Search

Objective: 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., Methods: 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., Results: 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., Conclusions: 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., Significance: Our measures correlated with different motor disabilities and identified distinctive brain network impairments., Competing Interests: Conflict of Interest None of the authors has potential conflicts of interest to be disclosed., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To assess functional organization of the motor cortex in patients with Unverricht-Lundborg disease (EPM1A) using a combined neurophysiologic and imaging approach., Methods: EPM1A patients underwent transcranial magnetic stimulation (TMS)-based cortical mapping of the motor hand area. Moreover, they performed neuroimaging studies to assess functional magnetic resonance imaging (fMRI) activation maps related to motor hand task and cortical thickness (CTH) on T1-weighted 3D images., Results: The hand cortical representation was different in EPM1A patients from that of the control subjects both in TMS and in fMRI brain mapping, characterized by a posterior dislocation and a mild reduction in the activation of motor areas. CTH analysis revealed a thinning of both precentral and paracentral areas in the patients., Conclusions: We hypothesize that the altered cortical motor map reflects a functional reorganization of the residual cortical neuronal pool of the sensorimotor hand areas driven by plastic reorganization and/or pathophysiological mechanisms., Significance: Both pathophysiological process and plastic changes may represent two sides of the same phenomenon in the EPM1A patients; structural and functional brain mapping may help to identify functional reorganization of the cortical motor system., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To explore the course of Unverricht-Lundborg disease (EPM1) and identify the risk factors for severity, we investigated the time course of symptoms and prognostic factors already detectable near to disease onset., Methods: We retrospectively evaluated the features of 59 Italian patients carrying the CSTB expansion mutation, and coded the information every 5 years after the disease onset in order to describe the cumulative time-dependent probability of reaching disabling myoclonus, relevant cognitive impairment, and inability to work, and evaluated the influence of early factors using the log-rank test. The risk factors were included in a Cox multivariate proportional hazards regression model., Results: Disabling myoclonus occurred an average of 32 years after disease onset, whereas cognitive impairment occurred a little later. An age at onset of less than 12 years, the severity of myoclonus at the time of first assessment, and seizure persistence more than 10 years after onset affected the timing of disabling myoclonus and cognitive decline. Most patients became unable to work years before the appearance of disabling myoclonus or cognitive decline., Conclusions: A younger age at onset, early severe myoclonus, and seizure persistence are predictors of a more severe outcome. All of these factors may be genetically determined, but the greater hyperexcitability underlying more severe seizures and myoclonus at onset may also play a role by increasing cell damage due to reduced cystatin B activity., (© 2017 American Academy of Neurology.)

Background: To explore the cortical network sustaining action myoclonus and to found markers of the resulting functional impairment, we evaluated the distribution of the cortico-muscular coherence (CMC) and the frequency of coherent cortical oscillations with magnetoencephalography (MEG). All patients had EPM1 (Unverricht-Lundborg) disease known to present with prominent and disabling movement-activated myoclonus., Methods: Using autoregressive models, we evaluated CMC on MEG sensors grouped in regions of interests (ROIs) above the main cortical areas. The movement was a repeated sustained isometric extension of the right hand and right foot. We compared the data obtained in 10 EPM1 patients with those obtained in 10 age-matched controls., Results: As expected, CMC in beta band was significantly higher in EPM1 patients compared to controls in the ROIs exploring the sensorimotor cortex, but, it was also significantly higher in adjacent ROIs ipsilateral and contralateral to the activated limb. Moreover, the beta-CMC peak occurred at frequencies significantly slower and more stable frequencies in EPM1 patients with respect to controls. The frequency of the beta-CMC peak inversely correlated with the severity of myoclonus., Conclusions: the high and spatially extended beta-CMC peaking in a restricted range of low-beta frequencies in EPM1 patients, suggest that action myoclonus may result not only from an enhanced local synchronization but also from a specific oscillatory activity involving an expanded neuronal pool. The significant relationship between beta-CMC peak frequency and the severity of the motor impairment can represent a useful neurophysiological marker for the patients' evaluation and follow-up.

Objective: We aimed the present study at estimating the appropriateness of generalised partial directed coherence (GPDC) in detecting myoclonus-related EEG-EMG connectivity pattern and the information flow between sensorimotor cortex and muscles in patients with typical cortical myoclonus due to Unverricht-Lundborg disease., Methods: In 13 patients with cortical myoclonus, we analysed the EEG and EMG signals recorded during simple voluntary motor activities using GPDC, a frequency domain linear index of connectivity estimated from a multivariate autoregressive model. The results were compared with those obtained in 12 healthy controls., Results: The GPDC revealed a peculiar pattern characterising patients with cortical myoclonus with respect to healthy subjects. Patients consistently had significant more robust outflow toward activated muscle originating from cortical areas exceeding the motor one. Moreover, they also had a more robust EMG outflow directed toward a wider cortical area contralateral to activated hand and sometimes also toward the ipsilateral central region., Conclusions: Our results clearly indicate the recruitment of extensive cortical network in afferent and efferent EEG-EMG relationships., Significance: Given that robust cortical outflow can be considered as the pathogenic mechanism sustaining myoclonus, the perturbation from the EMG outflow could lead to the involvement of large cortical area implied in sensorimotor integration and became capable of generating and maintaining the jerk recurrence., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: To define the clinical spectrum and etiology of progressive myoclonic epilepsies (PMEs) in Italy using a database developed by the Genetics Commission of the Italian League against Epilepsy., Methods: We collected clinical and laboratory data from patients referred to 25 Italian epilepsy centers regardless of whether a positive causative factor was identified. PMEs of undetermined origins were grouped using 2-step cluster analysis., Results: We collected clinical data from 204 patients, including 77 with a diagnosis of Unverricht-Lundborg disease and 37 with a diagnosis of Lafora body disease; 31 patients had PMEs due to rarer genetic causes, mainly neuronal ceroid lipofuscinoses. Two more patients had celiac disease. Despite extensive investigation, we found no definitive etiology for 57 patients. Cluster analysis indicated that these patients could be grouped into 2 clusters defined by age at disease onset, age at myoclonus onset, previous psychomotor delay, seizure characteristics, photosensitivity, associated signs other than those included in the cardinal definition of PME, and pathologic MRI findings., Conclusions: Information concerning the distribution of different genetic causes of PMEs may provide a framework for an updated diagnostic workup. Phenotypes of the patients with PME of undetermined cause varied widely. The presence of separate clusters suggests that novel forms of PME are yet to be clinically and genetically characterized.

Objective: To evaluate the relationship between sensory hyperexcitability as revealed by giant SEPs and the SEP recovery function (SEP-R) in a series of patient with progressive myoclonic epilepsy of Unverricht-Lundborg type, identified as epilepsy, progressive myoclonic 1A (EPM1A), MIM #254800., Methods: We evaluated SEPs by applying median nerve stimuli and SEP-R using paired stimuli at inter-stimulus intervals (ISIs) of between 20 and 600 ms in 25 patients and 20 controls. The SEPs were considered "giant" if the N20P25 and P25N33 amplitudes exceeded normal mean values by +3SD., Results: During the paired-stimulus protocol, the SEPs elicited by the second stimulus (S2) were detectable at all ISIs but consistently suppressed in the 13 patients with giant SEPs reflecting a significantly delayed SEP-R. Maximal suppression roughly corresponded to the plateau of a broad middle latency (>100 ms) wave pertaining to the S1 response., Conclusions: The cortical processing dysfunction generating giant SEPs in EPM1A patients consistently combines with a long-lasting suppression of hyperexcitability that leads to a delayed giant SEP-R without obstructing the response to incoming stimuli., Significance: The delayed SEP-R is not due to true inhibition but the suppression of aberrant hyper-synchronisation sustaining giant SEPs. A broad middle latency SEP component adds a significantly suppressive effect. This suggests that cortico-subcortical circuitries contribute to both the gigantism and the delayed SEP-R., (Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Electrophysiological studies indicate that Unverricht-Lundborg's disease (ULD), the most common form of progressive myoclonus epilepsy in Europe, is characterized by the involvement of multiple cortical regions in degenerative changes that lead to enhanced excitation and deficient inhibition. We searched for the haemodynamic correlates of these effects using functional MRI (fMRI) of self-paced index extensions, a well-accepted task highlighting significant differences. EEG and fMRI were simultaneously acquired in 11 ULD patients and 16 controls, performing the index extensions individually (event-related task) as well as repetitively (block task). ERD/ERS analysis was performed for the EEG data in the alpha and beta bands. fMRI time-series were analyzed using the traditional general linear model, as well as with an assumption-free approach, and by means of cross-region correlations representing functional connectivity. In line with the existing literature, ULD patients had enhanced desynchronization in the alpha band and reduced post-movement synchronization in the beta band. By contrast, fMRI did not reveal any difference between the two groups; there were no activation intensity, latency or extent effects, no significant engagement of additional regions, and no changes to functional connectivity. We conclude that, so long as the patients are executing a task which does not induce obvious action myoclonus, the hypothesized abnormalities in pyramidal neuron and interneuron dynamics are relatively subtle, embodied in processes which are not metabolically-demanding and take place at a time-scale invisible to fMRI.

Myoclonus has different clinical and neurophysiological features in patients with Unverricht-Lundborg (ULD) and Lafora body disease (LBD), probably because of a different cortical hyperexcitability profile. To investigate the role of intracortical inhibition in such different presentations, we used paired-pulse transcranial magnetic stimulation (TMS) in ten ULD and five LBD patients, all with a positive molecular diagnosis. All of the patients were treated with antiepileptic drugs (AEDs). In comparison with healthy subjects, both patient groups had significantly defective short intracortical inhibition (SICI), however LBD patients, but not ULD and healthy subjects, had a clear inhibition at ISI 6 ms and ISI 10 ms. Moreover, defective long interval cortical inhibition (LICI) was found in LBD but not ULD patients. The substantial reduction in SICI suggests that both ULD and LBD patients have impaired inhibitory interneuron pools which are involved in the generation of cortical reflex myoclonus, whereas the inhibition found in LBD patients at ISI 6 and 10 ms, as well the reduced inhibition found at long intervals, suggest a more complex circuitry dysfunction possibly involving both excitatory and inhibitory systems. These findings are probably related to the high epileptogenic propensity characterizing LBD with respect to ULD and to the more severely distorted neuronal network resulting from the pathogenesis of LBD., (Copyright 2010 Elsevier B.V. All rights reserved.)

We performed simultaneous acquisition of EEG-fMRI in seven patients with Unverricht-Lundborg disease (ULD) and in six healthy controls using self-paced finger extension as a motor task. The event-related desynchronization/synchronization (ERD/ERS) analysis showed a greater and more diffuse alpha desynchronization in central regions and a strongly reduced post-movement beta-ERS in patients compared with controls, suggesting a significant dysfunction of the mechanisms regulating active movement and movement end. The event-related hemodynamic response obtained from fMRI showed delayed BOLD peak latency in the contralateral primary motor area suggesting a less efficient activity of the neuronal populations driving fine movements, which are specifically impaired in ULD.

We studied changes in event-related desynchronization/synchronization (ERD/ERS) patterns in patients with Unverricht-Lundborg disease (ULD), presenting with prominent action myoclonus. We analyzed the movement-related ERD/ERS in alpha and beta frequency bands in 15 patients using self-paced finger extension as a motor paradigm and we compared the results with those obtained in 12 healthy volunteers. In all ULD patients, alpha- and beta-ERD regularly occurred with onset and location similar to that found in healthy controls, but the desynchronization of alpha activity was significantly greater than in controls (C3: -64.4+/-9.8% vs. -49.7+/-14.8%; p=0.004). Moreover, in the patients, both alpha- and beta-ERD spread toward frontal electrodes. In controls, the post-movement beta-ERS regularly occurred; it was absent in eight patients with severe action myoclonus, while, in seven patients with mild or moderate myoclonus, the beta-peak was significantly smaller with respect to that measured in controls (55.6+/-15.1% vs. 153.9+/-99.8%, p=0.006). The failure of beta-ERS well-correlated with motor impairment resulting from action myoclonus, whereas SSEPs and long-loop reflexes performed to detect signs of cortical hyperexcitability showed inconsistent changes. In ULD patients, ERD/ERS changes indicate an increased activation of motor cortex during movement planning and a great reduction of post-excitatory inhibition of motor cortex. The changes involving beta-ERS had a significant relationship with the functional disability in individual patients and might play a pathogenic role in the motor dysfunction.

Objective: To investigate whether Unverricht-Lundborg disease (ULD) and Lafora body disease (LBD) can be differentiated on the basis of their neurophysiologic profiles., Methods: Somatosensory evoked potentials (SSEPs), long-loop reflexes (LLRs), and the influence of conditioning nerve stimulation on the motor potentials evoked by transcranial stimulation in 8 patients with LBD and 10 patients with ULD were investigated., Results: Both groups showed sensorimotor cortex hyperexcitability, but their electrophysiologic profiles were different. Enlarged P25 to N33 SSEP components and enhanced LLRs were common in the ULD patients, whereas medium-latency "giant" SSEP components and less consistently enhanced LLRs were more frequently found in the patients with LBD. Cortical relay time was extremely brief in ULD but varied in LBD. Conditioning somatosensory stimuli differently affected motor cortex excitability, leading to early facilitation in ULD and delayed and prolonged facilitation in LBD., Conclusions: Patients with Unverricht-Lundborg disease (ULD) and Lafora body disease (LBD) have different electrophysiologic profiles. The ULD findings point to an aberrant subcortical or cortical loop (possibly short-cutting the somatosensory cortex) that is involved in generating the prominent action myoclonus characterizing the disorder. The LBD findings highlight sustained hyperexcitability of the sensorimotor cortex in response to afferent stimuli, which fit with a more severe impairment of inhibitory mechanisms.