median age of 8.8 years old (range 7.2–8.9). We observed a median seizure reduction of 75% (range 25–100%) after vigabatrin introduction. This effect persisted all over the follow-up (median 15 months, range 6–72). The Clinical Global Impression (CGI) test administered to parents revealed an overall improvement (one case “very much improved”, two cases “much improved”, one case “minimal improved”). In addition, parents reported an increase of attention in three patients. The functional disruption of GABAAR sub-units could be the biologic mechanism involved in epileptogenesis, and in the specific sensitivity to vigabatrin in patients with BFPP. The evidence linking epilepsy with dysfunction of GABAergic inhibition is well documented, and GABAAR is a major target of antiepileptic drugs (AEDs). Functional studies demonstrated that the sub-unit composition of GABAAR determines its electrophysiologic and pharmacologic properties. In our patients, different drugs active on the GABA pathway were used: benzodiazepines (clobazam and clonazepam) and barbiturates (phenobarbital) failed. The function of GABAARs can be modulated through the allosteric site, or directly activated through the orthosteric site. Vigabatrin increases the availability of GABA in synaptic space (inhibition of the GABA catabolism), and might be effective through the direct activation of the orthosteric site. Loss-of-function of allosteric sites, caused by downregulation of GABAARs sub-units, might be an explanation for the inefficacy of other GABA agents tested. The selectivity of benzodiazepine responsiveness of GABAARs is determined by specific alpha subunits (those abnormally expressed in the animal model of polymicrogyria). Similarly, the main antiseizure mechanism of barbiturates is likely the allosteric effect on GABAARs: some evidence related with beta sub-units. One similar model is stiripentol effectiveness in Dravet syndrome: positive modulation by stiripentol was most effective on GABAARs containing an alpha-3 subunit, those characteristics of the immature brain. GABAARs are established targets for AEDs, but data regarding the specificity of AEDs in different syndromes are lacking. Our report suggests that also in rare diseases, a better knowledge of the AED’s mechanism of action and the understanding of the disease pathophysiology could allow a tailored treatment.

Peri-ictal water drinking: a rare automatic behaviour in temporal lobe epilepsy

Peri-ictal water drinking (PIWD) has been reported as the action of drinking during or within two minutes of an electroclinical seizure. It is considered a peri-ictal vegetative symptom, evident both during childhood and adulthood epilepsy. The aim of this paper was to describe the clinical and electroencephalographic features of two new adult subjects suffering from symptomatic temporal lobe epilepsy with episodes of PIWD recorded by VIDEO-EEG and to review literature data in order to better define this peculiar event during seizures, a rare and probably underestimated semiological sign. To date, 51 cases with focal epilepsy and seizures associated with PIWD have been reported. All patients presented with temporal lobe epilepsy. All cases but one had symptomatic epilepsy. Most of the patients had an involvement of the right hemisphere. Water drinking was reported as an ictal sign in the majority of patients, and less frequently was reported as postictal. We believe that PIWD might be considered a rare automatic behaviour, like other automatisms. Automatisms are more frequently described in patients with temporal lobe epilepsy. PIWD was reported also to have lateralizing significance in the non-dominant temporal lobe, however, because of its rarity, this finding remains unclear.