Functional MRI and structural MRI as tools for understanding comorbid conditions in children with epilepsy

Children with epilepsy are at risk for behavioral and cognitive comorbidities. Potential etiologies can be assessed in part by neuroimaging. Functional magnetic resonance imaging (MRI) has a major role in presurgical evaluation and prediction of postoperative outcome by mapping of language and memory. Structural MRI and functional MRI have shown changes in children and adolescents with attention deficit hyperactivity disorder and disruptive behavior, common comorbidities in children with epilepsy. Neuroimaging has the potential for significantly increasing understanding of the basis of cognitive and behavioral problems in children with epilepsy.This article is part of a Special Issue entitled “The Future of Translational Epilepsy Research”.     

Functional MRI applications in epilepsy surgery

Functional magnetic resonance imaging (fMRI) is a non-invasive neuroimaging technique that has grown rapidly in popularity over the past decade. It is already prevalent in psychology, cognitive and basic neuroscience research and is being used increasingly as a tool for clinical decision-making in epilepsy. It has been used to determine language location and laterality in patients, sometimes eliminating the need for invasive tests. fMRI can been used pre-surgically to guide resection margins, preserving eloquent cortex. Other fMRI paradigms assessing memory, visual and somatosensory systems have limited clinical applications currently, but show great promise. Simultaneous recording of electroencephalogram (EEG) and fMRI has also provided insights into the networks underlying seizure generation and is increasingly being used in epilepsy centres. In this review, we present some of the current clinical applications for fMRI in the pre-surgical assessment of epilepsy patients, and examine a number of new techniques that may soon become clinically relevant.     

Clinical functional MRI of the language domain in children with epilepsy

Functional MRI (fMRI) for the assessment of language functions is increasingly used in the diagnostic workup of patients with epilepsy. Termed "clinical fMRI," such an approach is also feasible in children who may display specific patterns of language reorganization. This study was aimed at assessing language reorganization in pediatric epilepsy patients, using fMRI. We studied 26 pediatric epilepsy patients (median age, 13.05 years; range, 5.6-18.7 years) and 23 healthy control children (median age, 9.37 years; range, 6.2-15.4 years), using two child-friendly fMRI tasks and adapted data-processing streams. Overall, 81 functional series could be analyzed. Reorganization seemed to occur primarily in homotopic regions in the contralateral hemisphere, but lateralization in the frontal as well as in the temporal lobes was significantly different between patients and controls. The likelihood to find atypical language organization was significantly higher in patients. Additionally, we found significantly stronger activation in the healthy controls in a primarily passive task, suggesting a systematic confounding influence of antiepileptic medication. The presence of a focal cortical dysplasia was significantly associated with atypical language lateralization. We conclude that important confounds need to be considered and that the pattern of language reorganization may be distinct from the patterns seen in later-onset epilepsy.     

Functional connectivity changes in patients with absence epilepsy studied using resting-state functional MRI

Functional connectivity is altered in several mental disorders. We used resting-state functional MRI to examine the alterations in functional connectivity that occur in patients with absence epilepsy. We found an altered functional connectivity within and between functional modules in patients with absence epilepsy. Some brain regions had a greater number of altered connections. The functional connectivity within and between modules in absence epilepsy patients showed an increase in the number of positive connections and a decrease in the number of the negative connections. In particular, the superior frontal gyrus demonstrated both an increased number of connections with other nodes of the frontal default mode network and a decreased number of connections with the limbic system. These findings provide a new perspective and shed light on how the balance of connections within and between modules may contribute to the development of absence epilepsy.     

Functional neuroimaging in the preoperative evaluation of children with drug-resistant epilepsy

Functional neuroimaging Although the primary imaging modality in the management of epilepsy is magnetic resonance imaging MRI, functional neuroimaging with positron-emission tomography (PET) and single photon emission computed tomography (SPECT) often provides complementary information and, in a number of situations, provides unique information that cannot be obtained with MRI. The most commonly used PET tracers used for epilepsy evaluation are 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) and [¹¹C]flumazenil (FMZ). Recently, interictal PET with alpha-[¹¹C]methyl-l-tryptophan was found to be highly specific for the epileptic focus and can differentiate between epileptogenic and nonepileptogenic lesions in the same patient (e.g., in patients with tuberous sclerosis).Discussion In this review, we discuss clinical applications of these three PET tracers in drug-resistant temporal and extratemporal lobe epilepsy, selected epilepsy syndromes of childhood, lesional and nonlesional epilepsy, and the challenges of imaging secondary epileptic foci. A brief discussion of SPECT applications in epilepsy is also included. With further development of new tracers highly sensitive and specific for epileptogenic brain regions, the presurgical evaluation of refractory epilepsy will be greatly facilitated. Approximately 0.5 to 1.0% of the population suffer from epilepsy, of which 15–20% are intractable. Infants and children, whose seizures have a focal onset are refractory to anticonvulsants and are prolonged, tend to have the worst cognitive outcome [Meador KJ, Neurology 58 (Suppl 5):S21–S26, 2002]. Seizures themselves affect the developing brain and contribute to an adverse neurologic outcome (Holmes, Pediatric Neurology 33:1–110, 2005).Conclusion Therefore, in treating children with intractable epilepsy, it is important to consider seizure control and to give allowance for normal cognitive development.     

Functional MRI reveals declined prefrontal cortex activation in patients with epilepsy on topiramate therapy

Functional magnetic resonance imaging of covert word generation was used to examine brain activation abnormalities associated with topiramate-induced cognitive language impairment in patients with epilepsy. Compared with a control epilepsy group, in the topiramate-treated group, there was significantly less activation in the language-mediating regions of the prefrontal cortex; the topiramate group also had significantly lower neuropsychological language scores. These findings suggest that topiramate has a critical effect on the cerebral neural systems that mediate expressive language.     

Functional MRI of facial emotion processing in left temporal lobe epilepsy

Temporal lobe epilepsy (TLE) may negatively affect the ability to recognize emotions. This study aimed to determine the cortical correlates of facial emotion processing (happy, sad, fearful, and neutral) in patients with well-characterized left TLE (LTLE) and to examine the effect of seizure control on emotion processing. We enrolled 34 consecutive patients with LTLE and 30 matched healthy control (HC) subjects. Participants underwent functional MRI (fMRI) with an event-related facial emotion recognition task. The seizures of seventeen patients were controlled (no seizure in at least 3 months; LTLE−sz), and 17 continued to experience frequent seizures (LTLE+sz). Mood was assessed with the Beck Depression Inventory (BDI) and the Profile of Mood States (POMS). There were no differences in demographic characteristics and measures of mood between HC subjects and patients with LTLE. In patients with LTLE, fMRI showed decreased blood oxygenation level dependent (BOLD) signal in the hippocampus/parahippocampus and cerebellum in processing of happy faces and increased BOLD signal in occipital regions in response to fearful faces. Comparison of groups with LTLE+sz and LTLE−sz showed worse BDI and POMS scores in LTLE+sz (all p < 0.05) except for POMS tension/anxiety (p = 0.067). Functional MRI revealed increased BOLD signal in patients with LTLE+sz in the left precuneus and left parahippocampus for “fearful” faces and in the left periarcheocortex for “neutral” faces. There was a correlation between the fMRI and Total Mood Disturbance in the left precuneus in LTLE−sz (p = 0.019) and in LTLE+sz (p = 0.018). Overall, LTLE appears to have a relatively minor effect on the cortical underpinnings of facial emotion processing, while the effect of seizure state (controlled vs. not controlled) is more pronounced, indicating a significant relationship between seizure control and emotion processing.     

Functional MRI predicts memory performance after right mesiotemporal epilepsy surgery

PURPOSE: Anterior temporal lobe resection (ATR) is a treatment option in drug-resistant epilepsy. An important risk of ATR is loss of memory because mesiotemporal structures contribute substantially to memory function. We investigated whether memory-activated functional MRI (fMRI) can predict postoperative memory loss after anterior temporal lobectomy in right-sided medial temporal lobe epilepsy (MTLE). METHODS: We included 16 patients (10 women) aged 16-54 years. The mean age at epilepsy onset was 12.5 years (range, 1-26 years). The patients' mean Wechsler IQ score was 95.2 (range, 62-125). The activation condition of fMRI consisted of retrieval from long-term memory induced by self-paced performance of an imaginative walk. All but one patient had left-sided speech dominance according to speech-activated fMRI. Outside the scanner, we evaluated the pre- and postoperative visual memory retention by using Rey Visual Design Learning Test. RESULTS: We found a correlation between the preoperative asymmetry index of memory-fMRI and the change between pre- and postsurgical measures of memory retention. Reduced activation of the mesiotemporal region ipsilateral to the epileptogenic region correlated with a favorable memory outcome after right-sided ATR. CONCLUSIONS: In light of the postoperative results, the theoretical implication of our study is that fMRI based on a simple introspective retrieval task measures memory functions. The main clinical implication of our study is that memory-fMRI might replace the invasive Wada test in MTLE by using a simple fMRI paradigm. Predictive power, however, will be studied in larger patient samples. Other studies are required for left-sided MTLE and neocortical epilepsies to assess the clinical usefulness of memory-fMRI.     

Functional MRI in children with congenital structural abnormalities of the occipital cortex

Functional MRI techniques were used to map the position of visual cortex in an awake and a sedated child with congenital anomalies of the posterior hemispheres. In one subject with cortical heterotopia, an activated cortex was found distinct from the structurally abnormal area detected on conventional MRI. In a sedated patient with holoprosencephaly, activated cortical areas in the posterior-medial portions of the hemispheres were identified. This study demonstrates the utility of functional MRI in such patients, both awake and sedated.     

Anxiety in children with epilepsy

Although the prevalence is unknown, affective disorders are more common in children with epilepsy than in healthy controls. The purpose of the present study was to examine the occurrence of anxiety in children and adolescents with epilepsy and to determine factors associated with elevation of these symptoms. Children and adolescents (n=101) between the ages of 6 and 16 years were given the Revised Children's Manifest Anxiety Scale (RCMAS). Mild to moderate symptoms of anxiety were reported by 23% of the patients. Based on regression analysis, factors significantly associated with increased anxiety included the presence of comorbid learning or behavioral difficulties, ethnicity, and polytherapy. Results suggest the need to monitor children and adolescents with epilepsy for affective symptoms in order to provide appropriate interventions.     

Overtreatment in children with epilepsy

Children with epilepsy are at risk for overtreatment, defined as the use of an excessive number or amount of antiepiletic drugs (AEDs). While the extent of overtreatment of epilepsy in children is not known, there is increasing awareness that overtreatment with AEDs contributes to the morbidity associated with childhood epilepsy. Reasons for overtreatment include using AEDs in a child with seizures who does not require therapy, choosing an inappropriate AED for the seizure type or syndrome; treating non-epileptic behaviors as seizures, use of polytherapy when monotherapy would suffice, and inadequate therapeutic options. Despite the introduction of eight new AEDs in the United States during the last decade, many children continue to be treated with the older generation sedative AEDs. Numerous investigators have now demonstrated that sedative AEDs can be safely removed from the drug regimen of children with epilepsy with resultant improvement in behavior, alertness, and improved seizure control. However, the biggest obstacle to overtreatment is the lack of effective therapies for many of the childhood epileptic syndromes. Until there are more effective therapies developed it is highly likely that children will continue to be over-medicated on ineffective and detrimental AEDs.     

Neuronal migrational disorders in children with epilepsy: MRI,interictal SPECT and EEG comparisons

Single-photon emission computed tomography (SPECT) is being increasingly used in the investigation of children with epilepsy and may provide insights into congenital malformations. We analyzed the interictal⁹⁹Tc-HMPAOSPECT in a series of seven children with developmental disorders of the neocortex, each of them representing a prototype of cerebral dysgenesis, such as lissencephaly, pachygyria, opercular dysplasia, polymicrogyria, nodular heterotopia and band heterotopia. The patients studied were selected among 22 epileptic children with neuronal migrational disorders (NMDs). Interictal SPECT hypoperfusion was observed in the area homologous to MRI findings in all the examined children. In three patients low perfusion was also present in the opposite hemisphere, probably due to functional involvement or related to an underlying microdysgenesis, not revealed by structural imaging. EEG features were in agreement with low perfusion areas, both anatomically and functionally, in all children. In one patient hypoperfusion area differed from that revealed by MRI and EEG. Ictal SPECT has been considered a useful tool for accurately locating the epileptic focus. Nevertheless, interictal brain perfusion studies, together with proton magnetic resonance spectroscopy, may play an important role in detecting anatomic substrate in developmental disorders of the neocortex.     

High-resolution MRI enhances identification of lesions amenable to surgical therapy in children with intractable epilepsy

PURPOSE: Many children with refractory epilepsy can achieve better seizure control with surgical therapy. An abnormality on magnetic resonance imaging (MRI), along with corroborating localization by other modalities, markedly increases chances of successful surgical outcome. We studied the impact of high-resolution MRI on the surgical outcome of intractable epilepsy. METHODS: High-resolution MRI using four-coil phased surface array was obtained as part of the comprehensive presurgical protocol for children with focal onset intractable seizures evaluated by our epilepsy center during the first half of 2002. RESULTS: Thirteen consecutive children, ages 5 to 18 years, entered this prospective study. For four patients with a lesion on a recent MRI examination with a standard head coil, management did not change with high-resolution MRI. Standard MRI in the other nine patients did not identify a lesion. However, high-resolution MRI with the phased-array surface coil found previously undiagnosed focal abnormalities in five of nine patients. These abnormalities included hippocampal dysplasia, hippocampal atrophy, and dual pathology with frontal cortical dysplasia. In four of nine patients, no identifiable lesion was identified on the high-resolution MRI. All patients underwent invasive monitoring. In three of five patients, newly diagnosed lesions correlated with EEG abnormalities, and resection was performed. CONCLUSIONS: In our center, high-resolution MRI identified lesions not detected by standard MRI in more than half the children (56%). Technical advances such as four-coil phased surface array MRI can help identify and better delineate lesions, improving the diagnosis of patients who are candidates for surgical treatment of refractory epilepsy.     

Functional MRI connectivity as a predictor of the surgical outcome of epilepsy

Purpose: In planning epilepsy surgery, it is important to be able to assess the likelihood of success of surgery for each patient so that the possible risk and benefit can be properly considered. In this study, functional connectivity was investigated as a means for predicting surgical outcome from the preoperative functional magnetic resonance imaging (fMRI) of epilepsy patients. Methods: Resting‐state simultaneous electroencephalography (EEG)–fMRI data were collected from 18 patients with intractable epilepsy before surgery and from 14 healthy subjects. For each patient, EEG‐spike correlated fMRI analysis was performed and an activation cluster that overlapped the most with the planned resection area for each patient was chosen as the seed for the functional connectivity analysis. After the functional connectivity maps were computed, laterality indices of functional connectivity were contrasted between patients who had seizures after surgeries (seizure‐recurrence group) and those who did not have them for at least a year (seizure‐free group). Key Findings: Patients in the seizure‐recurrence group had less‐lateralized functional connectivity than patients in the seizure‐free group (t₁₆ = 2.3, after control subtracted and Fisher transformed, p < 0.05, two‐tailed). Significance: This study suggests the potential for using preoperative fMRI connectivity analysis as a predictive outcome measure. If confirmed by further research, a high laterality will be an important addition to the other predictors of better surgical outcome such as febrile seizures, mesial temporal sclerosis, tumors, abnormal MRI, and EEG/MRI concordance.     

Functional MRI of task switching in children with Specific Language Impairment (SLI)

The objective of this study was to examine executive functioning in children with Specific Language Impairment (SLI) using functional MRI. Six children with SLI and seven control children participated in this study and received a task-switching paradigm. No specific deficit in executive control was observed at the behavioral level in children with SLI. However, the neuroimaging data did show remarkable differences between the SLI and control children. The children with SLI recruited frontal and cingulate areas, normally associated with executive control, even when the task did not require them in the children without SLI. This might indicate that the task was more demanding for the SLI group and that compensatory mechanisms were engaged for successful task performance.     

Drug-resistant epilepsy in children with partial onset epilepsy treated with carbamazepine

Objective: To evaluate the outcome, including drug-resistant epilepsy (DRE) in children with newly diagnosed partial onset epilepsy treated with carbamazepine (CBZ). Methods: A retrospective medical records review and telephone questionnaire were undertaken on a total of 100 subjects. Results: Long-term follow-up was obtained on 79 children with a mean duration of 7.1 years from CBZ initiation. A total of 66 (83.5%) subjects achieved 2-year seizure remission, 48 (72.7%) subjects did so with CBZ monotherapy. Seven (10.6%) had seizure recurrence after 2-year seizure remission. DRE was diagnosed in seven (8.9%) subjects and five subjects had epilepsy surgery. The mean duration from seizure onset to epilepsy surgery was 5.3 (±2.1) years. Contributing factors for the prolonged duration from seizure onset to epilepsy surgery were identified including: relapsing–remitting course of seizure, family reluctance for epilepsy surgery and uncontrolled psychological problems. Conclusions: Over 80% of children with newly diagnosed partial onset epilepsy who were initially treated with CBZ achieved 2-year seizure remission, and more than 70% of this group did so with CBZ monotherapy. The majority of these patients maintained seizure remission overtime. However, 8.9% of this population met the criteria for DRE and most of them had epilepsy surgery. The duration from seizure onset to epilepsy surgery is an important potential area for improvement in DRE patient care.     

MEG predicts outcome following surgery for intractable epilepsy in children with normal or nonfocal MRI findings

PURPOSE: To identify the predictors of postsurgical seizure freedom in children with refractory epilepsy and normal or nonfocal MRI findings. METHODS: We analyzed 22 children with normal or subtle and nonfocal MRI findings, who underwent surgery for intractable epilepsy following extraoperative intracranial EEG. We compared clinical profiles, neurophysiological data (scalp EEG, magnetoencephalography (MEG) and intracranial EEG), completeness of surgical resection and pathology to postoperative seizure outcomes. RESULTS: Seventeen children (77%) had a good postsurgical outcome (defined as Engel class IIIA or better), which included eight (36%) seizure-free children. All children with postsurgical seizure freedom had an MEG cluster in the final resection area. Postsurgical seizure freedom was obtained in none of the children who had bilateral MEG dipole clusters (3) or only scattered dipoles (1). All five children in whom ictal onset zones were confined to < or = 5 adjacent intracranial electrodes achieved seizure freedom compared to three of 17 children with ictal onset zones that extended over >5 electrodes (p = 0.002). None of six children with more than one type of seizure became seizure-free, compared to eight of 16 children with a single seizure type (p = 0.04). Complete resection of the preoperatively localized epileptogenic zone resulted in seizure remission in 63% (5/8) and incomplete resections, in 21% (3/14) (p = 0.06). Age of onset, duration of epilepsy, number of lobes involved in resection, and pathology failed to correlate with seizure freedom. CONCLUSIONS: Surgery for intractable epilepsy in children with normal MRI findings provided good postsurgical outcomes in the majority of our patients. As well, restricted ictal onset zone predicted postoperative seizure freedom. Postoperative seizure freedom was less likely to occur in children with bilateral MEG dipole clusters or only scattered dipoles, multiple seizure types and incomplete resection of the proposed epileptogenic zone. Seizure freedom was most likely to occur when there was concordance between EEG and MEG localization and least likely to occur when these results were divergent.