Anton de Louw

Pulsed and continous radiofrequency current adjacent to the cervical dorsal root ganglion of the rat induces late cellular activity in the dorsal horn

Background: Pulsed radiofrequency treatment has recently been described as a non-neurodestructive or minimally neurodestructive alternative to radiofrequency heat lesions. In clinical practice long-lasting results of pulsed radiofrequency treatment adjacent to the cervical dorsal root ganglion for the management of chronic radicular spinal pain have been reported without neurologic complications. However, the mode of action is unclear. An early (3 h) effect of pulsed radiofrequency as measured by an increase of c-Fos in the pain-processing neurons of the dorsal horn of rats has been described in the literature. This effect was not mediated by tissue heating. The authors investigated a possible late or long-term effect of three different radiofrequency modalities. Methods: Cervical laminectomy was performed in 19 male Wistar rats. The cervical dorsal root ganglion was randomly exposed to one of the four interventions: sham, continuous radiofrequency current at 67 centigrades, or pulsed radiofrequency current for 120 s or 8 min. The animals were sacrificed and the spinal cord was prepared for c-Fos labeling 7 days after the intervention. Results: The number of c-Fos immunoreactive cells in the dorsal horn was significantly increased in the three different radiofrequency modalities as compared with sham. No significant difference was demonstrated between the three active intervention groups. Conclusions: The authors demonstrated a late neuronal activity in the dorsal horn after exposure of the cervical dorsal root ganglion to different radiofrequency modalities, which was not temperature dependent.

Frontal lobe connectivity and cognitive impairment in pediatric frontal lobe epilepsy

Purpose:  Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its etiology is unknown. With functional magnetic resonance imaging (fMRI), we have explored the relationship between brain activation, functional connectivity, and cognitive functioning in a cohort of pediatric patients with FLE and healthy controls.

Reduced structural connectivity between sensorimotor and language areas in rolandic epilepsy

Introduction Rolandic epilepsy (RE) is a childhood epilepsy with centrotemporal (rolandic) spikes, that is increasingly associated with language impairment. In this study, we tested for a white matter (connectivity) correlate, employing diffusion weighted MRI and language testing. Methods Twenty-three children with RE and 23 matched controls (age: 8–14 years) underwent structural (T1-weighted) and diffusion-weighted MRI (b = 1200 s/mm2, 66 gradient directions) at 3T, as well as neuropsychological language testing. Combining tractography and a cortical segmentation derived from the T1-scan, the rolandic tract were reconstructed (pre- and postcentral gyri), and tract fractional anisotropy (FA) values were compared between patients and controls. Aberrant tracts were tested for correlations with language performance. Results Several reductions of tract FA were found in patients compared to controls, mostly in the left hemisphere; the most significant effects involved the left inferior frontal (p = 0.005) and supramarginal (p = 0.004) gyrus. In the patient group, lower tract FA values were correlated with lower language performance, among others for the connection between the left postcentral and inferior frontal gyrus (p = 0.043, R = 0.43). Conclusion In RE, structural connectivity is reduced for several connections involving the rolandic regions, from which the epileptiform activity originates. Most of these aberrant tracts involve the left (typically language mediating) hemisphere, notably the pars opercularis of the inferior frontal gyrus (Broca’s area) and the supramarginal gyrus (Wernicke’s area). For the former, reduced language performance for lower tract FA was found in the patients. These findings provide a first microstructural white matter correlate for language impairment in RE.

Reduced functional integration of the sensorimotor and language network in rolandic epilepsy

Introduction Over the last years, evidence has accumulated that rolandic epilepsy (RE) is associated with serious cognitive comorbidities, including language impairment. However, the cerebral mechanism through which epileptiform activity in the rolandic (sensorimotor) areas may affect the language system is unknown. To investigate this, the connectivity between rolandic areas and regions involved in language processing is studied using functional MRI (fMRI). Materials and methods fMRI data was acquired from 22 children with rolandic epilepsy and 22 age-matched controls (age range: 8–14 years), both at rest and using word-generation and reading tasks. Activation map analysis revealed no group differences (FWE-corrected, p < 0.05) and was therefore used to define regions of interest for pooled (patients and controls combined) language activation. Independent component analysis with dual regression was used to identify the sensorimotor resting-state network in all subjects. The associated functional connectivity maps were compared between groups at the regions of interest for language activation identified from the task data. In addition, neuropsychological language testing (Clinical Evaluation of Language Fundamentals, 4th edition) was performed. Results Functional connectivity with the sensorimotor network was reduced in patients compared to controls (p = 0.011) in the left inferior frontal gyrus, i.e. Brocas area as identified by the word-generation task. No aberrant functional connectivity values were found in the other regions of interest, nor were any associations found between functional connectivity and language performance. Neuropsychological testing confirmed language impairment in patients relative to controls (reductions in core language score, p = 0.03; language content index, p = 0.01; receptive language index, p = 0.005). Conclusion Reduced functional connectivity was demonstrated between the sensorimotor network and the left inferior frontal gyrus (Brocas area) in children with RE, which might link epileptiform activity/seizures originating from the sensorimotor cortex to language impairment, and is in line with the identified neuropsychological profile of anterior language dysfunction.

Aberrant functional connectivity between motor and language networks in rolandic epilepsy

INTRODUCTION Rolandic epilepsy (RE) is an idiopathic focal childhood epilepsy with a well-established neuropsychological profile of language impairment. The aim of this study is to provide a functional correlate that links rolandic (sensorimotor) pathology to language problems using functional MRI. MATERIALS AND METHODS Twenty-three children with RE (8-14 years old) and 21 matched controls underwent extensive language assessment (Clinical Evaluation of Language Fundamentals). fMRI was performed at rest and using word generation, reading, and finger tapping paradigms. Since no activation group differences were found, regions of interest (ROIs) were defined at pooled (patients and controls combined) activation maxima and in contralateral homotopic cortex, and used to assess language lateralization as well as for a resting-state connectivity analysis. Furthermore, the association between connection strength and language performance was investigated. RESULTS Reduced language performance was found in the children with RE. Bilateral activation was found for both language tasks with some predominance of the left hemisphere in both groups. Compared to controls, patient connectivity was decreased between the left sensorimotor area and right inferior frontal gyrus (p<0.01). For this connection, lower connectivity was associated with lower language scores in the patient group (r=0.49, p=0.02), but not in the controls. CONCLUSION Language laterality analysis revealed bilateral language representation in the age range under study (8-14 years). As a consequence, the connection of reduced functional connectivity we found represents an impaired interplay between motor and language networks, and aberrant functional connectivity associated with poorer language performance. These findings provide a first neuronal correlate in terms of aberrant resting-state functional connectivity for language impairment in RE.

Early onset of cortical thinning in children with rolandic epilepsy

Introduction Rolandic epilepsy, a childhood epilepsy associated with language impairments, was investigated for language-related cortical abnormalities. Methods Twenty-four children with rolandic epilepsy and 24 controls (age 8–14 years) were recruited and underwent the Clinical Evaluation of Language Fundamentals test. Structural MRI was performed at 3 T (voxel size 1 × 1 × 1 mm3) for fully automated quantitative assessment of cortical thickness. Regression analysis was used to test for differences between patients and controls and to assess the effect of age and language indices on cortical thickness. Results For patients the core language score (mean ± SD: 92 ± 18) was lower than for controls (106 ± 11, p = 0.0026) and below the norm of 100 ± 15 (p = 0.047). Patients showed specific impairments in receptive language index (87 ± 19, p = 0.002) and language content index (87 ± 18, p = 0.0016). Cortical thickness was reduced in patients (p < 0.05, multiple-comparisons corrected) in left perisylvian regions. Furthermore, extensive cortical thinning with age was found in predominantly left-lateralized frontal, centro-parietal and temporal regions. No associations were found between cortical thickness and language indices in the regions of aberrant cortex. Conclusion The cortical abnormalities described represent subtle but significant pathomorphology in this critical phase of brain development (8–14 years) and suggest that rolandic epilepsy should not be considered merely a benign condition. Future studies employing longitudinal designs are prompted for further investigations into cerebral abnormalities in RE and associations with cognitive impairment and development.

Functional and structural network impairment in childhood frontal lobe epilepsy.

In childhood frontal lobe epilepsy (FLE), cognitive impairment and educational underachievement are serious, well-known co-morbidities. The broad scale of affected cognitive domains suggests wide-spread network disturbances that not only involves, but also extends beyond the frontal lobe. In this study we have investigated whole brain connectional properties of children with FLE in relation to their cognitive impairment and compared them with healthy controls. Functional connectivity (FC) of the networks was derived from dynamic fluctuations of resting state fMRI and structural connectivity (SC) was obtained from fiber tractograms of diffusion weighted MRI. The whole brain network was characterized with graph theoretical metrics and decomposed into modules. Subsequently, the graph metrics and the connectivity within and between modules were related to cognitive performance. Functional network disturbances in FLE were related to increased clustering, increased path length, and stronger modularity compared to healthy controls, which was accompanied by stronger within- and weaker between-module functional connectivity. Although structural path length and clustering appeared normal in children with FLE, structural modularity increased with stronger cognitive impairment. It is concluded that decreased coupling between large-scale functional network modules is a hallmark for impaired cognition in childhood FLE.

Behavioral side-effects of levetiracetam in children with epilepsy: A systematic review

PURPOSE Children with epilepsy are more likely to have behavioral problems compared to children without epilepsy. Literature suggests that levetiracetam leads to behavioral side-effects in children with epilepsy. The objective of this study is to provide a better overview of the frequency and variety of behavioral side-effects, which can be initiated by levetiracetam therapy in children with epilepsy. METHOD Electronic databases used in the search were PubMed, Medline, Cochrane and Embase. Studies were eligible for inclusion when they included children from one month to 18 years of age with a diagnosis of epilepsy, used levetiracetam, had other AEDs on a stable regimen for at least two months, reported about behavioral side-effects and had a follow-up of at least two weeks. Quality assessments and data collection were carried out for all eligible studies. RESULTS Thirteen studies, including 727 patients using levetiracetam, were included in this systematic review. Three randomized controlled trials showed a total of 62 behavioral side-effects in 203 patients, effects which led to discontinuation of levetiracetam in only two of 102 patients (2.0%). Hostility, nervousness and aggression were reported mostly. Meta-analysis showed a statistically significant relative risk of 2.18 for the total number of behavioral side-effects for levetiracetam versus placebo. Observational studies showed mixed results with both behavioral deteriorations and improvements following levetiracetam. CONCLUSION Based on the findings in this systematic review, children using levetiracetam have a risk of developing several behavioral side-effects such as aggression, hostility and nervousness compared to children who do not use levetiracetam.

Delayed convergence between brain network structure and function in rolandic epilepsy

Introduction: Rolandic epilepsy (RE) manifests during a critical phase of brain development, and has been associated with language impairments. Concordant abnormalities in structural and functional connectivity (SC and FC) have been described before. As SC and FC are under mutual influence, the current study investigates abnormalities in the SC-FC synergy in RE. Methods: Twenty-two children with RE (age, mean ± SD: 11.3 ± 2.0 y) and 22 healthy controls (age 10.5 ± 1.6 y) underwent structural, diffusion weighted, and resting-state functional magnetic resonance imaging (MRI) at 3T. The probabilistic anatomical landmarks atlas was used to parcellate the (sub)cortical gray matter. Constrained spherical deconvolution tractography and correlation of time series were used to assess SC and FC, respectively. The SC-FC correlation was assessed as a function of age for the non-zero structural connections over a range of sparsity values (0.01–0.75). A modularity analysis was performed on the mean SC network of the controls to localize potential global effects to subnetworks. SC and FC were also assessed separately using graph analysis. Results: The SC-FC correlation was significantly reduced in children with RE compared to healthy controls, especially for the youngest participants. This effect was most pronounced in a left and a right centro-temporal network, as well as in a medial parietal network. Graph analysis revealed no prominent abnormalities in SC or FC network organization. Conclusion: Since SC and FC converge during normal maturation, our finding of reduced SC-FC correlation illustrates impaired synergy between brain structure and function. More specifically, since this effect was most pronounced in the youngest participants, RE may represent a developmental disorder of delayed brain network maturation. The observed effects seem especially attributable to medial parietal connections, which forms an intermediate between bilateral centro-temporal modules of epileptiform activity, and bear relevance for language function.

Cost-effectiveness of the ketogenic diet and vagus nerve stimulation for the treatment of children with intractable epilepsy

PURPOSE The objective of this study was to estimate the expected cost-utility and cost-effectiveness of the ketogenic diet (KD), vague nerve stimulation (VNS) and care as usual (CAU), using a decision analytic model with a 5-year time horizon. METHODS A Markov decision analytical model was constructed to estimate the incremental costs, quality-adjusted life years (QALYs) and successfully treated patient (i.e. 50% or more seizure reduction) of the treatment strategies KD, VNS and CAU, from a health care perspective. The base case considered children with intractable epilepsy (i.e. two or more antiepileptic drugs had failed) aged between 1 and 18 years. Data were derived from literature and expert meetings. Deterministic and probabilistic sensitivity analyses were performed. RESULTS Our results suggest that KD is more effective and less costly, and thus cost-effective compared with VNS, after 12 months. However, compared to CAU, neither KD nor VNS are cost-effective options, they are both more effective but also more expensive (€346,899 and €641,068 per QALY, respectively). At 5 years, VNS is cost-effective compared with KD and CAU (€11,378 and €68,489 per QALY, respectively) and has a 51% probability of being cost-effective at a ceiling ratio of €80,000 per QALY. CONCLUSIONS Our results suggest that on average the benefits of KD and VNS fail to outweigh the costs of the therapies. However, these treatment options should not be ignored in the treatment for intractable epilepsy in individual or specific groups of patients. There is a great need for high quality comparative studies with large patient samples which allow for subgroup analyses, long-term follow-up periods and outcome measures that measure effects beyond seizure frequency (e.g. quality of life). When this new evidence becomes available, reassessment of the cost-effectiveness of KD and VNS in children with intractable epilepsy should be carried out.