Surgical resection for intractable epilepsy in "double cortex" syndrome yields inadequate results.

PURPOSE: To analyze the results of surgical treatment of intractable epilepsy in patients with subcortical band heterotopia, or double cortex syndrome, a diffuse neuronal migration disorder. METHODS: We studied eight patients (five women) with double cortex syndrome and intractable epilepsy. All had a comprehensive presurgical evaluation including prolonged video-EEG recordings and magnetic resonance imaging (MRI). RESULTS: All patients had partial seizures, with secondary generalization in six of them. Neurologic examination was normal in all. Three were of normal intelligence, and five were mildly retarded. Six patients underwent invasive EEG recordings, three of them with subdural grids and three with stereotactic implanted depth electrodes (SEEG). Although EEG recordings showed multilobar epileptic abnormalities in most patients, regional or focal seizure onset was recorded in all. MRI showed bilateral subcortical band heterotopia, asymmetric in thickness in three. An additional area of cortical thickening in the left frontal lobe was found in one patient. Surgical procedures included multiple subpial transections in two patients, frontal lesionectomy in one, temporal lobectomy with amygdalohippocampectomy in five, and an additional anterior callosotomy in one. Five patients had no significant improvement, two had some improvement, and one was greatly improved. CONCLUSION: Our results do not support focal surgical removal of epileptogenic tissue in patients with double cortex syndrome, even in the presence of a relatively localized epileptogenic area.

Alzheimer's disease: in vivo detection of differential vulnerability of brain regions.

The severe cognitive impairment during the later stages of Alzheimer's disease is usually preceded by a selective disturbance in the ability to remember new experiences. With quantitative, high-resolution magnetic resonance imaging techniques, it is now possible to determine, in vivo, differences in the pattern of anatomical changes that might reflect behavioral symptomatology during different stages of the disease. In the present investigation, magnetic resonance imaging examinations were carried out in aged controls and in clinically diagnosed Alzheimer's disease patients who were divided into three groups based upon dementia severity. Atrophy of the hippocampal formation, a region important for memory function, was observed even in Alzheimer's disease patients with the mildest dementia. With more prominent dementia, atrophy extended to the parahippocampal gyrus and the temporal neocortex.

Cholinergic synapses in human cerebral cortex: an ultrastructural study in serial sections.

Cholinergic axons in the human cerebral cortex were analyzed by electron microscopy. Choline acetyltransferase (ChAT) immunoreactivity was used to identify cholinergic axons in samples of anterior temporal lobe removed at surgery. A systematic survey of labeled axon varicosities, visualized in complete serial sections, showed that 67% of all varicosities formed identifiable synaptic specializations. These synapses were usually symmetric and quite small, often present in only one to two serial sections. However, an occasional synapse was asymmetric and larger, seen in five to seven serial sections. The postsynaptic processes at cholinergic synapses were often identified as spiny dendrites or spines. The existence of cholinergic axons in the human cerebral cortex has been demonstrated in numerous studies. Our findings provide the first ultrastructural evidence that these axons make synaptic contact with cortical neurons in the human brain.

Synapse restructuring associated with the maintenance phase of hippocampal long-term potentiation.

Synapses in the middle molecular layer of the rat dentate gyrus were analyzed by electron microscopy during the maintenance phase of long-term potentiation (LTP). LTP was induced by high-frequency stimulation of the medial perforant path carried out on each of 4 consecutive days. The dentate gyrus was examined electron microscopically 13 days following the fourth stimulation. At this time point, synaptic responses were still significantly enhanced relative to baseline, although the extent of their potentiation was lower than 1 hour after the last high-frequency stimulation. Stimulated, but not potentiated, rats served as controls. Using the stereological double disector method, estimates of the number of different morphological types of synapses per postsynaptic neuron were obtained. The number of asymmetrical axodendritic synapses increased (by 28%) during LTP maintenance, whereas the number of other synaptic types was not significantly altered. Our previous work demonstrated that the induction of LTP is followed by a selective increase in the number of axospinous perforated synapses with multiple, completely partitioned, transmission zones. Thus, the induction and maintenance phases of LTP are characterized by different structural synaptic alterations. These alterations may be related to each other as indicated by another finding of the present study regarding the existence of perforated synapses that appear to be transitional between axospinous and axodendritic junctions. This suggests a model of structural synaptic plasticity associated with LTP in which some axospinous perforated synapses increase in numbers shortly after the induction of LTP and are then converted into axodendritic ones during LTP maintenance.

Landau-Kleffner syndrome. Treatment with subpial intracortical transection.

Landau-Kleffner syndrome (LKS) is an acquired epileptic aphasia occurring in childhood and associated with a generally poor prognosis for recovery of speech. It is thought to be the result of an epileptogenic lesion arising in speech cortex during a critical period of development. Utilizing a new surgical technique designed to eliminate the capacity of cortical tissue to generate seizures while preserving the normal cortical physiological function, we have treated 14 children with aphasia, seizures and a severely abnormal EEG by multiple subpial transection of the epileptogenic cortex. Seven of the 14 patients (50%) have recovered age-appropriate speech, are in regular classes in school and no longer require speech therapy. Four of the 14 (29%) have shown marked improvement, are speaking and understanding verbal instruction but are still receiving speech therapy. Thus, 11 of the 14 (79%), none of whom had used language to communicate for at least 2 years, are now speaking--a rate of sustained improvement considered unusual in this disorder. This study documents the value of a treatment modality not previously used in LKS. Success depends on selection of cases having severe epileptogenic abnormality that can be demonstrated to be unilateral in origin despite a bilateral electrographic manifestation.

Tailored anterior temporal lobectomy. Relation between extent of resection of mesial structures and postsurgical seizure outcome.

OBJECTIVE: The purpose of this study was to assess the relationship between the extent of resection of mesial temporal structures and postsurgical seizure outcome in a group of patients who had undergone a tailored anterior temporal lobectomy. METHODS: Twenty-four patients with unilateral interictal and ictal foci restricted to anterior/mesial temporal regions underwent resection of mesial and temporal lateral structures, the extent of which was tailored by intraoperative electrocorticographic findings and functional mapping of eloquent cortex. The extent of resection was determined with postoperative magnetic resonance imaging scans, using a semiquantitative method, based on a 20-compartment model of the temporal lobe. The magnetic resonance imaging scans were rated by three investigators blinded to seizure outcome. Follow-up period ranged between 18 months and 5 years. RESULTS: Amygdala and hippocampus were spared in six patients; nine patients had a partial to total resection of amygdala, eight patients had a resection of amygdala and the anterior third of the hippocampus, and one patient underwent resection of amygdala and anterior two thirds of hippocampus. Twenty-one of the 24 patients were seizure free (Engel's class I) and three had rare seizures (Engel's class II). Among these three patients, one had a resection of amygdala; one had resection of amygdala and anterior third of hippocampus; while in the third patient, mesial structures were spared. CONCLUSION: These data suggest that in patients with an anterotemporal seizure focus, the sparing or limited resection of amygdala and/or hippocampus is not necessarily associated with a poor seizure outcome, as had been previously suggested, provided that the decision not to resect is based on the absence of epileptiform activity during intraoperative electrocorticography or during recordings with depth electrodes.

Structural synaptic correlate of long-term potentiation: formation of axospinous synapses with multiple, completely partitioned transmission zones.

Synapses were analyzed in the middle molecular layer (MML) and inner molecular layer (IML) of the rat dentate gyrus following the induction of long-term potentiation (LTP) by high-frequency stimulation of the medial perforant path carried out on each of 4 consecutive days. Potentiated animals were sacrificed 1 hour after the fourth high frequency stimulation. Stimulated but not potentiated and implanted but not stimulated animals served as controls. Using the stereological disector technique, unbiased estimates of the number of synapses per postsynaptic neuron were differentially obtained for various subtypes of axospinous junctions: For atypical (giant) nonperforated synapses with a continuous postsynaptic density (PSD), and for perforated ones distinguished by (1) a fenestrated PSD and focal spine partition, (2) a horseshoe-shaped PSD and sectional spine partition, (3) a segmented PSD and complete spine partition(s), and (4) a fenestrated, (5) horseshoe-shaped, or (6) segmented PSD without a spine partition. The major finding of this study is that the induction of LTP in the rat dentate gyrus is followed by a significant and marked increase in the number of only those perforated axospinous synapses that have multiple, completely partitioned transmission zones. No other synaptic subtype exhibits such a change as a result of LTP induction. Moreover, this structural alteration is limited to the terminal synaptic field of activated axons (MML) and does not involve an immediately adjacent one (IML) that was not directly activated by potentiating stimulation. The observed highly selective modification of synaptic connectivity involving only one particular synaptic subtype in the potentiated synaptic field may represent a structural substrate of the long-lasting enhancement of synaptic responses that characterizes LTP.

Age-related loss of axospinous synapses formed by two afferent systems in the rat dentate gyrus as revealed by the unbiased stereological dissector technique.

Previous attempts to elucidate whether a loss of hippocampal synapses occurs during aging provided conflicting results, possibly due to the unavailability, at the time, of unbiased methods for synapse quantitation. This study was designed to reexamine the issue by means of modern technical procedures that provide unbiased estimates of synaptic numbers. Groups of 14 young adult (5 months old) and 14 aged (28 months old) male Fischer-344 rats were compared. Synapses were examined in the middle (MML) and inner (IML) molecular layer of the hippocampal dentate gyrus, where synaptic contacts are predominantly formed by different systems of afferents, the entorhinal and commissural-associational fibers, respectively. The number of synapses per neuron was estimated with the aid of the stereological dissector technique. The results showed that the total number of synaptic contacts per neuron was significantly diminished in the MML (by 23.6%) and IML (by 22.7%) of aged rats relative to young adults. This age-related synaptic loss involved axospinous, but not axodendritic, junctions of the MML (-24.4%) and IML (-24.0%). Both perforated and nonperforated axospinous synapses (distinguished by a discontinuous or continuous postsynaptic density, respectively) exhibited an age-dependent decrease in numbers, though this decrease did not reach statistical significance in the case of perforated junctions of the IML. The observed age-related loss of axospinous synapses may underlie the reduction in the amplitude of excitatory postsynaptic potentials and the decline in functional synaptic plasticity detected in the dentate gyrus of senescent rats.

Structural synaptic plasticity associated with the induction of long-term potentiation is preserved in the dentate gyrus of aged rats.

Changes in synaptic numbers were examined in the hippocampal dentate gyrus of aged (28 months old) rats following the induction of long-term potentiation (LTP) by high-frequency stimulation of the medial perforant path carried out on each of 4 consecutive days. Potentiated animals were sacrificed 1 hour after the fourth stimulation. Stimulated but not potentiated and implanted but not stimulated rats of the same chronological age served as controls. Synapses were analyzed in the middle (MML) and inner (IML) molecular layer of the dentate gyrus. Using the stereological dissector technique, unbiased estimates of the number per neuron were obtained for the following morphological varieties of synapses: axodendritic synaptic junctions involving dendritic shafts, nonperforated axospinous synapses having a continuous postsynaptic density (PSD), and perforated ones distinguished by a fenestrated, horseshoe-shaped, or segmented PSD. The induction of LTP resulted in a selective increase in the number of synapses with segmented PSDs. This change was detected only in the potentiated synaptic field (MML), but not in an immediately adjacent one (IML), which was not directly stimulated during the induction of LTP. Comparison of these data with the results of our previous LTP study in young adult rats (Geinisman, Y. et al., 1991, Brain Res. 566:77-88) showed that the only significant difference in the absolute number of synaptic contacts per neuron between potentiated animals of the two chronological ages was an age-related reduction in segmented synapses of the MML. Relative increases in the number of segmented synapses per neuron were, however, virtually of the same magnitude in potentiated rats of both ages as compared with their respective controls. This finding may explain why senescent rats can be potentiated to the same extent as young ones.

Epileptiform activity in chronically isolated cerebral cortex in humans.

The ability of neuronally isolated human cerebral cortex to sustain epileptiform rhythms over long time intervals is unknown. We report here two patients after functional hemispherectomy for infantile hemiplegia and infantile meningoencephalitis. Both patients had intractable seizures. EEG performed early and up to 3 years after surgery showed persistent epileptiform activity in the isolated frontal cortex in both cases. This indicates that human isolated cortex retains its epileptogenic potential for years, independently of subcortical influences. Previous related animal and human studies are briefly reviewed.

Increase in the number of axospinous synapses with segmented postsynaptic densities following hippocampal kindling.

Kindling results from intermittent electrical stimulation of a local brain region and leads to a virtually permanent augmentation of synaptic responsiveness in the stimulated circuit. It has been hypothesized that an increase in the number of synapses may represent a structural basis for the enduring expression of synaptic plasticity following kindling, but such an alteration has not been demonstrated unequivocally. The present report provides evidence that hippocampal kindling is indeed accompanied by an increase in synaptic numbers. Young adult rats were kindled via medial perforant path stimulation and sacrificed 4 weeks after reaching a criterion of 5 generalized seizures. Stimulated but not kindled and implanted but not stimulated rats served as controls. Synapses were analyzed in the middle (MML) and inner (IML) molecular layer of the hippocampal dentate gyrus. Using the stereological disector technique, unbiased estimates of the number of synapses per neuron were differentially obtained for 3 morphological subtypes of perforated axospinous synapses characterized by a fenestrated, horseshoe-shaped or segmented postsynaptic density (PSD). A significant increase in synaptic numbers was found to selectively involve only those perforated synapses which are distinguished by a segmented PSD consisting of 2-5 discrete plates. This structural modification was restricted to the terminal synaptic field of stimulated axons (MML), but was not observed in an immediately adjacent synaptic field (IML) which was not directly stimulated during kindling. Since synapses distinguished by a segmented PSD may represent specialized synaptic contacts of an unusually high efficacy, a selective increase in their numbers is likely to provide a structural substrate of the augmented synaptic gain associated with kindling.