Emmanuel Raffo

A Pulse Rapamycin Therapy for Infantile Spasms and Associated Cognitive Decline

Infantile spasms are seizures manifesting within a spectrum of epileptic encephalopathies of infancy that often lead to cognitive impairment. Their current therapies, including adrenocorticotropic hormone (ACTH), high dose steroids, or vigabatrin, are not always effective and may be associated with serious side effects. Overactivation of the TORC1 complex of the mTOR pathway is implicated in the pathogenesis of certain genetic and acquired disorders that are linked with infantile spasms, like tuberous sclerosis. Here, we tested the therapeutic potential of rapamycin, a TORC1 inhibitor, as a potential treatment for infantile spasms in the multiple-hit rat model of ACTH-refractory symptomatic infantile spasms, which is not linked to tuberous sclerosis. Rapamycin or vehicle was given after spasms appeared. Their effects on spasms, other seizures, performance in Barnes maze, and expression of the phosphorylated S6 ribosomal protein (pS6: a TORC1 target) in the cortex, using immunofluorescence, were compared. Rapamycin suppressed spasms dose-dependently and improved visuospatial learning, although it did not reduce the frequency of other emerging seizures. High-dose pulse rapamycin effected acute and sustained suppression of spasms and improved cognitive outcome, without significant side effects. Therapeutically effective rapamycin doses normalized the pS6 expression, which was increased in perilesional cortical regions of pups with spasms. These findings support that pathological overactivation of TORC1 may be implicated in the pathogenesis of infantile spasms, including those that are not linked to tuberous sclerosis. Furthermore, a high-dose, pulse rapamycin treatment is a promising, well tolerated and disease-modifying new therapy for infantile spasms, including those refractory to ACTH.

De novo mutations in HCN1 cause early infantile epileptic encephalopathy

Hyperpolarization-activated, cyclic nucleotide–gated (HCN) channels contribute to cationic Ih current in neurons and regulate the excitability of neuronal networks. Studies in rat models have shown that the Hcn1 gene has a key role in epilepsy, but clinical evidence implicating HCN1 mutations in human epilepsy is lacking. We carried out exome sequencing for parent-offspring trios with fever-sensitive, intractable epileptic encephalopathy, leading to the discovery of two de novo missense HCN1 mutations. Screening of follow-up cohorts comprising 157 cases in total identified 4 additional amino acid substitutions. Patch-clamp recordings of Ih currents in cells expressing wild-type or mutant human HCN1 channels showed that the mutations had striking but divergent effects on homomeric channels. Individuals with mutations had clinical features resembling those of Dravet syndrome with progression toward atypical absences, intellectual disability and autistic traits. These findings provide clear evidence that de novo HCN1 point mutations cause a recognizable early-onset epileptic encephalopathy in humans.

A model of symptomatic infantile spasms syndrome.

Infantile spasms are characterized by age-specific expression of epileptic spasms and hypsarrhythmia and often result in significant cognitive impairment. Other epilepsies or autism often ensue especially in symptomatic IS (SIS). Cortical or subcortical damage, including white matter, have been implicated in the pathogenesis of SIS. To generate a model of SIS, we recreated this pathology by injecting rats with lipopolysaccharide and doxorubicin intracerebrally at postnatal day (P) 3 and with p-chlorophenylalanine intraperitoneally at P5. Spasms occurred between P4 and 13 and were associated with ictal EEG correlates, interictal EEG abnormalities and neurodevelopmental decline. After P9 other seizures, deficits in learning and memory, and autistic-like behaviors (indifference to other rats, increased grooming) were observed. Adrenocorticotropic hormone (ACTH) did not affect spasms. Vigabatrin transiently suppressed spasms at P5. This new model of SIS will be useful to study the neurobiology and treatment of SIS, including those that are refractory to ACTH.

Mutations in SLC13A5 Cause Autosomal-Recessive Epileptic Encephalopathy with Seizure Onset in the First Days of Life

Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy.

Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease

Purpose:  Lafora disease (LD) is an autosomal recessive form of progressive myoclonus epilepsy with onset in childhood or adolescence and with fatal outcome caused by mutations in two genes: EPM2A and NHLRC1. The aim of this study was to characterize the mutation spectrum in a cohort of unrelated patients with presumed LD.

Modeling new therapies for infantile spasms

Infantile spasms are the classical seizure type of West syndrome. Infantile spasms often herald a dismal prognosis, due to the high probability to evolve into intractable forms of epilepsies with significant cognitive deficits, especially if not adequately treated. The current therapies—high doses of adrenocorticotropic hormone, steroids, or the γ‐aminobutyric acid (GABA) transaminase inhibitor vigabatrin—are often toxic and may not always be effective. The need to identify new therapies for spasms has led to the generation of a number of rodent models of infantile spasms. These include acute and chronic models of infantile spasms, with cryptogenic or symptomatic origin, many of which are based on specific etiologies. In this review, we summarize the clinical experience with treating infantile spasms and the main features of the new animal models of infantile spasms and discuss their utility in the preclinical development of new therapies for infantile spasms.

Bitemporal form of partial reading epilepsy: Further evidence for an idiopathic localization‐related syndrome

Idiopathic partial reading epilepsy (RE) is a rare syndrome. We report the clinical and electroencephalographic characteristics of two right‐handed patients with the following: reading‐induced independent bilateral temporal lobe seizures, accompanied by alexia in left (dominant) sided seizures recorded on video‐EEG (electroencephalography); subclinical activation over left posterior temporal and occipital electrodes during reading; no spontaneous seizure and no other trigger than reading; onset in adolescence; and history of varying resistance to treatment. Bilateral independent temporal lobe reflex seizures are part of the clinical spectrum of RE. It may result from hyperexcitability of bilateral cortical networks involved in the early steps of the reading process.

Posterior glucose hypometabolism in Lafora disease: Early and late FDG-PET assessment

Establishing an early diagnosis of Lafora disease (LD) is often challenging. We describe two cases of LD presenting as myoclonus and tonic–clonic seizures, initially suggesting idiopathic generalized epilepsy. The subsequent course of the disease was characterized by drug‐resistant myoclonic epilepsy, cognitive decline, and visual symptoms, which oriented the diagnosis toward progressive myoclonic epilepsy and, more specifically, LD. Early in the evolution in the first case, and before histopathologic and genetic confirmation of LD in both cases, [18]Fluorodeoxyglucose positron emission tomography (FDG‐PET) revealed posterior hypometabolism, consistent with the well‐known posterior impairment in this disease. This suggests that FDG‐PET could help to differentiate LD in early stages from other progressive myoclonic epilepsies, but confirmation is required by a longitudinal study of FDG‐PET in progressive myoclonic epilepsy.

Paralysie vélopalatine isolée aiguë réversible de l’enfant

Resume Introduction La paralysie velopalatine unilaterale de l’enfant est une situation rare qui pose principalement le probleme de son diagnostic etiologique et donc de l’extension du bilan pour y parvenir. Observation Nous rapportons les cas des deux enfants âges respectivement de 10 et 11 ans, jusque-la en bonne sante, presentant une paralysie velopalatine transitoire unilaterale, associee dans un cas a une paralysie de l’hemipharynx homolateral. Resultats La confrontation des donnees de ces deux observations a celles de la litterature suggere le diagnostic d’une neuropathie peripherique idiopathique. Conclusion Compte tenu de la rarete de ce tableau clinique, il parait necessaire de colliger d’autres cas similaires afin d’affirmer le caractere benin de l’affection, et d’eviter la multiplication d’examens complementaires invasifs.