Jung H. Kim

Variations in the natural history and survival of patients with supratentorial low-grade astrocytomas.

Data from 55 consecutive patients with low-grade astrocytomas treated between 1982 and 1990 were analyzed to determine specific outcome factors, including time to recurrence, incidence of anaplastic transformation, and survival. Gender, type of symptoms, contrast enhancement, and timing of radiation therapy were not significant in determining outcome. Patients who had symptoms for > 2 years and underwent gross-total resection of the tumor, with age as a continuous variable, were associated with significantly longer time to recurrence and survival. Within the population of patients with low-grade astrocytomas, patients with chronic epilepsy clearly had the best prognoses. There were no tumor recurrences or deaths in 27 patients with chronic epilepsy, regardless of the extent of surgery and without the use of radiotherapy. Ten-year survival was 100% for 31 patients who underwent gross-total tumor resection, regardless of the length of preoperative symptoms. Immediate postoperative radiotherapy did not prolong the time to recurrence, reduce the incidence of transition to more malignant tumors at recurrence, or increase the length of survival when compared with delayed radiotherapy. Because recurrence with a high-grade lesion caused 92% of the mortality in our series, the benefit in patients who underwent aggressive surgery seems to result from a significant decrease in the risk of recurrence when compared with patients who underwent anything less than gross-total resection. Our data also suggest that variability in the natural history of low-grade astrocytomas has a strong influence in determining survival and that tumors associated with chronic epilepsy are much less likely to become more malignant over time.

Verbal memory impairment correlates with hippocampal pyramidal cell density

Thirty-five patients with medically refractory epilepsy localized to the temporal lobe (18 left, 17 right) completed the verbal Selective Reminding Test before surgery. Verbal memory impairments existed before surgery regardless of the lateralization of the seizure focus, but patients with left temporal seizure foci were significantly more impaired. After surgical removal of the mesial temporal lobe structures, 2 blinded observers established volumetric cell densities for hippocampal subfields CA1, CA2, CA3, the hilar area, and the granule cell layer of the area dentata. Statistically significant correlations existed between presurgical memory impairment and cell counts (in CA3 and the hilar area, only) for patients with left temporal seizure foci. These findings support the hippocampal model of memory and complement prior research documenting the memory impairments present after surgical removal of the mesial temporal structures.

Hippocampal neuronal density in temporal lobe epilepsy with and without gliomas

SummaryThe majority of patients with temporal lobe epilepsy show hippocampal sclerosis, which pathologically represents neuronal loss and gliosis. We studied volumetric neuronal density on a representative mid to mid-posterior level slice of hippocampi surgically removed from intractable temporal lobe epilepsy cases, and compared the results between 25 non-tumor epilepsy (NTE) cases and 5 tumor-associated epilepsy (TAE) cases. Eleven age-matched non-epileptic autopsy cases were studied as controls. Cells were counted in the CA1 through CA4 fields and the stratum granulosum of the dentate fascia. In NTE every hippocampal field showed statistically significant loss of neurons, the neuronal density in each field ranging from 35% to 50% of that of control. The mean neuronal density between the TAE and NTE groups also showed statistically significant differences in all hippocampal fields. The neuronal density of hippocampal fields of NTE ranged from 43% to 58% of that of TAE. Tumor-associated epilepsy cases, however, failed to show any statistically significant deviation from the control in their neuronal density. The etiology of the difference in neuronal density between the TAE and NTE groups is discussed.

Morphological Patterns of Seizures Recorded Intracranially

Summary: We analyzed the frequency and morphological characteristics of the initial EEG manifestations of spontaneous seizures recorded from depth and subdural electrodes in 26patients for whom pathological analysis of the area of seizure onset was available after resective surgery. Pathological features considered to be positive findings included well‐defined structural lesions (hamartoma, neoplasm) or strictly defined mesial temporal sclerosis. Seizure onset was characterized by the frequency of the rhythmic discharge >2 Hz in the first second and by the presence or absence of periodic low‐frequency spikes (<2 Hz) preceding this stable change in background frequency. These features were correlated with the presence or absence of pathologic abnormalities in temporal and extratemporal locations. Although all patterns and frequencies of seizure onset were recorded in both medial temporal and extratemporal locations, medial temporal seizure onset was significantly more likely to have high frequency (>13 Hz, p < 0.05) and no periodic spikes before seizure onset tended to periodic spikes prior to the seizure when it was associated with medial temporal sclerosis compared to when it was not. Extratemporal seizure onset associated with abnormal pathological substrate was significantly more likely to have a lower frequency (<13 Hz, p < 0.05) and no periodic spikes before seizure onset (p < 0.00001) than extratemporal seizure onset recorded from areas without pathological findings. Variability of seizure onset frequency was a characteristic of temporal, but not extra temporal, seizures (p < 0.01). The existence of such differences between seizures of temporal and extratemporal origin suggests that the underlying anatomy may in part determine these patterns, and that interpretation of EEG records of seizures beginning in different cerebral locations requires recognition of these differences.

A Retrospective Analysis of Hippocampal Pathology in Human Temporal Lobe Epilepsy: Evidence for Distinctive Patient Subcategories

Summary:  Purpose: This study is a retrospective analysis of the pathology of the hippocampus from patients with medically intractable temporal lobe epilepsy. We attempted to relate neuronal density, immunohistochemistry, electrophysiologic data, and surgical outcome.

n-3 Fatty Acids Preserve Insulin Sensitivity In Vivo in a Peroxisome Proliferator–Activated Receptor-α–Dependent Manner

Recent studies have suggested that n-3 fatty acids, abundant in fish oil, protect against high-fat diet–induced insulin resistance through peroxisome proliferator–activated receptor (PPAR)-α activation and a subsequent decrease in intracellular lipid abundance. To directly test this hypothesis, we fed PPAR-α null and wild-type mice for 2 weeks with isocaloric high-fat diets containing 27% fat from either safflower oil or safflower oil with an 8% fish oil replacement (fish oil diet). In both genotypes the safflower oil diet blunted insulin-mediated suppression of hepatic glucose production (P < 0.02 vs. genotype control) and PEPCK gene expression. Feeding wild-type mice a fish oil diet restored hepatic insulin sensitivity (hepatic glucose production [HGP], P < 0.002 vs. wild-type mice fed safflower oil), whereas in contrast, in PPAR-α null mice failed to counteract hepatic insulin resistance (HGP, P = NS vs. PPAR-α null safflower oil–fed mice). In PPAR-α null mice fed the fish oil diet, safflower oil plus fish oil, hepatic insulin resistance was dissociated from increases in hepatic triacylglycerol and acyl-CoA but accompanied by a more than threefold increase in hepatic diacylglycerol concentration (P < 0.0001 vs. genotype control). These data support the hypothesis that n-3 fatty acids protect from high-fat diet–induced hepatic insulin resistance in a PPAR-α–and diacylglycerol-dependent manner.

Glutamate-glutamine cycling in the epileptic human hippocampus.

Summary:  Purpose: Several findings suggest that energy metabolism and the glutamate–glutamine cycle may be impaired in epilepsy. Positron emission tomography often shows interictal hypometabolism of the epileptogenic hippocampus. In vivo microdialysis studies show that seizure‐associated glutamate release is doubled, and clearance is slowed. We hypothesized that the glutamate–glutamine cycle between neurons and glia may be decreased in the epileptic human hippocampus.

Monomorphous Angiocentric Glioma: A Distinctive Epileptogenic Neoplasm With Features of Infiltrating Astrocytoma and Ependymoma

We present 8 examples of a neoplasm with features of both astrocytoma and ependymoma that may represent a distinct clinicopathologic entity. The cerebral hemispheric tumors occurred in patients that were 3, 4, 12, 14, 15, 26, 30, and 37 years of age. All presented with seizures that, with the exception of 2, began in childhood. Magnetic resonance imaging studies showed ill-defined, T2-hyperintense, generally noncontrast-enhancing lesions that, although centered on the cortex or amygdala, extended into the underlying white matter for a short distance. Histologically, the variably infiltrative tumors were distinctively angiocentric with well-developed perivascular pseudorosettes in some cases. Longitudinal and/or circumferential orientations of perivascular cells were common also. The cells were uniform in their cytologic features from case to case and were bipolar in all but one case. A glial nature was inferred from immunoreactivity for GFAP, and ependymal differentiation was suggested by positivity for EMA in three cases and ultrastructural features in one. Overall, the tumors were biologically indolent except for one that recurred and ultimately proved fatal.

Ultrastructural Pathological Features of Cerebrovascular Malformations: A Preliminary Report

OBJECTIVE Although cerebrovascular malformations have been characterized histologically, a systematic examination of such lesions by transmission electron microscopy has not been previously published. In this preliminary study, we describe the ultrastructural pathological features of cerebral arteriovenous malformations (AVMs) and cavernous malformations (CMs). METHODS Using transmission electron microscopy, we examined three CMs and three AVMs microsurgically harvested from patients, for conventional indications. Normal control cerebral tissue was obtained from two patients undergoing surgery for epilepsy. Specific attention was directed at components of the vascular wall, endothelial cell (EC) morphology, intercellular tight junctions, and the subendothelial layer. RESULTS In embolized AVM vessels, ECs were disrupted, with preservation of the underlying subendothelial vessel wall. Nidal vessel walls of AVMs showed disorganized collagen bundles. In CM specimens, ECs lined attenuated cavern walls that were composed of an amorphous material lacking organized collagen. Peripheral to the CMs, capillaries were often surrounded by rings of hemosiderin. Tight junctions between ECs were present in AVMs and control specimens, but substantial inter-EC gaps were found in CMs. Subendothelial smooth muscle cells were present in AVM and control specimens, but they were sparse or poorly characterized in CMs. CONCLUSION Surgically resected vascular malformations demonstrate abnormal ultrastructural pathological features. The preoperative embolization of AVMs results in EC denudation, with preservation of vessel wall structural integrity. The thin walls of CMs, lacking significant subendothelial support, along with the rarity of intact tight junctions between ECs, may contribute to the known propensity of CMs for recurrent microhemorrhage.

Limbic and neocortical gliomas associated with intractable seizures: a distinct clinicopathological group.

The authors studied 65 patients with intractable seizures and glial tumors who were treated between 1978 and 1991. Most of the tumors were in the temporal (63%) or occipital lobe (18%) and were commonly found in limbic or perilimbic neocortical locations. The majority of these gliomas (83%) involved the gray matter of allocortex, neocortex, or transitional cortex. These tumors spanned a wide range of glial differentiation: Most (61%) were low-grade astrocytomas, but 17% were histologically malignant. However, their biological behavior was strikingly indolent, as suggested by a stable clinical history during many years of chronic seizures (mean, 15 yr). The median follow-up time since the onset of symptoms in these patients was 17.2 years, and only one patient in the entire series died from the tumor. The mainstay of the surgical treatment was resection of the gliomas to histologically confirmed, tumor-free margins. The resection was not guided by intraoperative electrocorticography. Of the 60 patients who had a postoperative follow-up of more than 1 year, 82% were seizure free. Of the 31 patients who had auras with their seizures, 87% did not retain their auras postoperatively. Of the patients who were rendered seizure free, only one patient continued to have auras. Failure in seizure control was associated with an incomplete resection of the lesion. In patients with temporal lobe tumors, seizure outcome was not significantly related to the extent of medial temporal resection. It is suggested that limbic and perilimbic gliomas associated with intractable seizures constitute a distinct clinicopathologic group of glial tumors that involve the gray matter, arise in a young host, and exhibit stable biological behavior over many years. Surgical treatment that includes complete resection of these tumors can achieve excellent seizure control.