Biomedical subjects

Andreas Hufnagel

Publications and source records attributed to Andreas Hufnagel.

11 recordsLinked to original sources

PubMed2005

Expression time course and spatial distribution of activated caspase-3 after experimental status epilepticus: contribution of delayed neuronal cell death to seizure-induced neuronal injury.

Pilocarpine-induced status epilepticus (PCSE) is a widely used model to study neurodegeneration in limbic structures after prolonged epileptic seizures. However, mechanisms mediating neuronal cell death in this model require further characterization. Examining the expression time course and spatial distribution of activated caspase-3, we sought to determine the role of apoptosis in PCSE-mediated neuronal cell death. Expression of activated caspase-3, predominantly located in neurons, was detected 24 h (amygdala; piriform and temporal cortex) and 7 days (hippocampus; amygdala; piriform, temporal and parietal cortex; thalamus) after PCSE with strongest induction being observed in the amygdala, the piriform cortex, and the hippocampus. Further analysis revealed TUNEL positivity (24 h and 7 days after SE) and a significant, progressive neuronal cell loss in all brain regions displaying caspase-3 activation. Corresponding to high levels of activated caspase-3 expression, neuronal cell loss was most pronounced in the amygdala, piriform cortex, and dorsal CA-1 hippocampus. These results demonstrate that apoptosis contributes significantly to PCSE-induced neuronal cell death.

Animals↗

PubMed2005

Brain perfusion following single seizures.

PURPOSE: The aim of this study was to assess the regional relative interictal and postictal perfusion changes in temporal and parietal lobe epilepsy. METHODS: We investigated interictal and postictal magnet resonance perfusion changes in five patients with temporal lobe epilepsy either with hippocampal sclerosis (n = 3) or without (n = 2), and in one patient with extratemporal (parietal lobe) epilepsy. T(2)*-weighted single-shot echo-planar images were acquired after bolus application of 0.2 mmol/kg gadolinium-diethylene triamine pentaacetic acid (GD-DTPA) at baseline and after intervals of 2-12 min, 15-23 min, 28-50 min, 63-72 min, and 180-240 min. The bolus-peak ratio was calculated in regions of interest in the hippocampus (HIP), parahippocampal gyrus (PHG), thalamus (THA), cortex (COR), and white matter (WM), yielding relative perfusion changes. RESULTS: Interictally, we found relative hyperperfusion of the ictogenic side in five of six patients in the HIP. Postictally, the perfusion decreased in the HIP by 25-39% as compared to baseline, whereas the PHG showed a reverse pattern. In the late postictal phase, perfusion increased in the HIP again and decreased in the PHG. In the THA, the inter- and postictal changes were small (5-19%). COR and WM showed equivocal results. CONCLUSION: Postictal relative hypoperfusion in the HIP appears to be associated with the cessation of neuronal ictal discharge, whereas postictal hyperperfusion in the PHG lags behind and may reflect increased metabolism to restore the interictal state of neuronal excitability.

Adult↗

PubMed2004

Levetiracetam inhibits Na+-dependent Cl-/HCO3- exchange of adult hippocampal CA3 neurons from guinea-pigs.

The novel anticonvulsant levetiracetam (LEV) was tested for effects on bioelectric activity and intracellular pH (pHi) regulation of hippocampal CA3 neurons from adult guinea-pigs. In 4-aminopyridine-treated slices, LEV (10-100 microm) reduced the frequency of action potentials and epileptiform bursts of CA3 neurons by 30-55%, while the shape of these potentials remained largely unchanged. Suppressive effects were reversed by an increase of pHi with trimethylamine (TMA). Using BCECF-AM-loaded slices, we found that LEV (10-50 microm) reversibly lowered neuronal steady-state pHi by 0.19 +/- 0.07 pH units in the presence of extracellular CO2/HCO3- buffer. In the nominal absence of extracellular CO2/HCO3- or in Na+-free CO2/HCO3(-)-buffered solution, LEV had no effect on steady-state pHi. Recovery of pHi subsequent to ammonium prepulses remained unchanged in the absence of CO2/HCO3- buffer, but was significantly reduced by LEV in the presence of CO2/HCO3- buffer. These findings show that LEV inhibits HCO3(-)-dependent acid extrusion, but has no effect on Na+/H+ exchange. LEV did not affect Na+-independent Cl-/HCO3- exchange because intracellular alkalosis upon withdrawal of extracellular Cl- remained unchanged. These data show that LEV at clinically relevant concentrations inhibits Na+-dependent Cl-/HCO3- exchange, lowers neuronal pHi, and thereby may contribute to its anticonvulsive activity.

Action Potentials↗

PubMed2003

Clinical characteristics of patients with comorbidity of migraine and epilepsy.

OBJECTIVE: Neuronal hyperexcitability might explain the comorbidity of migraine and epilepsy. Spreading depression, a postulated pathophysiological mechanism of epileptic seizures and migraine with aura, may hypothetically be the link between the disorders in these comorbid conditions. The aim of the present study was to determine whether certain clinical characteristics associated with spreading depression are overrepresented in patients with comorbidity. METHODS: In an outpatient clinic-based series, clinical characteristics of 61 patients with a comorbidity of migraine and epilepsy were compared to those of 280 patients with epilepsy alone and 248 patients with migraine alone. Patients were interviewed with a standardized questionnaire. RESULTS: The proportion of females was significantly higher in patients with comorbidity and patients with migraine as compared to patients with epilepsy (P <.001). Comparing patients with epilepsy and comorbidity, the frequency of epilepsy syndromes and seizure types was not significantly different. Comparing patients with migraine and comorbidity, migraine with aura was significantly more frequent in patients with comorbidity (P =.019). Other migraine features such as moderate to severe pain intensity, worsening of pain on activity, phonophobia, and photophobia were significantly more frequent in patients with comorbidity as compared to patients with migraine (P < or =.001). CONCLUSION: No specific epileptic characteristics could be found in patients with comorbidity. Altered cerebral excitability resulting in an increased occurrence of spreading depression may explain the differences in migraine attacks in patients with comorbidity as compared to patients with migraine alone.

Adult↗

PubMed2003

Brain diffusion after single seizures.

PURPOSE: Diffusion-weighted magnetic resonance imaging (DWI) after focal status epilepticus has demonstrated focal alterations of the apparent diffusion coefficient (ADC) in the epileptogenic zone. We hypothesized that localized dynamic alterations of brain diffusion during the immediate postictal state will be detectable by serial DWI and correlate with the epileptogenic zone. METHODS: Nine adult patients (four men, five women) with medically intractable epilepsy were prospectively examined with a total of 25 DWI scans taken 2-210 min after a seizure. RESULTS: The interictal ADC was significantly (p < 0.05) elevated in the ictogenic hippocampus in all patients with temporal lobe epilepsy. The following postictal changes of the ADC were seen: (a) decreases by maximally 25-31%, which were most pronounced in the epileptogenic zone (n = 2); (b) generalized ADC changes after generalized seizures (n = 1) or prolonged complex partial seizures (n = 2); (c) no major changes after short-lived seizures or if the time to first DWI scan was >15 min or both (n = 3); and (d) widespread bilateral ADC increases after a flumazenil-induced seizure (n = 1). CONCLUSIONS: ADC changes seen during serial postictal DWI are complex and appear to reflect origin and spread of the preceding seizure. A delineation of the epileptogenic zone appears to be possible only in complex-partial seizures of >60 s duration that do not secondarily generalize.

Adult↗

PubMed2003

Presurgical evaluation of epilepsy by brain diffusion: MR-detected effects of flumazenil on the epileptogenic focus.

PURPOSE: After focal status epilepticus, focal alterations of the apparent diffusion coefficient (ADC) have been demonstrated in the epileptogenic zone by using diffusion-weighted magnetic resonance (MR)imaging (DWI). Effects of flumazenil on an epileptogenic focus have been demonstrated by EEG recordings, but not by functional MRI. We hypothesized that dynamic spatiotemporal alterations of brain diffusion of the epileptogenic focus after application of flumazenil will be detectable by DWI and correlate with the epileptogenic zone. METHODS: Twelve adult patients considered for epilepsy surgery with medically intractable temporal lobe epilepsy (TLE; n = 7), extratemporal lobe epilepsy (ETE; n = 2), and TLE+ETE (n = 3) were prospectively examined with DWI interictally (serving as baseline) and 10 min after application of 1 mg flumazenil i.v. RESULTS: The baseline interictal ADC was significantly elevated in the hippocampus on the ictogenic side in the patients with TLE (p = 0.002) as compared with healthy volunteers. The following changes of the mean ADC were seen in different regions of interest (ROIs) after injection of flumazenil: decreases in the hippocampus on the seizure-onset side by 14.8% (p = 0.005); decreases in the parahippocampal gyrus on both sides by 6.8% (epileptogenic side; p = 0.044) or 7.9% (nonepileptogenic side; NS), respectively; decreases in the cortex on the nonictogenic side by 7.9% (p = 0.047); and no significant changes of the ADC in the other ROIs. CONCLUSIONS: ADC decreases measured after application of flumazenil were seen in the seizure-onset zone as revealed by EEG and structural MRI and are an indicator of focus localization in patients with TLE.

Adult↗

PubMed2003

A new Chrna4 mutation with low penetrance in nocturnal frontal lobe epilepsy.

PURPOSE: To identify and characterize the mutation(s) causing nocturnal frontal lobe epilepsy in a German extended family. METHODS: Neuronal nicotinic acetylcholine receptor (nAChR) subunit genes were screened by direct sequencing. Once a CHRNA4 mutation was identified, its biophysical and pharmacologic properties were characterized by expression experiments in Xenopus oocytes. RESULTS: We report a new CHRNA4 mutation, causing a alpha4-T265I amino acid exchange at the extracellular end of the second transmembrane domain (TM). Functional studies of alpha4-T265I revealed an increased ACh sensitivity of the mutated receptors. alpha4-T265I is associated with an unusual low penetrance of the epilepsy phenotype. Sequencing of the TM1-TM3 parts of the 1 known nAChR subunits did not support a two-locus model involving a second nAChR sequence variation. CONCLUSIONS: nAChR mutations found in familial epilepsy are not always associated with an autosomal dominant mode of inheritance. alpha4-T265I is the first nAChR allele showing a markedly reduced penetrance consistent with a major gene effect. The low penetrance of the mutation is probably caused by unknown genetic or environmental factors or both.

Adolescent↗

PubMed2002

Clinical outcome and neuropsychological deficits after right decompressive hemicraniectomy in MCA infarction.

BACKGROUND AND PURPOSE: The purpose of this study was to analyse in detail the functional outcome and the neuropsychological deficits in patients with space-occupying infarction of the non-dominant hemisphere one year after surgery. METHODS: Postoperative complications and retrospective consent to surgery were assessed in a semi-structured interview in 26 patients. Functional outcome was measured with the Barthel-Index (BI) and Rankin-Scale. Neuropsychological tests in 14 patients focused on visuo-spatial and visuo-constructive abilities, attention, spatial span and self-rated mood. RESULTS: The one-year survival rate was 69 % (18 of 26). The functional outcome was good (BI >/= 90) in 3 patients, fairly good (BI 75-85) in 6, moderate (BI 30-70) in 6, and poor (BI 0-25) in 3 patients. Age was an independent predictor of outcome, patients above 52 years had a BI of 50 or below. Neuropsychological tests (14 of 18) showed profound attention deficits in all patients, and visuo-spatial and visuo-constructive deficits in patients with lower formal education. Retrospectively, 4 of 18 patients would not give consent to surgery again, mostly because of the bad quality of life postoperatively. CONCLUSION: Older patients do not seem to benefit from decompressive hemicraniectomy; more than half of the surviving younger patients have a good outcome and live independently. Attention deficits are prominent in all patients; visuo-spatial and constructive deficits are less pronounced in patients with higher formal education. Retrospective agreement to decompressive hemicraniectomy is high in patients with good functional outcome.

Adolescent↗

PubMed2002

Brain diffusion during hyperventilation: diffusion-weighted MR-monitoring in patients with temporal lobe epilepsy and in healthy volunteers.

Hyperventilation (HV) can be used to provoke epileptiform activity and occasionally seizures in generalised and in focal epilepsies. Based on the hypothesis that HV might alter brain diffusion in the epileptogenic areas of patients with temporal lobe epilepsy (TLE), we examined these alterations using quantitative diffusion MR imaging (DI) in four patients with TLE and unilateral hippocampal sclerosis (TLE-HS) and six patients with TLE without hippocampal sclerosis (TLE-pure), and in 10 healthy volunteers. Brain diffusion was measured at baseline and immediately after 4 min of HV. In all patients with TLE HV was repeated two times, 4 min each, followed by subsequent DI. The apparent diffusion coefficient (ADC) was quantified in predefined regions of interest. In controls, the ADC did not differ between baseline and HV and between right and left side. Compared to controls TLE-HS patients showed significantly higher ADC at baseline in the hippocampus of the ictogenic side (111+/-13 vs. 87.5+/-4.26 x 10(-5) mm(2)/s, P=0.029). During HV ADC decreased significantly in the ictogenic hippocampus compared to controls (-17.3+/-7.1 vs. -3.34+/-8.7, P=0.004). In TLE-pure patients ADC of the ictogenic hippocampus was higher than in normals (99.3+/-14.2 vs. 87.5+/-4.26 x 10(-5) mm(2)/s, P=0.031) but there was no significant decrease during HV. Serial HV did not further enhance this decrease. No significant HV-induced changes were seen in other brain areas. In conclusion, our results show that HV can induce dynamic changes of brain diffusion in patients with sclerotic hippocampi but not in non-sclerotic hippocampi. These findings may be utilized for lateralisation of the epileptogenic hippocampus during presurgical evaluation of TLE.

Adult↗

PubMed2002

Valproate acidifies hippocampal CA3-neurons--a novel mode of action.

Various hypotheses try to explain the anticonvulsive and mood stabilizing effects of valproate. Among them, amplification of GABAergic inhibition and reduction of membrane excitability is favored. Here we show that superfusion with 0.1-1 mM valproate induced a moderate intracellular acidification of BCECF-AM-loaded CA3-neurons (hippocampal slices, guinea pig) which was measured as the difference between intracellular pH before (baseline pH(i)) and during valproate treatment (deltapH(i)). In two groups of neurons treated with 1 mM and 0.1-0.5 mM, deltapH(i) values amounted to 0.20 +/- 0.10 and 0.10 +/- 0.04 (deltapH(i) +/- S.D.), respectively, suggesting a dependence on the used valproate-concentration. DeltapH(i) did not correlate with the baseline pH(i). Furthermore, the acidification seems to be independent from an activation of postsynaptic GABA-A receptors, as it was not influenced by 0.1 mM picrotoxin. Since our previous studies clearly demonstrated a reduction of membrane excitability during moderate intracellular acidification, we suggest that the valproate-mediated intracellular acidification may substantially contribute to its anticonvulsive and mood stabilizing properties.

Animals↗

PubMed2002

Carbonic anhydrase inhibitor sulthiame reduces intracellular pH and epileptiform activity of hippocampal CA3 neurons.

PURPOSE: Sulthiame is a carbonic anhydrase (CA) inhibitor with an anticonvulsant effect in the treatment of benign and symptomatic focal epilepsy in children. The aim of the study was to elucidate the mode of action of sulthiame with respect to possible changes of intracellular pH (pHi) that might develop along with sulthiame's anticonvulsant properties. METHODS: The effects of sulthiame (a) on pHi of 2',7-bis(2-carboxyethyl)-5(6)-carboxyfluorescein-acetoxymetyl ester (BCECF-AM) loaded CA3 neurones as well as (b) on epileptiform activity (induced by 50 microM 4-aminopyridine) were compared with those of the CA inhibitors acetazolamide and benzolamide. RESULTS: In the majority of neurons, sulthiame (1.0-1.5 mM; n = 8) as well as the membrane permeant acetazolamide (0.5-1.0 mM; n = 6) reversibly decreased pHi by 0.18 +/- 0.05 (SD) and 0.17 +/- 0.10 (SD) pH units, respectively, within 10 min. The poor membrane permeant benzolamide (1.0-2.0 mM) had no influence on pHi (n = 8). Sulthiame (1.0-2.5 mM) and acetazolamide (1.0-2.0 mM) reversibly reduced the frequency of action potentials and epileptiform bursts after 10-15 min (n = 9, n = 7), whereas benzolamide (1.0-2.0 mM) had no effect (n = 6). CONCLUSIONS: The results suggest that sulthiame acts as a membrane-permeant CA inhibitor whose beneficial effect on epileptiform activity results at least in part from a modest intracellular acidosis of central neurons.

Acetazolamide↗