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Frontiers in Neurology 2024To investigate whether changes occur in the dynamic functional connectivity (dFC) of motor cerebellum with cerebral cortex in juvenile myoclonic epilepsy (JME).
OBJECTIVE
To investigate whether changes occur in the dynamic functional connectivity (dFC) of motor cerebellum with cerebral cortex in juvenile myoclonic epilepsy (JME).
METHODS
We adopted resting-state electroencephalography-functional magnetic resonance imaging (EEG-fMRI) and a sliding-window approach to explore the dFC of motor cerebellum with cortex in 36 JME patients compared with 30 and age-matched health controls (HCs). The motor cerebellum was divided into five lobules (I-V, VI, VIIb, VIIIa, and VIIIb). Additionally, correlation analyses were conducted between the variability of dFC and clinical variables in the Juvenile Myoclonic Epilepsy (JME) group, such as disease duration, age at disease onset, and frequency score of myoclonic seizures.
RESULTS
Compared to HCs, the JME group presented increased dFC between the motor cerebellum with SMN and DMN. Specifically, connectivity between lobule VIIb and left precentral gyrus and right inferior parietal lobule (IPL); between lobule VIIIa and right inferior frontal gyrus (IFG) and left IPL; and between lobule VIIIb and left middle frontal gyrus (MFG), bilateral superior parietal gyrus (SPG), and left precuneus. In addition, within the JME group, the strength of dFC between lobule VIIIb and left precuneus was negatively ( = -0.424, = 0.025, Bonferroni correction) related with the frequency score of myoclonic seizures.
CONCLUSION
In patients with JME, there is a functional dysregulation between the motor cerebellum with DMN and SMN, and the variability of dynamic functional connectivity may be closely associated with the occurrence of motor symptoms in JME.
PubMed: 38903166
DOI: 10.3389/fneur.2024.1373125 -
International Journal of Molecular... May 2024, the gene encoding for the Nav1.1 channel, exhibits dominant interneuron-specific expression, whereby variants disrupting the channel's function affect the initiation...
, the gene encoding for the Nav1.1 channel, exhibits dominant interneuron-specific expression, whereby variants disrupting the channel's function affect the initiation and propagation of action potentials and neuronal excitability causing various types of epilepsy. Dravet syndrome (DS), the first described clinical presentation of SCN1A channelopathy, is characterized by severe myoclonic epilepsy in infancy (SMEI). Variants' characteristics and other genetic or epigenetic factors lead to extreme clinical heterogeneity, ranging from non-epileptic conditions to developmental and epileptic encephalopathy (DEE). This current study reports on findings from 343 patients referred by physicians in hospitals and tertiary care centers in Greece between 2017 and 2023. Positive family history for specific neurologic disorders was disclosed in 89 cases and the one common clinical feature was the onset of seizures, at a mean age of 17 months (range from birth to 15 years old). Most patients were specifically referred for investigation (Sanger Sequencing and MLPA) and only five for next generation sequencing. Twenty-six variants were detected, including nine novel causative variants (c.4567A>Τ, c.5564C>A, c.2176+2T>C, c.3646G>C, c.4331C>A, c.1130_1131delGAinsAC, c.1574_1580delCTGAGGA, c.4620A>G and c.5462A>C), and are herein presented, along with subsequent genotype-phenotype associations. The identification of novel variants complements SCN1A databases extending our expertise on genetic counseling and patient and family management including gene-based personalized interventions.
Topics: Humans; NAV1.1 Voltage-Gated Sodium Channel; Male; Female; Child; Adolescent; Infant; Phenotype; Child, Preschool; Epilepsy; Infant, Newborn; Mutation; Adult; Young Adult
PubMed: 38891831
DOI: 10.3390/ijms25115644 -
Frontiers in Pharmacology 2024In recent years, with the continuous expansion of the application scope of Tranexamic acid (TXA), its usage has surged. Despite numerous studies demonstrating its...
BACKGROUND
In recent years, with the continuous expansion of the application scope of Tranexamic acid (TXA), its usage has surged. Despite numerous studies demonstrating its powerful efficacy, concerns regarding its adverse reactions persist, necessitating comprehensive safety assessment. This study analyzed real-world data from the U.S. Food and Drug Administration to investigate TXA-related adverse events, aiming to elucidate its safety and optimize patient treatment.
METHODS
The adverse drug event data concerning TXA from 2004 Q1 to 2023 Q3 were collected. Following data standardization, a variety of signal quantification techniques, including the reporting odds ratios, proportional reporting ratios, Bayesian confidence propagation neural network, and empirical Bayes geometric mean were used for analysis.
RESULTS
After analyzing 16,692,026 adverse event reports, a total of 1,574 cases of adverse events related to TXA were identified, spanning 23 system organ classes and 307 preferred terms. In addition to the common thrombosis-related Vascular disorders ( = 386) and Cardiac disorders ( = 377), adverse reactions in the Nervous system disorders category were also observed ( = 785), including Myoclonus ( = 70), Status epilepticus ( = 43), and Myoclonic epilepsy ( = 17). Furthermore, this study uncovered adverse effects such as Renal cortical necrosis, Hepatic cyst rupture, and Vascular stent stenosis, which were not previously mentioned in the instructions. Although these occurred infrequently, they exhibited high signal strength. Both Retinal artery occlusion and Vascular stent thrombosis disorder were frequent and exhibited high signal strength as well. It is worth noting that 78 cases of adverse reactions were caused by confusion between incorrect product administration.
CONCLUSION
Our research suggests that TXA has some adverse reactions that are being overlooked. As a cornerstone medication in hemorrhage treatment, it's crucial to monitor, identify, and address these adverse reactions effectively.
PubMed: 38863974
DOI: 10.3389/fphar.2024.1388138 -
Seizure Jul 2024Epilepsy is a hallmark of IQSEC2-related encephalopathy within a phenotypic variability ranging between early onset epileptic and developmental encephalopathy and...
BACKGROUND
Epilepsy is a hallmark of IQSEC2-related encephalopathy within a phenotypic variability ranging between early onset epileptic and developmental encephalopathy and X-linked intellectual disability with epilepsy.
PATIENTS AND METHODS
Data including demographic aspects, gene variants, seizure semiology and timing, EEG features, neuroimaging and response to therapy were retrospectively collected in patients with IQSEC2-related epilepsy referring to 8 Italian tertiary centres.
RESULTS
The reported cohort included 11 patients (8 males and 3 females). Mean age at the onset of epilepsy was 3.90±2.80 years. No cases were reported in the first year of life. No specific epileptic syndromes were recognized. Predominant seizure-types in the age range 12-36 months included focal onset tonic seizures with impaired awareness, myoclonic seizures, and late onset spasms. Generalized motor seizures were predominant in patients between 3 and 6 years and between 12 and 18 years while focal motor seizures with impaired awareness were the most represented types between 6 and 12 years. No patients experienced status epilepticus. EEG patterns included a delayed maturation of EEG organization, irregular focal or diffuse slow activity, multifocal or diffuse epileptiform abnormalities. No structural epileptogenic lesions were detected at MRI. Valproate, lamotrigine, clobazam, topiramate and levetiracetam were the most used antiseizure medication. Complete seizure freedom was achieved only in 2 patients.
CONCLUSIONS
Onset of epilepsy after the first year of age, predominance of focal seizures with impaired awareness and generalized motor seizures, no pathognomonic underlying epileptic syndrome and infrequent occurrence of status epilepticus emerged as the main features of IQSEC2-related epilepsy phenotype.
Topics: Humans; Male; Female; Child; Child, Preschool; Adolescent; Retrospective Studies; Italy; Phenotype; Electroencephalography; Epilepsy; Guanine Nucleotide Exchange Factors; Infant; Anticonvulsants; Age of Onset
PubMed: 38851096
DOI: 10.1016/j.seizure.2024.06.002 -
Neurobiology of Disease Jun 2024Progressive myoclonus ataxia (PMA) is a rare clinical syndrome characterized by the presence of progressive myoclonus and ataxia, and can be accompanied by mild...
Progressive myoclonus ataxia (PMA) is a rare clinical syndrome characterized by the presence of progressive myoclonus and ataxia, and can be accompanied by mild cognitive impairment and infrequent epileptic seizures. This is the first study to describe the natural history of PMA and identify clinical, electrophysiological, and genetic features explaining the variability in disease progression. A Dutch cohort of consecutive patients meeting the criteria of the refined definition of PMA was included. The current phenotype was assessed during in-person consultation by movement disorders experts, and retrospective data was collected to describe disease presentation and progression, including brain imaging and therapy efficacy. Extensive genetic and electrophysiological tests were performed. The presence of cortical hyperexcitability was determined, by either the identification of a cortical correlate of myoclonic jerks with simultaneous electromyography-electroencephalography or a giant somatosensory evoked potential. We included 34 patients with PMA with a median disease duration of 15 years and a clear progressive course in most patients (76%). A molecular etiology was identified in 82% patients: ATM, CAMTA1, DHDDS, EBF3, GOSR2, ITPR1, KCNC3, NUS1, POLR1A, PRKCG, SEMA6B, SPTBN2, TPP1, ZMYND11, and a 12p13.32 deletion. The natural history is a rather homogenous onset of ataxia in the first two years of life followed by myoclonus in the first 5 years of life. Main accompanying neurological dysfunctions included cognitive impairment (62%), epilepsy (38%), autism spectrum disorder (27%), and behavioral problems (18%). Disease progression showed large variability ranging from an epilepsy free PMA phenotype (62%) to evolution towards a progressive myoclonus epilepsy (PME) phenotype (18%): the existence of a PMA-PME spectrum. Cortical hyperexcitability could be tested in 17 patients, and was present in 11 patients and supported cortical myoclonus. Interestingly, post-hoc analysis showed that an absence of cortical hyperexcitability, suggesting non-cortical myoclonus, was associated with the PMA-end of the spectrum with no epilepsy and milder myoclonus, independent of disease duration. An association between the underlying genetic defects and progression on the PMA-PME spectrum was observed. By describing the natural history of the largest cohort of published patients with PMA so far, we see a homogeneous onset with variable disease progression, in which phenotypic evolution to PME occurs in the minority. Genetic and electrophysiological features may be of prognostic value, especially the determination of cortical hyperexcitability. Furthermore, the identification of cortical and non-cortical myoclonus in PMA helps us gain insight in the underlying pathophysiology of myoclonus.
PubMed: 38844245
DOI: 10.1016/j.nbd.2024.106555 -
Cureus Apr 2024The objective of this case report is to describe and document a case of respiratory syncytial virus (RSV) in a pediatric patient with Dravet syndrome (DS), also known as...
The objective of this case report is to describe and document a case of respiratory syncytial virus (RSV) in a pediatric patient with Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy. Febrile seizures are often a complication in a patient with DS and can lead to status epilepticus, necessitating measures to prevent triggers such as fever, electrolyte imbalance, or dehydration. An increased awareness and understanding of DS can facilitate the identification of warning signs. A two-year-old female with a past medical history of DS with focal and generalized features presented to the pediatric emergency department (ED) with a five-day history of cough, fever, and decreased oral intake. The patient's parents accompanied her and expressed concerns regarding the risk of seizures associated with a rise in body temperature, as they had been alternating between acetaminophen and ibuprofen to manage her fever with a maximum recorded temperature of 101.5℉. She exhibited signs of increased work of breathing, necessitating the administration of supplemental oxygen via nasal cannula. Blood samples were obtained and resulted in the development of metabolic acidosis. A respiratory panel confirmed the presence of an RSV infection, promoting the administration of breathing treatment with albuterol and ipratropium bromide. The patient was admitted for dehydration and was started on ½ normal saline/potassium chloride 20 mEq at 40 mL/hr. Additionally, her home medication regimen was resumed to minimize the risk of seizures. Given the patient's complications and increased risk of seizure, she was transferred to higher-level care where her status improved after the placement of a percutaneous endoscopic gastrostomy (PEG). This case underscores the complexities involved in managing patients with DS, particularly when complicated by respiratory illness and electrolyte imbalances that can lower the seizure threshold. This patient received a combination of diet and medications to prevent seizures, as well as allow for recovery and correction of the underlying metabolic acidosis. The transfer to a higher level of care in this case was necessary to allow for the specialized resources and expertise needed to handle this case.
PubMed: 38826591
DOI: 10.7759/cureus.59405 -
Neurology. Genetics Jun 2024Epilepsies are associated with differences in cortical thickness (TH) and surface area (SA). However, the mechanisms underlying these relationships remain elusive. We...
BACKGROUND AND OBJECTIVES
Epilepsies are associated with differences in cortical thickness (TH) and surface area (SA). However, the mechanisms underlying these relationships remain elusive. We investigated the extent to which these phenotypes share genetic influences.
METHODS
We analyzed genome-wide association study data on common epilepsies (n = 69,995) and TH and SA (n = 32,877) using Gaussian mixture modeling MiXeR and conjunctional false discovery rate (conjFDR) analysis to quantify their shared genetic architecture and identify overlapping loci. We biologically interrogated the loci using a variety of resources and validated in independent samples.
RESULTS
The epilepsies (2.4 k-2.9 k variants) were more polygenic than both SA (1.8 k variants) and TH (1.3 k variants). Despite absent genome-wide genetic correlations, there was a substantial genetic overlap between SA and genetic generalized epilepsy (GGE) (1.1 k), all epilepsies (1.1 k), and juvenile myoclonic epilepsy (JME) (0.7 k), as well as between TH and GGE (0.8 k), all epilepsies (0.7 k), and JME (0.8 k), estimated with MiXeR. Furthermore, conjFDR analysis identified 15 GGE loci jointly associated with SA and 15 with TH, 3 loci shared between SA and childhood absence epilepsy, and 6 loci overlapping between SA and JME. 23 loci were novel for epilepsies and 11 for cortical morphology. We observed a high degree of sign concordance in the independent samples.
DISCUSSION
Our findings show extensive genetic overlap between generalized epilepsies and cortical morphology, indicating a complex genetic relationship with mixed-effect directions. The results suggest that shared genetic influences may contribute to cortical abnormalities in epilepsies.
PubMed: 38817246
DOI: 10.1212/NXG.0000000000200143 -
Journal of Integrative Neuroscience May 2024To explore the time-frequency structure and cross-scale coupling of electroencephalography (EEG) signals during seizure in juvenile myoclonic epilepsy (JME),...
BACKGROUND
To explore the time-frequency structure and cross-scale coupling of electroencephalography (EEG) signals during seizure in juvenile myoclonic epilepsy (JME), correlations between different leads, as well as dynamic evolution in epileptic discharge, progression and end of seizure were examined.
METHODS
EEG data were obtained for 10 subjects with JME and 10 normal controls and were decomposed using gauss continuous wavelet transform (CWT). The phase amplitude coupling (PAC) relationship between the 11th (4.57 Hz) and 17th (0.4 Hz) scale was investigated. Correlations were examined between the 11th and 17th scale EEG signals in different leads during seizure, using multi-scale cross correlation analysis.
RESULTS
The time-frequency structure of JME subjects showed strong rhythmic activity in the 11th and 17th scales and a close PAC was identified. Correlation analysis revealed that the ictal JME correlation first increased in the anterior head early in seizure and gradually expanded to the posterior head.
CONCLUSION
PAC was exhibited between the 11th and 17th scales during JME seizure. The results revealed that the correlation in the anterior leads was higher than the posterior leads. In the perictal period, the 17th scale EEG signal preceded the 11th scale signal and remained for some time after a seizure. This suggests that the 17th scale signal may play an important role in JME seizure.
Topics: Humans; Myoclonic Epilepsy, Juvenile; Electroencephalography; Male; Female; Young Adult; Adult; Adolescent; Wavelet Analysis; Brain; Brain Waves; Signal Processing, Computer-Assisted
PubMed: 38812390
DOI: 10.31083/j.jin2305097 -
Frontiers in Psychiatry 2024Epileptologists and psychiatrists have long observed a correlation between epilepsy and personality disorders (PDs) in their clinical practice. We conducted a... (Review)
Review
Epileptologists and psychiatrists have long observed a correlation between epilepsy and personality disorders (PDs) in their clinical practice. We conducted a comprehensive PubMed search looking for evidence on PDs in people with epilepsy (PwE). Out of over 600 results obtained without applying any time restriction, we selected only relevant studies (both analytical and descriptive) limited to English, Italian, French and Spanish languages, with a specific focus on PDs, rather than traits or symptoms, thus narrowing our search down to 23 eligible studies. PDs have been investigated in focal epilepsy (predominantly temporal lobe epilepsy - TLE), juvenile myoclonic epilepsy (JME) and psychogenic non-epileptic seizures (PNES), with heterogeneous methodology. Prevalence rates of PDs in focal epilepsy ranged from 18 to 42% in surgical candidates or post-surgical individuals, with Cluster C personality disorders or related traits and symptoms being most common. In JME, prevalence rates ranged from 8 to 23%, with no strong correlation with any specific PDs subtype. In PNES, prevalence rates ranged from 30 to 60%, with a notable association with Cluster B personality disorders, particularly borderline personality disorder. The presence of a PD in PwE, irrespective of subtype, complicates treatment management. However, substantial gaps of knowledge exist concerning the neurobiological substrate, effects of antiseizure medications and epilepsy surgery on concomitant PDs, all of which are indeed potential paths for future research.
PubMed: 38800062
DOI: 10.3389/fpsyt.2024.1404856 -
BioRxiv : the Preprint Server For... May 2024Mutations in human (ciliogenesis associated kinase 1) are linked to ciliopathies and epilepsy. Homozygous point and nonsense mutations that extinguish kinase activity...
Mutations in human (ciliogenesis associated kinase 1) are linked to ciliopathies and epilepsy. Homozygous point and nonsense mutations that extinguish kinase activity impair primary cilia function, whereas mutations outside the kinase domain are not well understood. Here, we produced a knock-in mouse equivalent of the human A615T variant identified in juvenile myoclonic epilepsy (JME). This residue is in the C-terminal region of CILK1 separate from the kinase domain. Mouse embryo fibroblasts (MEF) with either heterozygous or homozygous A612T mutant alleles exhibited a higher ciliation rate, shorter individual cilia and up-regulation of ciliary Hedgehog signaling. Thus, a single A612T mutant allele was sufficient to impair primary cilia and ciliary signaling in MEFs. Gene expression profiles of wild type versus mutant MEFs revealed profound changes in cilia-related molecular functions and biological processes. CILK1 A615T mutant protein was not increased to the same level as the wild type protein when co-expressed with scaffold protein KATNIP (katanin-interacting protein). Our data show that KATNIP regulation of a JME-associated single residue variant of CILK1 is compromised and this impairs the maintenance of primary cilia and Hedgehog signaling.
PubMed: 38798407
DOI: 10.1101/2024.05.14.594243