Elena Gardella

Lesionectomy in epileptogenic gangliogliomas: Seizure outcome and surgical results

We retrospectively analysed seizure outcome and surgical results in a series of 21 patients with ganglioglioma treated with lesionectomy. The 21 patients (13 males, eight females) had a history of epilepsy longer than 1 year and post-operative follow up of at least 1 year. Information on the duration of the seizures, type and frequency was retrieved from medical records. In all patients, surgery was limited to the tumour. The interval between onset of seizures and surgery ranged from 1 to 35 years (mean 11). Patient age ranged from 6 to 61 years (mean 27.5). Fifteen patients (71.4%) had complex partial seizures and six had simple partial seizures. Secondary generalisation was present in 10 patients (47.6%). Seizure frequency varied from several per day to one per month. Sixteen tumours were temporal (76.1%; 11 temporo-mesial, five temporo-lateral), and five were extratemporal (23.8%). The mean follow-up period was 5.4 years (range: 1.25-10 years). No tumour progression was observed. No patient died during surgery or the post-operative course. Fourteen patients (66.6%) were Engel class I (five temporo-mesial, five temporo-lateral, four extratemporal) and seven (33.3%) were Engel class II. Post-operative complications were observed in six patients (28.6%), two of whom had cerebellar haemorrhage, possibly due to increased transmural venous pressure. In our patients with temporal neocortical and extratemporal ganglioglioma, lesionectomy allowed good seizure control. The unsatisfactory outcome for mesiotemporal gangliogliomas might indicate the need for extensive neurophysiological presurgical evaluation in order to perform tailored surgery. To avoid cerebellar haemorrhage, attention should be paid to those factors involved in transmural venous pressure increases.

Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.

Mutations in KCNT1 cause a spectrum of focal epilepsies

Autosomal dominant mutations in the sodium‐gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI. In contrast to the 100% penetrance so far reported for KCNT1 mutations, we observed incomplete penetrance. It is notable that we report that the one KCNT1 mutation, p.Arg398Gln, can lead to either of the two distinct phenotypes, ADNFLE or MMFSI, even within the same family. This indicates that genotype–phenotype relationships for KCNT1 mutations are not straightforward. We demonstrate that KCNT1 mutations are highly pleiotropic and are associated with phenotypes other than ADNFLE and MMFSI. KCNT1 mutations are now associated with Ohtahara syndrome, MMFSI, and nocturnal focal epilepsy. They may also be associated with multifocal epilepsy and cardiac disturbances.

Diagnostic accuracy of the Salzburg EEG criteria for non-convulsive status epilepticus: a retrospective study

BACKGROUND Several EEG criteria have been proposed for diagnosis of non-convulsive status epilepticus (NCSE), but none have been clinically validated. We aimed to assess the diagnostic accuracy of the EEG criteria proposed by a panel of experts at the fourth London-Innsbruck Colloquium on Status Epilepticus in Salzburg, 2013 (henceforth called the Salzburg criteria). METHODS We did a retrospective, diagnostic accuracy study using EEG recordings from patients admitted for neurological symptoms or signs to three centres in two countries (Danish Epilepsy Centre, Dianalund, Denmark; Aarhus University Hospital, Aarhus, Denmark; and Paracelsus Medical University, Salzburg, Austria). Participants were included from the Danish centres if they were aged 4 months or older, and from the Austrian centre if aged 18 years or older. Participants were sorted into two groups: consecutive patients under clinical suspicion of having NCSE (the clinical validation group) or consecutive patients with abnormal EEG findings but no clinical suspicion of NCSE (the control group). Two raters blinded to all other patient data retrospectively analysed the EEG recordings and, using the Salzburg criteria, categorised patients as in NCSE or not in NCSE. By comparing with a reference standard inferred from all clinical and para-clinical data, therapeutic response, and the final outcome, we calculated sensitivity, specificity, overall diagnostic accuracy, positive and negative predictive values, and inter-rater agreement for the Salzburg criteria. The reference standard was inferred by two raters who were blinded to the scorings of the Salzburg criteria. FINDINGS We retrospectively reviewed EEG data from 220 patients. EEGs in the clinical validation group were recorded in 120 patients between Jan 1, and Feb 28, 2014 (Austria), and Aug 1, 2014, and Jan 31, 2015 (Denmark). EEGs in the control group were recorded in 100 patients between Jan 13 and Jan 22, 2014 (Austria) and Jan 12 and Jan 26, 2015 (Denmark). According to the reference standard, 43 (36%) of the 120 patients in the validation group had NCSE. In the validation cohort sensitivity was 97·7% (95% CI 87·9-99·6) and specificity was 89·6% (80·8-94·6); overall accuracy was 92·5% (88·3-97·5). Positive predictive value was 84·0% (95% CI 74·1-91·5) and negative predictive value was 98·6% (94·4-100). Three people in the control group (n=100) fulfilled the Salzburg criteria and were therefore false positives (specificity 97·0%, 95% CI 91·5-99·0; sensitivity not calculable). Inter-rater agreement was high for both the Salzburg criteria (k=0·87) and for the reference standard (k=0·95). Therapeutic changes occurred significantly more often in the group of patients fulfilling Salzburg criteria (42 [84%] of 50 patients) than in those who did not (11 [16%] of 70; p<0·0001). INTERPRETATION The Salzburg criteria for diagnosis of NCSE have high diagnostic accuracy and excellent inter-rater agreement, making them suitable for implementation in clinical practice. FUNDING None.

Telephone-induced Seizures: A New Type of Reflex Epilepsy

Summary:  Purpose: To report a new form of reflex epilepsy in which the seizures are repeatedly and exclusively triggered by answering the telephone.

Focal epilepsies in adult patients attending two epilepsy centers: classification of drug-resistance, assessment of risk factors, and usefulness of "new" antiepileptic drugs

Purpose:  To classify the grade of antiepileptic drug (AED) resistance in a cohort of patients with focal epilepsies, to recognize the risk factors for AED resistance, and to estimate the helpfulness of “new‐generation” AEDs.

Idiopathic generalized epilepsy (IGE) syndromes in development: IGE with absences of early childhood, IGE with phantom absences, and perioral myoclonia with absences

The classification of idiopathic generalized epilepsies (IGEs) is still controversial, with special reference to absence epilepsy syndromes. Strict, well‐defined criteria for syndromic definitions are necessary to delineate homogeneous conditions; however, this approach may leave a considerable group of patients unclassified, leading to the effort to categorize them in possible distinct subsyndromes. In this report, we review some of these possible IGE subsyndromes, such as IGE with absences of early childhood, IGE with phantom absences, and perioral myoclonia with absences, briefly commenting on the issues regarding their recognition as individual entities.

Autosomal Dominant Early‐onset Cortical Myoclonus, Photic‐induced Myoclonus, and Epilepsy in a Large Pedigree

Summary:  Purpose: Cortical tremor, a form of rhythmic cortical myoclonus (rhythmic CM), and epilepsy have been described in families with autosomal dominant inheritance. Linkage analyses revealed two putative loci on chromosome 2p and 8q. Clinical photosensitivity was not a prominent feature in such families. We describe a large Italian family with rhythmic CM, photosensitivity, and epilepsy.

Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies

&NA; Recently, de novo mutations in the gene KCNA2, causing either a dominant‐negative loss‐of‐function or a gain‐of‐function of the voltage‐gated K+ channel Kv1.2, were described to cause a new molecular entity within the epileptic encephalopathies. Here, we report a cohort of 23 patients (eight previously described) with epileptic encephalopathy carrying either novel or known KCNA2 mutations, with the aim to detail the clinical phenotype associated with each of them, to characterize the functional effects of the newly identified mutations, and to assess genotype‐phenotype associations. We identified five novel and confirmed six known mutations, three of which recurred in three, five and seven patients, respectively. Ten mutations were missense and one was a truncation mutation; de novo occurrence could be shown in 20 patients. Functional studies using a Xenopus oocyte two‐microelectrode voltage clamp system revealed mutations with only loss‐of‐function effects (mostly dominant‐negative current amplitude reduction) in eight patients or only gain‐of‐function effects (hyperpolarizing shift of voltage‐dependent activation, increased amplitude) in nine patients. In six patients, the gain‐of‐function was diminished by an additional loss‐of‐function (gain‐and loss‐of‐function) due to a hyperpolarizing shift of voltage‐dependent activation combined with either decreased amplitudes or an additional hyperpolarizing shift of the inactivation curve. These electrophysiological findings correlated with distinct phenotypic features. The main differences were (i) predominant focal (loss‐of‐function) versus generalized (gain‐of‐function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss‐of‐function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain‐of‐function mutations; and (iii) most severe early‐onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalized and focal seizures and EEG abnormalities for patients with gain‐ and loss‐of‐function mutations. Our study thus indicates well represented genotype‐phenotype associations between three subgroups of patients with KCNA2 encephalopathy according to the electrophysiological features of the mutations.

Seizure-related automatic locomotion triggered by intracerebral electrical stimulation

We describe the case of an eight-year-old boy, who underwent a video-stereo EEG (SEEG) investigation for the presurgical assessment of drug-resistant epilepsy, related to a right fronto-lateral cortical dysplasia and who became seizure-free after epilepsy surgery. The unexpected finding of the investigations was that intracerebral, high frequency (50 Hz) electrical stimulation (HFS) triggered the emergence of automatic and involuntary forward-backward locomotion during a focal seizure while the boy was standing. This clinical manifestation was different from the chaotic motor activity described during epileptic wanderings. The stimulation of the same fronto-lateral region, while the patient was lying, produced only the subjective sensation that the legs were moving, although there was no physical manifestation of this. Human locomotion is an innate motor behavior that is normally due to the activation of the spinal network for locomotion (central pattern generator). The emergence of different stereotyped motor behaviors during focal epileptic seizures or sleep disorders has recently been interpreted as a release of subcortical central pattern generators (Tassinari et al. 2005). In view of this, we hypothesize that the involuntary and robot-like locomotion of our patient could be the ictal expression of the release of subcortical locomotor CPGs.