Muscarinic receptor loss and preservation of presynaptic cholinergic terminals in hippocampal sclerosis.

PURPOSE: Prior single-photon emission tomography studies showed losses of muscarinic acetylcholine receptor (MAChR) binding in patients with refractory mesial temporal lobe epilepsy. Experimental animal studies demonstrated transient losses of MAChR due to electrically induced seizures originating in the amygdala. However, the relations between cholinergic synaptic markers, seizures, and underlying neuropathology in human temporal lobe epilepsy are unknown. We tested the hypotheses that human brain MAChR changes are attributable to hippocampal sclerosis (HS), and that HS resembles axon-sparing lesions in experimental animal models. METHODS: We measured MAChR binding-site density, an intrinsic neuronal marker, within the hippocampal formation (HF) in anterior temporal lobectomy specimens from 10 patients with HS and in 10 autopsy controls. Binding-site density of the presynaptic vesicular acetylcholine transporter (VAChT) was measured as a marker of extrinsic cholinergic afferent integrity. MAChR and VAChT results were compared with neuronal cell counts to assess their relations to local neuronal losses. RESULTS: Reduced MAChR binding-site density was demonstrated throughout the HF in the epilepsy specimens compared with autopsy controls and correlated in severity with reductions in cell counts in several HF regions. In contrast to MAChR, VAChT binding-site density was unchanged in the epilepsy specimens compared with autopsy controls. CONCLUSIONS: Reduction in MAChR binding in HS is attributable to intrinsic neuronal losses. Sparing of afferent septal cholinergic terminals is consistent with the hypothesis that an excitotoxic mechanism may contribute to the development of HS and refractory partial epilepsy in humans.

Late-onset generalized disorder of peroxisomes.

We diagnosed a unique peroxisomal disorder in a 32-year-old man with profound mental retardation, mild facial dysmorphism, retinal pigmentary degeneration, seizures, and sensorineural deafness. Although plasma very-long-chain fatty acid profile suggested X-linked adrenoleukodystrophy, marked reduction in fibroblast lignoceric acid oxidation and the presence of cytosolic catalase were consistent with Zellweger syndrome (ZS). Unlike ZS, functional peroxisomes were present as indicated by the density of peroxisomes (1.175 gm/ml) similar to peroxisomes from control cells and by partial deficiencies of fibroblast phytanic acid oxidation and dihydroxyacetone phosphate acyltransferase activity. These findings indicate that this patient has a previously undescribed group 3 peroxisomal disorder (multiple peroxisomal enzyme deficiencies with preserved peroxisomes).

Temporal lobe central benzodiazepine binding in unilateral mesial temporal lobe epilepsy.

PET-demonstrated decreases in [11C]flumazenil binding occur in anterior mesial temporal structures on the side of epileptogenesis in unilateral mesial temporal lobe epilepsy. We performed quantitative autoradiography on anterior mesial and lateral temporal specimens from 11 subjects with unilateral mesial temporal lobe epilepsy and six neurologically normal controls to identify the predominant in vitro correlates of the decreased [11C]flumazenil binding. In anterior mesial temporal regions exhibiting the greatest neuronal cell loss, decreases in agonist and antagonist binding to type 1 and 2 (central) benzodiazepine binding sites were highly correlated with neuronal cell counts. Cell loss and decreased binding were particularly prominent in the lateral portion of hippocampal region CA1, adjacent to CA2. Lateral temporal central benzodiazepine binding was diffusely increased, achieving statistical significance in cortical laminae V and VI. These findings suggest that the predominant source of PET-demonstrated decreases in [11C]flumazenil binding in mesial temporal epilepsy is hippocampal sclerosis, rather than down-regulation of central benzodiazepine binding sites on surviving hippocampal neurons.

Felbamate pharmacology and use in epilepsy.

Felbamate, 2-phenyl-1,3-propanediol dicarbamate, is an antiepileptic drug recently approved by the United States Food and Drug Administration. It has a novel mechanism of action whereby it may decrease excitation by inhibiting glycine binding at the NMDA receptor, and it appears to have neuroprotective properties in addition to antiepileptic ones. A number of animal models have demonstrated felbamate to have a broad range of efficacy as well as a favorable safety profile. In humans it has been potentially linked to some cases of aplastic anemia. It is effective in the treatment of partial and secondarily generalized tonic-clonic seizures as well as seizures associated with the Lennox-Gastaut syndrome, especially drop attacks. It may also be effective against atypical absence as well as other seizure types. Felbamate monotherapy is generally well tolerated, with such side effects as insomnia and anorexia occurring most commonly. Felbamate shows great promise as a useful antiepileptic drug, but its role in clinical practice awaits further investigation of recently reported cases of aplastic anemia.

Quantitative autoradiography of [3H]t-butylbicycloorthobenzoate binding to the gamma-aminobutyric acid receptorA complex.

The picrotoxinin ligand [3H]t-butylbicycloorthobenzoate ([3H] TBOB) was evaluated as an autoradiographic ligand to study gamma-aminobutyric acidA (GABAA) receptors. Specific [3H]TBOB binding was approximately 80% of total binding, was saturable and identified a single population of binding sites with regional Kd approximating 30 nM. [3H]TBOB binding was inhibited by picrotoxin, isoguvacine and pregnenolone sulfate. The benzodiazepines clonazepam and zolpidem produced complex effects with concentration-dependent inhibition and enhancement of [3H] TBOB binding. [3H]TBOB binding was regionally heterogeneous with high levels of binding in globus pallidus and layer IV of neocortex, intermediate levels of binding in other neocortical laminae and the cerebellar molecular layer and low levels of binding in the striatum and septum. The regional distribution of [3H]TBOB binding correlated poorly with the regional distribution of [3H]muscimol binding, somewhat better with the regional distribution of [3H]flunitrazepam binding and [35S]t-butylbicyclophosphorothionate binding and quite well with the regional distribution of [3H]zolpidem binding. [3H]TBOB binding site autoradiography is a convenient technique for studying GABAA receptor pharmacology in a regionally specific manner.

Transcranial Doppler sonographic monitoring in the intensive care unit.

Transcranial Doppler sonography noninvasively measures flow velocities within the basal cerebral arteries. It has been used for the management of patients with ischemic cerebrovascular disease and subarachnoid hemorrhage, as well as in the determination of brain death. Its role and technical limitations in the intensive care unit are reviewed.