Neuroradiological findings in patients with "non-lesional" focal epilepsy revealed by research protocol.

AIM: To evaluate whether a dedicated epilepsy research protocol with expert image re-evaluation can increase identification of patients with lesions and to attempt to ascertain the potential reasons why lesions were not identified previously on earlier clinical magnetic resonance imaging (MRI). MATERIALS AND METHODS: Forty-three patients (26 female) with focal refractory epilepsy who had failed at least two trials of anti-epileptic drug treatments were studied. Patients were recruited prospectively into the study if previous clinical MRI was deemed to be "non-lesional" by the clinicians involved in the initial assessment. Three-dimensional (3D) T1-weighted (T1W), T2-weighted (T2W), T2 fluid-attenuated inversion recovery (T2-FLAIR) sequences, and two-dimensional (2D) coronal T1-/T2W FLAIR were assessed by a neuroradiologist, including the previous clinical MRI of individual patients. RESULTS: Twenty-nine or 43 (67%) patients remained MRI-negative after scanning with the epilepsy-dedicated protocol and image reappraisal by expert consultant neuroradiologists; however, 14/43 (33%) patients were found to have potentially epileptogenic brain lesions. The lesion that most frequently escaped the attention of clinicians was hippocampal sclerosis (nine cases, of which two had an additional focal cortical dysplasia, FCD), followed by single FCDs (two cases), and others including gliosis, encephalocoele, and amygdala enlargement (one case each). Eleven of the 14 (79%) previously "non-lesional" patients had electroencephalogram (EEG) imaging-concordant localisation features, rendering them potential candidates for resective surgery. CONCLUSIONS: The primary factors explaining the newly identified lesions were the choice of MRI sequences, imaging parameters, data quality, lesion not reported (human factor), and loss of information through incomplete documentation. It is important for all clinicians to proceed meticulously in the detailed assessment of epilepsy-dedicated in-vivo MRI and discuss difficult patient cases in multidisciplinary team meetings.

Efficacy and tolerability of anti-epileptic drugs-an internet study.

OBJECTIVE: To ascertain efficacy and tolerability of carbamazepine (CBZ), sodium valproate (VPA), lamotrigine (LTG) and levetiracetam (LEV) using the UKAED register (www.ukaed.info). METHODS: Patients on CBZ (n=91), VPA (n=61), LTG (n=105), LEV (n=72) and healthy control subjects (CTR) on no medication (n=51) were extracted. All patients had anonymously provided information on seizure type and frequency and completed the Liverpool Adverse Event Profile (LAEP). RESULTS: The number of seizure-free patients in the last 4 weeks was overall CBZ/VPA/LTG/LEV=60%/79%/67%/67%, for generalized epilepsy was CBZ/VPA/LTG/LEV=67%/89%/65%/94%, and for localization-related epilepsy was CBZ/VPA/LTG/LEV=59%/71%/67%/57%. Mean LAEP scores were CBZ/VPA/LTG/LEV/CTR=42.21/39.66/39.86/43.01/29.69. The mean LAEP was significantly higher in patients reporting depression and in patients with active epilepsy than in patients without depression and remission. Central nervous system (CNS) adverse effects including memory problems, difficulty concentrating, depression, unsteadiness, restlessness, feelings of anger, shaky hands and dizziness were significantly more frequent in CBZ, VPA, LTG and LEV than in CTR. The feeling of anger was significantly more frequent in LEV, and depression was significantly more frequent in CBZ compared to the other drugs. CONCLUSION: In this Internet-based register of self-reported efficacy and tolerability, CBZ, VPA, LTG and LEV were similar. Self-reported CNS adverse effects were significantly more frequent than in controls. In addition, anger was associated with LEV and depression with CBZ. Confounding factors were depression and uncontrolled epilepsy.

The role of the corpus callosum in seizure spread: MRI lesion mapping in oligodendrogliomas.

BACKGROUND: Some patients with oligodendrogliomas have generalized tonic-clonic seizures (GTCS) while others have only partial seizures (PS). We investigated the relationship between tumour localization and seizure generalization using quantitative lesion mapping on magnetic resonance images. METHODS: Twenty one patients with histologically proven oligodendrogliomas and GTCS (n=11) or PS (n=10) were studied. Data were acquired on a 3 Tesla MRI System. We performed lesion mapping techniques to compare the spatial distribution of oligodendrogliomas between patient groups, and quantitatively determined the extent to which lesions intersected each probabilistic regions-of-interest, including the cerebral lobes, thalamus, striatum, and genu of the corpus callosum. RESULTS: In patients experiencing GTCS, the greatest lesion load was observed in mesial frontal regions, including cortex connected to the genu. In contrast, the greatest lesion load in patients experiencing PS was observed more caudo-laterally in orbitofrontal and temporal lobes, but typically sparing cortex connected to the genu. The number of lesion intersections with genu region of interest was significantly greater in patients experiencing GTCS relative to patients with PS (p=0.03). There were no significant differences between patient groups with respect to lesion intersection with the individual cerebral lobes, thalamus and striatum, or with respect to overall oligodendroglioma size. CONCLUSION: Our data suggest that the genu of the corpus callosum may be a major pathway for seizure generalization in patients with oligodendrogliomas.

Self-reported symptoms in patients on antiepileptic drugs in monotherapy.

OBJECTIVE: To ascertain the frequency of self-reported symptoms in patients taking antiepileptic drugs (AED). METHODS: We included patients on carbamazepine (CBZ) n = 36, valproate (VPA) n = 21, levetiracetam (LEV) n = 12, phenytoin (PHT) n = 11, lamotrigine (LTG) n = 20, patients not taking anticonvulsive drugs n = 19, and healthy control subjects (CTRL) n = 41 to complete the Liverpool Adverse Event Profile (LAEP). RESULTS: The mean LAEP scores were CBZ/PHT/LEV/VPA/LTG/noAED/CTRL = 44.97/42.00/41.00/40.33/32.42/42.00/30.80. LEV scored overall in the same range as the older AED but had a different adverse effect profile with self-reported anger (33%) and shaky hands (42%) particularly frequent. Patients with depression or uncontrolled epilepsy had significantly higher LAEP scores than patients without depression or uncontrolled epilepsy. CONCLUSION: Our unblinded observational study of self-reported symptoms suggested LTG was overall the drug with the least self-reported symptoms. Larger studies are needed to determine whether this was a truly significant difference. LEV had a different side effect profile to older AED. Confounding factors were depression and uncontrolled epilepsy. This observation should be further tested with randomized studies.

Risk factors for early post-operative psychiatric symptoms in patients undergoing epilepsy surgery for temporal lobe epilepsy.

OBJECTIVE: De-novo psychiatric symptoms may develop within 3 months after a temporal lobectomy for epilepsy. The objective of this study was to identify presurgical risk factors for psychiatric symptoms. METHODS: Twenty-seven patients who had a temporal lobectomy for epilepsy were included. Twenty-four had hippocampal sclerosis or gliosis, and three had cavernous haemagiomata. Twelve had operations on the left, and 15 on the right side. Twenty-four patients were rendered free of seizures (SZ) with loss of awareness, three had early post-operative convulsions, one continued to have habitual SZ. RESULTS: Nine patients (33%) developed low mood, anxiety and emotional lability within 3 months after surgery. Patients with early post-operative psychiatric symptoms were younger (27.9/34.8 years, P = 0.01), and more anxious on the presurgical Hospital Anxiety and Depression Scale (12/8.44, P = 0.02) than patients without post-operative psychiatric symptoms. There was also an association between right temporal lobectomies and early post-surgical symptoms (P = 0.02 Fisher's exact test). CONCLUSION: Potential risk factors were age, anxiety and operation on the right side. Larger studies are required to determine if these risk factors are independent.

Predictors of outcome after temporal lobectomy for refractory temporal lobe epilepsy.

OBJECTIVE: To identify predictors of outcome after epilepsy surgery in patients with temporal lobe epilepsy (TLE). METHODS: Seventy-six patients with normal magnetic resonance imaging (MRI) or hippocampal sclerosis on MRI who underwent anterior temporal lobe resections were included. Outcome 2 years after surgery was classified as good (Engel I and II) or poor (Engel III and IV). Gender, age at onset and duration of epilepsy, history of febrile convulsions, auras, right- or left-sided TLE, memory ipsilateral to seizure onset (Wada test), hippocampal asymmetry (HA) and T2 relaxation time, amygdala, temporal lobe and hemispheral volume were tested for associations with outcome. RESULTS: Sixty-seven percent had a good outcome. Of all parameters tested, only a history of febrile convulsions and HA on quantitative MRI were significantly associated with a good seizure outcome. The absence of these parameters did not exclude a good outcome, but only five of 18 patients (28%) without HA and without a history of febrile convulsions had a good outcome. CONCLUSION: Febrile convulsions and HA were predictors of outcome after epilepsy surgery in TLE. Subtle volume loss in amygdala, temporal lobe or hemispheres and the memory ipsilateral to the side of resection were not associated with outcome.

The seizure outcome after amygdalohippocampectomy and temporal lobectomy.

The aim of this study was to compare the seizure outcome of two different types of epilepsy surgery, selective amygdalohippocampectomy (AHE) and anterior temporal lobectomy (ATLE) in patients with temporal lobe epilepsy. We included 114 patients who had mesio-temporal lobe epilepsy and hippocampal sclerosis or gliosis on histology. Patients had ATLE if the non-dominant hemisphere was affected or if the whole temporal lobe was atrophic. Patients had AHE if the dominant hemisphere was affected. Standardized seizure outcome at 1 year following surgery was used. Overall 40% of the 114 patients who had temporal lobe epilepsy surgery were seizure-free at 1-year (Engel's class Ia). A good outcome (Engel's classes I and II) was significantly more frequent in ATLE than in AHE. (66% and 44%, respectively, P = 0.03). ATLE had a better seizure outcome than AHE.

Degree of hippocampal atrophy is related to side of seizure onset in temporal lobe epilepsy.

BACKGROUND AND PURPOSE: Temporal lobe epilepsy (TLE) is associated with pathologic changes in hippocampal physiology and morphology. Our aim was to quantify volume reduction of the right and left hippocampus in patients with TLE and to investigate whether the degree of hippocampal atrophy is related to the side of seizure onset. METHODS: The volume of the right and left hippocampus was estimated for 50 controls and 101 patients with TLE, by applying the unbiased Cavalieri method on MR images. RESULTS: Pairwise comparisons, within a multivariate analysis of variance and adjusted by using the Bonferroni correction, revealed that both right and left hippocampal volumes were, on average, significantly smaller in patients with right-sided seizure onset (R-patients) relative to those of controls (P < .001 and P = .04, respectively). Furthermore, left hippocampal volume was significantly smaller in patients with left-sided seizure onset (L-patients) compared with controls (P < .001), but the right-sided hippocampal volume was not significantly smaller (P = .71). Moreover, a correlation analysis revealed that the strong linear association between the right and left hippocampal volumes existing in the control population (r = 0.73) is partially lost in patients with TLE (r < or = 0.48), and this loss in correlation appears to be more pronounced in L-patients than in R-patients. CONCLUSION: Our MR imaging results suggest that although the major damage in patients with TLE is located in the hippocampus ipsilateral to the side of seizure onset, R-patients are more likely to have bilateral hippocampal volume reduction. These findings support the hypothesis that cerebral hemispheres may not only differ in their functionality organization but also in their vulnerability to a neurologic insult.

Clinical application of neuroimaging in epilepsy.

OBJECTIVE: To evaluate the use of neuroimaging in clinical practice and to assess the prevalence of detected structural abnormalities in epilepsy patients in a clinical set up. METHODS: 919 outpatients were identified and the scan results reviewed. A total of 677 patients had chronic active epilepsy (88 had idiopathic generalised epilepsy (IGE), 588 had localisation related epilepsy, one had symptomatic generalised epilepsy), 57 had a single epileptic seizure, 46 were in remission, and 139 had non-epileptic attacks. RESULTS: 391 patients had no scan (53 patients in this group had IGE, 182 had localisation related epilepsy, one had generalised symptomatic epilepsy, 18 had single epileptic attacks, 21 were in remission, 116 had non-epileptic attacks). Altogether 528 patients had a scan, the results were not available in 33, 163 had x ray computed tomography (CT) only, 178 had standard magnetic resonance imaging (MRI) (slice thickness 5 mm), and 154 had high resolution MRI (including a T1 weighted sequence with 1.5 mm thick slices). Some 252 of 495 scans (51%) were abnormal. Abnormalities were hippocampal sclerosis (n=128), atrophy or non-specific white matter lesions (n=35), vascular abnormalities (n=27), tumours (n=25), brain damage (n=24), malformations of cortical development (n=13). Excluding atrophy and non-specific white matter lesions the prevalence of detected abnormalities was 54% in localisation related epilepsy, 18% in single seizure patients, 16% in epilepsy in remission, and 0% in IGE and non-epileptic attacks. CONCLUSIONS: Abnormalities were detected in more than half of all patients with localisation related epilepsy, and in about one in five patients with single seizures or epilepsy in remission. Many patients had no scan or only CT or standard MRI. The true prevalence of structural abnormalities may be have been higher. Scanning did not add any information in patients with IGE or non-epileptic attacks.

Foramen ovale recordings: a presurgical investigation in epilepsy.

The aim of our study was to determine when foramen ovale recordings add useful information to scalp EEG recordings and magnetic resonance imaging (MRI) with hippocampal measurements. We evaluated the outcome of 79 patients with non-lesional partial epilepsy with presumed temporal seizure onset. Ictal foramen ovale recordings were performed in 16 patients with normal MRI ('MRI-negative group') and 41 patients with lateralizing MRI but non-lateralizing scalp EEG ('discordant group'). 22 patients with concordant MRI and scalp EEG were not investigated with foramen ovale recordings ('concordant group'). The seizure-free rate was higher in concordant than discordant patients despite additional investigation with foramen ovale electrodes (71 and 55% seizure free, respectively). No useful localizing information was added with foramen ovale recordings in MRI-negative patients.

Voxel based morphometry of grey matter abnormalities in patients with medically intractable temporal lobe epilepsy: effects of side of seizure onset and epilepsy duration.

OBJECTIVES: To investigate the use of whole brain voxel based morphometry (VBM) and stereological analysis to study brain morphology in patients with medically intractable temporal lobe epilepsy; and to determine the relation between side, duration, and age of onset of temporal lobe epilepsy, history of childhood febrile convulsions, and grey matter structure. METHODS: Three dimensional magnetic resonance images were obtained from 58 patients with left sided seizure onset (LSSO) and 58 patients with right sided seizure onset (RSSO), defined using EEG and foramen ovale recordings in the course of presurgical evaluation for temporal lobectomy. Fifty eight normal controls formed a comparison group. VBM was used to characterise whole brain grey matter concentration, while the Cavalieri method of modern design stereology in conjunction with point counting was used to estimate hippocampal and amygdala volume. Age and sex were used as confounding covariates in analyses. RESULTS: LSSO and RSSO patients showed significant reductions in volume (using stereology) and grey matter concentration (using VBM) of the hippocampus, but not of the amygdala, in the presumed epileptogenic zone when compared with controls, but hippocampal (and amygdala) volume and grey matter concentration were not related to duration or age of onset of epilepsy. LSSO and RSSO patients with a history of childhood febrile convulsions had reduced hippocampal volumes in the presumed epileptogenic zone compared with patients without such a history. Left amygdala volume was also reduced in LSSO patients with a history of childhood convulsions. VBM results indicated bilateral thalamic, prefrontal, and cerebellar GMC reduction in patients, which correlated with duration and age of onset of epilepsy. CONCLUSIONS: Hippocampal sclerosis is not necessarily the consequence of recurrent temporal lobe seizures. A major cause of hippocampal sclerosis appears to be an early aberrant neurological insult, such as childhood febrile seizures. Secondary brain abnormalities exist in regions outside the presumed epileptogenic zone and may result from recurrent seizures.

Combined functional magnetic resonance imaging and diffusion tensor imaging demonstrate widespread modified organisation in malformation of cortical development.

A patient with a mild left hemiparesis and a malformation of cortical development in the right hemisphere was investigated with fMRI (functional magnetic resonance imaging) and DTI (diffusion tensor imaging). The motor cortex was studied using a finger tapping fMRI experiment. The fibre orientation was studied by displaying the principal eigenvector of the diffusion tensor in the spatially normalised brain of the patient and of control subjects. In addition, the anisotropy (directionality) of water diffusion of the patient was statistically compared with control subjects. The malformation was located in the right central region in the expected position of the motor cortex. fMRI showed activation anterior and posterior to the malformation. DTI disclosed that fibres with rostrocaudal orientation, presumably representing the pyramidal tract, were deviating from their normal orientation and passing around the malformation. There were widespread regions of reduced anisotropy affecting both hemispheres. In conclusion, fMRI and DTI provided concordant information showing widespread modified functional and structural organisation including regions which appeared normal on standard imaging.

Changes in cerebral hemodynamics during simple partial motor seizures.

Changes in cerebral perfusion were studied during nine short-lasting simple partial motor seizures (SPS) in an 11-year-old girl. Blood flow velocity changes in both middle cerebral arteries (MCAs) were assessed by transcranial Doppler sonography during simultaneous EEG monitoring. Within 7.4 +/- 1.4 s after electroencephalographic seizure onset, flow velocity in the MCA ipsilateral to the electrical discharges started to increase and then gradually rose up to 70% above baseline values. Spread of the epileptic activity to the other hemisphere in the late stage of seizure was associated with a slight increase in blood flow velocity (<30%) in the contralateral MCA. After the end of the seizure, flow velocities returned to baseline within 47 +/- 7 s. Our findings indicate that focal epileptic seizures evoke asymmetric perfusion increases which are closely related to the onset and cessation of the electroencephalographic seizure activity.

Diffusion tensor imaging demonstrates deviation of fibres in normal appearing white matter adjacent to a brain tumour.

The objective was to study fibre orientation in the cerebral white matter of a patient with a brain tumour using diffusion tensor imaging (DTI). A patient with a mild left hemiparesis and a tumour in the right frontal lobe and 20 healthy volunteers were scanned with a DTI sequence. The scans were spatially normalised and the fibre orientation in the patient compared with the fibre orientation in normal controls. DTI disclosed a change of the orientation of fibres in the patient compared with normal controls. In the normal appearing white matter adjacent to the tumour fibres deviated from the normal superior inferior orientation in the corona radiata by about 30 degrees. This finding was consistent with a displacement by distant mass effect rather than a destruction of fibres, in agreement with the neurological examination. In conclusion, DTI demonstrated a deviation of fibres in normal appearing white matter adjacent to a tumour. The technique will improve understanding of the effects of structural abnormalities on fibres. This will assist the interpretation of clinical findings and functional imaging studies and guide neurosurgical interventions.

Reduced anisotropy of water diffusion in structural cerebral abnormalities demonstrated with diffusion tensor imaging.

We used diffusion tensor imaging (DTI) to investigate the behavior of water diffusion in cerebral structural abnormalities. The fractional anisotropy, a measure of directionality of the molecular motion of water, and the mean diffusivity, a measure of the magnitude of the molecular motion of water, were measured in 18 patients with longstanding partial epilepsy and structural abnormalities on standard magnetic resonance imaging and the results compared with measurements in the white matter of 10 control subjects. Structural abnormalities were brain damage (postsurgical brain damage, nonspecific brain damage, perinatal brain damage, perinatal infarct, ischemic infarct, perinatal hypoxia, traumatic brain damage (n = 3), mitochondrial cytopathy and mesiotemporal sclerosis), dysgenesis (cortical dysplasia (n = 2) and heterotopia) and tumors (meningioma (n = 2), hypothalamic hamartoma and glioma). Anisotropy was reduced in all structural abnormalities. In the majority of abnormalities this was associated with an increased mean diffusivity; however, 30% of all structural abnormalities (some patients with brain damage and dysgenesis) had a normal mean diffusivity in combination with a reduced anisotropy. There was no correlation between fractional anisotropy and mean diffusivity measurements in structural abnormalities (r = -0.1). Our findings suggest that DTI is sensitive for the detection of a variety of structural abnormalities, that a reduced anisotropy is the common denominator in structural cerebral abnormalities of different etiologies and that mean diffusivity and fractional anisotropy may be, in part, independent. Combined measurements of mean diffusivity and fractional anisotropy are likely to increase the specificity of DTI.

Multimodal MR imaging: functional, diffusion tensor, and chemical shift imaging in a patient with localization-related epilepsy.

PURPOSE: To demonstrate the integration of complementary functional and structural data acquired with magnetic resonance imaging (MRI) in a patient with localization-related epilepsy. METHODS: We studied a patient with partial and secondarily generalized seizures and a hemiparesis due to a malformation of cortical development (MCD) in the right hemisphere by using EEG-triggered functional MRI (fMRI), diffusion tensor imaging (DTI), and chemical shift imaging (CSI). RESULTS: fMRI revealed significant changes in regional blood oxygenation associated with interictal epileptiform discharges within the MCD. DTI showed a heterogeneous microstructure of the MCD with reduced fractional anisotropy, a high mean diffusivity, and displacement of myelinated tracts. CSI demonstrated low N-acetyl aspartate (NAA) concentrations in parts of the MCD. CONCLUSIONS: The applied MR methods described functional, microstructural, and biochemical characteristics of the epileptogenic tissue that cannot be obtained with other noninvasive means and thus improve the understanding of the pathophysiology of epilepsy.

Hippocampal layers on high resolution magnetic resonance images: real or imaginary?

To evaluate whether the lines occasionally detected on clinical magnetic resonance (MR) images are genuine hippocampal layers, a formalin fixed hippocampal specimen was scanned using T2 weighted sequences at 7 Tesla (voxel dimensions 0.064 x 0.064 x 1 mm) and at 1.5 Tesla (voxel dimensions: 0.156 x 0.156 x 1 mm) and compared with the results of histological examination. In addition, a healthy volunteer was scanned with a T2 weighted sequence at 1.5 Tesla (voxel dimensions: 0.469 x 0.469 x 2 mm). On 7 Tesla images hippocampal layers and the granule cell layer of the dentate were visible. On 1.5 Tesla images of the specimen, the hippocampal layers were again identified, but the granule cell layer of the dentate was not detectable. On 1.5 Tesla images of the hippocampus in vivo, 3 layers could be distinguished in the hippocampus on some slices. These mainly represented the alveus, pyramidal cell layer and stratum radiatum. A dark line consisting of a few pixels possibly represented the dentate gyrus. Our results show that the lines occasionally detected on clinical MR images are likely to be real hippocampal layers. However, the resolution currently used in clinical imaging (typically 0.469 x 0.469 x 2 mm or lower) is not sufficient for the detection of all hippocampal layers. For the reliable detection of all hippocampal layers on MR images an increase by a factor of approximately 20 would be necessary.

Wallerian degeneration in the optic radiation after temporal lobectomy demonstrated in vivo with diffusion tensor imaging.

PURPOSE: Diffusion tensor imaging allows the quantitative assessment of the microstructural organization of tracts in vivo (MR tractography). We used the new technique of MR tractography to demonstrate the effects of temporal lobectomy on the optic radiation. METHODS: Spatially normalised maps encoding magnitude of the bias (anisotropy) of diffusion of three patients with temporal lobe resections were compared with spatially normalised diffusion maps of 22 control subjects. All three patients were operated on for the treatment of medically intractable temporal lobe epilepsy and had a normal neurologic examination before surgery. One patient had an amygdalocorticectomy. Two patients had standard en bloc resections, one of whom developed a homonymous hemianopia after surgery. RESULTS: In the patient with hemianopia, a significant reduction of diffusion anisotropy (greater than mean+/-2 SD) consistent with wallerian degeneration was demonstrated in the optic radiation on the side of the temporal lobectomy, extending from the temporal to the occipital lobe. In the other patient with standard en bloc resection but clinically no hemianopia, the optic radiation was only marginally affected. In the third patient (amygdalocorticectomy), the diffusion anisotropy was within the normal range in the expected position of the optic radiation. CONCLUSIONS: Our findings show that MR tractography may be a useful tool to demonstrate wallerian degeneration in the optic radiation after temporal lobectomy in patients with hemianopia. This is the first time that this new method has been applied in postoperative imaging; it enables us to visualise the morphologic correlate of dysfunctional pathways after epilepsy surgery in vivo. The potential for using MR tractography to study other aspects of epilepsy is discussed.