Darrell V. Lewis

A comparison of automated segmentation and manual tracing for quantifying hippocampal and amygdala volumes

Large databases of high-resolution structural MR images are being assembled to quantitatively examine the relationships between brain anatomy, disease progression, treatment regimens, and genetic influences upon brain structure. Quantifying brain structures in such large databases cannot be practically accomplished by expert neuroanatomists using hand-tracing. Rather, this research will depend upon automated methods that reliably and accurately segment and quantify dozens of brain regions. At present, there is little guidance available to help clinical research groups in choosing such tools. Thus, our goal was to compare the performance of two popular and fully automated tools, FSL/FIRST and FreeSurfer, to expert hand tracing in the measurement of the hippocampus and amygdala. Volumes derived from each automated measurement were compared to hand tracing for percent volume overlap, percent volume difference, across-sample correlation, and 3-D group-level shape analysis. In addition, sample size estimates for conducting between-group studies were computed for a range of effect sizes. Compared to hand tracing, hippocampal measurements with FreeSurfer exhibited greater volume overlap, smaller volume difference, and higher correlation than FIRST, and sample size estimates with FreeSurfer were closer to hand tracing. Amygdala measurement with FreeSurfer was also more highly correlated to hand tracing than FIRST, but exhibited a greater volume difference than FIRST. Both techniques had comparable volume overlap and similar sample size estimates. Compared to hand tracing, a 3-D shape analysis of the hippocampus showed FreeSurfer was more accurate than FIRST, particularly in the head and tail. However, FIRST more accurately represented the amygdala shape than FreeSurfer, which inflated its anterior and posterior surfaces.

Facilitation of the induction of long-term potentiation by GABAB receptors

Long-term potentiation (LTP), an in vitro model of learning, was induced in hippocampal slices by 5-hertz stimulation. During induction, gamma-aminobutyric acid A (GABAA) inhibition decreased, causing the N-methyl-D-aspartate receptor-mediated excitation to increase. 2-OH Saclofen, a GABAB receptor antagonist, prevented the reduction of inhibition, the increase of excitation, and the induction of LTP. Therefore, disinhibition caused by GABAB receptors is required for induction of LTP by 5-hertz stimulation. GABAB receptor modulation of synaptic plasticity occurs at frequencies in the range of the endogenous hippocampal theta rhythm, which has been shown to modulate LTP in vivo.

Magnesium-free medium activates seizure-like events in the rat hippocampal slice ☆

The effect of magnesium-free medium on the electrical activity in CA3 of the rat hippocampal slice was examined. Magnesium removal resulted in the development of spontaneous and triggered interictal-like bursting, followed by spontaneous ictal-like events and finally periodic clustered bursts. The ictal-like events consisted of a tonic firing phase and a phase of clustered burst discharges resembling the tonic and clonic phases of seizures. The return to normal medium resulted in spontaneous and triggered interictal-like bursts.

The Pharmacology and Function of Central GabaB Receptors

In conclusion, GABAB receptors enable GABA to modulate neuronal function in a manner not possible through GABAA receptors alone. These receptors are present at both pre- and postsynaptic sites and can exert both inhibitory and disinhibitory effects. In particular, GABAB receptors are important in regulating NMDA receptor-mediated responses, including the induction of LTP. They also can regulate the filtering properties of neural networks, allowing peak transmission in the frequency range of theta rhythm. Finally, GABAB receptors are G protein-coupled to a variety of intracellular effector systems, and thereby have the potential to produce long-term changes in the state of neuronal activity, through actions such as protein phosphorylation. Although the majority of the effects of GABAB receptors have been reported in vitro, recent studies have also demonstrated that GABAB receptors exert electrophysiological actions in vivo. For example, GABAB receptor antagonists reduce the late IPSP in vivo and consequently can decrease inhibition of spontaneous neuronal firing following a stimulus (Lingenhöhl and Olpe, 1993). In addition, blockade of GABAB receptors can increase spontaneous activity of central neurons, suggesting the presence of GABAB receptor-mediated tonic inhibition (Andre et al., 1992; Lingenhöhl and Olpe, 1993). Despite these electrophysiological effects, antagonism of GABAB receptors has generally been reported to produce few behavioral actions. This lack of overt behavioral effects most likely reflects the modulatory nature of the receptor action. Nevertheless, two separate behavioral studies have recently reported an enhancement of cognitive performance in several different animal species following blockade of GABAB receptors (Mondadori et al., 1992; Carletti et al., 1993). Because of their small number of side effects, GABAB receptor antagonists may represent effective therapeutic tools for modulation of cognition. Alternatively, the lack of overt behavioral effects of GABAB receptors may indicate that these receptors are more important in pathologic rather than normal physiological states (Wojcik et al., 1989). For example, a change in receptor affinity or receptor number brought on by the pathology could enhance the effectiveness of GABAB receptors. Of significance, CGP 35348 has been shown to block absence seizures in genetically seizure prone animals, while inducing no seizures in control animals (Hosford et al., 1992; Liu et al., 1992). Thus, GABAB receptors may represent effective sites for pharmacological regulation of absence seizures. Perhaps further behavioral effects of these receptors will become apparent only after additional studies have been performed using the highly potent antagonists that have been recently introduced.(ABSTRACT TRUNCATED AT 400 WORDS)

Study of Heart and Renal Protection (SHARP): Randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease

BACKGROUND Lowering low-density lipoprotein (LDL) cholesterol with statin therapy has been shown to reduce the incidence of atherosclerotic events in many types of patient, but it remains uncertain whether it is of net benefit among people with chronic kidney disease (CKD). METHODS Patients with advanced CKD (blood creatinine ≥ 1.7 mg/dL [≥ 150 μmol/L] in men or ≥ 1.5 mg/dL [ ≥ 130 μmol/L] in women) with no known history of myocardial infarction or coronary revascularization were randomized in a ratio of 4:4:1 to ezetimibe 10 mg plus simvastatin 20 mg daily versus matching placebo versus simvastatin 20 mg daily (with the latter arm rerandomized at 1 year to ezetimibe 10 mg plus simvastatin 20 mg daily vs placebo). The key outcome will be major atherosclerotic events, defined as the combination of myocardial infarction, coronary death, ischemic stroke, or any revascularization procedure. RESULTS A total of 9,438 CKD patients were randomized, of whom 3,056 were on dialysis. Mean age was 61 years, two thirds were male, one fifth had diabetes mellitus, and one sixth had vascular disease. Compared with either placebo or simvastatin alone, allocation to ezetimibe plus simvastatin was not associated with any excess of myopathy, hepatic toxicity, or biliary complications during the first year of follow-up. Compared with placebo, allocation to ezetimibe 10 mg plus simvastatin 20 mg daily yielded average LDL cholesterol differences of 43 mg/dL (1.10 mmol/L) at 1 year and 33 mg/dL (0.85 mmol/L) at 2.5 years. Follow-up is scheduled to continue until August 2010, when all patients will have been followed for at least 4 years. CONCLUSIONS SHARP should provide evidence about the efficacy and safety of lowering LDL cholesterol with the combination of ezetimibe and simvastatin among a wide range of patients with CKD.

Human herpesvirus 6 limbic encephalitis after stem cell transplantation

Central nervous system complications are common in stem cell transplant recipients, but selective involvement of the medial temporal area is unusual. The 5 patients reported here presented after stem cell transplantation with increased hippocampal T2 signal on magnetic resonance imaging and increased hippocampal glucose uptake on [F‐18]fluorodeoxyglucose‐positron emission tomography (FDG‐PET) associated with short‐term memory loss, insomnia, and temporal lobe electrographic seizure activity. The initial scalp electroencephalograms (EEGs) failed to detect seizure activity in these patients, although the memory dysfunction along with the magnetic resonance imaging and FDG‐PET findings suggested subcortical seizure activity. However, extended EEG monitoring revealed repetitive temporal lobe electrographic seizure activity. Follow‐up MRIs in 2 patients and postmortem findings on 1 patient suggested that hippocampal sclerosis had developed following the clinical syndrome. Cerebrospinal fluid studies revealed the presence of human herpesvirus 6, variant B, DNA in all of 3 patients who had lumbar punctures. Immunohistochemical staining for the P41 and P101 human herpesvirus 6 protein antigens showed numerous immunoreactive astrocytes and neurons in the hippocampus of 1 of the patients who died from other causes. Because of its subtle clinical presentation, this syndrome may be underrecognized, but can be diagnosed with appropriate magnetic resonance imaging techniques, EEG monitoring, and cerebrospinal fluid viral studies.

Seizure outcome after temporal lobectomy for temporal lobe epilepsy A Kaplan-Meier survival analysis

Objective: To determine seizure outcome and its predictors in patients with medically refractory temporal lobe epilepsy (TLE) after temporal lobectomy (TL). Background: TL is the most common surgical procedure performed in adolescents and adults for the treatment of medically refractory TLE. Seizure outcome has been reported extensively during the first few postoperative years, but little is known beyond that time. Methods: The authors analyzed seizure outcome in 79 patients who underwent TL for epilepsy at the Duke University Medical Center from 1962 through 1984. Patients with less than 2 years of follow-up and degenerative disorders were excluded. Predictors of seizure outcome were analyzed using Kaplan-Meier survival analyses. Results: The mean follow-up was 14 years (range, 2.1 to 33.6 years). Using Engel’s classification, 65% of patients were class I, 15% were class II, 11% were class III, and 9% were class IV. At least one postoperative seizure occurred in 55% of subjects. The majority of recurrences (86%) took place within 2 years of surgery. Later recurrences tended not to lead to medical intractability. Higher monthly preoperative seizure frequency was associated with poor seizure outcome. A seizure-free state at 2 years was found to be a better predictor of long-term outcome than the 6-, 12-, and 18-month landmarks. Conclusions: TL provides sustained, long-term benefit in patients with medically refractory TLE. Seizure-free status at 2 years from the time of surgery is predictive of long-term remission.

Anterior temporal lobectomy for complex partial seizures Evaluation, results, and long‐term follow‐up in 100 cases

We report evaluation and results in 100 patients who had undergone anterior temporal lobectomy for intractable complex partial seizures. Average follow-up was 9.0 years (range, 2 to 21 years). In the 2nd postoperative year, 63% were seizure free, 16% were significantly improved, and 21% were considered not significantly improved. Mean number of seizures in the last group was 27% of preoperative levels. Surgical results did not change significantly in subsequent postoperative years; good outcomes tended to persist over the longer term. We also examined the utility of continuous depth electrode monitoring in the evaluation of patients with independent bitemporal interictal epileptiform activity. Despite limited numbers of subjects in this category, there was a trend toward improved surgical outcome when such subjects were evaluated with depth electrodes.

Magnetic resonance imaging evidence of hippocampal sclerosis in progression: a case report.

Summary: A 32‐month‐old child presented in status epilepticus (SE) involving the left side of the body. Fast spin‐echo magnetic resonance imaging (FSE‐MRI) with hippocampal volumetry performed ≤24 h after the seizure showed increased T2 signal of the right hippocampus, but no atrophy. Complex partial seizures (CPS) appeared at age 33 months, and three more episodes of SE occurred between 33 and 37 months of age. Follow‐up FSE‐MRI at 34 and at 45 months of age demonstrated progressive hippocampal atrophy with resolution of the increased T2 signal. Her CPS became intractable and, at age 51 months, she underwent right temporal lobectomy. In the ensuing 5 months, she has had only one major motor seizure. This case demonstrates that acute increased hippocampal T2 signal intensity can occur soon after SE and hippocampal sclerosis (HS) may become evident within months in the setting of recurrent early childhood SE. This observation may support the hypothesis that early childhood SE can lead to HS. Furthermore, this case suggests that years of temporal lobe CPS may not be necessary for development of HS.

Seizure-like events in brain slices: suppression by interictal activity

A major concern in epilepsy research is the relationship between ictal (seizure) electrophysiological activity and interictal (between seizure) activity. Much research is carried out in vitro using brain slice models. Although they allow detailed electrophysiology, the events recorded are generally more similar to interictal than ictal activity. We have described an in vitro model of epileptiform activity in the hippocampal slice (exposure to artificial cerebrospinal fluid containing no added magnesium) in which the events closely resemble those seen in vivo during seizures. However, this model is limited by the brief period during which this ictaform activity occurs before it is replaced by interictal-like activity. We now report that as the frequency of the interictal activity is suppressed by the GABAB agonist baclofen, the ictal activity returns. Moreover, when frequent interictal activity is reinduced, the ictal activity again is suppressed. These results suggest that interictal activity may decrease the probability of a seizure. Furthermore, they suggest that substances which may be shown to inhibit interictal activity in various models of epilepsy may not necessarily inhibit ictal activity.