Development Of Refractory Epilepsy Research Articles

Decreased excitatory drive onto hilar neuronal nitric oxide synthase expressing interneurons in chronic models of epilepsy

Excitation-inhibition imbalance of GABAergic interneurons is predisposed to develop chronic temporal lobe epilepsy (TLE). We have previously shown that virtually every neuronal nitric oxide synthase (nNOS)-positive cell is a GABAergic inhibitory interneuron in the denate gyrus. The present study was designed to quantify the number of nNOS-containing hilar interneurons using stereology in pilocapine- and kainic acid (KA)-exposed transgenic adult mice that expressed GFP under the nNOS promoter. In addition, we studied the properties of miniature excitatory postsynaptic current (mEPSC) and paired-pulse response ratio (PPR) of evoked EPSC in nNOS interneurons using whole cell recording techniques. Results showed that there were fewer nNOS-immunoreactive interneurons of chronically epileptic animals. Importantly, patch-clamp recordings revealed reduction in mEPSC frequency, indicating diminished global excitatory input. In contrast, PPR of evoked EPSC following the granule cell layer stimulation was increased in epileptic animals suggesting reduced neurotransmitter release from granule cell input. In summary, we propose that impaired excitatory drive onto hippocampal nNOS interneurons may be implicated in the development of refractory epilepsy.

Functional connectivity of amygdala in refractory epilepsy:a resting-state functional study of magnetic resonance imaging

To explore the functions of amygdala functional connectivity in the pathogenesis of refractory epilepsy with resting-state functional magnetic resonance imaging (RS-fMRI). A total of 19 patients with refractory epilepsy were recruited from August 2013 to June 2014. And 19 healthy persons were selected as the controls.No obvious epileptogenic lesions of intracranial structures were found on multi-modal neuroimaging.Ictal and interictal epileptic activities on long-term video electroencephalogram (EEG) showed spine spread spike and wave in bilateral cerebral hemispheres. All fMRI data were preprocessed after RS-fMRI scanning. Then left and right amygdalas were selected as regions of interest (ROIs) for calculating the linear correlation between amygdala and whole brain. As relative to the control group, the changes of brain areas in functional connectivity were examined for the intractable epilepsy group. Compared with the controls, left amygdala in refractory epilepsy group showed increased functional connectivity with bilateral fusiform gyrus, bilateral calcarine gyrus and right lingual, on the contrary decreased functional connectivity with bilateral cuneus, bilateral precuneus, bilateral caudatas and left thalamus.However, right amygdala demonstrated increased functional connectivity with bilateral calcarine gyrus and bilateral linguals, but decreased functional connectivity with bilateral caudatas and left putamen (P < 0.05). Altered functional connectivity of amygdala reflects its dysfunction in refractory epilepsy patients. It suggested that amygdala is an important component of "epileptic network" participating in the occurrence and development of refractory epilepsy.

Expression of β-amyloid precursor protein in refractory epilepsy

β-amyloid precursor protein (β-APP), also known as Aβ peptide, has a key role in the pathogenesis of Alzheimer's disease, and is also likely to be involved in the development of refractory epilepsy. The mechanism behind the association between β-APP and refractory epilepsy remains to be elucidated. The aim of the present study was to examine the levels of APP mRNA and β-APP protein in patients with refractory epilepsy. Tissue samples were obtained from patients with chronic pharmacoresistant epilepsy who underwent surgery. Levels of APP mRNA and β-APP protein in epileptic temporal lobe and hippocampal tissue were assessed using quantitative polymerase chain reaction, immunohistochemistry and immunofluorescence. The expression levels of protein significantly increased in the temporal cortex and the hippocampus of the patients with epilepsy. β-APP may thus contribute to the pathogenesis of refractory epilepsy.

Epilepsy associated with shaken baby syndrome

The shaken baby syndrome (SBS) is an important cause of developmental delay in infants. Epileptic seizures are a common feature of this syndrome. The aim if this study is to analyse the impact of the early and late seizures disorder. We have retrospectively reviewed the clinical and electrophysiological findings in a series of 404 children hospitalised with SBS. In the acute phase, clinical epileptic seizures of various semiologies were found in 73% of the infants. Only 11% of the children had a normal EEG on admission. A poor outcome was found in 88% of the children in case of persisting EEG anomalies despite anti-epileptic treatment with 48% mortality in these patients. The development of refractory epilepsy was also associated with a poor outcome in this series. In fact 96% of the children with seizure recurrence had behavioural problems. The early recognition and subsequent management of these seizures is vital to prevent further neurological injury. Delayed or recurrent epileptic seizures may occur with a different semiology to the seizures in the acute phase and are also associated with a poor prognosis.

Effects of common anti-epileptic drug monotherapy on serum levels of homocysteine, Vitamin B12, folic acid and Vitamin B6

There is emerging evidence to support the unfavorable effects of some anti-epileptic drugs on the plasma homocysteine concentrations. Elevated homocysteine levels induced by anti-epileptic drug administration can theoretically increase not only the risk of vascular occlusive diseases, but also the risk of resistance to anti-epileptics and development of refractory epilepsy. To investigate the effect of common anti-epileptic drugs on the homocysteine metabolism, a total of 75 epileptic patients receiving phenytoin (n=16), carbamazepine (n=19), or valproic acid (n=22) and no anti-epileptic drug (n=18) were enrolled. Eleven age- and sex-matched healthy subjects served as the control group. Blood concentrations of homocysteine, folic acid, Vitamin B12 and pyridoxal 5'-phosphate (active circulating form of Vitamin B6) were measured. Compared to the control group, epileptic patients on anti-epileptic drug had higher blood levels of homocysteine. No difference in homocysteine concentrations was observed among epileptic patients in terms of the anti-epileptic drug used. Patients receiving phenytoin had significantly lower folic acid levels and those receiving carbamazepine had marginally lower pyridoxal 5'-phosphate levels in comparison with those using other anti-epileptic drugs. A negative correlation between homocysteine and folic acid concentrations was detected in epileptic patients on anti-epileptic drug. The duration of anti-epileptic drug use was correlated to the decrease of folic acid levels, but not with changes observed in homocysteine, Vitamin B12 and pyridoxal 5'-phosphate levels. No relationship between seizure frequency and homocysteine levels was observed in epileptic patients. Our results confirm that common anti-epileptic drugs has disadvantageous effects on homocysteine status. Because there was no significant change in homocysteine concentrations in epileptic patients who were not receiving an anti-epileptic drug, and no positive correlation between seizure frequency and homocysteine levels, we suggest that increase of homocysteine levels may be due to anti-epileptic drug use, rather than being epileptic in origin. Additionally, the underlying mechanism for homocysteine increase seems to be a decrease of cofactor molecules in patients using carbamazepine and phenytoin (pyridoxal 5'-phosphate and folic acid, respectively). However, changes observed are not related to the alteration in the levels of cofactors and remain unclear in the patients using valproic acid.