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Biomedical subjects

C E Elger

Publications and source records attributed to C E Elger.

At least 91 records · Page 5Linked to original sources
PubMed2001

Vagus nerve stimulation: clinical experience in a large patient series.

During the last decade, intermittent electrical stimulation of the left cervical vagus nerve was established as a new add-on treatment of drug-resistant seizures. Particularly in Europe, the acceptance of vagus nerve stimulation (VNS) was tentative in the beginning because of unknown mechanisms of action. We report the outcome in a sample of 95 adult patients with drug-resistant seizures who have received implants since 1998. The last available follow-up data are included. Unavoidable medication changes (e.g., intoxication) were accepted to examine VNS under usual clinical conditions. Median percentage of reduction in seizure frequency as compared to baseline was 30%. The seizure responder rate (> or =50% reduction) was 45%. Four patients experienced total release from seizures. Adverse effects were mild in general. Seizure outcome was positively correlated with VNS duration. No potential clinical factor (e.g., syndrome, cause, or lesion) could be identified as an indicator of favorable outcome. Patients with on stimulation-on periods of 30 seconds (standard cycle) had a better outcome than patients with stimulation-on periods of 7 seconds (rapid cycle). During an embedded, randomized, controlled trial, no evidence was found for a differential outcome of initial standard cycle versus initial rapid cycle stimulation conditions. Taking into account the good cost-benefit ratio as well as positive effects on well-being, VNS has to be considered an appropriate strategy for the add-on treatment of drug-resistant seizures, particularly in cases not suitable for epilepsy surgery.

Adult↗
PubMed2001

Losigamone add-on therapy in partial epilepsy: a placebo-controlled study.

OBJECTIVES: To evaluate the efficacy and tolerability of losigamone (LSG). PATIENTS AND METHODS: Double-blind, placebo-controlled add-on study with 3x500 mg LSG/die for the treatment of chronic partial seizures in 203 patients (99 treated with LSG, 104 on placebo). RESULTS: The median percent change of seizures was 14.9% (LSG) versus 6.7% (placebo) (P=0.004). Seizure frequency was decreased by more than 50% in 22.3% (LSG) and 14.6% (placebo) of patients (P=0.13). Mean percent change of seizures was best in patients with only one additional anticonvulsant drug (LSG versus placebo, P=0.004). Adverse events (usually CNS-related side effects of mild to moderate intensity) were reported in 59.6% (LSG) and 37.5% (placebo) of patients. CONCLUSIONS: LSG proved to be an effective and well tolerated anticonvulsant drug for the treatment of chronic partial seizures.

Adolescent↗
PubMed2000

Limbic encephalitis not associated with neoplasm as a cause of temporal lobe epilepsy.

OBJECTIVE: To describe four patients with temporal lobe epilepsy with limbic encephalitis unrelated to neoplasm. METHODS: The authors performed a retrospective evaluation of patient data obtained during presurgical evaluation, with additional CSF analyses, serum analyses, and histopathologic investigations. RESULTS: The patients shared the following clinical features: onset of the disease in young adulthood with subacute onset or exacerbation of frequent intractable temporal lobe seizures, verbal and visual memory deficits, and affective abnormalities. MRI showed variably extended areas of increased T2 signal in limbic structures and adjacent areas. In the histopathologic investigation, chronic inflammation was observed without evidence of a viral origin. There was no evidence of an underlying malignancy. CONCLUSIONS: Nonparaneoplastic limbic encephalitis should be included in the differential diagnosis of adult patients with temporal lobe epilepsy.

Adult↗
PubMed2000

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

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.

Child, Preschool↗
PubMed2000

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.

Adult↗
PubMed2000

Serum androgens return to normal after temporal lobe epilepsy surgery in men.

BACKGROUND: Epileptic discharges from the temporal lobe may influence the release of hormones from the hypothalamic-pituitary axis. If epilepsy surgery influences the underlying epileptic disorder one might expect serum hormone concentrations to return to normal following surgery. PATIENTS: Twenty-two men with epilepsy aged 25 to 48 years (mean, 34.9 years) were investigated before surgery and at 3, 6, and 12 months after surgery. Medication (all patients received carbamazepine) was maintained following surgery. METHODS: Hormone measurements included luteinizing hormone, follicle stimulating hormone, estradiol, testosterone, free testosterone, androstenedione, prolactin, dehydroepiandrosterone sulfate, cortisol, growth hormone, and sex hormone-binding globulin. These hormone levels were compared with those of 105 healthy men (mean age, 33.9 years). RESULTS: Fourteen of the 22 patients (63.6%) achieved total seizure control following epilepsy surgery. The 14 patients with successful seizure control entered further analysis. Before surgery these patients' free testosterone and androstenedione concentrations were significantly lower compared with healthy men. In seven of the 14 patients a significant increase of hormone serum concentrations could be demonstrated for testosterone, free testosterone, and androstenedione. Laterality of epileptic focus, enzyme-inducing medication, stress, and the decreasing number of patients during the follow-up did not correlate with the finding of a normalization of serum androgens. PATIENTS without complete seizure control did not show an increase in serum androgen concentrations. CONCLUSION: Successful temporal lobe epilepsy surgery may lead to a normalization of serum androgen concentrations in men with epilepsy.

Adult↗
PubMed2000

Synaptic plasticity in the human dentate gyrus.

Activity-dependent plasticity is a fundamental feature of most CNS synapses and is thought to be a synaptic correlate of memory in rodents. In humans, NMDA receptors have been linked to verbal memory processes, but it is unclear whether NMDA receptor-dependent synaptic plasticity can be recruited for information storage in the human CNS. Here we have for the first time analyzed different forms of synaptic plasticity in human hippocampus. In human subjects who show a morphologically intact hippocampus that is not the primary seizure focus, NMDA receptor-dependent long-term potentiation (LTP) and forskolin-induced long-lasting potentiation are readily induced at the perforant path-dentate gyrus synapse. In this group, long-term potentiation could be partially depotentiated by low-frequency stimulation. Because patients with a hippocampal seizure focus showed a marked reduction in verbal memory performance in previous studies, we asked whether synaptic plasticity is similarly affected by the presence of a hippocampal primary seizure focus. We found that the amount of potentiation induced by high-frequency stimulation or perfusion of forskolin is dramatically reduced in this patient group. In addition, low-frequency stimulation is not effective in inducing synaptic depression. In summary, we show that activity-dependent synaptic plasticity with properties similar to the rodent is available for information storage in the human hippocampus. Because both verbal memory processes and synaptic plasticity are impaired by a hippocampal seizure focus, we suggest that impaired synaptic plasticity may contribute to deficient declarative memory in human temporal lobe epilepsy.

1-Methyl-3-isobutylxanthine↗
PubMed2000

Flux control of cytochrome c oxidase in human skeletal muscle.

In the present work, by titrating cytochrome c oxidase (COX) with the specific inhibitor KCN, the flux control coefficient and the metabolic reserve capacity of COX have been determined in human saponin-permeabilized muscle fibers. In the presence of the substrates glutamate and malate, a 2.3 +/- 0.2-fold excess capacity of COX was observed in ADP-stimulated human skeletal muscle fibers. This value was found to be dependent on the mitochondrial substrate supply. In the combined presence of glutamate, malate, and succinate, which supported an approximately 1.4-fold higher rate of respiration, only a 1.4 +/- 0.2-fold excess capacity of COX was determined. In agreement with these findings, the flux control of COX increased, in the presence of the three substrates, from 0.27 +/- 0.03 to 0.36 +/- 0.08. These results indicate a tight in vivo control of respiration by COX in human skeletal muscle. This tight control may have significant implications for mitochondrial myopathies. In support of this conclusion, the analysis of skeletal muscle fibers from two patients with chronic progressive external ophthalmoplegia, which carried deletions in 11 and 49% of their mitochondrial DNA, revealed a substantially lowered reserve capacity and increased flux control coefficient of COX, indicating severe rate limitations of oxidative phosphorylation by this enzyme.

Adenosine Diphosphate↗
PubMed2000

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.

Adolescent↗
PubMed2000

The voltage-gated sodium channel beta2-subunit gene and idiopathic generalized epilepsy.

Recent identification of ion channel gene mutations in Mendelian epilepsies suggests that genetically driven neuronal hyperexcitability plays an important role in epileptogenesis. In this study, we tested the hypothesis that genetic variation in the human SCN2B gene confers liability to common subtypes of idiopathic generalized epilepsies (IGE). A systematic search for mutations was performed in 92 IGE patients. We detected a novel single nucleotide polymorphism (SNP), however, allele frequencies did not differ between IGE patients and controls (chi2 = 0.19, df = 1, p = 0.744). Furthermore, a missense mutation in codon 209 (Asn209Pro) was identified in one patient, but was found to be absent in an affected sibling of the index patient. Thus, our results do not suggest a major role of the SCN2B gene in the etiology of common IGE subtypes.

Adult↗
PubMed2000

Metaplasticity of mossy fiber synaptic transmission involves altered release probability.

Activity-dependent synaptic plasticity is a fundamental feature of CNS synapses. Intriguingly, the capacity of synapses to express plastic changes is itself subject to considerable activity-dependent variation, or metaplasticity. These forms of higher order plasticity are important because they may be crucial to maintain synapses within a dynamic functional range. In this study, we asked whether neuronal activity induced in vivo by application of kainate can induce lasting changes in mossy fiber short- and long-term plasticity. Several weeks after kainate-induced status epilepticus, the mossy fiber, but not the associational-commissural pathway, exhibits a marked loss of paired-pulse facilitation, augmentation, and long-term potentiation (LTP). Because the adenylyl cyclase-protein kinase A cascade is involved in mossy fiber LTP induction, we have tested the integrity of this key pathway by pharmacological activation of either adenylyl cyclase or protein kinase A. These treatments resulted in LTP in control, but not in kainate-treated animals, indicating that status-induced changes occur downstream of protein kinase A. To test whether altered neurotransmitter release might account for these changes, we measured the size of the releasable pool of glutamate in mossy fiber terminals. We find that the size of the releasable pool of glutamate was significantly increased in kainate-treated rats, indicating an increased release probability at the mossy fiber-CA3 synapse. Therefore, we suggest that lasting changes in neurotransmitter release probability caused by neuronal activity may be a powerful mechanism for metaplasticity that modulates both short- and long-term plasticity in the mossy fiber-CA3 synapse after status epilepticus.

Animals↗
PubMed2000

Evaluation of methods for the determination of mitochondrial respiratory chain enzyme activities in human skeletal muscle samples.

The quantification of mitochondrial enzyme activities in skeletal muscle samples of patients suspected of having mitochondrial myopathies is problematic. Therefore, we have evaluated different methods for the determination of activities cytochrome c oxidase and NADH:CoQ oxidoreductase in human skeletal muscle samples. The measurement of cytochrome c oxidase activity in the presence of 200 microM ferrocytochrome c and the detection of NADH:CoQ oxidoreductase as rotenone-sensitive NADH:CoQ(1) reductase resulted in comparable citrate synthase-normalized respiratory chain enzyme activities of both isolated mitochondria and homogenates from control human skeletal muscle samples. These methods allowed the precise detection of deficiencies of respiratory chain enzymes in skeletal muscle of two patients harboring only 20 and 27% of deleted mitochondrial DNA, respectively. Therefore, citrate synthase-normalized respiratory chain activities can serve as stable reference values for the determination of a putative mitochondrial defect in human skeletal muscle.

Adult↗
PubMed2000

Surviving granule cells of the sclerotic human hippocampus have reduced Ca(2+) influx because of a loss of calbindin-D(28k) in temporal lobe epilepsy.

In mesial temporal lobe epilepsy (mTLE), the predominant form of epilepsy in adults, and in animal models of the disease, there is a conspicuous loss of the intracellular Ca(2+)-binding protein calbindin-D(28k) (CB) from granule cells (GCs) of the dentate gyrus. The role of this protein in nerve cell function is controversial, but here we provide evidence for its role in controlling Ca(2+) influx into human neurons. In patients with Ammon's horn sclerosis (AHS), the loss of CB from GCs markedly increased the Ca(2+)-dependent inactivation of voltage-dependent Ca(2+) currents (I(Ca)), thereby diminishing Ca(2+) influx during repetitive neuronal firing. Introducing purified CB into GCs restored Ca(2+) current inactivation to levels observed in cells with normal CB content harvested from mTLE patients without AHS. Our data are consistent with the possibility of neuroprotection secondary to the CB loss. By limiting Ca(2+) influx through an enhanced Ca(2+)-dependent inactivation of voltage-dependent Ca(2+) channels during prolonged neuronal discharges, the loss of CB may contribute to the resistance of surviving human granule cells in AHS.

Action Potentials↗
PubMed2000

Mutation screening of the chromosome 8q24.3-human activity-regulated cytoskeleton-associated gene (ARC) in idiopathic generalized epilepsy.

Idiopathic generalized epilepsy (IGE) comprises a heterogeneous group of disorders, in which a high genetic predisposition and a complex mode of inheritance have been suggested. However, genes, which confer liability to common IGE subtypes including juvenile myoclonic epilepsy (JME) and childhood absence epilepsy (CAE) have not been identified so far. Here, we tested the hypothesis that genetic variation in the human homolog of the <<< >>> (ARC) contributes to the etiology of common IGE disorders. The gene has recently been mapped to chromosome 8q24.3, a region which spans previously identified major IGE susceptibility loci. A systematic search for mutations was performed in 143 patients with a known family history of IGE. However, no evidence for functional variants was found in the ARC coding sequence. Nevertheless, we detected a novel common C489T single nucleotide polymorphism, which provides a useful marker in genetic linkage and association studies. By performing a population- and family-based study we however failed to show significant association between this novel single nucleotide polymorphism and IGE, a finding, which most likely rules out that genetic variation in or close to the ARC gene confers liability to common IGE subtypes.

Adult↗
PubMed2000

SATSCOM--Selective amobarbital test intraarterial SPECT coregistered to MRI: description of a method assessing selective perfusion.

For evaluation of potential functional deficits, an intraarterial amobarbital test is performed prior to neurosurgical or neuroradiological interventions. To visualize individual amobarbital perfusion patterns, simultaneous injection of (99m)Tc-HMPAO was performed previously. The present study describes for the first time a method of coregistration of intraarterial SPECT during selective amobarbital test to MRI. Three patients undergoing selective amobarbital test of the posterior cerebral artery were included. SATSCOM (Selective amobarbital test intraarterial SPECT coregistered to MRI) was performed by skull extraction in SPECT and MRI followed by surface matching. In all three patients, SATSCOM revealed accurate matching results. With this functional-anatomical mapping, suppression of higher cortical functions can be correlated to anatomical regions. Furthermore, a more precise mapping of amobarbital effect improves planning invasive interventions, particularly those close to eloquent areas.

Adult↗