Robert J. Simister

Cardiac arrhythmias in focal epilepsy: a prospective long-term study

BACKGROUND Patients with epilepsy are at risk of sudden unexpected death. Neurogenic cardiac arrhythmias have been postulated as a cause. Electrocardiograms (ECG) can be monitored by use of an implantable loop recorder for up to 18 months. We aimed to determine the frequency of cardiac arrhythmias in patients with refractory focal seizures over an extended period. METHODS 20 patients received an implantable loop recorder at one hospital in the UK. Devices were programmed to record automatically if bradycardia (<40 beats per min) or tachycardia (>140 beats per min) were detected. Additionally, in the event of a seizure, patients and relatives could initiate ECG recording with an external activator device. Data were analysed at regular intervals and correlated with seizure diaries. FINDINGS More than 220000 patient-hours were monitored over 24 months, during which ECGs were captured on implantable loop recorders in 377 seizures. One patient withdrew from the study. In 16 patients, median heart rate during habitual seizures exceeded 100 beats per min. Ictal bradycardia (<40 beats per min) was rare, occurring in eight (2.1%) recorded events, in seven patients. Four patients (21%) had bradycardia or periods of asystole with subsequent permanent pacemaker insertion. Three of these four (16% of total) had potentially fatal asystole. INTERPRETATION Clinical characteristics of patients with peri-ictal cardiac abnormalities are closely similar to those at greatest risk of sudden unexpected death in epilepsy. Asystole might underlie many of these deaths, which would have important implications for the investigation of similar patients and affect present cardiac-pacing policies.

Proton MRS reveals frontal lobe metabolite abnormalities in idiopathic generalized epilepsy.

Objective: To assess γ-aminobutyric acid (GABA) plus homocarnosine (GABA+) and glutamate plus glutamine (GLX) concentrations in the frontal lobes of patients with idiopathic generalized epilepsy (IGE). Methods: Twenty-one patients and 17 healthy volunteers were studied. A single voxel was prescribed in each frontal lobe for each subject. Point-resolved spectroscopy (PRESS)-localized short echo time MR spectroscopy (MRS) was performed to measure GLX and the metabolites N-acetylaspartate plus N-acetylaspartylglutamate (NAAt), creatine and phosphocreatine (Cr), choline-containing compounds (Cho), and myo-inositol (Ins). A double quantum GABA filter was used to measure GABA+. Segmented T1-weighted images gave the tissue composition of the prescribed voxel. Results: Group comparisons showed elevation of GLX and reduction of NAAt in the patient group (p < 0.05). The metabolite ratios GLX/NAAt and GLX/Ins also showed elevation in IGE (p = 0.01). No group effect was observed for GABA+, Cr, or Cho. Ins concentrations were not significantly reduced in the patient group but were less in the subgroup of patients who were taking sodium valproate. Conclusions: IGE was associated with bilateral frontal lobe metabolite changes. Elevation in GLX was observed, which may imply increased neuronal excitability, whereas reduction in NAAt suggests reduced overall neuronal numbers or neuronal dysfunction.

High-resolution diffusion tensor imaging of the hippocampus in temporal lobe epilepsy

PURPOSE To assess the quantitative diffusion characteristics of the hippocampus with high-resolution diffusion tensor imaging (DTI) in temporal lobe epilepsy (TLE). METHODS Thirteen controls and seven unilateral TLE patients (six with hippocampal sclerosis, one with normal magnetic resonance imaging (MRI)) were scanned with DTI using a zonally magnified oblique multislice echo planar imaging (ZOOM-EPI) acquisition. Fractional anisotropy (FA) and mean diffusivity (MD) were measured in the hippocampi. RESULTS The mean hippocampal MD ipsilateral to the seizure focus was higher than the contralateral MD in patients (p<0.05) and the mean MD in controls (p<0.001). Hippocampal FA ipsilateral to the seizure focus was lower than the mean FA in controls (p<0.05). MD asymmetry indexes were significantly different between the patient and control groups (p<0.01). All six individual HS patients had ipsilateral hippocampal MD >or=2 standard deviations (S.D.) above the control mean. The patient with normal structural MRI had bilaterally low hippocampal FA and high MD. DISCUSSION High-resolution DTI identifies lateralizing abnormalities of MD and FA in TLE patients. This quantitative data on hippocampal integrity may assist in evaluating TLE patients with normal MRI, and in longitudinal studies.

A Short‐echo‐time Proton Magnetic Resonance Spectroscopic Imaging Study of Temporal Lobe Epilepsy

Summary:  Purpose: We used short‐echo‐time proton magnetic resonance spectroscopy imaging (MRSI) to study metabolite concentration variation through the temporal lobe in patients with temporal lobe epilepsy (TLE) with and without abnormal MRI.

A proton magnetic resonance spectroscopy study of metabolites in the occipital lobes in epilepsy

Summary:  Purpose: γ‐Amino butyric acid (GABA) and glutamate, respectively the principal inhibitory and excitatory neurochemicals in the brain, are visible to proton magnetic resonance spectroscopy (MRS). We report a study of GABA+ (GABA plus homocarnosine) and GLX (glutamate plus glutamine) concentrations in the occipital lobes in patients with idiopathic generalised epilepsy (IGE) and in patients with occipital lobe epilepsy (OLE).

The effects of the dopamine agonist rotigotine on hemispatial neglect following stroke

Hemispatial neglect following right-hemisphere stroke is a common and disabling disorder, for which there is currently no effective pharmacological treatment. Dopamine agonists have been shown to play a role in selective attention and working memory, two core cognitive components of neglect. Here, we investigated whether the dopamine agonist rotigotine would have a beneficial effect on hemispatial neglect in stroke patients. A double-blind, randomized, placebo-controlled ABA design was used, in which each patient was assessed for 20 testing sessions, in three phases: pretreatment (Phase A1), on transdermal rotigotine for 7–11 days (Phase B) and post-treatment (Phase A2), with the exact duration of each phase randomized within limits. Outcome measures included performance on cancellation (visual search), line bisection, visual working memory, selective attention and sustained attention tasks, as well as measures of motor control. Sixteen right-hemisphere stroke patients were recruited, all of whom completed the trial. Performance on the Mesulam shape cancellation task improved significantly while on rotigotine, with the number of targets found on the left side increasing by 12.8% (P = 0.012) on treatment and spatial bias reducing by 8.1% (P = 0.016). This improvement in visual search was associated with an enhancement in selective attention but not on our measures of working memory or sustained attention. The positive effect of rotigotine on visual search was not associated with the degree of preservation of prefrontal cortex and occurred even in patients with significant prefrontal involvement. Rotigotine was not associated with any significant improvement in motor performance. This proof-of-concept study suggests a beneficial role of dopaminergic modulation on visual search and selective attention in patients with hemispatial neglect following stroke.

In vivo GABA+ measurement at 1.5T using a PRESS-localized double quantum filter.

A point‐resolved spectroscopy (PRESS)‐localized double quantum filter was implemented on a 1.5T clinical scanner for the estimation of γ‐amino butyric acid (GABA) concentrations in vivo. Several calibrations were found to be necessary for consistent results to be obtained. The apparent filter yield was approximately 38%; filter strength was sufficient to reduce the singlet metabolite peaks in vivo to below the level of the noise. Metabolite‐nulled experiments were performed, which confirmed that significant overlap occurred between macromolecule signals and the GABA resonance at 3.1 ppm. Although the multiplet arm at 2.9 ppm was confirmed to be relatively free of contamination with macromolecules, some contribution from these and from peptides is likely to remain; therefore, the term GABA+ is used. GABA+ concentrations were estimated relative to creatine (Cr) at the same echo time (TE) in a group of controls, studied on two occasions. The GABA+ concentration in 35‐ml regions of interest (ROIs) in the occipital lobe was found to be 1.4 ± 0.2 mM, with scan‐rescan repeatability of 38%. Magn Reson Med 48:233–241, 2002.

Long-term retention rates of new antiepileptic drugs in adults with chronic epilepsy and learning disability.

We compared the long-term retention rates of several newly licensed antiepileptic drugs (AEDs) in a residential community of adults with chronic epilepsy and learning disability. Data relating to duration of therapy, maximum dose, and tolerability of six new AEDs-gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), tiagabine (TIA), and topiramate (TPM)-were collected. Drug retention at 2 years was 85% (OXC), 57% (LTG), 56% (LEV), 45% (TPM), 24% (TIA) and 15% (GBP). OXC was used mainly as a substitute for carbamazepine. LTG, LEV, and TPM were all associated with retention rates higher than those of GBP or TIA. TPM had the highest rate of adverse event development at the maximum tried dose (60%), whereas LEV had the lowest (16%). Experience from this single epilepsy community study indicated limited impact for GBP or TIA but higher retention of OXC, LEV, LTG, and TPM in patients with chronic epilepsy and learning disability.

In vivo short echo time 1H-magnetic resonance spectroscopic imaging (MRSI) of the temporal lobes.

Two different methodologies for obtaining PRESS-localized magnetic resonance spectroscopic imaging (MRSI) data from the mesial and lateral temporal lobes were investigated. The study used short echo times (30 ms) and long repetition times (3000 ms) to minimize relaxation effects. Inhomogeneity and spectral distortions from the proximity of the temporal bones precluded the attainment of consistently good-quality data from both temporal lobes at once. Even when the right and left temporal lobes were studied separately, distortions often disturbed spectra from the anterior lateral temporal lobe. Quantitative analysis using LCModel was therefore performed only on the posterior lateral temporal lobe, and the posterior, middle, and anterior mesial temporal lobe. No significant left-right differences in metabolite content were found in a series of 10 controls. Significantly higher concentrations of myoinositol and choline were found in the anterior mesial temporal lobe, even when grey matter content was included as a covariate. The concentration of N-acetyl aspartate plus N-acetyl aspartyl glutamate (NAc) was not found to vary significantly along the length of the hippocampus. The previously observed lower anterior ratios of NAA to creatine plus choline (NAA/(Cr + Cho) may instead have been due to higher anterior choline. Large differences in metabolite concentrations were seen between posterior lateral temporal lobe (predominantly subcortical white matter) and the posterior mesial temporal lobe, most notably lower creatine, glutamate/glutamine, and myo-inositol, and higher NAA/(Cr + Cho) in the lateral than mesial temporal lobe. This pattern was similar to that previously seen for grey/white matter differences in the frontal, parietal and occipital regions.

Proton magnetic resonance spectroscopy of malformations of cortical development causing epilepsy

PURPOSE To use proton magnetic resonance spectroscopy (MRS) to measure concentrations of gamma-aminobutyric acid (GABA) and glutamate plus glutamine (GLX) in adult patients with refractory epilepsy associated with malformations of cortical development (MCD). METHODS We used MRS to measure N-acetyl aspartate (NAA), creatine plus phosphocreatine (Cr) and choline containing compounds (Cho), as well as GLX, and GABA. Fifteen patients with epilepsy attributable to MCD and 15 healthy controls were studied. Nine of the MCD group had heterotopia and six had polymicrogyria. Quantitative short echo time MRS [echo time (TE)=30 ms, repetition time (TR)=3000 ms] was performed in the MRI evident MCD and in the occipital lobes of the control group and the concentrations of NAA, Cr, Cho, and GLX were measured. GABA plus homocarnosine (GABA+) was measured in the same regions using a double quantum filter. RESULTS The dominant abnormalities in the patient group were elevation of Cho and GLX and reduction in NAAt compared to the control group. The ratios GLX/NAAt and GABA+/Cr were also increased in the patient group whilst the ratio NAAt/Cr was decreased. NAAt was significantly lower in polymicrogyria than heterotopia. CONCLUSIONS Large cortical malformations had abnormal levels of both GLX and GABA+/Cr. Low NAAt and high Cho were also observed. These results indicate that MCD show spectroscopic features of primitive tissue and abnormal metabolism of both inhibitory and excitatory neurotransmitters.