Epilepsy therapy is based on antiseizure drugs that treat the symptom, seizures, rather than the disease and are ineffective in up to 30% of patients. There are no treatments for modifying the disease—preventing seizure onset, reducing severity or improving prognosis. Among the potential molecular targets for attaining these unmet therapeutic needs, we focused on oxidative stress since it is a pathophysiological process commonly occurring in experimental epileptogenesis and observed in human epilepsy. Using a rat model of acquired epilepsy induced by electrical status epilepticus, we show that oxidative stress occurs in both neurons and astrocytes during epileptogenesis, as assessed by measuring biochemical and histological markers. This evidence was validated in the hippocampus of humans who died following status epilepticus. Oxidative stress was reduced in animals undergoing epileptogenesis by a transient treatment with N-acetylcysteine and sulforaphane, which act to increase glutathione levels through complementary mechanisms. These antioxidant drugs are already used in humans for other therapeutic indications. This drug combination transiently administered for 2 weeks during epileptogenesis inhibited oxidative stress more efficiently than either drug alone. The drug combination significantly delayed the onset of epilepsy, blocked disease progression between 2 and 5 months post-status epilepticus and drastically reduced the frequency of spontaneous seizures measured at 5 months without modifying the average seizure duration or the incidence of epilepsy in animals. Treatment also decreased hippocampal neuron loss and rescued cognitive deficits. Oxidative stress during epileptogenesis was associated with de novo brain and blood generation of high mobility group box 1 (HMGB1), a neuroinflammatory molecule implicated in seizure mechanisms. Drug-induced reduction of oxidative stress prevented HMGB1 generation, thus highlighting a potential novel mechanism contributing to therapeutic effects. Our data show that targeting oxidative stress with clinically used drugs for a limited time window starting early after injury significantly improves long-term disease outcomes. This intervention may be considered for patients exposed to potential epileptogenic insults.

A large body of evidence that has accumulated over the past decade strongly supports the role of inflammation in the pathophysiology of human epilepsy. Specific inflammatory molecules and pathways have been identified that influence various pathologic outcomes in different experimental models of epilepsy. Most importantly, the same inflammatory pathways have also been found in surgically resected brain tissue from patients with treatment-resistant epilepsy. New anti-seizure therapies may be derived from these novel potential targets. An essential and crucial question is whether targeting these molecules and pathways may result in anti-ictogenesis, anti-epileptogenesis and/or disease-modification effects. Therefore, preclinical testing in models mimicking relevant aspects of epileptogenesis is needed to guide integrated experimental and clinical trial designs. We discuss the most recent preclinical proof-of-concept studies validating a number of therapeutic approaches against inflammatory mechanisms in animal models that could represent novel avenues for drug development in epilepsy. Finally, we suggest future directions to accelerate preclinical to clinical translation of these recent discoveries.

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Cerebral palsy (CP) is associated with the presence of feeding disorders in almost 60% of the affected children with subsequent undernutrition reported in up to 46% of the subjects. Since undernutrition may have a detrimental impact on physical and cognitive development, the introduction of an adequate nutritional support should always be considered in children with neurological impairment. The aim of the present review is to provide a practical guide to the assessment of nutritional status in children with CP, in order to identify individuals at risk for malnutrition that need the introduction of an adequate and personalized nutritional support. This review summarizes the methods for the evaluation of oral-motor function, anthropometric parameters, body composition and energy balance in children with CP. Moreover, we reviewed the indications for the introduction of nutritional support, and the suggested modalities of intervention.

West syndrome or infantile spasms is one of the most frequent epileptic syndromes in the first year of life. The clinical symptoms of infantile spasms are very different than any other type of seizure because of both the absence of paroxysmal motor phenomena (i.e., as in a convulsion) and the lack of significant duration of loss of consciousness (i.e., as in absence epilepsy). Infantile spasms may lead to misdiagnosis by pediatricians and other primary care providers. We assessed the missed diagnoses prior to the diagnosis of infantile spasms. We hypothesized that a delay in treatment may have consequences on neurologic outcome. We conducted a multicenter, retrospective, observational study to evaluate occurrence of misdiagnosis and its possible consequences. We performed a multivariate analysis to evaluate the risk for the outcome 2 years after the diagnosis of infantile spasms. We included 83 infants over a 5-year period. The majority of consulted physicians (301 of 362) did not suggest any specific diagnosis while the others suggested gastroesophageal reflux (7 %), constipation (7 %), or colitis (3 %). Results indicated that a poor outcome was related to a delay in diagnosis, which was observed regardless of the existence of cognitive involvement prior to the start of infantile spasms (Relative Risk: RR 12.08 [1.52-96.3]). These results highlight the importance of making an early diagnosis of infantile spasms.

Summary Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule associated protein, that is predominantly expressed in post-mitotic neurons, and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.