Idiopathic focal epilepsies: the “lost tribe”

The term idiopathic focal epilepsies of childhood (IFE) is not formally recognised by the ILAE in its 2010 revision (Berg et al., 2010 ), nor are its members and boundaries precisely delineated. The IFEs are amongst the most commonly encountered epilepsy syndromes affecting children. They are fascinating disorders that hold many “treats” for both clinicians and researchers. For example, the IFEs pose many of the most interesting questions central to epileptology: how are functional brain networks involved in the manifestation of epilepsy? What are the shared mechanisms of comorbidity between epilepsy and neurodevelopmental disorders? How do focal EEG discharges impact cognitive functioning? What explains the age‐related expression of these syndromes? Why are EEG discharges and seizures so tightly locked to slow‐wave sleep? In the last few decades, the clinical symptomatology and the respective courses of many IFEs have been described, although they are still not widely appreciated beyond the specialist community. Most neurologists would recognise the core syndromes of IFE to comprise: benign epilepsy of childhood with centro‐temporal spikes or Rolandic epilepsy (BECTS/RE); Panayiotopoulos syndrome; and the idiopathic occipital epilepsies (Gastaut and photosensitive types). The Landau‐Kleffner syndrome and the related (idiopathic) epilepsy with continuous spikes and waves in sleep (CSWS or ESES) are also often included, both as a consequence of the shared morphology of the interictal discharges and their potential evolution from core syndromes, for example, CSWS from BECTS. Atypical benign focal epilepsy of childhood also has shared electro‐clinical features warranting inclusion. In addition, a number of less well‐defined syndromes of IFE have been proposed, including benign childhood seizures with affective symptoms, benign childhood epilepsy with parietal spikes, benign childhood seizures with frontal or midline spikes, and benign focal seizures of adolescence. The term “benign” is often used in connection with the IFEs and is increasingly being challenged. Certainly most of these disorders are not associated with the devastating cognitive and behavioural problems seen with early childhood epileptic encephalopathies, such as West or Dravet syndromes. However, it is clear that specific, and sometimes persistent, neuropsychological deficits in attention, language and literacy accompany many of the IFEs that, when multiplied by the large numbers affected, make up a significant public health problem. Understanding the nature, distribution, evolution, risk and management of these is an important area of current research. A corollary to such questions regarding comorbidities is the role of focal interictal spikes and their enduring impact on cognitive functioning. What explains the paradox that epilepsies characterised by abundant interictal epileptiform abnormalities are often associated with very few clinical seizures? This is an exciting area in both clinical and experimental arenas and will eventually have important implications for clinical management of the whole child, taking into account not just seizures, but also adaptive functioning and quality of life. For several decades, we have accepted an evidence‐free approach to using or not using antiepileptic drugs in IFEs. There is huge international variation and only a handful of studies examining neurocognitive outcomes. Clearly, this is a situation ready for an overhaul in practice. Fundamental to understanding treatment is knowledge of aetiology. In recent years, there have been several significant discoveries in IFEs from studies of copy number variation, exome sequencing, and linkage that prompt reconsideration of the “unknown cause” classification and strongly suggest a genetic aetiology. The IFE are strongly age‐related, both with regards to age of seizure onset and remission. Does this time window solely relate to a similar age‐related gene expression, or are there epigenetic factors involved that might also explain low observed twin concordance? The genetic (and epigenetic) models for different IFEs, their comorbidities, and their similarities to other neurodevelopmental disorders deserve investigation in the coming years. In so doing, we will probably learn much about normal brain functioning. This is because these disorders, perhaps more than any other human brain disease, are disorders of functional brain systems (even though these functional networks may not yet be fully defined). In June 2012, an international group of clinical and basic science researchers met in London under the auspices of the Waterloo Foundation to discuss and debate these issues in relation to IFEs. This Waterloo Foundation Symposium on the Idiopathic Focal Epilepsies: Phenotype to Genotype witnessed presentations that explored the clinical phenomenology, phenotypes and endophenotypes, and genetic approaches to investigation of these disorders. In parallel, the impact of these epilepsies on children and their families was reviewed. The papers in this supplement are based upon these presentations. They represent an updated state‐of‐the‐art thinking on the topics explored. The symposium led to the formation of international working groups under the umbrella of “Luke's Idiopathic Focal Epilepsy Project” to investigate various aspects of the idiopathic focal epilepsies including: semiology and classification, genetics, cognition, sleep, high‐frequency oscillations, and parental resources (see www.childhood-epilepsy.org ). The next sponsored international workshop, in June 2014, was on randomised controlled trials in IFEs and overnight learning outcome measures.     

Pulmonary vascular manifestations of hereditary hemorrhagic telangiectasia (rendu-osler disease)

Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is a genetic disorder with autosomal dominance and variable penetrance, characterized by epistaxis, telangiectasia and visceral manifestations of the disease. The estimated minimal prevalence is 1/10,000 inhabitants. The diagnosis is established on clinical criteria, and may be further confirmed by the identification of causative mutations in either the ENG or the ACVRL1 gene coding for endoglin and ALK1, respectively. Pulmonary vascular manifestations of HHT include pulmonary arteriovenous malformations (PAVMs; especially in patients with ENG mutations) and less frequently pulmonary hypertension (especially in patients with ACVRL1 mutations). In 15-33% of patients with HHT, PAVMs consist of abnormal communications between pulmonary arteries and pulmonary veins, causing right-to-left shunting, and thus, frequently hypoxemia and dyspnea on exertion, although PAVMs may remain asymptomatic and frequently undiagnosed unless complications occur. PAVMs result in severe and frequent complications often at a young age, which may reveal the diagnosis, e.g. transient ischemic attack and cerebral stroke (10-19% of patients), systemic severe infections and abscesses (including cerebral abscess in 5-19% of patients), and rarely massive hemoptysis or hemothorax. Infections in HHT are related to the right-to-left shunting that bypasses the pulmonary capillaries and facilitates the passage of septic or aseptic emboli into the systemic and especially cerebral circulation, and potentially to minor defects in innate immunity. Treatment of PAVMs based on transcatheter coil vaso-occlusion of the feeding artery significantly decreases right-to-left shunting, hypoxemia and dyspnea on exertion, and reduces the risk of systemic complications. Long-term follow-up is warranted after transcatheter vaso-occlusion of PAVMs due to frequent recanalization of treated PAVMs and development or growth of untreated PAVMs. Patients with HHT should be informed of the risk of PAVM and potentially severe complications occurring in heretofore asymptomatic subjects. All adult patients with HHT should be proposed systematic screening for PAVM, by contrast echocardiography (preceded by anteroposterior chest radiograph) or computed tomography of the chest. Pulmonary hypertension is rare in HHT, and may be due either to systemic arteriovenous shunting in the liver increasing cardiac output or be clinically and histologically indistinguishable from idiopathic pulmonary arterial hypertension. Pulmonary hypertension is detected by systematic examination of right cardiac cavities and tricuspid regurgitation flow at echocardiography, and the diagnosis is established by right heart catheterization.     

Protein kinase C phosphorylates the inositol 1,4,5-trisphosphate receptor type 2 and decreases the mobilization of Ca2+in pancreatoma AR4-2J cells

In non-excitable cells, the inositol 1,4,5-trisphosphate receptor channel, which plays a major (IP(3)R) is an intracellular Ca(2+) role in Ca(2+) signalling. Three isoforms of IP(3)R have been identified (IP(3)R-1, IP(3)R-2 and IP(3)R-3) and most cell types express different proportions of each isoform. The differences between the pharmacological and functional properties of the various isoforms of IP(3)R are poorly understood. AR4-2J cells, which express almost exclusively (~86%) the IP(3)R-2, represent an interesting model to study this particular isoform. Here, we investigated a regulatory mechanism by which protein kinase C (PKC) influences IP(3)R-2-mediated Ca(2+) release. Using an immunoprecipitation approach, we confirmed that AR4-2J cells express almost exclusively the IP(3)R-2 isoform. Using an in vitro phosphorylation assay, we showed that the immunopurified IP(3)R-2 was efficiently phosphorylated by exogenous PKC. In intact AR4-2J cells metabolically labelled with (32)Pi, we showed that phorbol-12-myristate-13-acetate (PMA) and Ca(2+) mobilizing agonists cause the phosphorylation of IP(3)R-2. In saponin-permeabilized AR4-2J cells, IP(3)-induced Ca(2+) release was reduced after a pre-treatment with PMA or with exogenous PKC. PMA also reduced the Ca(2+) response of intact AR4-2J cells stimulated with carbachol and epidermal growth factor, two agonists that use different receptor types to activate phospholipase C. These results demonstrate that PKC decreases the Ca(2+)mobilizing activity of IP(3)R-2 and thus exerts a negative feedback on the agonists-induced Ca(2+) response of AR4-2J cells.     

Treatment of chronic pelvic pain in men and women

Chronic pelvic pain syndrome (CPPS) is a common condition that is encountered by a variety of healthcare professionals. Unfortunately, physicians often misdiagnose this problem or recommend inappropriate and sometimes dangerous treatments that offer little hope of successful outcome. In addition, CPPS is typically a multifaceted disorder, simultaneously compromising psychological, peripheral nerve, autonomic, central nervous, visceral, connective tissue, hormonal and other systems. Thus, solo practitioners who may correctly diagnose CPSS are often ill-equipped to provide adequate comprehensive, multidisciplinary treatment. This article is intended as an overview of the most recent literature in support of various treatment modalities for chronic pelvic pain in men and women. We advocate a team-oriented approach in the treatment of CPPS, which employs the coordinated efforts of multiple practitioners, ideally in a subspecialty care setting.     

Evaluation of the care pathway in the context of the dispensing of emicizumab (Hemlibra) in community and hospital pharmacies in France: A patient satisfaction survey

Introduction

Since June 2021 in France, patients with haemophilia A with anti-factor VIII inhibitors and patients with severe haemophilia A without anti-factor VIII inhibitors, and treated with emicizumab (Hemlibra), have to choose the dispensing circuit community or hospital pharmacy.

Aim

To evaluate satisfaction of patients whether they choose dispensation from a community pharmacy or retained dispensation from the hospital pharmacy, to understand the main motivation for choosing the community or the hospital pharmacy.

Methods

All patients living in France, regardless of age, were eligible to participate. Between September 13, 2022, and January 9, 2023, 175 respondents answered the satisfaction survey, including 123 in community pharmacy and 52 in hospital pharmacy.

Results

Eighteen months after availability in community pharmacies, treatment accessibility is improved for the benefit of the patient. The door-to-door travel times are significantly reduced to the community pharmacy with an average gain of 16.5 min saved from the place of residence. Patients are mostly satisfied with the new dispensing circuit especially concerning the overall satisfaction (p < .0001), the travel time (p < .0001) and the strong relationship with the pharmacist (p = .0022) compared to hospital pharmacy.

Conclusion

Innovation in care pathways is showing its full potential in improving access to medication, made possible by the implementation of a rigorous organization accompanied by training to enable healthcare professionals involved in primary care to provide appropriate management.     

Immunolocalization of the multi-sarco/endoplasmic reticulum Ca2+ATPase system in human platelets

We recently identified a multi-SERCA (sarco/endoplasmic reticulum Ca²⁺ ATPase) system in haemopoietic cells comprising the SERCA 2b, SERCA 3 and a new monoclonal anti-Ca²⁺ ATPase antibody (PL/IM 430) recognizable SERCA isoforms. We have now investigated the subcellular localization of these enzymes in human platelets by Western blotting of subcellular membrane fractions and by immunoelectron microscopy. We precisely defined the recognition specificity of the polyclonal anti-SERCA 2b, anti-SERCA 3, anti-SERCA 1 antibodies as well as of the monoclonal antibody PL/IM 430 by testing their recognition of the tryptic fragments of the SERCA isoforms. The analysis of fragmented membranes enriched in plasma membrane and intracellular membrane components by Western blotting showed that the SERCA 2b and the SERCA 3 isoforms were found in both the plasma membrane and the intracellular membrane fractions, whereas the PL/IM 430 recognizable SERCA isoform was restricted to membranes associated with the plasma membrane fraction. The immunoelectron microscopical study of the SERCA isoforms in resting platelets showed that: (i) the SERCA 2b isoform was expressed in membranes associated with the plasma membrane and open canalicular system, some α-granules and in unidentified membranes; (ii) the SERCA 3 isoform was found associated with plasma and intracellular membranes; and (iii) the PL/IM 430 recognizable SERCA isoform was observed only in structures associated with the cytoplasmic face of the plasma membranes, as confirmed by flow cytometry. Finally, since the PL/IM 430 antibody was raised against intracellular membranes, we looked for a potential membrane redistribution during the isolation procedure used for the preparation of the immunizing membranes. Neuraminidase treatment indeed induced a translocation of the PL/IM 430 recognizable SERCA isoform from plasma to intracellular membranes. Thus, the multi-SERCA system in platelets: (i) is distributed over different platelet membranes, (ii) presents a sub-compartmental organization with some overlapping, and (iii) is partly associated with motile membranes, reflecting an unrecognized level of complexity of Ca²⁺ stores in these cells.     

Clinical and genomic analysis of a randomised phase II study evaluating anastrozole and fulvestrant in postmenopausal patients treated for large operable or locally advanced hormone-receptor-positive breast cancer

Background:

The aim of this study was to assess the efficacy of neoadjuvant anastrozole and fulvestrant treatment of large operable or locally advanced hormone-receptor-positive breast cancer not eligible for initial breast-conserving surgery, and to identify genomic changes occurring after treatment.

Methods:

One hundred and twenty post-menopausal patients were randomised to receive 1 mg anastrozole (61 patients) or 500 mg fulvestrant (59 patients) for 6 months. Genomic DNA copy number profiles were generated for a subgroup of 20 patients before and after treatment.

Results:

A total of 108 patients were evaluable for efficacy and 118 for toxicity. The objective response rate determined by clinical palpation was 58.9% (95% CI=45.0–71.9) in the anastrozole arm and 53.8% (95% CI=39.5–67.8) in the fulvestrant arm. The breast-conserving surgery rate was 58.9% (95% CI=45.0–71.9) in the anastrozole arm and 50.0% (95% CI=35.8–64.2) in the fulvestrant arm. Pathological responses >50% occurred in 24 patients (42.9%) in the anastrozole arm and 13 (25.0%) in the fulvestrant arm. The Ki-67 score fell after treatment but there was no significant difference between the reduction in the two arms (anastrozole 16.7% (95% CI=13.3–21.0) before, 3.2% (95% CI=1.9–5.5) after, n=43; fulvestrant 17.1% (95%CI=13.1–22.5) before, 3.2% (95% CI=1.8–5.7) after, n=38) or between the reduction in Ki-67 in clinical responders and non-responders. Genomic analysis appeared to show a reduction of clonal diversity following treatment with selection of some clones with simpler copy number profiles.

Conclusions:

Both anastrozole and fulvestrant were effective and well-tolerated, enabling breast-conserving surgery in over 50% of patients. Clonal changes consistent with clonal selection by the treatment were seen in a subgroup of patients.     

P-Selectin and Platelet Clearance

P-selectin is an adhesion receptor for leukocytes expressed byactivated platelets and endothelial cells. To assess a possible role ofP-selectin in platelet clearance, we adapted an in vivo biotinylationtechnique in mice. Wild-type and P-selectin-deficient mice wereinfused with N-hydroxysuccinimido biotin. The survival of biotinylatedplatelets was followed by flow cytometry after labeling withfluorescent streptavidin. Both wild-type and P-selectin-deficient platelets presented identical life spans of about 4.7 days, suggesting that P-selectin does not play a role in platelet turnover. When biotinylated platelets were isolated, activated with thrombin, andreinjected into mice, the rate of platelet clearance was unchanged. Incontrast, storage of platelets at 4°C caused a significant reduction in their life span in vivo but again no significant differences were observed between the two genotypes. The infused thrombin-activated platelets rapidly lost their surface P-selectin incirculation, and this loss was accompanied by the simultaneous appearance of a 100-kD P-selectin fragment in the plasma. This observation suggests that the platelet membrane P-selectin was shed bycleavage. In conclusion, this study shows that P-selectin, despite itsbinding to leukocytes, does not mediate platelet clearance. However,the generation of a soluble form of P-selectin on platelet activationmay have biological implications in modulating leukocyte recruitment orthrombus growth.     

Effect of choline and methionine treatment on cardiac dysfunction of diabetic rats

There is an abnormal lipid accumulation in the myocardium that might be involved in the congestive heart failure frequently associated with individuals with diabetes mellitus. Because choline and methionine have been reported to modify the incidence of myocardial necrosis in rats fed various fat diets, we decided in our study to assess their effect on the cardiac dysfunction of diabetic rats. Female Wistar rats were made diabetic with streptozocin (STZ, 55 mg/kg i.v.). One week after diabetes induction, one group received choline (0.3 mg/ml), another received methionine (0.25 mg/ml), a third received a combination of the same doses of choline and methionine, and a fourth received neither of these agents; all were administered in the drinking water. Animals were treated for 7 wk. Insulin levels were lower and glucose values higher in the serum of STZ rats relative to controls. Serum cholesterol and triglycerides were significantly elevated in all diabetic animals, and they were also elevated (P less than .05) in the hearts of untreated diabetics. In contrast, the myocardial values of the same lipids were drastically reduced in the treated diabetic animals. Cardiac performance was depressed in all STZ animals, but there was a significant improvement in heart function in treated diabetics relative to untreated ones. Thus, it appears that the buildup of cholesterol and triglycerides in the myocardium are important contributors to the cardiac dysfunction that frequently accompanies diabetes mellitus.