Abstract
White Matter Development in Children with Benign Childhood Epilepsy with Centro-Temporal Spikes
Ciumas C, Saignavongs M, Ilski F, Herbillon V, Laurent A, Lothe A, Heckemann AA, de Bellescize J, Panagiotakaki E, Hannoun S, Sappey Marinier D, Montavont A, Ostrowsky-Coste K, Bedoin N, Ryvlin P.
Benign childhood epilepsy with centro-temporal spikes (BCECTS) is a unique form of non-lesional age-dependent epilepsy with rare seizures, focal electroencepalographic abnormalities affecting the same well delineated cortical region in most patients, and frequent mild to moderate cognitive dysfunctions. In this condition, it is hypothesized that interictal electroencephalographic discharges might interfere with local brain maturation, resulting in altered cognition. Diffusion tensor imaging allows testing of this hypothesis by investigating the white matter microstructure, and has previously proved sensitive to epilepsy-related alterations of fractional anisotropy and diffusivity. However, no diffusion tensor imaging study has yet been performed with a focus on BCECTS. We investigated 25 children suffering from BCECTS and 25 age-matched control subjects using diffusion tensor imaging, 3D-T1 magnetic resonance imaging, and a battery of neuropsychological tests including Conner's scale and Wechsler Intelligence Scale for Children (fourth revision). Electroencephalography was also performed in all patients within 2 months of the magnetic resonance imaging assessment. Parametric maps of fractional anisotropy, mean-, radial-, and axial diffusivity were extracted from diffusion tensor imaging data. Patients were compared with control subjects using voxel-based statistics and family-wise error correction for multiple comparisons. Each patient was also compared to control subjects. Fractional anisotropy and diffusivity images were correlated to neuropsychological and clinical variables. Group analysis showed significantly reduced fractional anisotropy and increased diffusivity in patients compared with control subjects, predominantly over the left pre- and postcentral gyri and ipsilateral to the electroencephalographic focus. At the individual level, regions of significant differences were observed in 10 patients (40%) for anisotropy (eight reduced fractional anisotropy, one increased fractional anisotropy, one both), and 17 (56%) for diffusivity (13 increased, one reduced, three both). There were significant negative correlations between fractional anisotropy maps and duration of epilepsy in the precentral gyri, bilaterally, and in the left postcentral gyrus. Accordingly, 9 of 12 patients (75%) with duration of epilepsy 412 months showed significantly reduced fractional anisotropy versus none of the 13 patients with duration of epilepsy 412 months. Diffusivity maps positively correlated with duration of epilepsy in the cuneus. Children with BCECTS demonstrate alterations in the microstructure of the white matter, undetectable with conventional magnetic resonance imaging, predominating over the regions displaying chronic interictal epileptiform discharges. The association observed between diffusion tensor imaging changes, duration of epilepsy and cognitive performance appears compatible with the hypothesis that interictal epileptic activity alters brain maturation, which could in turn lead to cognitive dysfunction. However, such cross-sectional association does not demonstrate causality, and other hitherto unidentified factors could represent the common cause to part or all of the observed findings.
Rolandic Epilepsy Has Little Effect on Adult Life 30 Years Later
Camfield CS, Camfield PR. Neurology 2014;82:1162–1166.
OBJECTIVE: To establish the adult social outcome for childhood-onset rolandic epilepsy. METHODS: Patients with medication-treated rolandic epilepsy were identified from the Nova Scotia prospective population-based cohort of childhood-onset epilepsy. Epilepsy onset was in 1977–1985 and follow-up was in 2010–2013 with chart review plus structured telephone interview for those older than 21 years. RESULTS: Forty-two children developed rolandic epilepsy (6% of 692 incident epilepsy cases in the cohort). Thirty-two (76%) were contacted when they were older than 21 years. Epilepsy onset averaged 7.7 ± 2.3 years, follow-up 29.5 ± 2.8 years, and final age 37 ± 3.4 years. All had epilepsy remission and were off antiepileptic drug treatment for 21.4 ± 6.6 years. There were 2 minor injuries from seizures and only 1 death (from a snowmobile accident). Overall, 41% had >1 of 7 adverse social outcomes, 6 had 1, 4 had 2, and 3 had ≥3. These were failure to complete high school (n = 7), pregnancy outside of a stable relationship (<6 months) (n = 7), depression or other psychiatric diagnosis (n = 3), unemployment (n = 1), living alone (n = 5), never in a romantic relationship ≥3 months (n = 1), and poverty (n = 2). Those who did not complete high school were more likely to have parents with low academic achievement and/or low income (p < 0.02). By comparison, rates of ≥1 adverse social outcomes for other epilepsies with normal intelligence from this cohort varied from 62% to 76%. CONCLUSIONS: The adult social outcome for children with rolandic epilepsy is remarkably better than for those with other major epilepsies and normal intelligence.
Commentary
Seizures occurring in children diagnosed with rolandic epilepsy (RE) will almost always remit by mid-adolescence in the presence or absence of antiepileptic drug (AED) treatment (1). Concordant with this timeframe when centrotemporal interictal discharges predominate is a growing literature suggesting that children affected with RE demonstrate an array of cognitive difficulties., (2). Conventional structural magnetic resonance imaging (MRI) studies in RE are almost always unremarkable. However, studies are beginning to accumulate showing childhood epilepsy-related changes in white matter measures detected by diffusion tensor imaging (DTI) (3–5).
Recent studies using DTI have demonstrated white matter connectivity patterns in children with new-onset generalized and focal-onset epilepsies (3–5). For example, Yang et al. (2012) showed white matter integrity impairment in the basal gangliathalamocortical circuit of drug-naive childhood absence epilepsy (CAE) patients. The authors suggest that such changes may be related to increased cortical excitability and associated cognitive, linguistic, and behavioral/emotional deficits. However, with few exceptions, neuropsychological testing and social function patterns with long-term longitudinal group and individual-based follow up have not been well-studied in the childhood epilepsies.
Ciumas et al. (2014) present a benchmark study demonstrating a relationship between DTI changes and cognitive abnormalities in children with RE compared with a normal control cohort. The authors show a significant relationship between duration of interictal epileptiform activity and delayed or altered maturation of regional cognitively relevant neural networks. Group analysis of DTI measures demonstrate a reduced fractional anisotropy (FA) and increased mean diffusivity (MD) ipsilateral to the interictal epileptic source, particularly near the pre- and postcentral gyri. These findings are correlated to neuropsychological testing and clinical variables. Specifically, age of onset and duration of epilepsy indicate more abnormalities in subjects with a longer duration of epilepsy.
The ability to demonstrate the extent of a white matter connected epileptic circuit is possible by utilizing diffusion-based MR imaging. Such MR sequences have a relatively long history of detecting seizure-related changes in white matter-associated diffusion during complex partial status epilepticus (6). Diffusion weighted imaging (DWI) sequences measure the magnitude of water movement by applying an additional directional gradient to standard MR T2-weighted echo planar imaging sequences. These standard imaging sets acquire the data in the three cardinal planes (XYZ) and average the data to get an estimate of the total diffusion within a voxel. The result can be expressed as the apparent diffusion coefficient (ADC). So, the magnitude of diffusion in DWI is the average of the ADC. DTI is an evolution of this technique capable of visualizing seizure-associated changes capitalizing on directionality of water diffusion not possible with DWI and FLAIR (7–9).
DTI is based on the knowledge that the diffusion of water molecules within brain white matter is not equal in all directions. Diffusion is typically restricted by cell membranes of myelinated neurons, called anisotropic diffusion or FA. This measure represents the weighted directionality of water diffusion along white matter fiber tracts. Water does not diffuse across intact axonal fibers but rather along their major axes. So, intact brain white matter promotes anisotropic, where anisotropy indices tend toward 1. Conversely, isotropic diffusion, where water diffuses in no apparent direction, represents altered or disrupted white matter pathways. In this scenario, the FA index approaches 0. The MD, also known as “trace,” is a measurement of the amplitude of the diffusional motion, putatively reflective of cell hydration.
Chronic changes seen with DTI following years of focal-onset seizures have been well-described in the literature. For example, the usual pattern in mesial temporal sclerosis and cortical dysplasia is a reduced FA and increased MD on the involved side (8, 10). In support of secondary epileptogenesis in humans, chronic DTI-related changes are not confined to the ipsilateral hippocampus alone but are often seen contralaterally (11, 12), as well as in the relay pathways of the thalamus (13). In longstanding temporal lobe epilepsy, a significantly reduced FA is often also seen in the posterior corpus callosum in patients compared with controls, suggesting widespread changes due to bilateral hemispheric connectivity.
Conversely, acute or transient but evolving postictal changes in FA can be identified when compared with interictal DTI measures. Such a technique can be utilized to visualize the subacute remnants of the directionality of an epileptic circuit recruited by focal-onset seizures (7, 14, 15). These transient postictal measures are not typically useful in those patients in whom secondarily generalized seizures have occurred immediately prior to a postictal DTI. Such widespread propagation pathways may become too complex to analyze.
Ciumas et al. (2014) investigated 25 children with RE compared with age-matched control subjects using FA as well as axial and radial MD measures in conjunction with neurocognitive measures. In particular, the authors showed that subjects with RE performed at a lower level compared with controls on indices of hyperactivity/impulsivity and attention deficit hyperactivity disorder. A nonsignificant trend toward abnormal scores for conduct disorder and learning problems was also observed. In addition, subjects with RE demonstrated lower performance scores than control subjects on multiple subscales of the Wechsler Intelligence Scale for Children (WISC-IV). FA in the precentral gyrus was negatively correlated with anxiety and learning scores, and was positively correlated with processing speed on the WISC-IV. Both correlations indicated greater FA abnormalities in subjects with lower cognitive performance. MD did not correlate with neurocognitive testing. However, increased axial and radial MD values were seen in multiple regions, including the bilateral pre- and postcentral gyri, right parahippocampal and fusiform gyri, as well as bilateral middle and medial frontal gyri, particularly with a duration of RE lasting longer than 12 months. This study did not follow the cohort of subjects longitudinally over time. However, the authors do pose the possibility that cognitive function in these children may improve or normalize once the interictal epileptic sources have finally remitted during adolescence.
Normalization of complex white matter connectivity patterns into adulthood can be inferred, at least in part, based on the adult psychosocial outcomes of children with RE in a recent seminal population-based study published by Camfield and Camfield (2014). The authors documented measures of adult social function after 30 years of follow-up using the Nova Scotia population-based epilepsy cohort (1977–1985) from which 42 children (predominantly males) with RE were extracted. Characteristic of RE, all seizures remitted during adolescence and AEDs were discontinued for a mean of 21.4 years. The authors reported that no patients developed Landau–Kleffner syndrome or documented continuous spike-wave in slow-wave sleep syndrome.
As adults, this cohort of RE patients demonstrated a high rate of employment (97%), low rate of poverty, well-adjusted relationships, and rare incidence of mental health problems. In comparison, those adults diagnosed with CAE demonstrated high rates of social problems similar to individuals diagnosed with chronic rheumatoid arthritis (control group). Noteworthy in the epilepsy cohort is the marked association of poverty with juvenile myoclonic epilepsy (30%), idiopathic epilepsy (NOS) (40%), complex partial “dyscognitive” seizures (50%), and focal seizures with secondary generalization (26%). Of note, poverty rates in Nova Scotia between the years 2010–2012 were 8 to 10 percent. The authors admit that limitations in their study included a lack of a comparative gender- and age-matched control group from Nova Scotia who did not have childhood-onset epilepsy.
As diffusion tensor models evolve, improved visualization of affected neural circuits will likely be introduced in the diagnostic evaluation of widespread epileptic networks. For example, improved fiber tracking with an ability to resolve crossing fiber tracts will generate better modeling of deep cerebral epileptic networks extending throughout the brain.
Future longitudinal population-based studies focused on the childhood epilepsies performed in tandem with DTI-based analyses will provide powerful tools for understanding cognitive development in the presence of a history of idiopathic “genetic-based” childhood epilepsy. Such studies lay the foundation for inevitably deciphering with individual specificity, the extensive connectivity underpinnings, and trajectories of cognitive development for children with these epilepsies.