The etiology and pathogenesis of complex focal lesions associated with chronic, intractable epilepsy are largely unknown. Some data indicate that malformative changes of the central nervous system may precede the development of gangliogliomas and other epilepsy-associated neoplasms. In the present immunhistochemical study, we have examined epilepsy-associated lesions for CD34, a stem cell marker transiently expressed during early neurulation. Surprisingly, most tissue samples from patients with chronic epilepsy (n = 262) revealed neural cells immunoreactive for CD34. Prominent immunoreactivity was detected in gangliogliomas (74%), low-grade astrocytomas (62%) and oligodendrogliomas (59%). Only 52% of non-neoplastic, malformative pathologies, such as glio-neuronal hamartias or hamartomas showed solitary or small clusters of CD34-immunoreactive cells. None of the adult control tissues (n = 22), none of the specimens obtained from the developing human brain (n = 44) and none of those tumor samples from patients without epilepsy (n = 63) contained CD34-immunoreactive neural cells. However, a malignant teratoma with microscopic features of early neural differentiation displayed a focal CD34-immunoreactive staining pattern. The majority of CD34-immunoreactive cells co-localized with S-100 protein and a small subpopulation was also immunoreactive for neuronal antigens. CD34 may, thus, represent a valuable marker for the diagnostic evaluation of neoplastic and/or malformative pathological changes in epilepsy patients. The CD34 immunoreactivity of these lesions indicates an origin from dysplastic or atypically differentiated neural precursors. Further studies may elucidate the functional significance of CD34 expression during the pathogenesis of epilepsy-related focal lesions as well as during neurogenesis.
In rodents, cyclically fluctuating levels of gonadal steroid hormones modulate neural plasticity by altering synaptic transmission and synaptogenesis. Alterations of mood and cognition observed during the menstrual cycle suggest that steroid-related plasticity also occurs in humans. Cycle phase-dependent differences in cognitive performance have almost exclusively been found in tasks probing lateralized neuronal domains, i.e., cognitive domains such as language, which are predominantly executed by one hemisphere. To search for neural correlates of hormonally mediated neural plasticity in humans, we thus conducted a functional magnetic resonance imaging study measuring brain activity related to a semantic decision task in the language domain. This was contrasted with a letter-matching task in the perceptual domain, in which we expected no steroid hormone-mediated effect. We investigated 12 young healthy women in a counterbalanced repeated-measure design during low-steroid menstruation and high-steroid midluteal phase. Steroid serum levels correlated with the volume and lateralization of particular brain activations related to the semantic task but not with brain activity related to the perceptual task. More specifically, bilateral superior temporal recruitment correlated positively with progesterone and medial superior frontal recruitment with both progesterone and estradiol serum levels, whereas activations in inferior and middle frontal cortex were unaffected by steroid levels. In contrast to these specific interactions, testosterone levels correlated nonselectively with overall activation levels by neural and/or vascular factor(s). In conclusion, our data demonstrate steroid hormone responsivity in the adult human brain by revealing neural plasticity in the language domain, which appears hormone, task, and region specific.
Although adjunctive treatment with modern antiepileptic drugs (AEDs) is standard care in refractory epilepsy, it is unclear how much of the effect can be attributed directly to the AEDs and how much to the beneficial changes seen with placebo. Therefore, we performed a systematic review and meta-analysis of the evidence to determine the placebo-corrected net efficacy of adjunctive treatment with modern AEDs on the market for refractory epilepsy. Of 317 potentially eligible articles reviewed in full text, 124 (39%) fulfilled eligibility criteria. After excluding 69 publications, 55 publications of 54 studies in 11,106 adults and children with refractory epilepsy form the basis of evidence. The overall weighted pooled-risk difference in favor of AEDs over placebo for seizure-freedom in the total sample of adults and children was 6% [95% confidence interval (CI) 4-8, z = 6.47, p < 0.001] and 21% (95% CI 19-24, z = 17.13, p < 0.001) for 50% seizure reduction. Although the presence of moderate heterogeneity may reduce the validity of the results and limit generalizations from the findings, we conclude that the placebo-corrected efficacy of adjunctive treatment with modern AEDs is disappointingly small and suggest that better strategies of finding drugs are needed for refractory epilepsy, which is a major public health problem.
Summary: Purpose:The hippocampus is one of the principal target areas for neurosteroidal action, and the major neuroendocrine conversion of progesterone appears to be Sa-reduction and 301-hydroxysteroid oxidoreduction, leading to the potent neurosteroid 3~~,5~~-tetrahydroxyprogesterone. To investigate whether the human hippocampus is equipped with the enzymes 5a-reductase and 3a-hydroxysteroid oxidoreductase (301-HSOR), we studied the expression of 5a-reductase types 1 and 2 and 3a-HSOR types 1 and 2 in the resected hippocampi of patients with medically intractable chronic temporal lobe epilepsy.Methods: We studied tissue specimens from the hippocampi of 13 women, 25 men, and four children. Quantification of different mRNAs was achieved by competitive reverse transcription-polymerase chain reaction (RT-PCR).Results: Sa-Reductase 1 mRNA and 301-HSOR 2 mRNA were expressed in hippocampi of children and adults, whereas 5a-reductase 2 mRNA and 3a-HSOR 1 mRNA were not expressed. Neither Sa-reductase 1 mRNA nor 3a-HSOR 2 mRNA concentrations in hippocampal tissue showed any statistically significant differences between women and men or between children and adults.Conclusions: This study demonstrates for the first time mRNA expression of the type 1 isozyme of 501-reductase and the type 2 isozyme of 3a-HSOR in the human hippocampus. The finding that both 5a-reductase and 3a-HSOR are present in the hippocampus leads us to assume the synthesis of neuroactive steroids in this human brain area. Key Words: 5a-Reductase-3a-Hydroxysteroid oxidoreductase-Hippocampus-Neurosteroid-Epilepsy .From animal studies, it is known that sex steroid hormones may influence neuronal cerebral excitability, possibly by different modes of action (1,2). Sex steroid hormone metabolism, including aromatization, Sol-reduction and 17P-reduction, and 17P-oxidation has been proven to occur in the human temporal lobe (3-5). The major active products, estrogens and Sol-androstanes are responsible for many behavioral and physiologic effects of the parent steroid (6).Moreover, numerous animal studies have shown that in the central nervous system progesterone is rapidly metabolized to , which is subsequently further reduced to 3qSa-tetraAccepted September 23, 1999. Drs. Stoffel-Wagner and Beyenburg contributed equally to this work.
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