Abstract Unverricht–Lundborg disease (EPM1), the most common progressive myoclonic epilepsy, is associated with a defect of cystatin B (CSTB), a protease inhibitor. We used CSTB knockout mice to test ...the hypothesis that EPM1 onset is related to a latent hyperexcitability and that progression depends on higher susceptibility to seizure-induced cell damage. Hippocampal slices prepared from CSTB-deficient mice were hyperexcitable, as they responded to afferent stimuli in CA1 with multiple population spikes and kainate perfusion provoked the appearance of epileptic-like activity earlier than in WT mice. This hyperexcitability may depend on loss of inhibition, because the density of GABA-immunoreactive cells was reduced in the hippocampus of CSTB knockouts. In vivo , CSTB-deficient mice treated with kainate displayed increased susceptibility to seizures, with shorter latency to seizure onset and increased seizure severity compared with WT littermates. Furthermore, a greater degree of neuronal damage was observed in CSTB-deficient than in WT mice after seizures of identical grade, indicating increased susceptibility to seizure-induced cell death.
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•FAME2, compared to EPM1, had confined beta-cortico-muscular coherence (CMC) and increased centrality index in the sensorimotor region contralateral to movement.•In FAME2, CMC ...distribution and increased centrality index could counteract the severity and the spreading of the myoclonus.•In FAME2, there was a main decline in the network connectivity indexes, possibly linked to neuropsychological comorbidities.
Familial Adult Myoclonic Epilepsy (FAME) presents with action-activated myoclonus, often associated with epilepsy, sharing various features with Progressive Myoclonic Epilepsy (PMEs), but with slower course and limited motor disability. We aimed our study to identify measures suitable to explain the different severity of FAME2 compared to EPM1, the most common PME, and to detect the signature of the distinctive brain networks.
We analyzed the EEG-EMG coherence (CMC) during segmental motor activity and indexes of connectivity in the two patient groups, and in healthy subjects (HS). We also investigated the regional and global properties of the network.
In FAME2, differently from EPM1, we found a well-localized distribution of beta-CMC and increased betweenness-centrality (BC) on the sensorimotor region contralateral to the activated hand.
In both patient groups, compared to HS, there was a decline in the network connectivity indexes in the beta and gamma band, which was more obvious in FAME2.
In FAME2, better localized CMC and increased BC in comparison with EPM1 patients could counteract the severity and the spreading of the myoclonus.
Decreased indexes of cortical integration were more severe in FAME2.
Our measures correlated with different motor disabilities and identified distinctive brain network impairments.
Recurrent epileptiform activity occurs spontaneously in cultured CNS neurons and in brain slices in which GABA inhibition has been blocked. We demonstrate here that pharmacological treatments ...resulting in either the block of glutamine production by astrocytes or the inhibition of glutamine uptake by neurons suppress or markedly decrease the frequency of spontaneous epileptiform discharges both in primary hippocampal cultures and in disinhibited hippocampal slices. These data point to an important role for the neuron-astrocyte metabolic interaction in sustaining episodes of intense rhythmic activity in the CNS, and thereby reveal a new potential target for antiepileptic treatments.
Summary
Purpose: To characterize the fast EEG activities associated with infantile spasms in West syndrome, and their value in predicting the recurrence and localization of late seizures.
Methods: We ...selected 23 infants who were followed for at least 2 years. Selected EEG recordings underwent autospectra, coherence, and phase analyses in order to assess the changes during follow‐up.
Results: Short discharges of fast‐rhythms (331 ± 190 ms) with a lateralized onset were detected in 18 of the 23 infants (78.3%). There were no significant differences in the parameters characterizing ICTAL beta‐activity (frequency, duration, inter‐hemispheric coherence, or transfer time) between the infants with or without seizure recurrence. However, beta‐discharges with a consistent location formed part of the ICTAL EEG in all 10 infants with seizure recurrence, but only in eight (61.5%) of those who remained seizure‐free (SF) (p < 0.05). In all but one of the infants experiencing seizure recurrence, the ICTAL discharges associated with the late seizures apparently originated from the same hemisphere as that involved at the beginning of the spasm‐associated beta‐activity, although the precise location varied.
Conclusions: Spectral, coherence and phase analyses detected spasm‐associated runs of lateralized beta‐rhythms in many of our infants with West syndrome. This ICTAL pattern significantly correlated with seizure recurrence. The consistent lateralization of the ICTAL EEG events associated with both the early spasms and late seizures suggests that EEG beta‐activities should be considered as indicating local cortical dysfunction in infants who fail to respond to early treatment and often progress toward severe epilepsy.
Highlights • Using GPDC, we analysed the EEG-EMG connectivity during myoclonus in EPM1 patients. • EEG and EMG outflows were higher and more robust in patients with respect to controls. • A wide ...cortical network generates and maintains rhythmic myoclonus.
Objective
Familial adult myoclonic epilepsy (FAME) is an under‐recognized disorder characterized by cortical myoclonus, generalized tonic–clonic seizures, and additional clinical symptoms, which vary ...depending on the FAME subtype. FAME is caused by pentanucleotide repeat expansions of intronic TTTCA/TTTTA in different genes. FAME should be distinguished from a range of differential diagnoses.
Methods
The differential diagnoses and frequent presentations leading to misdiagnosis of FAME were investigated from the available literature and reported based on an expert opinion survey.
Results
The phenotypic features of FAME, including generalized tonic–clonic and myoclonic seizures, are also seen in other epilepsy syndromes, such as juvenile myoclonic epilepsy, with a resultant risk of misdiagnosis and lack of identification of the underlying cause. Cortical myoclonus may mimic essential tremor or drug‐induced tremor. In younger individuals, the differential diagnosis includes progressive myoclonus epilepsies (PMEs), such as Unverricht‐Lundborg disease, whereas, in adulthood, late‐onset variants of PMEs, such as sialidoses, myoclonus epilepsy, and ataxia due to potassium channel pathogenic variants should be considered. PMEs may also be suggested by cognitive impairment, cerebellar signs, or psychiatric disorders. Electroencephalography (EEG) may show similarities to other idiopathic generalized epilepsies or PMEs, with generalized spike–wave activity. Signs of cortical hyperexcitability may be seen, such as an increased amplitude of somatosensory evoked potentials or enhanced cortical reflex to sensory stimuli, together with the neurophysiological pattern of the movement disorder.
Significance
Recognition of FAME will inform prognostic and genetic counseling and diagnosis of the insidious progression, which may occur in older individuals who show mild cognitive deterioration. Distinguishing FAME from other disorders in individuals or families with this constellation of symptoms is essential to allow the identification of underlying etiology.
The ionic mechanisms underlying the termination of action-potential (AP) bursts and postburst afterhyperpolarization (AHP) in intrinsically bursting (IB) neocortical neurons were investigated by ...performing intracellular recordings in thin slices of rat sensorimotor cortex. The blockade of Ca(2+)-activated K(+) currents enhanced postburst depolarizing afterpotentials, but had inconsistent and minor effects on the amplitude and duration of AHPs. On the contrary, experimental conditions resulting in reduction of voltage-dependent Na(+) entry into the cells caused a significant decrease of AHP amplitude. Slice perfusion with a modified artificial cerebrospinal fluid in which LiCl (40 mM) partially replaced NaCl had negligible effects on the properties of individual APs, whereas it consistently increased burst length and led to an approximately 30% reduction in the amplitude of AHPs following individual bursts or short trains of stimulus-induced APs. Experiments performed by partially replacing Na(+) ions with choline revealed a comparable reduction in AHP amplitude associated with an inhibition of bursting activity. Moreover, in voltage-clamp experiments carried out in both in situ and acutely isolated neurons, partial substitution of extracellular NaCl with LiCl significantly and reversibly reduced the amplitude of K(+) currents evoked by depolarizing stimuli above-threshold for Na(+)-current activation. The above effect of Na(+)-to-Li(+) substitution was not seen when voltage-gated Na(+) currents were blocked with TTX, indicating the presence of a specific K(+)-current component activated by voltage-dependent Na(+) (but not Li(+)) influx. The above findings suggest that a Na(+)-activated K(+) current recruited by the Na(+) entry secondary to burst discharge significantly contributes to AHP generation and the maintenance of rhythmic burst recurrence during sustained depolarizations in neocortical IB neurons.
Summary
Purpose: Theory of mind (ToM) is an important prerequisite to social behavior. This study evaluated ToM in patients with temporal (TLE) or frontal lobe epilepsy (FLE) aiming to determine the ...cognitive aspects, severity, and pathophysiologic mechanisms of ToM impairment in focal epilepsy.
Methods: One hundred thirty‐eight patients with TLE (n = 109) or FLE (n = 29) and 69 healthy subjects underwent the Faux Pas task (FPT), which evaluates the recognition and comprehension of others’ mental states, and neuropsychological tests for other cognitive functions.
Key Findings: Factor analysis of all test scores yielded two ToM factors (Recognizing faux pas, FP; Excluding nonexistent FP) distinct from the Control, Language, Matching, and Praxis factors. With respect to healthy subjects, both TLE and FLE patients showed correct exclusion of nonexistent FPs but significantly lower recognition and comprehension of real FPs. FLE patients were also impaired with respect to TLE patients. In the whole patient group, schooling and group membership predicted ToM impairment. In FLE patients, the comprehension of mental states was predicted by disease duration, whereas TLE patients’ comprehension of affects and intentions was associated with early age of seizure onset and medial temporal lobe sclerosis (MTLS).
Significance: Focal epilepsy impairs advanced ToM abilities. FLE may affect online performances owing to long‐lasting dysfunctions of the prefrontal areas. MTLS may provoke selective ToM deficits due to medial temporal damage, prefrontal dysfunctions, or early interference with cognitive development. Future studies are needed to determine the implications of ToM impairment on behavior and quality of life.
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