Febrile infection–related epilepsy syndrome (FIRES, AERRPS, or DESC) is one of the most severe, mostly irreversible, and presumably immune-mediated epileptic encephalopathies affecting healthy children. Refractory status epilepticus or a cluster of seizures start a few days after the onset of an acute febrile illness; however, encephalitis cannot be proved. Sequelae of FIRES are drug-resistant epilepsy and neuropsychological impairments occurring without latency. Clinical knowledge is limited because FIRES is sporadic and extremely rare. Therefore, based on literature and our data, this review includes clinical features, terminology, epidemiology, diagnostic criteria and procedures, differential diagnoses, acute and chronic therapeutic options, and outcome data. Particular attention is paid to the epileptogenesis. We hypothesize that FIRES is an immune but not an autoimmune disease and discuss GABAergic therapy at high doses, avoidance of burst-suppression coma, and early introduction of enteral or even parenteral ketogenic diet as the most promising treatment. The lack of evidence requires both a network and a multinational web-based clinical registry to define the clinical spectrum for improving diagnosis and treatment and at the very least, to clarify the cause of FIRES. We conclude that the term “fulminant inflammatory response epilepsy syndrome” may be more appropriate.

https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-0036-1597271.pdf

Febrile Infection-Related Epilepsy Syndrome: Clinical Review and Hypotheses of Epileptogenesis.

Oxidative stress (OS) occurs in brains of patients with epilepsy and coincides with brain inflammation, and both phenomena contribute to seizure generation in animal models. We investigated whether expression of OS and brain inflammation markers co-occurred also in resected brain tissue of patients with epileptogenic cortical malformations: hemimegalencephaly (HME), focal cortical dysplasia (FCD) and cortical tubers in tuberous sclerosis complex (TSC). Moreover, we studied molecular mechanisms linking OS and inflammation in an in vitro model of neuronal function. Untangling interdependency and underlying molecular mechanisms might pose new therapeutic strategies for treating patients with drug-resistant epilepsy of different etiologies. Immunohistochemistry was performed for specific OS markers xCT and iNOS and brain inflammation markers TLR4, COX-2 and NF-κB in cortical tissue derived from patients with HME, FCD IIa, IIb and TSC. Additionally, we studied gene expression of these markers using the human neuronal cell line SH-SY5Y in which OS was induced using H2O2. OS markers were higher in dysmorphic neurons and balloon/giant cells in cortex of patients with FCD IIb or TSC. Expression of OS markers was positively correlated to expression of brain inflammation markers. In vitro, 100 µM, but not 50 µM, of H2O2 increased expression of TLR4, IL-1β and COX-2. We found that NF-κB signaling was activated only upon stimulation with 100 µM H2O2 leading to upregulation of TLR4 signaling and IL-1β. The NF-κB inhibitor TPCA-1 completely reversed this effect. Our results show that OS positively correlates with neuroinflammation and is particularly evident in brain tissue of patients with FCD IIb and TSC. In vitro, NF-κB is involved in the switch to an inflammatory state after OS. We propose that the extent of OS can predict the neuroinflammatory state of the brain. Additionally, antioxidant treatments may prevent the switch to inflammation in neurons thus targeting multiple epileptogenic processes at once.

/pdf/oxidative-stress-and-inflammation-in-a-spectrum-of-2npbvgo9ym.pdf

Oxidative stress and inflammation in a spectrum of epileptogenic cortical malformations: molecular insights into their interdependence.

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that presents with diverse and complex clinical features and involves multiple human systems. TSC-related neurological abnormalities and organ dysfunction greatly affect the quality of life and can even result in death in patients with TSC. It is widely accepted that most TSC-related clinical manifestations are associated with hyperactivation of the mammalian target of rapamycin (mTOR) pathway caused by loss‑of‑function mutations in TSC1 or TSC2. Remarkable progress in basic and translational research has led to encouraging clinical advances. Although mTOR inhibitors (rapamycin/everolimus) demonstrate great potential in TSC management, two major concerns hamper their generalized application. One is the frequent manifestation of adverse events, such as stomatitis, infections, and menstrual disorders; and the other is the poor response in certain patients. Thus, indicators are required to effectively predict the efficacy of mTOR inhibitors. Herein, we have summarized the current utilization of mTOR inhibitors in the treatment of TSC and focused on their efficacy and safety, in an attempt to provide a reference to guide the treatment of TSC. 

/pdf/perfect-match-mtor-inhibitors-and-tuberous-sclerosis-complex-1o79301p.pdf

Perfect match: mTOR inhibitors and tuberous sclerosis complex

Summary


The detection of antineural autoantibodies in patients with epilepsy has led to the new concept of “autoimmune epilepsy.” A particularly important implication is that knowledge of the antigenic target of the underlying antibody permits prognostic estimates. Patients with antibodies to the potassium channel complex (mostly to its leucine-rich glioma inactivated 1 [LGI1] component) have a high chance of becoming seizure free within days to months upon immunotherapy but less so with antiepileptic drug (AED) treatment alone. Seizures in the setting of antibodies to the N-methyl-d-aspartate receptor also have a high likelihood to remit, again especially with rapid institution of immunotherapy. In contrast to these antibodies to neuronal surface molecules, antibodies directed to intracellular antigens (onconeural antibodies, antibodies to glutamic acid decarboxylase) portend a low likelihood of seizure remission, regardless of the treatments chosen. These outcome differences are probably related to the underlying pathophysiology—with largely reversible functional effects of antibodies to surface antigens and irreversible destructive sequelae (probably caused by T cells) in patients with antibodies to intracellular antigens. With ongoing experience with these conditions, clinical and paraclinical clues to the diagnosis of autoimmune epilepsies are emerging.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/epi.12184

Value of autoantibodies for prediction of treatment response in patients with autoimmune epilepsy: Review of the literature and suggestions for clinical management

Objective The systematic review aimed to assess the neuropsychological outcomes of temporal lobe resections for epilepsy in children. Additional objectives included determining whether earlier age at surgery leads to better neuropsychological outcomes; the relationships between and predictors of these outcomes. Methods Using advanced search terms, a systematic review of electronic databases was conducted, comprising MEDLINE, Embase, PsycINFO, Global Health, Web of Science and CINAHL. Included studies reported on outcome following neurosurgical treatment for epilepsy. Specifically, studies were included if they reported neuropsychological outcomes and were concerned only with temporal lobe resection. Results 73 studies met inclusion criteria. For reported neuropsychological outcomes, the majority of participants remained stable after surgery; some declined and some improved. There was some evidence for increased material-specific memory deficits after temporal lobe surgery based on resection side, and more positive cognitive outcome for those with lower pre-surgical ability level. Significance Retrieved evidence highlights the need for improvements to quality of methodology and reporting. Appropriately designed prospective multicentre trials should be conducted with adequate follow-up for long-term outcomes to be measured. Core outcome measures should be agreed between centres. This would permit higher quality evidence so that clinicians, young people and their families may make better informed decisions about whether or not to proceed with surgery and likely post-operative profile.

Neuropsychological outcomes following paediatric temporal lobe surgery for epilepsies: Evidence from a systematic review

Tuberous sclerosis complex (TSC) is a rare genetic multisystem disorder, characterized by predominantly benign tumors in potentially all organ systems. System involvement, severity of clinical symptoms and the response to treatment are age-dependent and heterogeneous. Consequently, the disorder is still not recognized in a considerable number of patients. The diagnostic criteria and the guidelines for surveillance and management of patients with TSC were revised, and the establishment of specialized TSC-centers was strongly recommended during an International Consensus Conference in 2012. TOSCA (TuberOus SClerosis registry to increase disease Awareness), an international patient registry, was started to allow new insights into the causes of different courses. Finally, there are—since the approval of the mTOR inhibitor Everolimus—promising new therapeutic approaches. This review focuses on the various TSC related symptoms occurring at different ages, the novel recommendations for diagnosis and treatment as well as the need for multidisciplinary follow-up.

Tuberous Sclerosis Complex: new criteria for diagnostic work-up and management

Beneficial effect of epilepsy surgery in a case of childhood non-paraneoplastic limbic encephalitis.

D-galactose Supplementation for the Treatment of Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Epilepsy (MOGHE): A Pilot Trial of Precision Medicine After Epilepsy Surgery.

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Tuberous Sclerosis Complex: new criteria for diagnostic work-up and management

Beneficial effect of epilepsy surgery in a case of childhood non-paraneoplastic limbic encephalitis.

D-galactose Supplementation for the Treatment of Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Epilepsy (MOGHE): A Pilot Trial of Precision Medicine After Epilepsy Surgery.