Stefan Beyenburg

Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.

Idiopathic generalized epilepsy (IGE) is an inherited neurological disorder affecting about 0.4% of the worlds population. Mutations in ten genes causing distinct forms of idiopathic epilepsy have been identified so far1,2,3,4,5,6,7, but the genetic basis of many IGE subtypes is still unknown. Here we report a gene associated with the four most common IGE subtypes: childhood and juvenile absence epilepsy (CAE and JAE), juvenile myoclonic epilepsy (JME), and epilepsy with grand mal seizures on awakening (EGMA; ref. 8). We identified three different heterozygous mutations in the chloride-channel gene CLCN2 in three unrelated families with IGE. These mutations result in (i) a premature stop codon (M200fsX231), (ii) an atypical splicing (del74–117) and (iii) a single amino-acid substitution (G715E). All mutations produce functional alterations that provide distinct explanations for their pathogenic phenotypes. M200fsX231 and del74–117 cause a loss of function of ClC-2 channels and are expected to lower the transmembrane chloride gradient essential for GABAergic inhibition. G715E alters voltage-dependent gating, which may cause membrane depolarization and hyperexcitability.

Anxiety in patients with epilepsy: Systematic review and suggestions for clinical management

Up to 50 or 60% of patients with chronic epilepsy have various mood disorders including depression and anxiety. Whereas the relationship between epilepsy and depression has received much attention, less is known about anxiety disorders. It is now recognized that anxiety can have a profound influence on the quality of life of patients with epilepsy. The relationship between anxiety disorders and epilepsy is complex. It is necessary to distinguish between different manifestations of anxiety disorder: ictal, postictal, and interictal anxiety. Preexisting vulnerability factors, neurobiological factors, iatrogenic influences (antiepileptic drugs, epilepsy surgery), and psychosocial factors are all likely to play a role, but with considerable individual differences. Despite the high prevalence of anxiety disorders in patients with epilepsy, there are no systematic treatment studies or evidence-based guidelines for best treatment practice. Nevertheless, a practical approach based on the temporal relationship between anxiety and epileptic seizures allows clinicians to consider appropriate treatment strategies to reduce the psychiatric comorbidity in patients with epilepsy.

The CD34 epitope is expressed in neoplastic and malformative lesions associated with chronic, focal epilepsies.

Abstract 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 preceed 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.

Placebo-corrected efficacy of modern antiepileptic drugs for refractory epilepsy: systematic review and meta-analysis

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.

Androgen receptor mRNA expression in the human hippocampus.

The androgen receptor (AR) plays a central role in mediating androgen action. Since the hippocampus is a target of steroid modulation, we studied the expression of AR mRNAs in hippocampal tissue specimens from patients undergoing epilepsy surgery (n=42). AR mRNA expression was in the same order of magnitude than in prostate tissue, known for its high expression of AR. AR mRNA concentrations showed no significant difference in AR mRNA expression between men (49.3+/-8.0 arbitrary units (aU); mean+/-SEM) and women (54.3+/-11.2 aU) and no sex-specific hippocampal lateralization pattern was observed. No relationship could be detected between duration of epilepsy, individual seizure frequency, age of the patients and the expression levels of AR. The high expression of AR in the hippocampus suggests that this human brain area is an important target for androgen action.

Expression of 5α-Reductase and 3α-Hydroxisteroid Oxidoreductase in the Hippocampus of Patients with Chronic Temporal Lobe Epilepsy

Summary: Purpose: The hippocampus is one of the principal target areas for neurosteroidal action, and the major neuroen‐docrine conversion of progesterone appears to be 5α‐reduction and 3α‐hydroxysteroid oxidoreduction, leading to the potent neurosteroid 3α,5α‐tetrahydroxyprogesterone. To investigate whether the human hippocampus is equipped with the enzymes 5α‐reductase and 3α‐hydroxysteroid oxidoreductase (3α‐HSOR), we studied the expression of 5α‐reductase types 1 and 2 and 3α‐HSOR types 1 and 2 in the resected hippocampi of patients with medically intractable chronic temporal lobe epilepsy.

Allopregnanolone serum levels and expression of 5α-reductase and 3α-hydroxysteroid dehydrogenase isoforms in hippocampal and temporal cortex of patients with epilepsy

In the human central nervous system, progesterone is rapidly metabolised to 5α-dihydroprogesterone which subsequently is further reduced to allopregnanolone (AP). These conversions are catalysed by 5α-reductase and 3α-hydroxysteroid dehydrogenase (3α-HSD). Although different isoforms of both enzymes have been identified in the brain, our knowledge of their expression in the human brain remains limited. The aim of the present study was to investigate the mRNA expression of 5α-reductase 1 as well as 3α-HSD 1, 2, 3 and 20α-HSD in brain tissue from patients with pharmacoresistant temporal lobe epilepsy (TLE). Specimens were derived from either the hippocampus or the temporal lobe cortex and from the tumor-free approach corridor tissue of patients with brain tumors. Quantification of different mRNAs was achieved by real time PCR. In addition, we provide data on simultaneous evaluation of serum AP concentrations. We could demonstrate that 3α-HSD 1 was not expressed in the hippocampus and temporal lobe of patients with TLE. In the hippocampus and temporal lobe, the expression levels of 3α-HSD 2 were about 20% of that in liver tissue, those of 3α-HSD 3 about 7% and those of 20α-HSD about 2%, respectively. In patients with TLE, expression of 3α-HSD 2 was significantly higher in the hippocampus than in temporal lobe cortex tissue (P<0.006). AP concentrations did not correlate significantly with the mRNA expression levels of 5α-reductase 1, 3α-HSD 2 and 3 and 20α-HSD in any of the patient groups under investigation. In conclusion, the present study demonstrates mRNA expression of 5α-reductase 1 and 3α-HSD 2 and 3 and 20α-HSD in the hippocampus and temporal lobe of epileptic patients. These findings provide further molecular biological evidence for the formation and metabolism of neuroactive steroids in the human brain.

Expression of mineralocorticoid and glucocorticoid receptor mRNA in the human hippocampus

The genomic effects of corticosteroids in the brain are mediated through two receptors with a high affinity for cortisol: the glucocorticoid and mineralocorticoid receptor (GR/MR). We used competitive reverse transcription-polymerase chain reaction to quantify the amount of MR and GR mRNA in hippocampal tissue obtained from patients with temporal lobe epilepsy. MR and GR mRNA were expressed at approximately the same levels as in tissues known for high glucocorticoid/mineralocorticoid sensitivity, i.e. liver or kidney. MR mRNA concentrations were significantly higher in the hippocampus of women (0.24+/-0.04 aU, arbitrary units; mean+/-SEM) than in men (0.14+/-0.01 aU, P<0.006) or children (0.09+/-0.02, P<0. 007). No such differences were observed for GR mRNA expression.

Corticosteroid receptor mRNA expression in the brains of patients with epilepsy.

The effects of corticosteroids in the brain are mediated through the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). We used a sensitive competitive RT-PCR assay to quantify the amounts of GR and MR mRNA in human brain tissue specimens from patients with focal epilepsies. GR and MR mRNAs were expressed at approximately the same levels in the temporal lobe, frontal lobe, and hippocampus as compared to tissues with high glucocorticoid/mineralocorticoid receptor expression (liver/kidney). GR and MR mRNA concentrations in the temporal lobe increased markedly during childhood and reached adult levels at puberty. GR and MR mRNA expression was significantly higher in the temporal lobe and frontal lobe cortex of women than in those of men. In women, MR and GR mRNA concentrations were markedly lower in hippocampal tissue than in frontal and temporal lobe cortex tissue. In conclusion, our data demonstrate sex- and site-dependent expression of corticosteroid receptor mRNA in the human brain.

Epileptic vertigo: evidence for vestibular representation in human frontal cortex.

Article abstract The authors report a 5-year-old boy with episodes of epileptic rotational clockwise vertigo without nystagmus. Video-EEG monitoring showed a left frontocentral onset of epileptic discharges accompanied by complaints of vertigo. MRI showed a small low-grade astrocytoma in the left frontal middle gyrus. After lesionectomy, vertiginous seizures ceased. The patient’s vertigo seems to be induced by epileptic discharges in a vestibular representation area within the frontal cortex.