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CDKL5 deficiency disorder (CDD) is a rare, X-linked, developmental and epileptic encephalopathy characterised by severe global developmental impairment and seizures that can begin in the first few months after birth and are often treatment refractory. Ganaxolone, an investigational neuroactive steroid, reduced seizure frequency in an open-label, phase 2 trial that included patients with CDD. We aimed to further assess the efficacy and safety of ganaxolone in patients with CDD-associated refractory epilepsy.In the double-blind phase of this randomised, placebo-controlled, phase 3 trial, done at 39 outpatient clinics in eight countries (Australia, France, Israel, Italy, Poland, Russia, the UK, and the USA), patients were eligible if they were aged 2-21 years with a pathogenic or probably pathogenic CDKL5 variant and at least 16 major motor seizures (defined as bilateral tonic, generalised tonic-clonic, bilateral clonic, atonic, or focal to bilateral tonic-clonic) per 28 days in each 4-week period of an 8-week historical period. After a 6-week prospective baseline period, patients were randomly assigned (1:1) via an interactive web response system to receive either enteral adjunctive ganaxolone or matching enteral adjunctive placebo (maximum dose 63 mg/kg per day for patients weighing ≤28 kg or 1800 mg/day for patients weighing28 kg) for 17 weeks. Patients, caregivers, investigators (including those analysing data), trial staff, and the sponsor (other than the investigational product manager) were masked to treatment allocation. The primary efficacy endpoint was percentage change in median 28-day major motor seizure frequency from the baseline period to the 17-week double-blind phase and was analysed (using a Wilcoxon-rank sum test) in all patients who received at least one dose of trial treatment and for whom baseline data were available. Safety (compared descriptively across groups) was analysed in all patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov, NCT03572933, and the open-label extension phase is ongoing.Between June 25, 2018, and July 2, 2020, 114 patients were screened for eligibility, of whom 101 (median age 6 years [IQR 3 to 10]) were randomly assigned to receive either ganaxolone (n=50) or placebo (n=51). All patients received at least one dose of a study drug, but seizure frequency for one patient in the ganaxolone group was not recorded at baseline and so the primary endpoint was analysed in a population of 100 patients. There was a median percentage change in 28-day major motor seizure frequency of -30·7% (IQR -49·5 to -1·9) in the ganaxolone group and of -6·9% (-24·1 to 39·7) in the placebo group (p=0·0036). The Hodges-Lehmann estimate of median difference in responses to ganaxolone versus placebo was -27·1% (95% CI -47·9 to - 9·6). Treatment-emergent adverse events occurred in 43 (86%) of 50 patients in the ganaxolone group and in 45 (88%) of 51 patients in the placebo group. Somnolence, pyrexia, and upper respiratory tract infections occurred in at least 10% of patients in the ganaxolone group and more frequently than in the placebo group. Serious adverse events occurred in six (12%) patients in the ganaxolone group and in five (10%) patients in the placebo group. Two (4%) patients in the ganaxolone group and four (8%) patients in the placebo group discontinued the trial. There were no deaths in the double-blind phase.Ganaxolone significantly reduced the frequency of CDD-associated seizures compared with placebo and was generally well tolerated. Results from what is, to our knowledge, the first controlled trial in CDD suggest a potential treatment benefit for ganaxolone. Long-term treatment is being assessed in the ongoing open-label extension phase of this trial.Marinus Pharmaceuticals.

The purpose of this review is to provide a comprehensive update and highlight the distinct electroclinical features and discuss recent advances in the etiology, pathophysiology, and management strategies of epilepsy with eyelid myoclonia. Recent studies indicate that variations of certain genes including CHD2 (chromodomain helicase DNA-binding protein 2), KCNB1, KIAA2022, and NAA10 may occur in these patients. It has been postulated that the occipital cortex may play a role in the pathophysiology. Recent studies of functional imaging and connectivity of neuronal electrical activity have provided additional evidence to support this hypothesis. The frontal cortex has additionally been implicated, and it has been suggested that the epileptic cortex may extend beyond the occipital cortex to involve the posterior temporal cortex. We update the management strategies and describe tools that may predict seizure persistence. Epilepsy with eyelid myoclonias, or Jeavons syndrome, is an idiopathic generalized epilepsy characterized by the triad of eyelid myoclonia with or without absence seizures, eyelid closure-elicited electroencephalographic (EEG) paroxysms (epileptiform discharges and/or seizures), and photosensitivity. This condition may account for up to 13% of generalized epilepsies. However, it is frequently under-reported and under-recognized. Many of the patients develop medically refractory epilepsy, and seizures tend to persist throughout life.

Objective The objective of this study was to assess the priorities of patients with epilepsy and their caring physicians with reference to the timing and severity of the disease. Methods This is a national survey in which patients with epilepsy followed in 21 Italian epilepsy centers, and their caring physicians were asked to fill anonymous questionnaires to collect data on different aspects of the disease and their needs and priorities in its management. The collected information included demographics, clinical profile and diagnosis, treatment and outcome of epilepsy. The questions were designed to understand the expectations of the patients and their caring physicians and verify the degree of concordance between patient and doctor. The study population was divided in six prognostic categories: (1) Newly diagnosed epilepsy; (2) Absence of seizures for at least 2 years; (3) Absence of seizures for at least 1 year or occasional seizures; (4) Nondrug-resistant recurrent seizures; (5) drug-resistant seizures; (6) surgical candidate. Results Of the 787 patients enrolled, 432 were women and 355 men aged 15 to 88 years (median 41 years). Disease duration ranged from 6 months to 75 years. The sample included 53 patients with newly diagnosed epilepsy, 283 without seizures for at least 2 years, 162 seizure-free for at least 1 year or with occasional seizures, 123 with nondrug-resistant recurrent seizures, 128 with drug-resistant seizures, and 38 surgical candidates. Significant differences were found between patients and physicians in terms of priorities and needs with reference to the management of the disease. While physicians tend to prioritize the information on the diagnosis and treatment of epilepsy depending on timing and severity, patients focus on the search of the cause, the side effects of drugs, and the effects of any new treatment on the control of seizures regardless of the prognostic category. In addition, physicians tend to undervalue the communication of specific information, like the risk of sudden unexpected death in epilepsy (SUDEP) or the existence of lay associations, which might be of special interest for selected categories of patients. Significance Differences between patients with epilepsy and their caring physicians in terms of needs and priorities and suboptimal communication call for the implementation of programs aimed at addressing the factors deemed most relevant by patients and caregivers for the management of the disease.

The synthesis of five new complexes involving the ephedrinedithiocarbamate ligand (ephedtc) with group 13 and 15 metals (III) is reported. Complexes [As(ephedtc) 3 ] ( 1 ), [Sb(ephedtc) 3 ] ( 2 ), [Bi(ephedtc) 3 ] ( 3 ), and [In(ephedtc) 3 ] ( 5) were obtained from the ephedrinedithiocarbamate sodium salt [Na(ephedtc)] and the corresponding trichlorides MCl 3 , whereas for [Ga(ephedtc) 3 ], ( 4 ) Ga(NO 3 ) 3 was used. All compounds were characterized by elemental analyses, IR, mass spectrometry (FAB + ) and 1 H and 13 C NMR. In addition, single crystal structures of 2 and 5 were obtained showing two different coordination modes for the dithiocarbamate moiety, an anisobidentate coordination mode for 2 and an isobidentate coordination for 5 that generates a propeller-type structure. Compound 2 shows a distorted trigonal antiprismatic geometry around the metal atom while in 5 a distorted octahedral geometry is observed. Additionally, the crystalline structure of the ionic pair [ephedrinium] [ephedrinedithiocarbamate] ( 6 ) was determined. Antibacterial assay showed that 5 was the most active against ATCC bacterial strains and clinical isolate E. coli BLE (MIC 14.6–29.9 µM), and 3 against MRS strains (MIC 1.7 and 13.4 µM). The chemical hardness concept and the location of the HOMO and LUMO frontier orbitals on the molecular structures of 1 – 5 were employed to explain its particular antibacterial activity, using the DFT calculations.

Highlights • Two phenotypes of drug-resistant epilepsy were noted in children with prior leukemia, focal epilepsy, and epileptic encephalopathy in the form of Lennox-Gastaut syndrome. • Temporal lobectomy was effective in two children with mesial temporal sclerosis. • Corpus callosotomy and vagus nerve stimulation was tried in children with epileptic encephalopathy with variable outcomes., Children with leukemia are at risk for epilepsy due to primary disease or neurotoxic therapies. We describe the phenotypes of drug-resistant epilepsy in 10 children with history of leukemia. Of 10 cases, 6 had features of Lennox-Gastaut syndrome, and 4 had focal epilepsy. Mean age of epilepsy onset was 5 years in Lennox-Gastaut cases and 6.5 years in focal epilepsy cases. Mean latency between leukemia diagnosis and seizure onset was about 3 years. Brain MRI of 2 patients with epileptic encephalopathy had structural abnormalities – unclear if causative for epilepsy, and 4 had no overt structural abnormalities. In focal epilepsy group, 3 had temporal lobe epilepsy and one had fronto-temporal localization. All 10 patients had received intrathecal chemotherapy; 2 also had received whole brain irradiation. Seizures were poorly controlled in the epileptic encephalopathy group. Three underwent corpus callosotomy with variable response. Two patients with temporal lobe epilepsy had temporal lobectomy with Engel 1 outcome at 2 year follow-up in both. Two phenotypes of refractory epilepsy were observed in children with previous history of leukemia, focal epilepsy and epileptic encephalopathy. Children with temporal lobe epilepsy had good response to temporal lobectomy; response to palliative surgery was variable.

Introduction Focal epileptiform discharges in the posterior head regions [Viravan S et al. Epilepsia 2011; 52(7):1273–9] and focal occipital seizures [Giraldez BC and Serratosa JM Seizure 2015, 32: 72–4] has been previously reported in a patients with epilepsy with eyelid myoclonia (EM) with or without absence seizures or Jeavons syndrome. We describe the semiology and ictal EEG with temporal-perisylvian features in a 13-year -old female with Jeavons syndrome. Methods We describe the clinical and electroencephalographic findings of a 13-year -old female who presented with seizures from the age of 10 years. At the time of the evaluation the patient was treated with a therapeutic dose of lamotrigine. Seizure frequency was daily with presentation out of sleep and early morning. Video EEG recorded the typical seizures. Results Interictal EEG showed a normal awake and sleep patterns. Interictal EEG showed independent and bisynchronous right and left parieto-occipital sharp waves and polyspikes. There were sharp waves in the left posterior lateral and posterior temporal region (T7 and P7) seen in runs during sleep. Generalized photoparoxysmal response was noted at 10–20 Hz. There was eyelid myoclonia with increased bilateral posterior polyspikes elicited by eye closure (1 every 15–20 s.) that worsened at night when the room was dark (1 every 3–10 s). We recorded a 9 min habitual seizure out of sleep that began with a cluster of EM, 1 per second as the only ictal symptoms for 4.5 min. During this phase, the patient was responsive, able to speak and follow commands. Ictal EEG showed bursts of posterior dominant polyspikes concurrent with EM. Then the patient became unresponsive and had oral automatisms. Ictal EEG in this phase showed a rhythmic theta activity in the left posterior temporal region (maximum T7-P7 electrodes) that evolved into repetitive sharp waves in the same region. As the seizure progressed, the patient developed clonic activity in the right side of the neck that marched to the right arm and right leg. Postictally, there was a suppression of spikes in the left hemisphere while spikes persisted in the right posterior temporal region (P8 electrode). After load with intravenous Levetiracetam, photoparoxysmal response and eye closure activated interictal discharges dramatically resolved. Left temporal interictal epileptiform discharged persisted. Brain MRI was normal. FDG PET scan showed diffuse cortical hypometabolism maximum in the left hemisphere. Conclusion We report seizures with focal evolution in temporal region in a teenager with Jaevons syndrome. It is possible that she has two independent epileptic syndromes but the possibility of focal seizure being triggered by hyper excitable parieto-occipital cortex is also possible given the anatomic proximity and neuronal network connecting these regions.

Bronchial artery embolization with microspheres constitutes an effective, safe procedure for controlling hemoptysis. A 17-year-old girl with cystic fibrosis developed hemoptysis and underwent bilateral bronchial artery embolization with 300-500 μm and 500-700 μm microsphere particles. Afterward, she was delirious and complained of headache. On initial examination, she manifested altered mental status and diffuse hyperreflexia. Her left fifth digit was painful and cyanotic. Neuroimaging demonstrated multiple embolic infarcts in the cerebellum, thalamus, and cerebral hemispheres. An echocardiogram produced normal results. An evaluation of her thrombophilia revealed heterozygosity for a prothrombin 20210A mutation. Her functional neurologic recovery was complete. To our knowledge, this is the first pediatric case of cerebral and systemic embolism after bronchial artery embolization. Although this complication is not predictable, it should be suspected in patients with underlying chronic lung disease who develop acute neurologic signs after bronchial artery embolization, because these patients are prone to anomalous arterial-arterial shunt formation.

Introduction To describe the feasibility, safety and seizure outcome of a patient with generalized EEG features underwent tailored resection guided by sEEG in the setting of status epilepticus. Methods Case presentation. Results Patient is a 16 year old right handed male with history of drug-resistant epilepsy (characterized by tonic- asymmetric tonic, myoclonic, absence, GTC seizure). His first seizure was at age of 5. Interestingly, in term of semiology, he had stereotype right face tonic contraction right before asymmetric tonic seizure followed by urinary urgency. At age of 14, patient had cognitive decline in addition to school performance. At age 16, he had failed 12 AED and admitted to ICU with status epilepticus. Scalp EEG showed high-voltage frequent generalized spike and wave complex and polyspikes, maximum bifronto-central and vertex. No multifocal spike activity was noticed during multiple EMU admission. Ictally, patient has 20–70 seizures/day and scalp EEG showed generalized activity (90%) associated with all seizure types without returning to the normal baseline activity. Interesting, there were nonclinical electrographic seizure with scalp EEG lateralized left fronto-central region (20%). MRI was unremarkable. PET showed left frontal hypometabolism. MEG and ictal SPECT (injection 3 s) pointed bifrontal but predominantely left frontal regions(precentral dorsolateral region). StereoEEG was implanted with hypothesis of left and right superior frontal.mesial frontal and inferior frontal region. SEEG data was reviewed in the ICU under the propofol in addition to non-sedated data in the EMU. During the ICU, interictal and ictal activity were arising consistently from the left posterior superior frontal/precentral sulcus followed by rapid synchronization over left frontal operculum and right frontal region within 20–50 ms. Patient underwent left frontal tailored resection with sparing speech eloquent cortex. Post-operatively patient became seizure free but experienced SMA syndrome. At 6 months follow up, patient is seizure free on 4 AEDs. Pathology showed Type IIA Focal cortical dysplasia with nodular heterotopia (ILAE classification). At 10 month, family reported of patient having a break-through seizure in the setting of tapering valporic acid. Conclusion The present case illustrates non-lesional focal frontal lobe epilpsy may mimic features of generalized symptomatic epilepsy. This case also illustrates respective epilepsy surgery guided by stereoEEG is a safe and effective treatment option in selected cases with status epilepticus.

Introduction Down syndrome occurs in 1 in 650–1000 births. Epilepsy has been reported in 1–13% of patients with Down syndrome (Stafstrom et al., 1991) compared to 1.5–5 % in general population (Forsgren et al., 2005). Methods This was a single center retrospective medical record review of patients of less than 18 years of age with Down syndrome and epilepsy from January 2005 to December 2015. Sixteen patients were identified. Patients were grouped by seizure types and data was collected on EEG, MRI and outcome at last follow up. Results Children with Down syndrome and epilepsy can be grouped in four categories of seizures. Group 1: Infantile spasms – Seven out of sixteen patients in our cohort had infantile spasms with findings of hypsarrhythmia on the EEG. Five patients had MRI’s available for review and were normal. Five patients (70%) were seizure free, three of whom had a normal EEG and were off antiepileptic medications at their last follow up. The two remaining patients had refractory seizures and abnormal EEG findings which included regional sharp waves and hypsarrhythmia with multiregional sharp waves. Group 2: Generalized seizures – Six patients had generalized seizures (GTC, myoclonic, atonic) and regional/multiregional sharp waves on the EEG. Five off these patients had abnormal MRI findings: Two with MCA distribution infarcts and three with more diffuse abnormalities secondary to periventricular leukomalacia, traumatic brain injury and diffuse volume loss. Fifty percent of the patients were seizure free including one following a functional hemispherectomy. All patients continued to have abnormal EEGs at their last follow up. Group 3: Partial seizures – Two patients in our cohort had partial seizures (focal neonatal seizures and benign rolandic epilepsy with centrotemporal spikes) and both were seizure free at their last follow up. Group 4: Partial and Generalized seizures – One patient had partial and generalized seizures with multiregional sharp waves on EEG at diagnosis. This patient continues to have refractory seizures on medications and hypsarrhythmia on the last follow up EEG. Neuroimaging: Thirteen MRI’s were available for review, of which seven were abnormal. 50–55% of patients with normal or abnormal MRI’s became seizure free. Conclusion All patients except for one (background slowing only) had abnormal EEG’s with epileptiform discharges at diagnosis. Infantile spasms was the most common seizure type in our patient cohort with electro-clinical features resembling those of idiopathic West syndrome. Classic hypsarrhythmia was present in all patients at diagnosis. Patients with infantile spasms had a higher percentage of becoming seizure free with normalization of EEG on long term follow up compared to patients with generalized or partial seizures. Abnormal MRI does not appear to be helpful for predicting seizure outcome.

Background: Previous research has suggested that a subgroup of children with obsessive compulsive disorder (OCD) have neuropsychiatric sequelae of streptococcal pharyngitis, similar to that seen in the neurological manifestation of rheumatic fever (RF). Monoclonal antibody D8/17 demonstrates increased binding to B cells in patients with RF and in patients with neuropsychiatric disorders using immunofluorescent microscopy. Objective: The aim of this study was to determine if an earlier immunofluorescent microscopy study of monoclonal antibody D8/17 in childhood-onset OCD and/or chronic tic disorder (CTD) could be replicated using the more objective method of flow cytometric analysis. Method: D8/17 binding to B cells was determined in patients with OCD and or CTD (N=32), and healthy controls (N=12) by flow cytometric analysis. Results: Subjects with OCD/CTD showed increased mean cell binding (26.0%) of monoclonal antibody compared with healthy controls (9.1%) (p

Sydenham's chorea (SC) is a major manifestation of rheumatic fever characterized by an array of neuropsychiatric symptoms that vary in severity, timing, and character. Some of the same symptoms are seen in Tourette's syndrome and childhood-onset obsessive-compulsive disorder. Genetic vulnerability appears to play a role in all three conditions. The term PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcus) has been introduced to describe a putative subset of obsessive-compulsive disorder and Tourette's syndrome that bears some resemblance to Sydenham's chorea. This article discusses whether PANDAS should be subsumed under Sydenham's chorea, thus expanding the diagnostic boundaries of Sydenham's chorea to include primarily neuropsychiatric presentations now classified as cases of obsessive-compulsive disorder or Tourette's syndrome. We conclude that PANDAS is a useful construct, but that it would be premature to view it as a subset of Sydenham's chorea-whether defined narrowly or broadly.

Antiphospholipid antibodies (aPL) of various isotypes are known to occur in systemic lupus erythematosus (SLE), but the significance of this finding in the pediatric population remains unclear. Our aim was to determine whether children with lupus nephritis have an increased risk of thrombosis and whether antiphosphatidylserine (APS) or antiphosphatidylinositol (API) antibodies were predictive of thrombotic complications. Thirty-six children (27 girls/9 boys; 44% black) with SLE nephritis (WHO II, 1; WHO III, 7; WHO IV, 21; WHO V, 7) were evaluated for antiphosphatidylserine, antiphosphatidylinositol, and anticardiolipin immunoglobulin (Ig) G and IgM isotypes, using a modified solid-phase enzyme-linked immunoassay (ELISA). Twenty-four patients (67%) had at least one positive aPL. Longitudinal data on 26 patients showed fluctuations in the degree of positivity. Eight patients experienced thrombotic complications, with equal distribution between arterial and venous events. Other clinical manifestations included thrombocytopenia in seven patients (19%), hemolytic anemia (44%), lupus anticoagulant (6%) and false-positive Venereal Disease Research Laboratory (VDRL) test results (11%). Comparisons between those with and without a thrombotic event showed no detectable difference in the incidence of aPL positivity between the two groups. We conclude that neither APS, API, nor anticardiolipin (ACL) activity was predictive of thrombotic complications in our subset of patients with lupus nephritis.