Diffuse form of dysembryoplastic neuroepithelial tumour: the histological and immunohistochemical features of a distinct entity showing transition to dysembryoplastic neuroepithelial tumour and ganglioglioma.

AIMS: A diffuse variant of dysembryoplastic neuroepithelial tumour (dDNT) has previously been described, which although composed of oligodendroglia-like cells (OLC), astrocytes and mature neurones, lacks the multinodularity and 'specific component' of typical DNT. The dDNT poses a significant challenge to the neuropathologist. This study was undertaken to further characterize the histological and immunohistochemical features of dDNT. MATERIALS AND METHODS: Review of our archived material from epilepsy surgery identified 16 cases, in which features of dDNT predominated. Their histological and immunohistochemical features, including CD34 and nestin immunohistochemistry, were analysed. RESULTS: Seven cases had the characteristics of pure dDNT. A further two cases of dDNT showed extension into the white matter with occasional dysplastic neurones. Two additional cases had similar features but with the presence of either single, or multiple small nodular clusters of OLC, in keeping with transition to classical DNT. Five cases showed ganglioglioma-like areas, of which three cases had micronodule formation but with predominant dDNT pattern. In all the cases the dDNT areas showed strong CD34 and less intense nestin immunoreactivity and microglial activation highlighting the full extent of the lesions. There was variable overlap between CD34 and nestin positivity within the micronodular and/or ganglioglioma-like areas. CONCLUSIONS: Immunoreactivity for CD34 and nestin characterizes the dDNT and helps to distinguish it from other lesions associated with epilepsy. Histological evidence indicative of transition of dDNT to other forms of DNT and ganglioglioma suggests that dDNT might be an early histogenetic form of these glioneuronal tumours.

Imaging haemodynamic changes related to seizures: comparison of EEG-based general linear model, independent component analysis of fMRI and intracranial EEG.

BACKGROUND: Simultaneous EEG-fMRI can reveal haemodynamic changes associated with epileptic activity which may contribute to understanding seizure onset and propagation. METHODS: Nine of 83 patients with focal epilepsy undergoing pre-surgical evaluation had seizures during EEG-fMRI and analysed using three approaches, two based on the general linear model (GLM) and one using independent component analysis (ICA): The results were compared with intracranial EEG. RESULTS: The canonical GLM analysis revealed significant BOLD signal changes associated with seizures on EEG in 7/9 patients, concordant with the seizure onset zone in 4/7. The Fourier GLM analysis revealed changes in BOLD signal corresponding with the results of the canonical analysis in two patients. ICA revealed components spatially concordant with the seizure onset zone in all patients (8/9 confirmed by intracranial EEG). CONCLUSION: Ictal EEG-fMRI visualises plausible seizure related haemodynamic changes. The GLM approach to analysing EEG-fMRI data reveals localised BOLD changes concordant with the ictal onset zone when scalp EEG reflects seizure onset. ICA provides additional information when scalp EEG does not accurately reflect seizures and may give insight into ictal haemodynamics.

Misdiagnosis in epilepsy: a review and recognition of diagnostic uncertainty.

The diagnosis of first seizure or epilepsy may be challenging and misdiagnosis can occur. Studies carried out in various settings have reported misdiagnosis rates of between 4.6% and 30%. Misdiagnosis can lead to serious consequences including driving and employment restrictions and inappropriate treatments. Most studies focus on ways of reducing misdiagnosis. However, in some cases, it may be difficult to make a definite diagnosis at initial presentation. This is because of a number of reasons including overlapping clinical features with other conditions, inadequate available history and limitations of investigations. Consequently, diagnostic uncertainty is inevitable in epilepsy, although few studies acknowledge this. In this paper we review the literature on misdiagnosis rates, analyse reasons for misdiagnosis and consider limitations of available investigations. We propose that diagnostic uncertainty in epilepsy should be more widely acknowledged and addressed, and that this may reduce misdiagnosis rates.

Factors limiting the application of electrical impedance tomography for identification of regional conductivity changes using scalp electrodes during epileptic seizures in humans.

Electrical impedance tomography (EIT) has the potential to produce images during epileptic seizures. This might improve the accuracy of the localization of epileptic foci in patients undergoing presurgical assessment for curative neurosurgery. It has already been shown that impedance increases by up to 22% during induced epileptic seizures in animal models, using cortical or implanted electrodes in controlled experiments. The purpose of this study was to determine if reproducible raw impedance changes and EIT images could be collected during epileptic seizures in patients who were undergoing observation with video-electroencephalography (EEG) telemetry as part of evaluation prior to neurosurgery to resect the region of brain causing the epilepsy. A secondary purpose was to develop an objective method for processing and evaluating data, as seizures arose at unpredictable times from a noisy baseline. Four-terminal impedance measurements from 258 combinations were collected continuously using 32 EEG scalp electrodes in 22 seizure episodes from 7 patients during their presurgical assessment together with the standard EEG recordings. A reliable method for defining the pre-seizure baseline and recording impedance data and EIT images was developed, in which EIT and EEG could be acquired simultaneously after filtering of EIT artefact from the EEG signal. Fluctuations of several per cent over minutes were observed in the baseline between seizures. During seizures, boundary voltage changes diverged with a standard deviation of 1-54% from the baseline. No reproducible changes with the expected time course of some tens of seconds and magnitude of about 0.1% could be reliably measured. This demonstrates that it is feasible to acquire EIT images in parallel with standard EEG during presurgical assessment but, unfortunately, expected EIT changes on the scalp of about 0.1% are swamped by much larger movement and systematic artefact. Nevertheless, EIT has the unique potential to provide invaluable neuroimaging data for this purpose and may still become possible with improvements in electrode design and instrumentation.

A study of mortality after temporal lobe epilepsy surgery.

OBJECTIVE: To determine early and late mortality in a cohort of 305 consecutive patients who had temporal lobe epilepsy (TLE) surgery over a 20-year period. METHODS: Survival status, cause of death, and postoperative clinical details of those who died were ascertained in a cohort of 305 patients who had TLE surgery. Mortality was related to postoperative seizure status, operative pathology, and side of resection. RESULTS: The survival status of 299 patients was established. Twenty deaths occurred. Mortality was 1 per 136 person-years, with a standardized mortality ratio (SMR) of 4.5 (95% confidence interval [CI], 3.2 to 6.6). Six deaths were sudden and unexpected (SUDEP). The SUDEP rate was 1 per 455 person-years. The overall death and SUDEP rates were lower than those reported for similar patient populations with chronic epilepsy. Mortality in patients who had right-sided resections for mesial temporal sclerosis (MTS) remained considerably elevated with a mortality rate of 1 per 54 person-years, an SMR of 32.0 (95% CI, 24.7 to 40.5), and a SUDEP rate of 1 per 134 person-years. These patients had significantly lower seizure remission rates than left-sided patients, but the excess mortality was not simply explained by those patients whose partial seizures were uninfluenced by surgery. Patients who died had more severe or convulsive seizures despite an overall reduction in seizure frequency. CONCLUSIONS: The present findings confirm previous reports that TLE surgery lowers but does not normalize the overall mortality associated with chronic epilepsy. In patients with right-sided MTS, however, the postoperative mortality has remained similar to other groups with medically intractable seizures.

Coexistence of temporal lobe and idiopathic generalized epilepsies.

OBJECTIVE: To assess the interrelation of idiopathic generalized epilepsy (IGE) and temporal lobe epilepsy (TLE) when they coexist in the same patient. METHODS: The authors reviewed the electroclinical features of 350 consecutive patients who had temporal resection between 1975 and 1997 at the Maudsley and King's College Hospitals, London. RESULTS: Two patients had the unusual combination of TLE and IGE (0.57%). In the first, the clinical onset of juvenile myoclonic epilepsy followed the surgical resolution of his partial seizures but had been heralded for at least 5 years by subclinical spontaneous and photically induced generalized spike-wave discharges. In the second, TLE and juvenile absence epilepsy had a long parallel course before surgery. After surgery he had no further partial seizures. CONCLUSION: These cases suggest that when an idiopathic absence or myoclonic syndrome manifests in a patient with symptomatic TLE, the phenotype may not be a merged syndrome. Rather, the two conditions can retain their inherent electroclinical profile, responsiveness to treatment, and prognosis.

N-Acetylaspartate and creatine levels measured by (1)H MRS relate to recognition memory.

OBJECTIVES: To investigate the relationship between recognition memory and metabolite levels in medial structures of the temporal lobes in the living human brain. METHODS: Proton MRS ((1)H MRS) and the intracarotid amobarbital test were performed in 16 epileptic patients found suitable for temporal lobectomy. All patients had mesial temporal sclerosis. Metabolite ratios between N:-acetylaspartate (NAA), creatine and phosphocreatine (Cr + PCr), and choline-containing compounds (Cho) [NAA/(Cr + PCr), NAA/Cho, and NAA/(Cr + PCr + Cho)] were calculated for (1)H MRS voxels that included the amygdala, anterior half of the hippocampus, and underlying subiculum. Metabolite ratios were correlated with unilateral memory scores estimated by the intracarotid amobarbital test for words, objects, faces, and total score. RESULTS: The total memory score, memory for objects and faces, and NAA/(Cr + PCr) were significantly lower for the hemisphere ipsilateral to the resection. The asymmetry indexes for NAA/(Cr + PCr) correlated with asymmetry indexes for words (rho = 0.82, p = 0.0001) and total memory (rho = 0. 72, p = 0.002). Analysis of memory scores and metabolite ratios from all 32 hemispheres revealed a correlation between NAA/(Cr + PCr) and memory for words (rho = 0.45, p = 0.009). A correlation between memory for words and NAA/(Cr + PCr) existed in the contralateral (rho = 0.58, p = 0.019) and in the right (rho = 0.51, p = 0.045) hemispheres, and a trend was found in the left hemispheres (rho = 0. 48, p = 0.06). CONCLUSION: There is a correlation between memory for words and the NAA/(Cr + PCr) ratio from medial temporal structures in patients with mesial temporal sclerosis. The findings suggest that medial temporal structures and adjacent neocortex play a significant role in recognition memory in humans, particularly for words.

Significance of interictal bilateral temporal hypometabolism in temporal lobe epilepsy.

OBJECTIVE: To assess the clinical implications and the pathophysiologic determinants of interictal bitemporal hypometabolism (BTH) in temporal lobe epilepsy (TLE) not associated with bilateral MRI abnormalities or intracranial space-occupying lesions. METHODS: The authors compared the clinical, interictal, and ictal EEG, Wada test, and neuropsychology data of 15 patients with intractable complex partial seizures of temporal lobe origin and BTH with those of 13 consecutive patients with unilateral TLE associated with unilateral temporal hypometabolism (UTH) who remained seizure free for more than 3 years after anterior temporal lobectomy. 18F-fluorodeoxyglucose PET scans were analyzed visually and semiquantitatively, and ratios of counts in individual temporal areas to the rest of the cerebrum were compared with the corresponding values from 11 normal control subjects and with the nonepileptogenic hemisphere of the 13 patients with UTH. BTH was defined as more than 2.5 SDs below control values for two or more temporal areas on each side irrespective of any asymmetry. RESULTS: BTH reflected bilateral independent seizure onset in eight patients (53%). The topography of the metabolic depression was not a reliable predictor of epileptogenicity, but involvement of the inferior temporal gyrus was related specifically to ipsilateral seizure onset (70% sensitivity, 100% specificity). In patients with unilateral TLE, contralateral hypometabolism was associated with longer disease duration and worst memory performance during the Wada test, which amounted to global amnesia after ipsilateral injection in three patients, precluding surgical treatment. Contralateral seizure spread in the ictal EEG was significantly faster in patients with BTH. CONCLUSIONS: In TLE, symmetric or asymmetric BTH may signal bilateral independent seizure onset in approximately half the patients, especially when involving the inferior temporal gyrus. Alternatively, it may reflect an advanced stage of the disease process, characterized by a breakdown of the inhibitory mechanisms in the contralateral hemisphere, and secondary memory deficit associated with higher risk of postoperative memory decline. Patients with TLE and BTH but without bilateral MRI changes may still be operated on successfully, but surgical suitability should be proved by comprehensive intracranial EEG studies and Wada test.

Chronic encephalitis and temporal lobe epilepsy: a variant of Rasmussen's syndrome?

The authors report two adult patients with chronic temporal lobe epilepsy and pathologic features consistent with Rasmussen's encephalitis. Although seizures persisted after temporal lobe surgery no progressive cognitive or neurologic deficit has emerged. Prominent auditory auras in each suggested a persisting epileptogenic focus in the superior temporal gyrus. The current findings expand the clinical spectrum of Rasmussen's encephalitis and suggest that chronic nonprogressive encephalitis may serve as the pathologic substrate of medically intractable temporal lobe epilepsy.

Postictal psychosis after temporal lobectomy.

Three of 282 consecutive patients who had temporal resections for intractable epilepsy developed postoperative postictal psychosis. These three patients had seizure recurrence contralateral to the resection, whereas none of the patients with ipsilateral seizure recurrence developed any psychiatric symptoms after surgery. Two had left amygdalo-hippocampectomy and one right temporal lobectomy. The de novo occurrence of postoperative postictal psychosis is a well-defined complication of surgery for temporal lobe epilepsy, and may relate to contralateral epileptogenesis.

Clinical pharmacokinetics of newer antiepileptic drugs. Lamotrigine, vigabatrin, gabapentin and oxcarbazepine.

The clinical pharmacokinetics of the 4 antiepileptic drugs lamotrigine, vigabatrin, gabapentin and oxcarbazepine have been reviewed in this paper. All the drugs have linear kinetics and reliable absorption, although the saturation of transport across the gut may occur at high doses with gabapentin. All the drugs can be conveniently given as a twice daily dosage apart from gabapentin, which has a short half-life and a midday dose is needed. Unlike many of the older drugs, lamotrigine, vigabatrin and gabapentin have a predominantly renal excretion and are not metabolised through the cytochrome P450 system. They do not induce their own metabolism or that of other commonly used anticonvulsants. Similarly, clinically important interactions with other major classes of drugs metabolised this way, such as anticoagulants or steroid hormones, do not occur. Oxcarbazepine, however, can cause oral contraceptive pill failure. Oxcarbazepine is immediately metabolised to a hydroxy metabolite and could be considered a prodrug. It appears to have fewer pharmacokinetic interactions than carbamazepine. Valproic acid (sodium valproate) inhibits the glucuronidation of lamotrigine and increases its half-life; when used together, dosage modification of lamotrigine is needed to avoid toxicity.

Sources of error in comparing functional magnetic resonance imaging and invasive electrophysiological recordings.

OBJECT: Several authors have recently reported studies in which they aim to validate functional magnetic resonance (fMR) imaging against the accepted gold standard of invasive electrophysiological monitoring. The authors have conducted a similar study, and in this paper they identify and quantify two characteristics of these data that can make such a comparison problematic. METHODS: Eight patients in whom surgery for epilepsy was performed and five healthy volunteers underwent fMR imaging to localize the part of the sensorimotor cortex responsible for hand movement. In the patient group subdural electrode mats were subsequently implanted to identify eloquent regions of the brain and the epileptogenic zone. The fMR imaging data were processed to correct for motion during the study and then registered with a postimplantation computerized tomography (CT) scan on which the electrodes were visible. The motion during imaging in the two groups studied, and the deformation of the brain between the preoperative images and postoperative scans were measured. The patients who underwent epilepsy surgery moved significantly more during fMR imaging experiments than healthy volunteers performing the same motor task. This motion had a particularly increased out-of-plane component and was significantly more correlated with the stimulus than in the volunteers. This motion was especially increased when the patients were performing a task on the side affected by the lesion. The additional motion is hard to correct and substantially degrades the quality of the resulting fMR images, making it a much less reliable technique for use in these patients than in others. Also, the authors found that after electrode implantation, the brain surface can shift more than 10 mm relative to the skull compared with its preoperative location, substantially degrading the accuracy of the comparison of electrophysiological measurements made in the deformed brain and fMR studies obtained preoperatively. CONCLUSIONS: These two findings indicate that studies of this sort are currently of limited use for validating fMR imaging and should be interpreted with care. Additional image analysis research is necessary to solve the problems caused by patients' motion and brain deformation.

Thyroid status in patients with chronic renal failure.

Serum thyroid hormone concentrations have been measured in 21 patients with chronic renal failure, treated conservatively and compared with values from 19 control subjects. Many patients had serum total T3 and T4 concentrations below the reference ranges. The concentrations of free T4 and free T3 and the free thyroxine index were significantly lower in patients with abnormal total concentrations of the thyroid hormones than in the controls. Both the free and the total concentrations of T4 correlated inversely with the degree of renal failure. The concentration of thyroxine binding globulin (TBG), fell within the reference range in each of the patients, but was significantly lower in the patient group when compared with the controls. These TBG concentrations, however, were not sufficiently decreased to explain the low total thyroid hormone concentrations found in the patients. The affinity of TBG for T4 and T3 in the patient and control groups was not significantly different. The TSH response to TRH was diminished in many of the patients, but the measurement of other pituitary hormones indicated that pituitary function was normal in these patients. The possible mechanisms responsible for the changes observed in thyroid and pituitary hormones are discussed.

The course of untreated epilepsy.

As little is known about the course of untreated epilepsy the time intervals between untreated tonic clonic seizures were examined retrospectively in a series of 183 patients presenting to a neurological department having had two to five seizures. After the first seizure a second attack had occurred within one month in 56 patients, within three months in 93, and within one year in 159. The median interval between the first two seizures was 12 weeks (95% confidence interval 10 to 18 weeks), between the second and third eight weeks (four to 12 weeks), between the third and fourth four weeks (two to 20 weeks), and between the fourth and fifth three weeks (one to four weeks). When patients who had had three, four, or five untreated seizures were considered separately a similar pattern of decreasing intervals was seen. Successive intervals between seizures could be compared in 82 patients. In 48 the interval decreased, in 16 it did not change, and in 18 it increased. These results suggest that in many patients there is an accelerating disease process in the early stages of epilepsy.