Epilepsy is well-recognized as a disorder of brain networks. There is a growing body of research to identify critical nodes within dynamic epileptic networks with the aim to target therapies that ...halt the onset and propagation of seizures. In parallel, intracranial neuromodulation, including deep brain stimulation and responsive neurostimulation, are well-established and expanding as therapies to reduce seizures in adults with focal-onset epilepsy; and there is emerging evidence for their efficacy in children and generalized-onset seizure disorders. The convergence of these advancing fields is driving an era of 'network-guided neuromodulation' for epilepsy. In this review, we distil the current literature on network mechanisms underlying neurostimulation for epilepsy. We discuss the modulation of key 'propagation points' in the epileptogenic network, focusing primarily on thalamic nuclei targeted in current clinical practice. These include (i) the anterior nucleus of thalamus, now a clinically approved and targeted site for open loop stimulation, and increasingly targeted for responsive neurostimulation; and (ii) the centromedian nucleus of the thalamus, a target for both deep brain stimulation and responsive neurostimulation in generalized-onset epilepsies. We discuss briefly the networks associated with other emerging neuromodulation targets, such as the pulvinar of the thalamus, piriform cortex, septal area, subthalamic nucleus, cerebellum and others. We report synergistic findings garnered from multiple modalities of investigation that have revealed structural and functional networks associated with these propagation points - including scalp and invasive EEG, and diffusion and functional MRI. We also report on intracranial recordings from implanted devices which provide us data on the dynamic networks we are aiming to modulate. Finally, we review the continuing evolution of network-guided neuromodulation for epilepsy to accelerate progress towards two translational goals: (i) to use pre-surgical network analyses to determine patient candidacy for neurostimulation for epilepsy by providing network biomarkers that predict efficacy; and (ii) to deliver precise, personalized and effective antiepileptic stimulation to prevent and arrest seizure propagation through mapping and modulation of each patients' individual epileptogenic networks.
Around 1 in 5 children will have associated symptoms Refer patients with a confirmed or suspected diagnosis to a neurosurgeon for further investigations and management The key investigation is ...magnetic resonance imaging of the brain and whole spine. Lumbar puncture must not be performed in these patients Offer support for long term follow-up and management of symptoms. The modes of inheritance are not yet understood, but a familial association has been reported in 3-12% of patients with CM1.26 In a small neuroimaging study, 21% of first degree relatives of patients with CM1 were detected with asymptomatic CM1.5 There is not enough evidence to suggest variation by sex or ethnicity or influence of any modifiable or lifestyle risk factors. A single centre, retrospective study of 2813 patients with CM1 found that 12.7% had a hereditary connective tissue disorder, of which the hypermobility type of Ehlers-Danlos was the most common (5% of the cohort).15 Other conditions associated with CM1 include craniofacial conditions (such as Crouzon’s syndrome and Apert’s syndrome), hormonal disorders (such as growth hormone deficiency and acromegaly), bone disorders (such as Paget’s disease and rickets), and other genetic disorders (such as neurofibromatosis type 1 and cystic fibrosis), but the mechanisms are unclear.
Objective
The accurate prediction of seizure freedom after epilepsy surgery remains challenging. We investigated if (1) training more complex models, (2) recruiting larger sample sizes, or (3) using ...data‐driven selection of clinical predictors would improve our ability to predict postoperative seizure outcome using clinical features. We also conducted the first substantial external validation of a machine learning model trained to predict postoperative seizure outcome.
Methods
We performed a retrospective cohort study of 797 children who had undergone resective or disconnective epilepsy surgery at a tertiary center. We extracted patient information from medical records and trained three models—a logistic regression, a multilayer perceptron, and an XGBoost model—to predict 1‐year postoperative seizure outcome on our data set. We evaluated the performance of a recently published XGBoost model on the same patients. We further investigated the impact of sample size on model performance, using learning curve analysis to estimate performance at samples up to N = 2000. Finally, we examined the impact of predictor selection on model performance.
Results
Our logistic regression achieved an accuracy of 72% (95% confidence interval CI = 68%–75%, area under the curve AUC = .72), whereas our multilayer perceptron and XGBoost both achieved accuracies of 71% (95% CIMLP = 67%–74%, AUCMLP = .70; 95% CIXGBoost own = 68%–75%, AUCXGBoost own = .70). There was no significant difference in performance between our three models (all p > .4) and they all performed better than the external XGBoost, which achieved an accuracy of 63% (95% CI = 59%–67%, AUC = .62; pLR = .005, pMLP = .01, pXGBoost own = .01) on our data. All models showed improved performance with increasing sample size, but limited improvements beyond our current sample. The best model performance was achieved with data‐driven feature selection.
Significance
We show that neither the deployment of complex machine learning models nor the assembly of thousands of patients alone is likely to generate significant improvements in our ability to predict postoperative seizure freedom. We instead propose that improved feature selection alongside collaboration, data standardization, and model sharing is required to advance the field.
•Functional connectivity approaches show promise in uncovering epilepsy-related changes.•Nevertheless, brain wide connectivity changes lack consistency across studies.•The most consistent finding is ...reduced interhemispheric connectivity.•Focal epilepsy disrupts functional connectivity locally and in brain wide networks.
Epilepsy is increasingly recognised as a brain network disorder and many studies have investigated functional connectivity (FC) in children with epilepsy using functional MRI (fMRI). This systematic review of fMRI studies, published up to November 2023, investigated profiles of FC changes and their clinical relevance in children with focal epilepsy compared to healthy controls. A literature search in PubMed and Web of Science yielded 62 articles. We categorised the results into three groups: 1) differences in correlation-based FC between patients and controls; 2) differences in other FC measures between patients and controls; and 3) associations between FC and disease variables (for example, age of onset), cognitive and seizure outcomes. Studies revealed either increased or decreased FC across multiple brain regions in children with focal epilepsy. However, findings lacked consistency: conflicting FC alterations (decreased and increased FC) co-existed within or between brain regions across all focal epilepsy groups. The studies demonstrated overall that 1) interhemispheric connections often displayed abnormal connectivity and 2) connectivity within and between canonical functional networks was decreased, particularly for the default mode network. Focal epilepsy disrupted FC in children both locally (e.g., seizure-onset zones, or within-brain subnetworks) and globally (e.g., whole-brain network architecture). The wide variety of FC study methodologies limits clinical application of the results. Future research should employ longitudinal designs to understand the evolution of brain networks during the disease course and explore the potential of FC biomarkers for predicting cognitive and postsurgical seizure outcomes.
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•User-friendly semi-automatic perivascular spaces segmentation method is efficient in quantifying PVS from conventional T2-weighted MRI.•Semi-automatically determined perivascular spaces count and ...volume agree with visual ratings.•Semi-automatic perivascular spaces assessment proves useful for clinical studies and MRI protocols.•Rigorous statistical analysis evaluating the new method on a longitudinal stroke sample.•Potential for use in studies of cerebral small vessel disease and in a range of other neurological diseases.
Perivascular spaces (PVS) are associated with ageing, cerebral small vessel disease, inflammation and increased blood brain barrier permeability. Most studies to date use visual rating scales to assess PVS, but these are prone to observer variation.
We developed a semi-automatic computational method that extracts PVS on bilateral ovoid basal ganglia (BG) regions on intensity-normalised T2-weighted magnetic resonance images. It uses Analyze™10.0 and was applied to 100 mild stroke patients’ datasets. We used linear regression to test association between BGPVS count, volume and visual rating scores; and between BGPVS count & volume, white matter hyperintensity (WMH) rating scores (periventricular: PVH; deep: DWMH) & volume, atrophy rating scores and brain volume.
In the 100 patients WMH ranged from 0.4 to 119ml, and total brain tissue volume from 0.65 to 1.45l. BGPVS volume increased with BGPVS count (67.27, 95%CI 57.93 to 76.60, p<0.001). BGPVS count was positively associated with WMH visual rating (PVH: 2.20, 95%CI 1.22 to 3.18, p<0.001; DWMH: 1.92, 95%CI 0.99 to 2.85, p<0.001), WMH volume (0.065, 95%CI 0.034 to 0.096, p<0.001), and whole brain atrophy visual rating (1.01, 95%CI 0.49 to 1.53, p<0.001). BGPVS count increased as brain volume (as % of ICV) decreased (−0.33, 95%CI −0.53 to −0.13, p=0.002).
BGPVS count and volume increased with the overall increase of BGPVS visual scores (2.11, 95%CI 1.36 to 2.86 for count and 0.022, 95%CI 0.012 to 0.031 for volume, p<0.001). Distributions for PVS count and visual scores were also similar.
This semi-automatic method is applicable to clinical protocols and offers quantitative surrogates for PVS load. It shows good agreement with a visual rating scale and confirmed that BGPVS are associated with WMH and atrophy measurements.
A third of patients with epilepsy continue to have seizures despite receiving adequate antiseizure medication. Transcranial direct current stimulation (tDCS) might be a viable adjunct treatment ...option, having been shown to reduce epileptic seizures in patients with focal epilepsy. Evidence for the use of tDCS in genetic generalized epilepsy (GGE) is scarce. We aimed to establish the feasibility of applying tDCS during fMRI in patients with GGE to study the acute neuromodulatory effects of tDCS, particularly on sensorimotor network activity.
Seven healthy controls and three patients with GGE received tDCS with simultaneous fMRI acquisition while watching a movie. Three tDCS conditions were applied: anodal, cathodal and sham. Periods of 60 s without stimulation were applied between each stimulation condition. Changes in sensorimotor cortex connectivity were evaluated by calculating the mean degree centrality across eight nodes of the sensorimotor cortex defined by the Automated Anatomical Labeling atlas (primary motor cortex (precentral left and right), supplementary motor area (left and right), mid-cingulum (left and right), postcentral gyrus (left and right)), across each of the conditions, for each participant.
Simultaneous tDCS-fMRI was well tolerated in both healthy controls and patients without adverse effects. Anodal and cathodal stimulation reduced mean degree centrality of the sensorimotor network (Friedman's ANOVA with Dunn's multiple comparisons test; adjusted
= 0.02 and
= 0.03 respectively). Mean degree connectivity of the sensorimotor network during the sham condition was not different to the rest condition (adjusted
= 0.94).
Applying tDCS during fMRI was shown to be feasible and safe in a small group of patients with GGE. Anodal and cathodal stimulation caused a significant reduction in network connectivity of the sensorimotor cortex across participants. This initial research supports the feasibility of using fMRI to guide and understand network modulation by tDCS that might facilitate its clinical application in GGE in the future.
Neurosurgery is a safe and effective form of treatment for select children with drug-resistant epilepsy. Still, there is concern that it remains underutilized, and that seizure freedom rates have not ...improved over time. We investigated referral and surgical practices, patient characteristics, and postoperative outcomes over the past two decades.
We performed a retrospective cohort study of children referred for epilepsy surgery at a tertiary center between 2000 and 2018. We extracted information from medical records and analyzed temporal trends using regression analyses.
A total of 1443 children were evaluated for surgery. Of these, 859 (402 females) underwent surgical resection or disconnection at a median age of 8.5 years (interquartile range IQR = 4.6-13.4). Excluding palliative procedures, 67% of patients were seizure-free and 15% were on no antiseizure medication (ASM) at 1-year follow-up. There was an annual increase in the number of referrals (7%, 95% confidence interval CI = 5.3-8.6; p < .001) and surgeries (4% 95% CI = 2.9-5.6, p < .001) over time. Duration of epilepsy and total number of different ASMs trialed from epilepsy onset to surgery were, however, unchanged, and continued to exceed guidelines. Seizure freedom rates were also unchanged overall but showed improvement (odds ratio OR 1.09, 95% CI = 1.01-1.18; p = .027) after adjustment for an observed increase in complex cases. Children who underwent surgery more recently were more likely to be off ASMs postoperatively (OR 1.04, 95% CI = 1.01-1.08; p = .013). There was a 17% annual increase (95% CI = 8.4-28.4, p < .001) in children identified to have a genetic cause of epilepsy, which was associated with poor outcome.
Children with drug-resistant epilepsy continue to be put forward for surgery late, despite national and international guidelines urging prompt referral. Seizure freedom rates have improved over the past decades, but only after adjustment for a concurrent increase in complex cases. Finally, genetic testing in epilepsy surgery patients has expanded considerably over time and shows promise in identifying patients in whom surgery is less likely to be successful.
Background
Idiopathic intracranial hypertension (IIH) has an estimated incidence of one to three people per 100,000 people per year, and occurs most commonly in obese, young women. IIH is associated ...with severe morbidity, notably due to a significant threat to sight and severe headache. Several different management options have been proposed. Conservative measures centre on weight loss. Pharmacological therapy includes use of diuretics. Refractory and sight‐threatening cases demand surgical intervention, most often in the form of cerebrospinal fluid (CSF) diversion or optic nerve sheath fenestration. Other treatments include venous sinus stenting and bariatric surgery.
Objectives
To assess the effects of any intervention for IIH in any patient group.
Search methods
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015 Issue 6), Ovid MEDLINE, Ovid MEDLINE In‐Process and Other Non‐Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2015), EMBASE (January 1980 to July 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 22 July 2015.
Selection criteria
We included only randomised controlled trials (RCTs) in which any intervention was compared to placebo, or to another form of treatment, for people with a clinical diagnosis of IIH.
Data collection and analysis
Two review authors independently assessed the search results for trials to be included in the review. We resolved any discrepancies by third party decision.
Main results
We identified two completed RCTs (enrolling a total of 211 participants and conducted in the UK and US) and two ongoing trials that met the inclusion criteria. Both completed trials compared acetazolamide to placebo, in conjunction with a weight loss intervention in both groups. Attrition bias was a problem in both trials with high loss to follow‐up, in one study this loss to follow‐up occurred particularly in the acetazolamide arm. One trial was unmasked and we judged it to be at risk of performance and detection bias.
In these studies, change in visual acuity was similar in the treatment and control groups as measured by logMAR acuity. In one study people in the acetalomazide group had a similar change in logMAR acuity compared to the placebo group between baseline and 12 months in the right eye (MD 0.04 logMAR, 95% CI ‐0.08 to 0.16) and left eye (MD 0.03 logMAR, 95% CI ‐0.09 to 0.15). In the other study people in the acetalomazide group had a similar change in vision over six months compared with people in the placebo group (mean difference in change in letters read was 0.01 (95% CI ‐1.45 to 1.46). One study reported no cases of visual loss in 21 people treated with acetalomazide compared to 2/20 cases in the placebo group (odds ratio 0.17, 95% CI 0.01, 3.82).
The prespecified outcome for this review was reduction in CSF pressure to normal levels which was not reported by the two trials. One trial reported that, in a subsample of 85 participants who agreed to lumbar puncture at 6 months, people in the acetalomazide group on average had a greater reduction in CSF pressure (MD ‐59.9 mmH2O, 95% CI ‐96.4, ‐23.4).
In one study, people in the acetalozamide group on average experienced a greater reduction in papilloedema as assessed by fundus photographs MD ‐0.70 (95% CI ‐1.00 to ‐0.40) and by clinical grading MD ‐0.91 (95% CI ‐1.27 to ‐0.54) between baseline and six months in the study eye.
Headache was recorded as present/absent in one study at 12 months (OR 0.42, 95% CI 0.12,1.41, 41 participants). Both studies reported headache on visual analogue scales (different ones) but results were inconclusive (MD for change in headache score measured on 10‐point visual analogue scale at 12 months was 1.0 (‐1.80, 3.70, 41 participants) and MD for change in headache score on a 6 point scale measured at 6 months was ‐0.45 (‐3.5,2.6, number of participants unclear).
In one study, a similar proportion of people in the acetalomazide group were in remission (however, the trial authors did not state their definition of this term) at 12 months compared to the placebo group. However, the 95% CIs were wide and there is considerable uncertainty as to the effect (OR 1.13 (95% CI 0.32 to 3.90, 41 participants).
In one study of 185 participants, people in the acetalomazide group had an increased risk of decreased CO2, diarrhoea, dysgeusia, fatigue, nausea, paresthesia, tinnitus and vomiting compared to people in the placebo group. In general, the estimates of effect were uncertain with wide 95% CIs. Adverse effects were not reported in the other study.
One study reported that quality of life was better in acetazolamide‐treated patients based on the visual quality of life (VFQ‐25) (MD 6.35, 95% CI 2.22 to 10.47) and the physical (MD 3.02, 95% CI 0.34 to 5.70) and mental (MD 3.45, 95% CI 0.35 to 6.55) components of the 36‐Item Short Form Health Survey tool at six months. Costs were not reported in either study.
We judged the evidence to be low certainty (GRADE) downgrading for imprecision and risk of bias.
Authors' conclusions
Although the two included RCTs showed modest benefits for acetazolamide for some outcomes, there is insufficient evidence to recommend or reject the efficacy of this intervention, or any other treatments currently available, for treating people with IIH. Further high‐quality RCTs are required in order to adequately assess the effect of acetazolamide therapy in people with IIH.
Neuropsychological impairments are common in children with drug-resistant epilepsy. It has been proposed that epilepsy surgery may alleviate these impairments by providing seizure freedom; however, ...findings from prior studies have been inconsistent. We mapped long-term neuropsychological trajectories in children before and after undergoing epilepsy surgery, to measure the impact of disease course and surgery on functioning. We performed a retrospective cohort study of 882 children who had undergone epilepsy surgery at Great Ormond Street Hospital (1990-2018). We extracted patient information and neuropsychological functioning - obtained from IQ tests (domains: Full-Scale IQ, Verbal IQ, Performance IQ, Working Memory, and Processing Speed) and tests of academic attainment (Reading, Spelling and Numeracy) - and investigated changes in functioning using regression analyses. We identified 500 children (248 females) who had undergone epilepsy surgery (median age at surgery = 11.9 years, interquartile range = 7.8,15.0) and neuropsychology assessment. These children showed declines in all domains of neuropsychological functioning in the time leading up to surgery (all p-values ≤ 0.001; e.g., βFSIQ = -1.9, SEFSIQ = 0.3, pFSIQ < 0.001). Children lost on average one to four points per year, depending on the domain considered; 27-43% declined by 10 or more points from their first to their last preoperative assessment. At the time of presurgical evaluation, most children (46-60%) scored one or more standard deviations below the mean (<85) on the different neuropsychological domains; 37% of these met the threshold for intellectual disability (Full-Scale IQ < 70). On a group level, there was no change in performance from pre- to postoperative assessment on any of the domains (all p-values > 0.128). However, children who became seizure-free through surgery showed higher postoperative neuropsychological performance (e.g., rrb-FSIQ = 0.37, p < 0.001). These children continued to demonstrate improvements in neuropsychological functioning over the course of their long-term follow-up (e.g., βFSIQ = 0.9, SEFSIQ = 0.3, pFSIQ = 0.004). Children who had discontinued antiseizure medication (ASM) treatment at one-year follow-up showed an eight-to-13-point advantage in postoperative Working Memory, Processing Speed, and Numeracy, and greater improvements in Verbal IQ, Working Memory, Reading, and Spelling (all p-values < 0.034) over the postoperative period compared to children who were seizure-free and still receiving ASMs. In conclusion, by providing seizure freedom and the opportunity for ASM cessation, epilepsy surgery may not only halt but reverse the downward trajectory that children with drug-resistant epilepsy display in neuropsychological functioning. To halt this decline as soon as possible, or potentially prevent it from occurring in the first place, children with focal epilepsy should be considered for epilepsy surgery as early as possible after diagnosis.
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