Planimetry investigation of the corpus callosum in temporal lobe epilepsy patients

Objective: To evaluate the effects of temporal lobe epilepsy (TLE) on corpus callosum (CC) morphometry in patients with TLE. Methods: This retrospective study was conducted at the Faculty of Medicine, Tekirdag Namik Kemal University, Tekirdag, Turkey between November 2010 and December 2013. The epileptic syndrome diagnosis was based on International League Against Epilepsy criteria, and this study was conducted on the MRIs of 25 epilepsy patients and 25 control subjects. We classified the patients according to their duration of epilepsy: = 10 years. The projection area length (PAL) of the CC was also estimated. Total brain volumes (TBV) were measured on CT images. Results: The mean values of TBV for patients with TLE and the control group were not statistically different, but the CC PAL values were statistically different. The mean CC PAL values of under and over 25 years of age in patients with TLE were statistically different. The mean values of TBV of under and over 10 years duration of TLE were small statistically, but the CC PAL values were statistically different. Conclusion: The results indicate a clear influence of TLE on the structure of the CC rather than TBV

Pediatric-Onset Epilepsy and Developmental Epileptic Encephalopathies Followed by Early-Onset Parkinsonism

Genetic early-onset Parkinsonism is unique due to frequent co-occurrence of hyperkinetic movement disorder(s) (MD), or additional neurological of systemic findings, including epilepsy in up to 10–15% of cases. Based on both the classification of Parkinsonism in children proposed by Leuzzi and coworkers and the 2017 ILAE epilepsies classification, we performed a literature review in PubMed. A few discrete presentations can be identified: Parkinsonism as a late manifestation of complex neurodevelopmental disorders, characterized by developmental and epileptic encephalopathies (DE-EE), with multiple, refractory seizure types and severely abnormal EEG characteristics, with or without preceding hyperkinetic MD; Parkinsonism in the context of syndromic conditions with unspecific reduced seizure threshold in infancy and childhood; neurodegenerative conditions with brain iron accumulation, in which childhood DE-EE is followed by neurodegeneration; and finally, monogenic juvenile Parkinsonism, in which a subset of patients with intellectual disability or developmental delay (ID/DD) develop hypokinetic MD between 10 and 30 years of age, following unspecific, usually well-controlled, childhood epilepsy. This emerging group of genetic conditions leading to epilepsy or DE-EE in childhood followed by juvenile Parkinsonism highlights the need for careful long-term follow-up, especially in the context of ID/DD, in order to readily identify individuals at increased risk of later Parkinsonism

Mesial temporal sclerosis is linked with more widespread white matter changes in temporal lobe epilepsy

AbstractTemporal lobe epilepsy patients with unilateral mesial temporal sclerosis (TLE+uMTS) have been demonstrated to have extensive white matter abnormalities both ipsilateral and contralateral to the seizure onset zone. However, comparatively less is known about the white matter integrity of TLE patients without MTS (non-lesional TLE, nl-TLE). The purpose of the study was to investigate the diffusion properties of thirteen major white matter tracts in patients with TLE+uMTS and nl-TLE. Diffusion tensor imaging (DTI) was performed on 23 TLE+uMTS (15 left MTS and 8 right MTS), 15nl-TLE and 21 controls. Thirteen tracts were delineated by tractography and their diffusion parameters compared for the two TLE groups relative to controls, with left and right hemispheres combined per tract. A subgroup analysis investigated left and right MTS separately. Compared to controls, reduced anisotropy was detected in ten tracts for TLE+uMTS, but only the parahippocampal cingulum and tapetum for nl-TLE. Right MTS subgroup showed reduced anisotropy in 7 tracts bilaterally (3 limbic, 3 association, 1 projection) and 2 tracts ipsilaterally (1 association, 1 projection) and the body of the corpus callosum whereas the left MTS subgroup showed reduced anisotropy in 4 tracts bilaterally (2 limbic, 1 association, 1 projection) and 2 tracts ipsilaterally (1 limbic, 1 association). Diffusion abnormalities in tracts were observed within and beyond the temporal lobe in TLE+uMTS and were more widespread than in nl-TLE. Patients with right MTS had more extensive, bilateral abnormalities in comparison to left MTS. These findings suggest different dysfunctional networks in TLE patients with and without MTS

The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy

Primary dysfunction of autophagy due to Mendelian defects affecting core components of the autophagy machinery or closely related proteins have recently emerged as an important cause of genetic disease. This novel group of human disorders may present throughout life and comprises severe early-onset neurodevelopmental and more common adult-onset neurodegenerative disorders. Early-onset (or congenital) disorders of autophagy often share a recognizable "clinical signature," including variable combinations of neurological, neuromuscular and multisystem manifestations. Structural CNS abnormalities, cerebellar involvement, spasticity and peripheral nerve pathology are prominent neurological features, indicating a specific vulnerability of certain neuronal populations to autophagic disturbance. A typically biphasic disease course of late-onset neurodegeneration occurring on the background of a neurodevelopmental disorder further supports a role of autophagy in both neuronal development and maintenance. Additionally, an associated myopathy has been characterized in several conditions. The differential diagnosis comprises a wide range of other multisystem disorders, including mitochondrial, glycogen and lysosomal storage disorders, as well as ciliopathies, glycosylation and vesicular trafficking defects. The clinical overlap between the congenital disorders of autophagy and these conditions reflects the multiple roles of the proteins and/or emerging molecular connections between the pathways implicated and suggests an exciting area for future research. Therapy development for congenital disorders of autophagy is still in its infancy but may result in the identification of molecules that target autophagy more specifically than currently available compounds. The close connection with adult-onset neurodegenerative disorders highlights the relevance of research into rare early-onset neurodevelopmental conditions for much more common, age-related human diseases.Peer reviewe

Corpus Callosum and Word Reading in Adult Survivors of Childhood Posterior Fossa Tumors

Adult survivors of childhood posterior fossa tumors can experience reading difficulties related to white matter integrity. Previously, reading was shown to be related to cortical white matter tracts, however information transfer across the corpus callosum (CC) may also play a role in reading. The current study used both macro- and microstructural measures of the WM structure of the corpus callosum. The current study examined how white matter volume and fractional anisotropy (FA) in five divisions of the CC was related to degree of neurological risk and reading skill, and tested two mediation models predicting reading. Participants included 20 adult survivors of childhood posterior fossa tumor and 23 healthy controls. Volume and FA were measured in five divisions of the mid-sagittal corpus callosum. Total intracranial vault was used as a covariate in volume analyses. FA was reduced in CC1 and volume was reduced in each subregion in survivors. Volume but not FA was related to degree of neurological risk. Results identified that reduced volume in CC1 and CC5, and FA in CC5 appear to be specifically related to reading skill in line with the cortical reading regions that connect in these subregions of the CC. Mediation models indicate that processing speed is the mechanism by which volume is related to reading skill. These findings have implications for addressing processing speed in reading interventions in survivors and provide insight into the interhemispheric connections in the reading network

Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.

Microtubules help building the cytoskeleton of neurons and other cells. Several components of the gamma-tubulin (γ-tubulin) complex have been previously reported in human neurodevelopmental diseases. We describe two siblings from a consanguineous Turkish family with dysmorphic features, developmental delay, brain malformation, and epilepsy carrying a homozygous mutation (p.Glu311Lys) in TUBGCP2 encoding the γ-tubulin complex 2 (GCP2) protein. This variant is predicted to disrupt the electrostatic interaction of GCP2 with GCP3. In primary fibroblasts carrying the variant, we observed a faint delocalization of γ-tubulin during the cell cycle but normal GCP2 protein levels. Through mass spectrometry, we observed dysregulation of multiple proteins involved in the assembly and organization of the cytoskeleton and the extracellular matrix, controlling cellular adhesion and of proteins crucial for neuronal homeostasis including axon guidance. In summary, our functional and proteomic studies link TUBGCP2 and the γ-tubulin complex to the development of the central nervous system in humans

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0–49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease

The Cross Talk between Underlying Mechanisms of Multiple Sclerosis and Epilepsy May Provide New Insights for More Efficient Therapies

Despite the significant differences in pathological background of neurodegenerative diseases,epileptic seizures are a comorbidity in many disorders such as Huntington disease (HD), Alzheimer 'sdisease (AD), and multiple sclerosis (MS). Regarding the last one, specifically, it has been shownthat the risk of developing epilepsy is three to six times higher in patients with MS compared tothe general population. In this context, understanding the pathological processes underlying thisconnection will allow for the targeting of the common and shared pathological pathways involvedin both conditions, which may provide a new avenue in the management of neurological disorders.This review provides an outlook of what is known so far about the bidirectional association betweenepilepsy and M

The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy

Primary dysfunction of autophagy due to Mendelian defects affecting core components of the autophagy machinery or closely related proteins have recently emerged as an important cause of genetic disease. This novel group of human disorders may present throughout life and comprises severe early-onset neurodevelopmental and more common adult-onset neurodegenerative disorders. Early-onset (or congenital) disorders of autophagy often share a recognizable "clinical signature," including variable combinations of neurological, neuromuscular and multisystem manifestations. Structural CNS abnormalities, cerebellar involvement, spasticity and peripheral nerve pathology are prominent neurological features, indicating a specific vulnerability of certain neuronal populations to autophagic disturbance. A typically biphasic disease course of late-onset neurodegeneration occurring on the background of a neurodevelopmental disorder further supports a role of autophagy in both neuronal development and maintenance. In addition, an associated myopathy has been characterized in several conditions. The differential diagnosis comprises a wide range of other multisystem disorders, including mitochondrial, glycogen and lysosomal storage disorders, as well as ciliopathies, glycosylation and vesicular trafficking defects. The clinical overlap between the congenital disorders of autophagy and these conditions reflects the multiple roles of the proteins and/or emerging molecular connections between the pathways implicated and suggests an exciting area for future research. Therapy development for congenital disorders of autophagy is still in its infancy but may result in the identification of molecules that target autophagy more specifically than currently available compounds. The close connection with adult-onset neurodegenerative disorders highlights the relevance of research into rare early-onset neurodevelopmental conditions for much more common, age-related human diseases

Altered GABA Signaling in Early Life Epilepsies

The incidence of seizures is particularly high in the early ages of life. The immaturity of inhibitory systems, such as GABA, during normal brain development and its further dysregulation under pathological conditions that predispose to seizures have been speculated to play a major role in facilitating seizures. Seizures can further impair or disrupt GABAA signaling by reshuffling the subunit composition of its receptors or causing aberrant reappearance of depolarizing or hyperpolarizing GABAA receptor currents. Such effects may not result in epileptogenesis as frequently as they do in adults. Given the central role of GABAA signaling in brain function and development, perturbation of its physiological role may interfere with neuronal morphology, differentiation, and connectivity, manifesting as cognitive or neurodevelopmental deficits. The current GABAergic antiepileptic drugs, while often effective for adults, are not always capable of stopping seizures and preventing their sequelae in neonates. Recent studies have explored the therapeutic potential of chloride cotransporter inhibitors, such as bumetanide, as adjunctive therapies of neonatal seizures. However, more needs to be known so as to develop therapies capable of stopping seizures while preserving the age- and sex-appropriate development of the brain