Association between glymphatic dysfunction and neurocognitive decline in patients with frontal lobe epilepsy.

Background: The glymphatic system is essential for the maintenance of brain homeostasis. It may be impaired in patients with epilepsy, but its association with neurocognitive function remains unknown. In this study, we aimed to elucidate the association between changes in the glymphatic system and neurocognitive function in individuals diagnosed with frontal lobe epilepsy (FLE). Methods: This retrospective case-control research engaged a group of patients with FLE and age-, sex-, and education-matched healthy volunteers. All participants were subjected to extensive neurocognitive assessments, complemented by structural and diffusion-weighted imaging. The "diffusion tensor imaging analysis along the perivascular space" (DTI-ALPS) index was computed to ascertain differences in glymphatic system function between the groups. Univariate and multivariate analyses were conducted to explore associations between DTI-ALPS, clinical characteristics in patients with FLE, and the neurocognitive test outcomes for both groups. Results: Twenty-five patients [mean age ± standard deviation (SD): 26.28±8.12 years, 10 females] with FLE and 22 healthy control (HC) participants (average age ± SD: 25.86±6.15 years, 11 females) were included. The average ALPS-index in FLE group was significantly lower than that in HC group (1.387±0.127 vs. 1.468±0.114, P=0.026). Further, significant neurocognitive difference was noted in Trail Making Test (TMT), Stroop Color and Word Test (SCWT), Digit Span Test (DST) and similarity test (ST) between the two groups. ALPS-index scores exhibited a negative correlation with disease duration in patients with FLE (r=-0.415, P=0.039), and positive correlations with the Forward Digit Span Test (FDST, r=0.399, P=0.005) and Similarity Test (ST, r=0.395, P=0.006) in both groups. After adjusting for potential confounders, DTI-ALPS maintained a significant independent association with FDST and ST. Conclusions: The findings of the current study suggest a possible association between impairment in glymphatic function and FLE. Furthermore, results indicate that glymphatic dysfunction, as assessed via DTI-ALPS index, appears to be related to neurocognitive decline in FLE.

The network is more important than the node: stereo-EEG evidence of neurocognitive networks in epilepsy.

Introduction: Neuropsychological assessment forms an integral part of the presurgical evaluation for patients with medically refractory focal epilepsy. Our understanding of cognitive impairment in epilepsy is based on seminal lesional studies that have demonstrated important structure-function relationships within the brain. However, a growing body of literature demonstrating heterogeneity in the cognitive profiles of patients with focal epilepsy (e.g., temporal lobe epilepsy; TLE) has led researchers to speculate that cognition may be impacted by regions outside the seizure onset zone, such as those involved in the interictal or "irritative" network. Methods: Neuropsychological data from 48 patients who underwent stereoelectroencephalography (SEEG) monitoring between 2012 and 2023 were reviewed. Patients were categorized based on the site of seizure onset, as well as their irritative network, to determine the impact of wider network activity on cognition. Neuropsychological data were compared with normative standards (i.e., z = 0), and between groups. Results: There were very few distinguishing cognitive features between patients when categorized based purely on the seizure onset zone (i.e., frontal lobe vs. temporal lobe epilepsy). In contrast, patients with localized irritative networks (i.e., frontal or temporal interictal epileptiform discharges [IEDs]) demonstrated more circumscribed profiles of impairment compared with those demonstrating wider irritative networks (i.e., frontotemporal IEDs). Furthermore, the directionality of propagation within the irritative network was found to influence the manifestations of cognitive impairment. Discussion: The findings suggest that neuropsychological assessment is sensitive to network activity beyond the site of seizure onset. As such, an overly focal interpretation may not accurately reflect the distribution of the underlying pathology. This has important implications for presurgical work-up in epilepsy, as well as subsequent surgical outcomes.

Nocturnal paroxysmal dystonia to sleep-related hypermotor epilepsy: A critical review.

Sleep-related paroxysmal motor episodes (SPMEs) have been described by various names, including nocturnal paroxysmal dystonia, nocturnal frontal lobe epilepsy (NFLE), and sleep-related hypermotor epilepsy. The underlying pathophysiology has been debated over the years, with these episodes assumed to be a form of paroxysmal dystonia or parasomnia versus a form of epilepsy. In most studies published on SPMEs and their variants (paroxysmal arousals, nocturnal paroxysmal dystonia, and episodic nocturnal wanderings) in the early 1990s, the authors speculated on the pathophysiology but did not commit to one idea. It was not until the mid-1990s that epilepsy became the leading prospect. We performed a narrative review of the major articles that have described this syndrome in a chronological fashion. We identified three eras, 1972-1993, 1994-1998, and 1999 to the present, each era marked by a landmark study. Our critical review of these early studies shows that the neurophysiological data supporting epilepsy as the sole basis for all SPME cases is very weak. In 1994-1995, a familial pattern of this syndrome was described and the term autosomal dominant NFLE was coined, with the authors claiming that all their patients had a form of frontal lobe epilepsy. With the exception of a few reference cases, the neurophysiological evidence that all patients had frontal lobe epilepsy was very weak. Compared to articles published on surgical series of frontal lobe epilepsy, the percentage of SPME cases with positive interictal/ictal electroencephalograms remained very low, seriously questioning the epileptic basis of the syndrome. Our critical review and analysis of the published literature shows that the evidence presented in favor of SPMEs being a homogenous focal epilepsy syndrome is very weak. Neurologists must recognize that SPMEs could be a form of movement disorder, parasomnia, or epilepsy. We recommend a pragmatic semiology-based classification of these episodes using the four-dimensional classification system.

Theory of mind in epilepsy.

Epilepsy is characterized by recurrent, chronic, and unprovoked seizures. Epilepsy has a significant negative impact on a patient's quality of life even if seizures are well controlled. In addition to the distress caused by seizures, patients with epilepsy (PwE) may suffer from cognitive impairment with serious social consequences such as poor interpersonal relationships, loss of employment, and reduced social networks. Pathological changes and functional connectivity abnormalities observed in PwE can disrupt the neural network responsible for the theory of mind. Theory of mind is the ability to attribute mental states to other people (intentions, beliefs, and emotions). It is a complex aspect of social cognition and includes cognitive and affective constructs. In recent years, numerous studies have assessed the relationship between social cognition, including the theory of mind, in PwE, and suggested impairment in this domain. Interventions targeting the theory of mind can be potentially helpful in improving the quality of life of PwE.

Case Report: Focal, generalized, or both: does generalized network involvement preclude successful epilepsy surgery?

We present two cases with focal seizures where scalp electroencephalography (EEG) had prominent features of a developmental and epileptic encephalopathy (DEE): Case 1: a 17-year-old male with complex motor seizures whose EEG demonstrated a slow spike-and-wave pattern and generalized paroxysmal fast activity (GPFA). Case 2: a 12-year-old male with startle-induced asymmetric tonic seizures whose EEG also had a slow spike-and-wave pattern. Both patients had intracranial EEG assessment, and focal cortical resections resulted in long-term seizure freedom and resolution of generalized findings. These cases exemplify patients with focal epilepsy with networks that share similarities to generalized epilepsies, and importantly, these features did not preclude curative epilepsy surgery.

CABP4 mutation in mice shows alteration in protein expression level and neuron discharge frequency.

Background: The calcium-binding protein 4 (CABP4) gene is a newly identified epilepsy-related gene that might be associated with a rare type of genetic focal epilepsy; that is, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In vitro, mutant CABP4 causes an increased inward flow voltage of calcium ions and a significant increase in the electrical signal discharge in hippocampus neurons; however, the role of CABP4 in epilepsy has not yet been specifically described, and there is not yet a CABP4 mutant animal model recapitulating the epilepsy phenotype. Methods: We introduced a human CABP4 missense mutation into the C57BL/6J mouse genome and generated a knock-in strain carrying a glycine-to-aspartic acid mutation in the gene. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were performed to evaluate the CABP4 expression level. Slice patch-clamp recording was carried out on pyramidal cells of prefrontal cortex layers II and III. Results: The CABP4G155D/+ mutant mice were viable and born at an expected Mendelian ratio. Surprisingly, the heterozygous (HE) mice did not display either an abnormal appearance or an overt seizure phenotype, and there was no statistically significant difference between the HE and wild-type (WT) mice in terms of overall messenger RNA (mRNA) and protein expression. However, the HE mutant mice showed an imbalance in the amount of protein expressed in the brain regions. Additionally, the patch-clamp recordings from the HE mouse layer II/III cortical pyramidal cells revealed an increase in the frequency of micro-excitatory post-synaptic currents (mEPSCs) but no change in the amplitude was observed. Conclusions: The findings of this study suggest that the CABP4 p.G155D mutation might be one of the mechanisms underlying seizure onset.

Heart rate variability as a preictal marker for determining the laterality of seizure onset zone in frontal lobe epilepsy.

Determining the laterality of the seizure onset zone is challenging in frontal lobe epilepsy (FLE) due to the rapid propagation of epileptic discharges to the contralateral hemisphere. There is hemispheric lateralization of autonomic control, and heart rate is modulated by interactions between the sympathetic and parasympathetic nervous systems. Based on this notion, the laterality of seizure foci in FLE might be determined using heart rate variability (HRV) parameters. We explored preictal markers for differentiating the laterality of seizure foci in FLE using HRV parameters. Twelve patients with FLE (6 right FLE and 6 left FLE) were included in the analyzes. A total of 551 (460 left FLE and 91 right FLE) 1-min epoch electrocardiography data were used for HRV analysis. We found that most HRV parameters differed between the left and right FLE groups. Among the machine learning algorithms applied in this study, the light gradient boosting machine was the most accurate, with an AUC value of 0.983 and a classification accuracy of 0.961. Our findings suggest that HRV parameter-based laterality determination models can be convenient and effective tools in clinical settings. Considering that heart rate can be easily measured in real time with a wearable device, our proposed method can be applied to a closed-loop device as a real-time monitoring tool for determining the side of stimulation.

Neuropsychological outcome after frontal surgery for pediatric-onset epilepsy with focal cortical dysplasia in adolescent and young adult.

OBJECTIVE: We investigated neuropsychological outcome in patients with pharmacoresistant pediatric-onset epilepsy caused by focal cortical dysplasia (FCD), who underwent frontal lobe resection during adolescence and young adulthood. METHODS: Twenty-seven patients were studied, comprising 15 patients who underwent language-dominant side resection (LDR) and 12 patients who had languagenondominant side resection (n-LDR). We evaluated intelligence (language function, arithmetic ability, working memory, processing speed, visuo-spatial reasoning), executive function, and memory in these patients before and two years after resection surgery. We analyzed the relationship between neuropsychological outcome and resected regions (side of language dominance and location). RESULTS: Although 75% of the patients showed improvement or no change in individual neuropsychological tests after surgical intervention, 25% showed decline. The cognitive tests that showed improvement or decline varied between LDR and n-LDR. In patients who had LDR, decline was observed in Vocabulary and Phonemic Fluency (both 5/15 patients), especially after resection of ventrolateral frontal cortex, and improvement was observed in WCST-Category (7/14 patients), Block Design (6/15 patients), Digit Symbol (4/15 patients), and Delayed Recall (3/9 patients). In patients who underwent n-LDR, improvement was observed in Vocabulary (3/12 patients), but decline was observed in Block Design (2/9 patients), and WCST-Category (2/9 patients) after resection of dorsolateral frontal cortex; and Arithmetic (3/10 patients) declined after resection of dorsolateral frontal cortex or ventrolateral frontal cortex. General Memory (3/8 patients), Visual Memory (3/8 patients), Delayed Recall (3/8 patients), Verbal Memory (2/9 patients), and Digit Symbol (3/12 patients) also declined after n-LDR. CONCLUSION: Postoperative changes in cognitive function varied depending on the location and side of the resection. For precise presurgical prediction of neuropsychological outcome after surgery, further prospective studies are needed to accumulate data of cognitive changes in relation to the resection site.

MRI evidence for material-specific encoding deficits and mesial-temporal alterations in presurgical frontal lobe epilepsy patients.

OBJECTIVE: Neuroimaging studies reveal frontal lobe (FL) contributions to memory encoding. Accordingly, memory impairments are documented in frontal lobe epilepsy (FLE). Still, little is known about the structural or functional correlates of such impairments. Particularly, material specificity of functional changes in cerebral activity during memory encoding in FLE is unclear. METHODS: We compared 24 FLE patients (15 right-sided) undergoing presurgical evaluation with 30 healthy controls on a memory fMRI-paradigm of learning scenes, faces, and words followed by an out-of-scanner recognition task as well as regarding their mesial temporal lobe (mTL) volumes. We also addressed effects of FLE lateralization and performance level (normal vs. low). RESULTS: FLE patients had poorer memory performance and larger left hippocampal volumes than controls. Volume increase seemed, however, irrelevant or even dysfunctional for memory performance. Further, functional changes in FLE patients were right-sided for scenes and faces and bilateral for words. In detail, during face encoding, FLE patients had, regardless of their performance level, decreased mTL activation, while during scene and word encoding only low performing FLE patients had decreased mTL along with decreased FL activation. Intact verbal memory performance was associated with higher right frontal activation in FLE patients but not in controls. SIGNIFICANCE: Pharmacoresistant FLE has a distinct functional and structural impact on the mTL. Effects vary with the encoded material and patients' performance levels. Thus, in addition to the direct effect of the FL, memory impairment in FLE is presumably to a large part due to functional mTL changes triggered by disrupted FL networks. PLAIN LANGUAGE SUMMARY: Frontal lobe epilepsy (FLE) patients may suffer from memory impairment. Therefore, we asked patients to perform a memory task while their brain was scanned by MRI in order to investigate possible changes in brain activation during learning. FLE patients showed changes in brain activation during learning and also structural changes in the mesial temporal lobe, which is a brain region especially relevant for learning but not the origin of the seizures in FLE. We conclude that FLE leads to widespread changes that contribute to FLE patients' memory impairment.

Cathodal HD-tDCS and attention: A study on patients with intractable left lateral frontal lobe epilepsy.

OBJECTIVE: Defects in the attentional network in patients with epilepsy are influenced by factors such as the location of epileptic foci. Examining the impact of cathodal high-definition transcranial direct current stimulation (HD-tDCS) on attention components could provide insights into potential attention-related side effects of tDCS. This study aimed to investigate the effect of cathodal HD-tDCS on interictal epileptiform discharges (IEDs), auditory/visual (A/V) attention components, and reaction time (RT) in patients with intractable focal left lateral frontal lobe epilepsy (LFLE). METHODS: To control for variations in individual epilepsy syndrome, 12 adult participants diagnosed with drug-resistant left LFLE with focal cortical IEDs on C3 underwent repeated measurements at pretest, posttest, and follow-up steps. 4 × 1 ring electrodes (cathode on C3 and four anodes on F3, P3, T3, and Cz) delivered 2 mA DC for 20 min per session for 10 consecutive days. The integrated visual and auditory continuous performance test (IVA+) assessed the A/V attention components and RT. One-way repeated-measure ANOVA was used. RESULTS: The findings suggest a significant effect in reducing IEDs. The IVA+ results showed a significant improvement in auditory divided attention and visual selective and focused attention (p < 0.05). In the follow-up, these changes demonstrated lasting efficacy. A/V speed scales increased (p < 0.05), showing a significant decrease in reaction time. CONCLUSIONS: Cathodal HD-tDCS significantly reduced IEDs and improved the components of auditory divided attention, visual focused attention, and visual selective attention, with a reduction in patient reaction time. A significant lasting, side-effect-free positive effect was observed for up to one month after the intervention.