Predictive value of EFHC1 variants for the long-term seizure outcome in juvenile myoclonic epilepsy

ObjectiveThis study aimed to determine the contribution of EFHC1 variants to the phenotypic variability of juvenile myoclonic epilepsy (JME) and to evaluate their diagnostic value regarding previously identified clinical long-term seizure outcome predictors in a consecutive cohort of patients with JME.MethodsThirty-eight probands and three family members affected with JME were studied at a tertiary epilepsy center with a review of their medical records and a subsequent face-to-face interview. All coding EFHC1 exons and adjacent exon/intron boundaries were directly sequenced.ResultsThe previously reported EFHC1 mutation F229L was found in two cases who presented with early generalized tonic–clonic seizure (GTCS) onset and appeared to be associated with milder subtypes of JME. Variant R294H was identified in two further probands who had a subtype of JME developing from childhood absence epilepsy. However, segregation of the phenotype with this variant could not be confirmed in one family.ConclusionsOur findings corroborate the heterogeneity of JME as an electroclinical epilepsy syndrome and provide evidence that genetic factors may influence and help predict the long-term seizure outcome in patients with JME.     

A modality-specific somatosensory evoked potential test protocol for clinical evaluation: A feasibility study

ObjectiveWe aimed to establish an objective neurophysiological test protocol that can be used to assess the somatosensory nervous system.MethodsIn order to assess most fiber subtypes of the somatosensory nervous system, repetitive stimuli of seven different modalities (touch, vibration, pinprick, cold, contact heat, laser, and warmth) were synchronized with the electroencephalogram (EEG) and applied on the cheek and dorsum of the hand and dorsum of the foot in 21 healthy subjects and three polyneuropathy (PNP) patients. Latencies and amplitudes of the modalities were assessed and compared. Patients received quantitative sensory testing (QST) as reference.ResultsWe found reproducible evoked potentials recordings for touch, vibration, pinprick, contact-heat, and laser stimuli. The recording of warm-evoked potentials was challenging in young healthy subjects and not applicable in patients. Latencies were shortest within Aβ-fiber-mediated signals and longest within C-fibers. The test protocol detected function loss within the Aβ-fiber and Aδ-fiber-range in PNP patients. This function loss corresponded with QST findings.ConclusionIn this pilot study, we developed a neurophysiological test protocol that can specifically assess most of the somatosensory modalities. Despite technical challenges, initial patient data appear promising regarding a possible future clinical application.SignificanceEstablished and custom-made stimulators were combined to assess different fiber subtypes of the somatosensory nervous system using modality-specific evoked potentials.     

Dysregulation of sphingosine 1 phosphate receptor-1 (S1P1) signaling and regulatory lymphocyte-dependent immunosuppression in a model of post-fingolimod MS rebound

Fingolimod affords protection from MS by sequestering lymphocytes in secondary lymphoid organs via down regulation of their sphingosine 1 phosphate receptor (S1P1). Unexpectedly, accumulating evidence indicates that patients who discontinue fingolimod treatment may be at risk of rehearsal of magnetic resonance (MR) and clinical disease activity, sometimes featuring dramatic rebound.We therefore developed in vivo and in vitro models of post-fingolimod MS rebound to unravel its cellular and molecular mechanisms. The impact of fingolimod withdrawal on T regulatory lymphocytes was also investigated by means of cytofluorimetric analysis and antigen-specific lymphocyte proliferation assays. We show that mice with relapsing-remitting experimental autoimmune encephalomyelitis (EAE) undergo extremely severe, chronic disease rebound upon discontinuation of fingolimod. Remarkably, rebound is preceded by a burst of S1P1 overexpression in lymph node-entrapped lymphocytes that correlates with subsequent massive lymphocyte egress and widespread CNS immune infiltration. Also, consistent with the ability of S1P1 to counteract polarization and function of T regulatory lymphocytes their number and suppression of effector T cells is reduced by fingolimod suspension. Data disclose the first pathogenic mechanisms of post-fingolimod rebound that may be targeted for therapeutic intervention.