Drug-resistant juvenile myoclonic epilepsy: A literature review.

The ILAE's Task Force on Nosology and Definitions revised in 2022 its definition of juvenile myoclonic epilepsy (JME), the most common idiopathic generalized epilepsy disorder, but this definition may well change again in the future. Although good drug response could almost be a diagnostic criterion for JME, drug resistance (DR) is observed in up to a third of patients. It is important to distinguish this from pseudoresistance, which is often linked to psychosocial problems or psychiatric comorbidities. After summarizing these aspects and the various definitions applied to JME, the present review lists the risk factors for DR-JME that have been identified in numerous studies and meta-analyses. The factors most often cited are absence seizures, young age at onset, and catamenial seizures. By contrast, photosensitivity seems to favor good treatment response, at least in female patients. Current hypotheses on DR mechanisms in JME are based on studies of either simple (e.g., cortical excitability) or more complex (e.g., anatomical and functional connectivity) neurophysiological markers, bearing in mind that JME is regarded as a neural network disease. This research has revealed correlations between the intensity of some markers and DR, and above all shed light on the role of these markers in associated neurocognitive and neuropsychiatric disorders in both patients and their siblings. Studies of neurotransmission have mainly pointed to impaired GABAergic inhibition. Genetic studies have generally been inconclusive. Increasing restrictions have been placed on the use of valproate, the standard antiseizure medication for this syndrome, owing to its teratogenic and developmental risks. Levetiracetam and lamotrigine are prescribed as alternatives, as is vagal nerve stimulation, and there are several other promising antiseizure drugs and neuromodulation methods. The development of better alternative treatments is continuing to take place alongside advances in our knowledge of JME, as we still have much to learn and understand.

EFHC1 gene mutation profile of Turkish JME patients and its association with disease risk.

OBJECTIVES: Juvenile myoclonic epilepsy (JME) is a common form of generalized epilepsy with an important genetic component. This cohort study aimed to examine the frequency of EFHC1 gene variants in Turkish JME patients and a healthy control group and evaluate the association between these mutations and disease risk. METHODS: We screened 72 JME patients with a mean age of 31.8 ± 9.9 (20-65) years and 35 controls with a mean age of 29.1 ± 7.6 (17-50) years from southern Turkey using direct sequencing analyses. RESULTS: EFCH1 single nucleotide variants were detected in 24 of 72 JME patients and 3 of 35 controls. The most common mutations were R182H in JME patients (p = 0.010) and 3'UTR in the control group (p < 0.001). The R182H mutation is a common variant in JME (95 % CI: 1.232-76.580, p = 0.031) and the 3'UTR mutation may be associated with lower risk of JME in the Turkish population (95 % CI: 13.89-166.67, p < 0.001). SIGNIFICANCE: Our results indicate that EFHC1 gene variants carry a risk for JME and the 3'UTR variant may have a protective role against JME in the Turkish population. Screening for other genes is needed to further clarify the genetic inheritance of JME in Turkish patients.

[Reflex triggers in juvenile myoclonic epilepsy]. / Los desencadenantes reflejos en la epilepsia mioclónica juvenil.

INTRODUCTION: Juvenile myoclonic epilepsy (JME) is an epileptic syndrome with onset in childhood and adolescence with myoclonus, absences, and generalized tonic-clonic seizures. Reflex stimuli such as sensitivity to light or photosensitivity, eyelid opening and closing, and praxis induction produce epileptiform discharges and seizures. These reflex triggers are not all systematically studied. OBJECTIVE: Examine reflex features in patients with JME. METHODS: One hundred adolescents and adults with JME who received different anti-seizure treatments were evaluated consecutively. A standard electroencephalogram was performed with an intermittent light stimulation (SLI) protocol and another for the evaluation of praxias through neurocognitive activity (CNA). The statistical analysis was descriptive and of correlation with a p > 0.05. RESULTS: Current age was 28±11 (14-67). The seizure began at 15 years ±3 (Range 8-25 years). They presented myoclonus and generalized tonic-clonic seizures in 58%. 50% received valproic acid and 31% continued with seizures. Epileptiform discharges at rest 20%; hyperventilation 30%; eyelid opening and closing 12%; photoparoxysmal response in SLI 40%; CNA 23%. Higher percentage of discharges and delay in performing CNA in those who presented seizures. Valproic acid compared to other drugs did not demonstrate superiority in seizure control. CONCLUSIONS: These findings confirm the importance of studying reflex traits for diagnosis, follow-up, and therapeutic control.

Introducción: La epilepsia mioclónica juvenil (EMJ) es un síndrome epiléptico de inicio en la infancia y adolescencia con mioclonías, convulsiones tónico-clónicas generalizadas y ausencias. Los estímulos reflejos como la sensibilidad a la luz o fotosensibilidad, la apertura y cierre palpebral y la inducción por praxias producen descargas epileptiformes y crisis. Estos desencadenantes reflejos no son todos sistemáticamente estudiados. OBJETIVO: Examinar los rasgos reflejos en pacientes con EMJ. Métodos: Se evaluaron en forma consecutiva 100 adolescentes y adultos con EMJ que recibían diferentes tratamientos anticrisis. Se realizó un electroencefalograma standard con un protocolo de estimulación luminosa intermitente (ELI) y otro para la evaluación de las praxias a través de una actividad neurocognitiva (ANC). El análisis estadístico fue descriptivo y de correlación. Se consideró significativa una p > 0.05. RESULTADOS: La edad actual fue de 28±11 (14-67). Las crisis comenzaron a los 15 años ±3 (Rango 8-25 años). EL 58% presentaron mioclonías y convulsiones tónico clónicas generalizadas. El 50% recibían ácido valproico y el 31% continuaban con crisis. Descargas epileptiformes en reposo 20%; hiperventilación 30%; apertura y cierre palpebral 12%; respuesta fotoparoxística en la ELI 40%; ANC 23%. Mayor porcentaje de descargas y demora en la realización de la ANC en los que presentaban crisis. El ácido valproico comparado con los otros fármacos no demostró superioridad en el control de las crisis. CONCLUSIONES: Estos hallazgos confirman la importancia del estudio de los rasgos reflejos para el diagnóstico, seguimiento y el control terapéutico.

Clinical and electroencephalographic findings prior to the onset of juvenile myoclonic epilepsy: A case series.

The purpose of this study was to investigate the timing of generalized electroencephalographic abnormalities in patients with juvenile myoclonic epilepsy who were followed up long term before the onset of juvenile myoclonic epilepsy. We enrolled juvenile myoclonic epilepsy patients whose course of epilepsy had been observed for >5 years before the onset of juvenile myoclonic epilepsy, those who had undergone electroencephalogram recording more than twice before the onset of juvenile myoclonic epilepsy, and those who had terminated antiseizure medications for at least 2 years before the onset of juvenile myoclonic epilepsy. Patients who had transitioned from childhood absence epilepsy to juvenile myoclonic epilepsy were excluded. We retrospectively reviewed the medical records and neurophysiological data of the patients. Four patients met the inclusion criteria. One patient was diagnosed with febrile seizures during childhood, and the remaining three had transitioned to juvenile myoclonic epilepsy from other epileptic disorders, such as self-limited epilepsy with autonomic seizures, genetic epilepsy with febrile seizure plus, or nonspecific genetic generalized epilepsy. All patients exhibited generalized spike-wave discharges or photoparoxysmal responses for >2 years before the onset of juvenile myoclonic epilepsy. The four patients had transitioned to juvenile myoclonic epilepsy from other epileptological preconditions. Patients with juvenile myoclonic epilepsy may show generalized electroencephalographic abnormality many years prior to the onset of symptoms. Generalized spike-waves on the electroencephalogram during the course of any type of epilepsy or febrile seizure may be a risk factor for developing juvenile myoclonic epilepsy.

Dynamic flexibility and controllability of network communities in juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is the most common syndrome within the idiopathic generalized epilepsy spectrum, manifested by myoclonic and generalized tonic-clonic seizures and spike-and-wave discharges (SWDs) on electroencephalography (EEG). Currently, the pathophysiological concepts addressing SWD generation in JME are still incomplete. In this work, we characterize the temporal and spatial organization of functional networks and their dynamic properties as derived from high-density EEG (hdEEG) recordings and MRI in 40 JME patients (25.4 ± 7.6 years, 25 females). The adopted approach allows for the construction of a precise dynamic model of ictal transformation in JME at the cortical and deep brain nuclei source levels. We implement Louvain algorithm to attribute brain regions with similar topological properties to modules during separate time windows before and during SWD generation. Afterwards, we quantify how modular assignments evolve and steer through different states towards the ictal state by measuring characteristics of flexibility and controllability. We find antagonistic dynamics of flexibility and controllability within network modules as they evolve towards and undergo ictal transformation. Prior to SWD generation, we observe concomitantly increasing flexibility (F(1,39) = 25.3, corrected p < 0.001) and decreasing controllability (F(1,39) = 55.3, p < 0.001) within the fronto-parietal module in γ-band. On a step further, during interictal SWDs as compared to preceding time windows, we notice decreasing flexibility (F(1,39) = 11.9, p < 0.001) and increasing controllability (F(1,39) = 10.1, p < 0.001) within the fronto-temporal module in γ-band. During ictal SWDs as compared to prior time windows, we demonstrate significantly decreasing flexibility (F(1,14) = 31.6; p < 0.001) and increasing controllability (F(1,14) = 44.7, p < 0.001) within the basal ganglia module. Furthermore, we show that flexibility and controllability within the fronto-temporal module of the interictal SWDs relate to seizure frequency and cognitive performance in JME patients. Our results demonstrate that detection of network modules and quantification of their dynamic properties is relevant to track the generation of SWDs. The observed flexibility and controllability dynamics reflect the reorganization of de-/synchronized connections and the ability of evolving network modules to reach a seizure-free state, respectively. These findings may advance the elaboration of network-based biomarkers and more targeted therapeutic neuromodulatory approaches in JME.

Differential diagnosis of familial adult myoclonic epilepsy.

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.

Neurophysiology of Juvenile and Progressive Myoclonic Epilepsy.

SUMMARY: Myoclonus can be epileptic or nonepileptic. Epileptic myoclonus has been defined in clinical, neurophysiological, and neuroanatomical terms. Juvenile myoclonic epilepsy (JME) is typically considered to be an adolescent-onset idiopathic generalized epilepsy with a combination of myoclonic, generalized tonic-clonic, and absence seizures and normal cognitive status that responds well to anti-seizure medications but requires lifelong treatment. EEG shows generalized epileptiform discharges and photosensitivity. Recent observations indicate that the clinical picture of JME is heterogeneous and a number of neuropsychological and imaging studies have shown structural and functional abnormalities in the frontal lobes and thalamus. Advances in neurophysiology and imaging suggest that JME may not be a truly generalized epilepsy, in that restricted cortical and subcortical networks appear to be involved rather than the entire brain. Some patients with JME may be refractory to anti-seizure medications and attempts have been made to identify neurophysiological biomarkers predicting resistance. Progressive myoclonic epilepsy is a syndrome with multiple specific causes. It is distinct from JME because of the occurrence of progressive neurologic dysfunction in addition to myoclonus and generalized tonic-clonic seizures but may sometimes be difficult to distinguish from JME or misdiagnosed as drug-resistant JME. This article provides an overview of progressive myoclonic epilepsy and focuses on the clinical and neurophysiological findings in the two most commonly recognized forms of progressive myoclonic epilepsy-Unverricht-Lundborg disease (EPM1) and Lafora disease (EPM2). A variety of neurophysiological tests can be used to distinguish between JME and progressive myoclonic epilepsy and between EPM1 and EPM2.

Cluster analysis of a large dataset of patients with juvenile myoclonic epilepsy: Predicting response to treatment.

OBJECTIVES: The purpose of the current study was to apply Two-step cluster analysis on a large dataset of patients with juvenile myoclonic epilepsy (JME). We hypothesized that there are distinct subgroups of patients with similar clinical characteristics. We also hypothesized that the seizure outcome is different between these clusters. METHODS: This was a retrospective study of a prospectively developed database. All patients with a diagnosis of JME were studied at the epilepsy center at Shiraz University of Medical Sciences, Shiraz, Iran, from 2008 until 2022. The Two-Step cluster analysis (Schwarz's Bayesian Criterion) was applied to the whole dataset. In the next step, the seizure outcome was compared between the clusters of patients. RESULTS: Two hundred and ninety-five patients were included. Two-Step cluster analysis showed that there were two distinct clusters of homogeneous subgroups of patients with JME, presenting with more or less similar clinical characteristics, with a fair (0.4) silhouette measure of cohesion and separation. One hundred and eighty-one patients had a follow up duration of 12 months or longer at our center. Response to treatment at 12 months of follow-up was different between the clusters (as a trend): 43 patients (39.1%) from cluster 1 and 18 people (25.4%) from cluster 2 were free of all seizure types (p = 0.076). CONCLUSION: The Two-Step cluster analysis identified two distinct clusters of patients with JME. Individuals with JME, who also have absence seizures, are less likely to enjoy a seizure free state with ASMs.

Paroxysmal Slow-Wave Events Are Uncommon in Parkinson's Disease.

Background: Parkinson's disease (PD) is currently considered to be a multisystem neurodegenerative disease that involves cognitive alterations. EEG slowing has been associated with cognitive decline in various neurological diseases, such as PD, Alzheimer's disease (AD), and epilepsy, indicating cortical involvement. A novel method revealed that this EEG slowing is composed of paroxysmal slow-wave events (PSWE) in AD and epilepsy, but in PD it has not been tested yet. Therefore, this study aimed to examine the presence of PSWE in PD as a biomarker for cortical involvement. Methods: 31 PD patients, 28 healthy controls, and 18 juvenile myoclonic epilepsy (JME) patients (served as positive control), underwent four minutes of resting-state EEG. Spectral analyses were performed to identify PSWEs in nine brain regions. Mixed-model analysis was used to compare between groups and brain regions. The correlation between PSWEs and PD duration was examined using Spearman's test. Results: No significant differences in the number of PSWEs were observed between PD patients and controls (p > 0.478) in all brain regions. In contrast, JME patients showed a higher number of PSWEs than healthy controls in specific brain regions (p < 0.023). Specifically in the PD group, we found that a higher number of PSWEs correlated with longer disease duration. Conclusions: This study is the first to examine the temporal characteristics of EEG slowing in PD by measuring the occurrence of PSWEs. Our findings indicate that PD patients who are cognitively intact do not have electrographic manifestations of cortical involvement. However, the correlation between PSWEs and disease duration may support future studies of repeated EEG recordings along the disease course to detect early signs of cortical involvement in PD.

[Idiopathic generalized epilepsies: Analysis of 101 patients]. / Epilepsias generalizadas idiopáticas: análisis de 101 pacientes.

INTRODUCTION: Idiopathic generalized epilepsies (IGI) are an electroclinical syndrome that includes four subsyndromes according to the ILAE 2017 classification. The long-term prognosis of these syndromes is uncertain due to the scarcity and heterogeneity of the studies. The objective of this study is to analyze the long-term prognosis of these syndromes, pharmacological treatment and the seizure recurrence. METHOD: Observational and retrospective study of a serie of patients diagnosed with EGI. Epidemiological variables, pharmacological treatment, freedom of seizures and recurrence after withdrawal of treatment were collected. RESULTS: We included 101 patients, the majority women (56.4%), with a median evolution of epilepsy of 17 years (interquartile range: 7-31). The most frequent syndrome was juvenile myoclonic epilepsy (46.5%), followed by epilepsy with generalized tonic-clonic seizures alone (25.7%), juvenile absence epilepsy (13.9%) and childhood absence epilepsy (13.9%). The 71.29% were on monotherapy and 20.79% on polytherapy, with significant differences between the different syndromes (P=.001). The most widely used drug was valproic acid. 39.6% presented seizure remission at 5 years, but we did not observe significant differences between the different syndromes (P=.982). The recurrence rate was 71.4% after withdrawal of treatment. CONCLUSION: Juvenile myoclonic epilepsy was the most frequent subtype of IGE. We observed significant differences in terms of polytherapy in the different syndromes, although not in the rates of remission of seizures at one year and at five years. The majority of patients with treatment withdrawal relapsed.

Seizure and social outcomes in patients with juvenile myoclonic epilepsy (JME).

OBJECTIVES: To investigate the seizure outcome in patients with juvenile myoclonic epilepsy (JME) and its associated factors. We also investigated the social outcome of these patients. METHODS: This was a retrospective study. All patients with a diagnosis of JME were studied at the outpatient epilepsy clinic at Shiraz University of Medical Sciences, Shiraz, Iran, from 2008 until 2019. In a phone call to the patients, at least 24 months after their diagnosis at our center, we investigated their current seizure control state and social status. RESULTS: One hundred and thirty-five patients were studied [92 women (68.1%) and 43 men (31.9%)]. Fifty-three patients (39.3%) were seizure-free (of all seizure types) during the past 12 months; 91 patients (67.4%) reported to be free of generalized tonic-clonic seizures. At the time of the follow-up call, 71 patients (52.6%) reported having a college education, 56 patients (41.5%) were employed, 87 patients (64.4%) were married, and 57 patients (42.2%) reported driving a motor vehicle in their routine daily lives. In total, 101 patients (74.8%) reported that their status (generally, and considering all the variables) was better than that it used to be five years ago. CONCLUSION: We may conclude that JME at tertiary referral centers is not as benign as it was suggested by some authors before. Furthermore, the employment status of patients with JME is significantly worse than that in the corresponding general populations. However, most patients with JME may enjoy marital status and educational levels comparable to those by the general public.

Seizure outcome trajectories in a well-defined cohort of newly diagnosed juvenile myoclonic epilepsy patients.

OBJECTIVE: To investigate the temporal course of medication response and associated prognostic factors in a cohort of juvenile myoclonic epilepsy (JME) patients over a long-term follow-up. MATERIALS AND METHODS: Data from 113 JME patients diagnosed according to recently proposed class II criteria were retrospectively reviewed. Early sustained remission was defined as 4-year seizure remission starting within 2 years from the first antiseizure medication (ASM) intake, as opposed to delayed sustained remission. Spontaneous relapse rate (ie, not related to ASM withdrawal) was also investigated, along with factors associated with seizure relapse. RESULTS: Four-year seizure remission was obtained by 76/113 (67.3%) subjects. Early sustained remission was achieved by 45/76 (59.2%) patients. Absence seizures were significantly associated with no-remission at multivariable multinomial logistic regression analysis. Catamenial seizures and earlier age at epilepsy onset significantly predicted delayed sustained remission. Spontaneous seizure relapse after 4-year remission occurred in 15.7% of patients with early sustained remission and in 35.5% of those with delayed sustained remission (p = 0.045). The most common concomitant factors for a spontaneous relapse were irregular lifestyle habits and pregnancy-related switch from valproate to another ASM. Patients with a history of catamenial seizures were more likely to experience a spontaneous generalized tonic-clonic seizure relapse after 4-year remission at univariable analysis. SIGNIFICANCE: Our data support the prognostic relevance of early medication response in JME patients. Furthermore, the prognostic significance of catamenial seizures and the impact of valproate switch on seizure relapse after a prolonged remission account for the challenging therapeutic management of women with childbearing potential.

Different circuitry dysfunction in drug-naive patients with juvenile myoclonic epilepsy and juvenile absence epilepsy.

RATIONALE: Juvenile myoclonic epilepsy (JME) and juvenile absence epilepsy (JAE) are generalized epileptic syndromes presenting in the same age range. To explore whether uneven network dysfunctions may underlie the two different phenotypes, we examined drug-naive patients with JME and JAE at the time of their earliest presentation. METHODS: Patients were recruited based on typical JME (n = 23) or JAE (n = 18) presentation and compared with 16 age-matched healthy subjects (HS). We analyzed their awake EEG signals by Partial Directed Coherence and graph indexes. RESULTS: Out-density and betweenness centrality values were different between groups. With respect to both JAE and HS, JME showed unbalanced out-density and out-strength in alpha and beta bands on central regions and reduced alpha out-strength from fronto-polar to occipital regions, correlating with photosensitivity. With respect to HS, JAE showed enhanced alpha out-density and out-strength on fronto-polar regions. In gamma band, JAE showed reduced Global/Local Efficiency and Clustering Coefficient with respect to HS, while JME showed more scattered values. CONCLUSIONS: Our data suggest that regional network changes in alpha and beta bands underlie the different presentation distinguishing JME and JAE resulting in motor vs non-motor seizures characterizing these two syndromes. Conversely, impaired gamma-activity within the network seems to be a non-local marker of defective inhibition.

Diagnostic and therapeutic approach to drug-resistant juvenile myoclonic epilepsy.

INTRODUCTION: Juvenile myoclonic epilepsy (JME), also known as Janz syndrome, is a common form of generalized epilepsy of presumed genetic origin representing up to 10% of all epilepsy cases. Despite adequate anti-seizure medication (ASM) treatment, seizures persist in one-third of JME patients. AREAS COVERED: A literature search was conducted using Pubmed search on the topics of drug-resistant JME. EXPERT OPINION: About 30% of JME patients are drug-resistant. Valproate (VPA) is considered the first-choice drug. In women of childbearing potential, levetiracetam (LEV) should represent the first-choice treatment. Alternative monotherapy or add-on therapy should be considered in subjects with resistant seizures after the exclusion of pseudo-drug resistance. The choice of the add-on ASM depends on the predominant seizure type. In subjects with persistent bilateral tonic-clonic seizures, LEV or lamotrigine should be firstly considered. In patients with difficult-to-treat myoclonic seizures, clonazepam or LEV are recommended. In case of persistent absences, ethosuximide should be considered. With appropriate selection and safeguards in place, VPA should remain available as an option in women of childbearing potential whose seizures are resistant to other treatments.

Juvenile myoclonic epilepsy: Long-term prognosis and risk factors.

OBJECTIVE: Our goal was to investigate the long-term clinical course of juvenile myoclonic epilepsy (JME) in a cohort of patients and to identify prognostic factors for refractoriness and seizure relapse after anti-seizure medications (ASMs) withdrawal. A literature review is also presented to consolidate and compare our findings with the previously reported cases. METHODS: We retrospectively studied a series of patients diagnosed with JME with 15 years or more of evolution. We collected clinical, neurophysiological and neuroimaging data from patients who met defined inclusion and exclusion criteria. RESULTS: Study involved 61 patients (65.5% female) with mean age at study of 37.6 years, and mean age at its outset of 14.8 years. Median follow-up was 31.0 years (mean 28.9, range 15-53). They presented more frequently with a combination of myoclonic and generalized tonic-clonic seizures (GTCS) (65.6%). Sixty-five percent of patients (n = 40) had a 5-year terminal remission with a mean age at last seizure of 27.4 years. Thirty-two percent of seizure-free patients (n = 13) withdrew ASMs: 6 out of 13 had a recurrence of the seizures while 7 remained seizure-free (mean age at ASMs withdrawal 21.0 versus 35.7 years, p < 0.05). In the multivariate model, a high GTCS frequency at onset (p = 0.026) was a prognostic factor of drug resistance. CONCLUSION: JME is often regarded as a benign epileptic syndrome, although a quarter of the individuals have refractory epilepsy. The possibility of withdrawing ASMs in patients who have been free of seizures over an extended time seems feasible.

A computational biomarker of juvenile myoclonic epilepsy from resting-state MEG.

OBJECTIVE: For people with idiopathic generalized epilepsy, functional networks derived from their resting-state scalp electrophysiological recordings have shown an inherent higher propensity to generate seizures than those from healthy controls when assessed using the concept of brain network ictogenicity (BNI). Herein we tested whether the BNI framework is applicable to resting-state magnetoencephalography (MEG) from people with juvenile myoclonic epilepsy (JME). METHODS: The BNI framework consists in deriving a functional network from apparently normal brain activity, placing a mathematical model of ictogenicity into the network and then computing how often such network generates seizures in silico. We considered data from 26 people with JME and 26 healthy controls. RESULTS: We found that resting-state MEG functional networks from people with JME are characterized by a higher propensity to generate seizures (i.e., higher BNI) than those from healthy controls. We found a classification accuracy of 73%. CONCLUSIONS: The BNI framework is applicable to MEG and was capable of differentiating people with epilepsy from healthy controls. SIGNIFICANCE: The BNI framework may be applied to resting-state MEG to aid in epilepsy diagnosis.

Long-term prognosis of juvenile myoclonic epilepsy: A systematic review searching for sex differences.

PURPOSE: Juvenile myoclonic epilepsy (JME), like other forms of idiopathic generalized epilepsy, shows a marked female predominance. However, few studies have specifically addressed the role of sex in its long-term prognosis. We performed a systematic review of the literature relevant to JME prognosis, focusing on sex-based differences in prognostic factors and outcome. METHODS: A comprehensive literature search of the PubMed and Scopus databases was performed, considering all articles up to April 2020 in which long-term prognosis in JME had been explored and sex differences in outcome or prognostic factors were specified. RESULTS: We included 25 articles published between 1984 and 2020. Sex differences in epilepsy outcome were explored by 21 of the 25 studies, but only three reported different outcomes in male vs female patients. All three found female sex to be associated with a later response to antiseizure medications, worse seizure control, and a higher risk of relapse in their entire study samples, which included JME patients. Eight studies found sex-based differences in possible predictors of long-term outcome: prolonged epileptiform EEG runs and the presence of eye closure sensitivity, both more frequent in women, were factors possibly linked to a poorer prognosis, as were praxis induction and generalized EEG asymmetric changes, which instead were more common in men. Valproate use, more frequent in men, was associated with a better outcome. CONCLUSION: Most studies do not highlight sex differences in JME prognosis. However, some sex specificities do emerge, especially with regard to particular reflex traits and EEG abnormalities. Finally, sex may condition therapeutic choices, and thus have a possible impact on long-term outcome.

Electroencephalographic findings in asymptomatic relatives of patients with juvenile myoclonic epilepsy: relationship with the degree of kinship.

INTRODUCTION: A prevalence of 1 to 71% of electroencephalogram (EEG) abnormalities has been reported in asymptomatic relatives of patients with juvenile myoclonic epilepsy (JME). OBJECTIVE: To determine the frequency of EEG abnormalities in asymptomatic relatives of patients with JME according to the degree of kinship. METHODS: Prospective, analytical study. First-, second, and third-degree relatives of patients with JME who agreed to participate and signed informed consent were included. The analysis was descriptive, bivariate. RESULTS: 209 asymptomatic relatives were included, out of which 115 (55%) were females and 94 (45%) were males, with a mean age of 35.9 ± 16.9 (range between 6 and 73 years). Forty-four (21.1%) relatives had abnormal EEGs. First-degree relatives (12%) had abnormalities more frequently in comparison with second- and third-degree relatives (p = 0.007). CONCLUSIONS: EEG abnormalities were observed in one third of asymptomatic relatives. It is important to highlight that there were more alterations among first-degree relatives. In the future, these findings might enable for the risk of clinically developing the disease to be estimated and for genetic counseling to be provided.

INTRODUCCIÓN: Se ha reportado de 1 a 71 % de prevalencia de anormalidades en el electroencefalograma (EEG) de familiares asintomáticos de pacientes con epilepsia mioclónica juvenil (EMJ). OBJETIVO: Determinar la frecuencia de anormalidades en el EEG en familiares asintomáticos de pacientes con EMJ de acuerdo con el grado de parentesco. MÉTODOS: Estudio prospectivo y analítico. Se incluyeron familiares de primer, segundo y tercer grado de pacientes con EMJ, quienes aceptaron participar y firmaron el consentimiento informado. El análisis fue descriptivo bivariado. RESULTADOS: Se incluyeron 209 familiares asintomáticos, 115 (55 %) mujeres y 94 (45 %) hombres, con edad media de 35.9 ± 16.9 (rango entre seis y 73 años); 44 familiares (21.1 %) tuvieron EEG anormal. Los familiares de primer grado (12 %) cursaron con mayor frecuencia con anormalidades en comparación con los de segundo y tercer grado (p = 0.007). CONCLUSIONES: Se observaron anormalidades en el EEG de una tercera parte de los familiares asintomáticos. Es importante resaltar que existieron más alteraciones entre los familiares de primer grado. En un futuro, estos hallazgos permitirán estimar el riesgo de desarrollar la enfermedad clínicamente y brindar consejo genético.

Potential role of brivaracetam in pediatric epilepsy.

Brivaracetam (BRV) is a new antiseizure medication (ASM) that is currently approved for adjunctive treatment in patients with focal onset seizures. Similarly to levetiracetam (LEV), BRV works by binding SV2A vesicles with a high affinity and a linear pharmacokinetic profile. Retrospective studies and randomized clinical trials have already proven the efficacy of BRV, even in patients who failed treatment with LEV. Most studies about the efficacy and tolerability conducted so far were performed in adult cohorts, whereas few studies have been performed in children; however, BRV was proven to be a useful ASM for pediatric focal epilepsies, with fewer studies and conflicting results among patients with generalized epilepsies and epileptic syndromes. Retention rates were high in the cohorts analyzed, and no serious treatment-emergent adverse events were reported in the majority of patients, with somnolence, drowsiness, irritability, aggression, and decreased appetite being the most frequently reported side effects. Although there are few original papers published on the subject so far, the analysis of the literature data demonstrated the efficacy and safety of BRV in pediatric patients, with more evidence for children aged 4-16 years with an onset of focal seizures. However, a positive response was also achieved in patients affected by encephalopathic epilepsies (eg, Jeavons' epilepsy, Dravet syndrome, Lennox-Gastaut syndrome, and juvenile myoclonic epilepsy), and ongoing studies are now testing BRV in order to widen its application to other forms of epilepsy and to test its effectiveness when used in monotherapy. This review aims to provide a comprehensive analysis of the literature surrounding the efficacy and tolerability of BRV for pediatric patients.

Automated Detection of Juvenile Myoclonic Epilepsy using CNN based Transfer Learning in Diffusion MRI.

Epilepsy is one of the largest neurological diseases in the world, and juvenile myoclonic epilepsy (JME) usually occurs in adolescents, giving patients tremendous burdens during growth, which really needs the early diagnosis. Advanced diffusion magnetic resonance imaging (MRI) could detect the subtle changes of the white matter, which could be a non-invasive early diagnosis biomarker for JME. Transfer learning can solve the problem of insufficient clinical samples, which could avoid overfitting and achieve a better detection effect. However, there is almost no research to detect JME combined with diffusion MRI and transfer learning. In this study, two advanced diffusion MRI methods, high angle resolved diffusion imaging (HARDI) and neurite orientation dispersion and density imaging (NODDI), were used to generate the connectivity matrix which can describe tiny changes in white matter. And three advanced convolutional neural networks (CNN) based transfer learning were applied to detect JME. A total of 30 participants (15 JME patients and 15 normal controls) were analyzed. Among the three CNN models, Inception_resnet_v2 based transfer learning is better at detecting JME than Inception_v3 and Inception_v4, indicating that the "short cut" connection can improve the ability to detect JME. Inception_resnet_v2 achieved to detect JME with the accuracy of 75.2% and the AUC of 0.839. The results support that diffusion MRI and CNN based transfer learning have the potential to improve the automated detection of JME.