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Progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous rare diseases. Over 70% of PME cases can now be molecularly solved. Known PME genes encode a variety of proteins, many involved in lysosomal and endosomal function. We performed whole-exome sequencing (WES) in 84 (78 unrelated) unsolved PME-affected individuals, with or without additional family members, to discover novel causes. We identified likely disease-causing variants in 24 out of 78 (31%) unrelated individuals, despite previous genetic analyses. The diagnostic yield was significantly higher for individuals studied as trios or families (14/28) versus singletons (10/50) (OR = 3.9, p value = 0.01, Fisher's exact test). The 24 likely solved cases of PME involved 18 genes. First, we found and functionally validated five heterozygous variants in NUS1 and DHDDS and a homozygous variant in ALG10, with no previous disease associations. All three genes are involved in dolichol-dependent protein glycosylation, a pathway not previously implicated in PME. Second, we independently validate SEMA6B as a dominant PME gene in two unrelated individuals. Third, in five families, we identified variants in established PME genes; three with intronic or copy-number changes (CLN6, GBA, NEU1) and two very rare causes (ASAH1, CERS1). Fourth, we found a group of genes usually associated with developmental and epileptic encephalopathies, but here, remarkably, presenting as PME, with or without prior developmental delay. Our systematic analysis of these cases suggests that the small residuum of unsolved cases will most likely be a collection of very rare, genetically heterogeneous etiologies.
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Dolicóis/metabolismo , Mutação/genética , Epilepsias Mioclônicas Progressivas/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Estudos de Coortes , Variações do Número de Cópias de DNA/genética , Feminino , Glicosilação , Humanos , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Epilepsias Mioclônicas Progressivas/classificação , Sequenciamento do Exoma , Adulto JovemRESUMO
OBJECTIVE: Familial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome; its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippocampal sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in individuals with FMTLE. METHODS: We studied 134 families with ≥ 2 first or second-degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one individual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls. RESULTS: The age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13-28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug-resistance and/or hippocampal sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007); in contrast, no enrichment for the febrile seizure PRS was observed. INTERPRETATION: FMTLE is a generally mild drug-responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub-genome-wide significant focal epilepsy genome-wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023;94:825-835.
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Epilepsia do Lobo Temporal , Convulsões Febris , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/diagnóstico , Estudo de Associação Genômica Ampla , Convulsões Febris/genética , Imageamento por Ressonância Magnética , Eletroencefalografia , Síndrome , HipocampoRESUMO
OBJECTIVE: Epilepsy with generalized tonic-clonic seizures alone (GTCA) is a common but poorly characterized idiopathic generalized epilepsy (IGE) syndrome. Hence, we investigated electroclinical features, seizure outcome, and antiseizure medication (ASM) withdrawal in a large cohort of GTCA patients. METHODS: In this multicenter retrospective study, GTCA patients defined according to the diagnostic criteria of the International League Against Epilepsy (2022) were included. We investigated prognostic patterns, drug resistance at the last visit, and ASM withdrawal, along with their prognostic factors. RESULTS: We included 247 patients with a median (interquartile range [IQR]) age at onset of 17 years (13-22) and a median follow-up duration of 10 years (IQR = 5-20). Drug resistance at the last visit was observed in 40 (16.3%) patients, whereas the median latency to achieve 2-year remission was 24 months (IQR = 24-46.5) with a median number of 1 (IQR = 1-2) ASM. During the long-term follow-up (i.e., 202 patients followed ≥5-years after the first ASM trial), 69 (34.3%) patients displayed an early remission pattern and 36 (17.9%) patients displayed a late remission pattern, whereas 16 (8%) and 73 (36.3%) individuals had no-remission and relapsing-remitting patterns, respectively. Catamenial seizures and morning predominance of generalized tonic-clonic seizures (GTCS) independently predicted drug resistance at the last visit according to multivariable logistic regression. Treatment withdrawal was attempted in 63 (25.5%) patients, with 59 (93.7%) of them having at least a 12-month follow-up after ASM discontinuation. At the last visit, 49 (83%) of those patients had experienced GTCS recurrence. A longer duration of seizure freedom was the only factor predicting a higher chance of successful ASM withdrawal according to multivariable Cox regression. SIGNIFICANCE: GTCA could be considered a relatively easily manageable IGE syndrome, with a low rate of drug resistance and a high prevalence of early response to treatment. Nevertheless, a considerable proportion of patients experience relapsing patterns of seizure control, highlighting the need for appropriate counseling and lifestyle recommendations.
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Epilepsias Parciais , Epilepsia Generalizada , Epilepsia Tônico-Clônica , Glucosídeos , Tiazóis , Humanos , Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Prognóstico , Estudos Retrospectivos , Epilepsias Parciais/tratamento farmacológico , Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/tratamento farmacológico , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Recidiva , Imunoglobulina E/uso terapêutico , Epilepsia Tônico-Clônica/tratamento farmacológicoRESUMO
Regulatory agencies have recently discouraged the prescription of topiramate (TPM) to women of childbearing potential with epilepsy due to growing evidence of the teratogenic and neurodevelopmental risks associated with its use during pregnancy. It remains, however, unclear whether the use of TPM in this population can be supported to some extent by its high effectiveness. In this multicenter, retrospective, cohort study performed at 22 epilepsy centers, we investigated the comparative effectiveness of TPM and levetiracetam (LEV) given as first-line antiseizure medication in a cohort of women of childbearing potential with idiopathic generalized epilepsy (IGE). A total of 336 participants were included, of whom 24 (7.1%) received TPM and 312 (92.9%) LEV. Women treated with TPM had significantly higher risks of treatment failure and treatment withdrawal and were less likely to achieve seizure freedom at 12 months compared to women treated with LEV. In conclusion, this study highlighted a low tendency among clinicians to use TPM in women of childbearing potential with IGE, anticipating the recently released restrictions on its use. Furthermore, the available data on effectiveness do not appear to support the use of TPM in this population.
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Epilepsia Generalizada , Epilepsia , Gravidez , Humanos , Feminino , Topiramato/efeitos adversos , Anticonvulsivantes/efeitos adversos , Teratogênicos/toxicidade , Estudos Retrospectivos , Estudos de Coortes , Frutose/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia Generalizada/tratamento farmacológico , Levetiracetam/efeitos adversos , Imunoglobulina E/uso terapêuticoRESUMO
OBJECTIVE: Women of childbearing age with juvenile absence epilepsy (JAE) face treatment challenges due to limited access to safe and effective anti-seizure medications (ASMs). In a previous study we compared the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) in women with idiopathic generalized epilepsy (IGE), highlighting a superiority of LEV in juvenile myoclonic epilepsy. In this study, we specifically reanalyzed, through a Bayesian approach and by expanding the previously published cohort, the comparative effectiveness of these ASMs as initial monotherapy in JAE. METHODS: We conducted a multicenter, retrospective, comparative effectiveness study on women of childbearing age diagnosed with JAE and prescribed LEV or LTG as the initial ASM. Inverse probability treatment weighting (IPTW) Bayesian Cox proportional hazard models were employed to evaluate treatment failure (TF) due to ineffectiveness and ASM retention. The patients' center of provenance and year of prescription were considered as random effect factors. Posterior probabilities and relative log-risk distribution were computed, and the distribution of posterior draws was analyzed to assess the evidence supporting LTG superiority over LEV. RESULTS: Of 123 patients, those treated with LTG (n = 67) demonstrated lower TF and higher ASM retention than those treated with LEV (n = 56), with the IPTW-weighted Bayesian Cox proportional hazards model showing a 99.2% posterior probability of LTG being superior on TF and a 99.5% probability on ASM retention. Additional analyses on ≥50% and ≥75% seizure reduction through IPTW-weighted Bayesian logistic regression largely confirmed these findings, whereas the two ASMs did not show evident differences in terms of seizure freedom. The two ASMs showed comparable safety profiles, with only a minority of patients discontinuing treatment due to side effects. SIGNIFICANCE: Bayesian reanalysis supports LTG as first-line monotherapy for JAE in women of childbearing age, emphasizing the importance of individualized treatment strategies in women with IGE. This study underscores the value of Bayesian methods in refining clinical research and treatment decisions.
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OBJECTIVE: There are few comparative data on the third-generation antiseizure medications (ASMs). We aimed to assess and compare the effectiveness of brivaracetam (BRV), eslicarbazepine acetate (ESL), lacosamide (LCM), and perampanel (PER) in people with epilepsy (PWE). Efficacy and tolerability were compared as secondary objectives. METHODS: This multicenter, retrospective study collected data from 22 Italian neurology/epilepsy centers. All adult PWE who started add-on treatment with one of the studied ASMs between January 2018 and October 2021 were included. Retention rate was established as effectiveness measure and described using Kaplan-Meier curves and the best fitting survival model. The responder status and the occurrence of adverse events (AEs) were used to evaluate efficacy and safety, respectively. The odds of AEs and drug efficacy were estimated by two multilevel logistic models. RESULTS: A total of 960 patients (52.92% females, median age = 43 years) met the inclusion criteria. They mainly suffered from structural epilepsy (52.29%) with monthly (46.2%) focal seizures (69.58%). Compared with LCM, all the studied ASMs had a higher dropout risk, statistically significant in the BRV levetiracetam (LEV)-naïve (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.17-3.29) and PER groups (HR = 1.64, 95% CI = 1.06-2.55). Women were at higher risk of discontinuing ESL (HR = 5.33, 95% CI = 1.71-16.61), as well as PER-treated patients with unknown epilepsy etiology versus those with structural etiology (HR = 1.74, 95% CI = 1.05-2.88). BRV with prior LEV therapy showed lower odds of efficacy (odds ratio [OR] = .08, 95% CI = .01-.48) versus LCM, whereas a higher efficacy was observed in women treated with BRV and LEV-naïve (OR = 10.32, 95% CI = 1.55-68.78) versus men. PER (OR = 6.93, 95% CI = 3.32-14.44) and BRV in LEV-naïve patients (OR = 6.80, 95% CI = 2.64-17.52) had a higher chance of AEs than LCM. SIGNIFICANCE: Comparative evidence from real-world studies may help clinicians to tailor treatments according to patients' demographic and clinical characteristics.
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Epilepsias Parciais , Epilepsia , Nitrilas , Piridonas , Masculino , Adulto , Humanos , Feminino , Anticonvulsivantes/efeitos adversos , Epilepsias Parciais/tratamento farmacológico , Estudos Retrospectivos , Levetiracetam/uso terapêutico , Lacosamida/uso terapêutico , Epilepsia/tratamento farmacológico , Pirrolidinonas/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 healthy controls across 22 sites from the global ENIGMA-Epilepsy working group. METHODS: A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in (1) all epilepsies, (2) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), (3) nonlesional temporal lobe epilepsy, (4) genetic generalized epilepsy, and (5) extratemporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness. RESULTS: Across all epilepsies, reduced total cerebellar volume was observed (d = .42). Maximum volume loss was observed in the corpus medullare (dmax = .49) and posterior lobe gray matter regions, including bilateral lobules VIIB (dmax = .47), crus I/II (dmax = .39), VIIIA (dmax = .45), and VIIIB (dmax = .40). Earlier age at seizure onset ( η ρ max 2 = .05) and longer epilepsy duration ( η ρ max 2 = .06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE, with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls. SIGNIFICANCE: We provide robust evidence of deep cerebellar and posterior lobe subregional gray matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in nonmotor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellar subregional damage into neurobiological models of epilepsy.
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Epilepsia do Lobo Temporal , Síndromes Epilépticas , Adulto , Humanos , Epilepsia do Lobo Temporal/complicações , Fenitoína , Estudos Transversais , Síndromes Epilépticas/complicações , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Convulsões/complicações , Imageamento por Ressonância Magnética/métodos , Atrofia/patologiaRESUMO
BACKGROUND AND PURPOSE: 'Dancing-like' semiology is extremely rare and described in few case reports. It is characterized by rhythmic, oscillatory movements of the pelvis and/or limbs during which the subject appears to be dancing. It has been associated with both the frontal and temporal epileptic zone; however, the possible network involved in these fascinating seizures is unclear. METHODS: The case of a 45-year-old woman suffering from drug-resistant focal epilepsy with multi-day seizures of bizarre semiology is described. A structural and perfusion magnetic resonance imaging study (interictal and peri-ictal) and video-electroencephalograms were carried out, and several home videos were employed. A vagal stimulator was implanted. RESULTS: Home videos documented the 'dancing' semiology of seizures better than video- electroencephalogram recordings. The imaging study revealed a focal frontal polymicrogyria with a peri-ictal cerebral blood flow increase at the perisylvian lesion foci. The combination of add-on cenobamate and vagal nerve stimulation resulted in complete seizure freedom. CONCLUSION: The unusual and complex dancing-like semiology observed during our patient's seizures adds to the repertoire of fascinating complex motor manifestations of frontal lobe epilepsy.
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Eletroencefalografia , Humanos , Feminino , Pessoa de Meia-Idade , Convulsões/fisiopatologia , Convulsões/etiologia , Convulsões/diagnóstico por imagem , Estimulação do Nervo Vago , Imageamento por Ressonância Magnética , Lobo Frontal/fisiopatologia , Lobo Frontal/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsia do Lobo Frontal/fisiopatologia , Epilepsia do Lobo Frontal/diagnóstico por imagem , Epilepsia do Lobo Frontal/diagnósticoRESUMO
BACKGROUND: Antiseizure medications remain the cornerstone of treatment for epilepsy, although a proportion of individuals with the condition will continue to experience seizures despite appropriate therapy. Treatment choices for epilepsy are based on variables related to both the individual patient and the available medications. Brivaracetam is a third-generation agent antiseizure medication. METHODS: We carried out a Delphi consensus exercise to define the role of brivaracetam in clinical practice and to provide guidance about its use as first add-on ASM and in selected clinical scenarios. A total of 15 consensus statements were drafted by an expert panel following review of the literature and all were approved in the first round of voting by panelists. The consensus indicated different clinical scenarios for which brivaracetam can be a good candidate for treatment, including first add-on use. RESULTS: Overall, brivaracetam was considered to have many advantageous characteristics that render it a suitable option for patients with focal epilepsy, including a fast onset of action, favorable pharmacokinetic profile with few drug-drug interactions, broad-spectrum activity, and being well tolerated across a range of doses. Brivaracetam is also associated with sustained clinical response and good tolerability in the long term. CONCLUSIONS: These characteristics also make it suitable as an early add-on for the elderly and for patients with post-stroke epilepsy or status epilepticus as highlighted by the present Delphi consensus.
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Anticonvulsivantes , Consenso , Técnica Delphi , Epilepsias Parciais , Pirrolidinonas , Humanos , Pirrolidinonas/uso terapêutico , Pirrolidinonas/administração & dosagem , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/administração & dosagem , Epilepsias Parciais/tratamento farmacológico , Quimioterapia CombinadaRESUMO
Although a striking female preponderance has been consistently reported in epilepsy with eyelid myoclonia (EEM), no study has specifically explored the variability of clinical presentation according to sex in this syndrome. Here, we aimed to investigate sex-specific electroclinical differences and prognostic determinants in EEM. Data from 267 EEM patients were retrospectively analyzed by the EEM Study Group, and a dedicated multivariable logistic regression analysis was developed separately for each sex. We found that females with EEM showed a significantly higher rate of persistence of photosensitivity and eye closure sensitivity at the last visit, along with a higher prevalence of migraine with/without aura, whereas males with EEM presented a higher rate of borderline intellectual functioning/intellectual disability. In female patients, multivariable logistic regression analysis revealed age at epilepsy onset, eyelid myoclonia status epilepticus, psychiatric comorbidities, and catamenial seizures as significant predictors of drug resistance. In male patients, a history of febrile seizures was the only predictor of drug resistance. Hence, our study reveals sex-specific differences in terms of both electroclinical features and prognostic factors. Our findings support the importance of a sex-based personalized approach in epilepsy care and research, especially in genetic generalized epilepsies.
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Epilepsia Tipo Ausência , Epilepsia Generalizada , Epilepsia , Deficiência Intelectual , Mioclonia , Humanos , Masculino , Feminino , Estudos Retrospectivos , Prognóstico , Eletroencefalografia , Epilepsia/complicações , Epilepsia/epidemiologia , Mioclonia/epidemiologia , PálpebrasRESUMO
PURPOSE: Status epilepticus (SE) is defined by abnormally prolonged seizures that may lead to brain damage and death. Our aim was to evaluate the efficacy and tolerability (effectiveness) of intravenous brivaracetam (BRV) as a second-line treatment. METHODS: Twenty-one patients (median age 68 years ± 17.28) were prospectively recruited between June 2019 and December 2022. Patients were treated with BRV (50-200 mg) as a second-line add-on therapy for SE. We evaluated the response of SE to the administration of BRV in terms of SE termination and recurrence of epileptic seizures at 6, 12, and 24 h, also monitoring safety. The first-line therapy was represented by intravenous benzodiazepines (mainly diazepam). RESULTS: Almost a quarter of patients had generalized seizures, whereas the vast majority (76.2%) presented focal seizures. In 52.4% of patients, the underlying cause was cerebrovascular. Fourteen (66.7%) patients displayed a good early response in the subsequent 6 h. At 12 and 24 h, 8 (38%) and 11 (52.4%) patients, respectively, did not present seizures. CONCLUSION: The present study highlights the potential of BRV when used as an early add-on therapy in SE, further confirming its good safety profile.
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Anticonvulsivantes , Estado Epiléptico , Humanos , Idoso , Anticonvulsivantes/efeitos adversos , Resultado do Tratamento , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/induzido quimicamente , Convulsões/tratamento farmacológico , Pirrolidinonas/efeitos adversos , Quimioterapia CombinadaRESUMO
The diagnosis of herpes simplex encephalitis (HSE) can present challenges for neurologists and neuroradiologists due to its variable clinical presentation and atypical radiological features. Brain magnetic resonance imaging (MRI) plays a crucial role by identifying some mimicking conditions, including ischemic strokes, through the accurate interpretation of specific sequences. This report highlights a case of misdiagnosed HSE, aiming to discuss the management of similar cases and underscore the relevance of MRI in the emergency setting.
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Encefalite por Herpes Simples , AVC Isquêmico , Humanos , Encefalite por Herpes Simples/diagnóstico por imagem , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/patologia , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , RadiografiaRESUMO
OBJECTIVE: Epilepsy with eyelid myoclonia (EEM) has been associated with marked clinical heterogeneity. Early epilepsy onset has been recently linked to lower chances of achieving sustained remission and to a less favorable neuropsychiatric outcome. However, much work is still needed to better delineate this epilepsy syndrome. METHODS: In this multicenter retrospective cohort study, we included 267 EEM patients from 9 countries. Data about electroclinical and demographic features, intellectual functioning, migraine with or without aura, family history of epilepsy and epilepsy syndromes in relatives were collected in each patient. The impact of age at epilepsy onset (AEO) on EEM clinical features was investigated, along with the distinctive clinical characteristics of patients showing sporadic myoclonia over body regions other than eyelids (body-MYO). RESULTS: Kernel density estimation revealed a trimodal distribution of AEO and Fisher-Jenks optimization disclosed three EEM subgroups: early-onset (EO-EEM), intermediate-onset (IO-EEM) and late-onset subgroup (LO-EEM). EO-EEM was associated with the highest rate of intellectual disability, antiseizure medication refractoriness and psychiatric comorbidities and with the lowest rate of family history of epilepsy. LO-EEM was associated with the highest proportion of body-MYO and generalized tonic-clonic seizures (GTCS), whereas IO-EEM had the lowest observed rate of additional findings. A family history of EEM was significantly more frequent in IO-EEM and LO-EEM compared with EO-EEM. In the subset of patients with body-MYO (58/267), we observed a significantly higher rate of migraine and GTCS but no relevant differences in other electroclinical features and seizure outcome. SIGNIFICANCE: Based on AEO, we identified consistent EEM subtypes characterized by distinct electroclinical and familial features. Our observations shed new light on the spectrum of clinical features of this generalized epilepsy syndrome and may help clinicians towards a more accurate classification and prognostic profiling of EEM patients.
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OBJECTIVE: Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multicenter cross-sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS) correlate with clinical features. METHODS: We extracted regional measures of cortical thickness, surface area, and subcortical brain volumes from T1-weighted (T1W) magnetic resonance imaging (MRI) scans collected by the ENIGMA-Epilepsy consortium, comprising 804 people with MTLE-HS and 1625 healthy controls from 25 centers. Features with a moderate case-control effect size (Cohen d ≥ .5) were used to train an event-based model (EBM), which estimates a sequence of disease-specific biomarker changes from cross-sectional data and assigns a biomarker-based fine-grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age at onset, and antiseizure medicine (ASM) resistance. RESULTS: In MTLE-HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume, and finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated with duration of illness (Spearman ρ = .293, p = 7.03 × 10-16 ), age at onset (ρ = -.18, p = 9.82 × 10-7 ), and ASM resistance (area under the curve = .59, p = .043, Mann-Whitney U test). However, associations were driven by cases assigned to EBM Stage 0, which represents MTLE-HS with mild or nondetectable abnormality on T1W MRI. SIGNIFICANCE: From cross-sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE-HS subjects in other cohorts and help establish connections between imaging-based progression staging and clinical features.
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Epilepsia do Lobo Temporal , Epilepsia , Atrofia/patologia , Biomarcadores , Estudos Transversais , Epilepsia/complicações , Epilepsia do Lobo Temporal/patologia , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Esclerose/complicaçõesRESUMO
BACKGROUND: We assessed levels of depression, anxiety, stress, anhedonia, somatization, psychological distress, sleep, and life quality in patients with mesial temporal lobe epilepsy (MTLE) after one year of containment measures started in Italy to stem the COVID-19 pandemic. METHODS: We consecutively enrolled 51 patients with MTLE, administering an online survey that compared the year before and after the COVID-19 propagation. We analyzed clinical data (e.g., seizure frequency, life quality) and neuropsychological assessment through Somatic Symptom Scale-8 (SSS-8), Beck Depression Inventory (BDI-2), State-Trait Anxiety Inventory (STAI-Y), Depression, Anxiety and Stress Scale (DASS-21), Pittsburgh Sleep Quality Index (PSQI), Snaith-Hamilton Pleasure Scale (SHAPS), Impact of Event Scale-Revised (IES-R). The BDI-2 and STAI-Y scores were compared to those acquired in the same patients before the COVID-19 outbreak. RESULTS: Comparing our population with MTLE before and after COVID-19 outbreak, we found a significant worsening in life quality (pâ¯=â¯0.03), SSS-8 (pâ¯=â¯0.001), BDI-2 (pâ¯=â¯0.032), and STAI-Y scores (pâ¯<â¯0.001). After one year of pandemic, 88.2% of patients obtained pathological scores at PSQI, 19.6% at SHAPS, 29.4% at IES-R. Reduction of life quality correlated with anxiety, depression, stress, and somatization. Higher levels of anhedonia correlated with stress, depression, and anxiety. Somatization correlated with depression, anxiety, and sleep quality. Distress levels correlated with anxiety, somatization, and depression. CONCLUSIONS: We demonstrated a significant worsening of depression, anxiety, life quality, and somatization in patients with MTLE after one year of COVID-19 beginning. Concomitantly, results suggest that the pandemic had a negative impact on sleep quality, psychological distress, and anhedonia, but not on epilepsy itself.
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COVID-19 , Epilepsia do Lobo Temporal , Ansiedade/epidemiologia , Ansiedade/etiologia , Ansiedade/psicologia , Depressão/epidemiologia , Depressão/etiologia , Depressão/psicologia , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/epidemiologia , Humanos , Estudos Longitudinais , Pandemias , SARS-CoV-2RESUMO
BACKGROUND: Identifying late epileptic seizures (LS) following cerebral venous thrombosis (CVT) can be useful for prognosis and management. We systematically reviewed the literature to identify risk factors for LS due to CVT. METHODS: We systematically searched PubMed, Scholar, and Scopus databases (May 2021) to identify studies reporting data on prevalence and risk factors for CVT-LS. The methodological quality was assessed with the Ottawa-Newcastle Scale. The risk of developing CVT-LS was summarized in meta-analyses and expressed as odds ratio (OR) and corresponding 95% confidence intervals (CIs) using random-effects models. RESULTS: Out of the 332 records retrieved, four studies were eventually included with a total of 1309 patients with CVT and 142 (11%) with CVT-LS. The most relevant predictors of CVT-LS were symptomatic seizures (OR 5.66, 95% CI 3.83-8.35), stupor/coma (OR 6.81, 95% CI 1.18-39.20), focal neurologic signs (OR 6.81, 95% CI 1.18-39.2), hemorrhagic component (OR 3.52, 95% CI 2.45-5.06), and superior sagittal sinus involvement (OR 1.52, 95% CI 1.04-2.21). CONCLUSION: There are several risk factors for CVT-LS that should be considered in clinical practice. Further high-quality studies are warranted to develop predictive models for individualized risk stratification and prediction of CVT-LS.
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Epilepsia , Trombose Intracraniana , Trombose Venosa , Epilepsia/complicações , Humanos , Trombose Intracraniana/complicações , Trombose Intracraniana/epidemiologia , Fatores de Risco , Convulsões/diagnóstico , Convulsões/epidemiologia , Convulsões/etiologia , Trombose Venosa/complicações , Trombose Venosa/epidemiologiaRESUMO
Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy; it is considered a network disorder associated with structural changes. Incomplete knowledge of the pathological changes in TLE complicates a therapeutic approach; indeed, 30 to 50% of patients with TLE are refractory to drug treatment. Non-coding RNAs (ncRNAs), acting as epigenetic factors, participate in the regulation of the pathophysiological processes of epilepsy and are dysregulated during epileptogenesis. Abnormal expression of ncRNA is observed in patients with epilepsy and in animal models of epilepsy. Furthermore, ncRNAs could also be used as biomarkers for the diagnosis and prognosis of treatment response in epilepsy. In summary, ncRNAs can represent important mechanisms and targets for the modulation of brain excitability and can provide information on pathomechanisms, biomarkers and novel therapies for epilepsy. In this review, we summarize the latest research advances concerning mainly molecular mechanisms, regulated by ncRNA, such as synaptic plasticity, inflammation and apoptosis, already associated with the pathogenesis of TLE. Moreover, we discuss the role of ncRNAs, such as microRNAs, long non-coding RNAs and circular RNAs, in the pathophysiology of epilepsy, highlighting their use as potential biomarkers for future therapeutic approaches.
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Epilepsia do Lobo Temporal , Epilepsia , MicroRNAs , RNA Longo não Codificante , Animais , Biomarcadores/metabolismo , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA não Traduzido/genética , RNA não Traduzido/metabolismoRESUMO
The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analysed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippocampal sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182) and non-lesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fibre tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P < 0.001). Across 'all epilepsies' lower fractional anisotropy was observed in most fibre tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. There were also less robust increases in mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Individuals with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced reductions in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and increased mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of diffusion abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibres in a large multicentre study of epilepsy. Overall, patients with epilepsy showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding more detailed insights into pathological substrates that may explain cognitive and psychiatric co-morbidities and be used to guide biomarker studies of treatment outcomes and/or genetic research.
Assuntos
Encéfalo/patologia , Síndromes Epilépticas/patologia , Substância Branca/patologia , Adulto , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To investigate neuroanatomical changes in patients with psychogenic nonepileptic seizures (PNES) compared to major depressive disorder (MDD) and healthy controls. METHODS: Forty-two drug-naïve PNES subjects and 25 patients with MDD, matched for demographic characteristics and level of depression (as measured by Beck Depression Inventory-II, BDI-II), were consecutively recruited. Patients performed an extensive neuropsychiatric assessment including: Hamilton Anxiety Rating Scale, Traumatic Experience Checklist, Dissociative Experiences Scale, Toronto Alexithymia Scale and Somatoform Dissociation Questionnaire (SDQ-20). All patients, together with 78 healthy matched controls, underwent 3T brain MRI followed by surface-based morphometry. RESULTS: Cortical thickness analysis revealed significant cortical thinning in bilateral medial orbitofrontal cortex (OFC) and left rostral anterior cingulate cortex (ACC) in patients with MDD compared to subjects with PNES and controls. Interestingly, increased thickness of the right pars triangularis was found in PNES subjects compared to controls. PNES showed higher scores in SDQ-20 (pâ¯<â¯0.001) compared to MDD, which was corroborated by neuroimaging data, where somatoform dissociation scores correlated with morphological changes in the left medial OFC. CONCLUSION: Our results show selective cortical thinning over the medial OFC in patients with PNES compared to wider regions of thinning in patients with MDD. Somatoform dissociation was the only psychopathological assessment significantly different in PNES and MDD.
Assuntos
Transtorno Depressivo Maior , Ansiedade , Transtornos de Ansiedade , Transtornos Dissociativos , Humanos , ConvulsõesRESUMO
OBJECTIVES: In the present study, we evaluated if the presence of sexual abuse in the clinical history of patients with psychogenic non-epileptic seizures (PNES) is associated with a different psychopathological profile. MATERIALS AND METHODS: In a consecutive population of 63 PNES patients, we compared two demographically and clinically matched groups of patients with (no. 15) and without (no. 48) a history of sexual abuse using a comprehensive psychopathological assessment (Beck Depression Inventory, Hamilton Anxiety Rating Scale, Dissociative Experience Scale, Somatoform Dissociation Questionnaire, and Toronto Alexithymia Scale). RESULTS: We found that the group of patients reporting sexual abuse is characterized by higher scores on Dissociative Experience Scale (p = 0.003) and Beck Depression Inventory (p = 0.001) with respect to the other group. No significant statistical differences in Hamilton Anxiety Rating Scale (p = 0.103), Toronto Alexithymia Scale (p = 0.137), and Somatoform Dissociation Questionnaire (p = 0.486) were captured. Moreover, we found that the negative effect on dissociate symptoms was also hampered by the increasing of seizure frequency. CONCLUSIONS: This study reinforces the importance of traumatic screening in the clinical spectrum of PNES in order to implement and improve specific therapeutic strategies.