Evaluation of GABA system and cell damage in parahippocampus of patients with temporal lobe epilepsy showing antiepileptic effects after subacute electrical stimulation

PURPOSE: The gamma-aminobutyric acid (GABA) system and neuronal loss were evaluated in the parahippocampal cortex (PHC) of patients with intractable mesial temporal lobe epilepsy (MTLE) who received subacute electrical stimulation and showed antiepileptic effects. METHODS: GABA tissue content, GABA(A) and benzodiazepine (BZD) receptor levels, as well as neuronal density were determined in PHC of five patients (ESAE group) with an MTLE history of 14.8 +/- 2.5 years and seizure frequency of 11 +/- 2.9 per month, two (40%) of them with mesial sclerosis. This group demonstrated antiepileptic effects after subacute electrical stimulation (130 Hz, 450 micros, 200-400 microA), applied continuously during 16 to 20 days in PHC. Values were compared with those obtained from patients with severe MTLE (history of 21.7 +/- 2.8 years and seizure frequency of 28.2 +/- 14 per month) in whom electrical stimulation did not induce antiepileptic effects (ESWAE group, n = 4), patients with MTLE in whom no electrical stimulation was applied (MTLE group, n = 4), and autopsy material acquired from subjects without epilepsy (n = 4 obtained from three subjects). RESULTS: The ESAE group demonstrated high GABA tissue levels (219%), as well as a significantly higher cell count (58.5%) when compared with the MTLE group. The ESWAE group showed enhanced BZD-receptor levels (38%), whereas their values for GABA tissue levels and GABA(A) receptor were similar to those obtained from the MTLE group. CONCLUSIONS: It is suggested that subacute electrical stimulation of PHC is more effective in patients with less severe epilepsy, an effect associated with a high GABA tissue content and a low rate of cell loss.     

The prognostic significance of interictal epileptiform activity in postoperative EEGs of patients with mesial temporal lobe epilepsy.

It has not been established whether electroencephalography (EEG) is a contributing factor in predicting the outcome of surgery for epilepsy. We conducted a prospective study on 26 patients (M/F 14/12, age: 33 +/- 7.5 years, range 19-48) with mesial temporal lobe epilepsy (MTLE) who were followed for 2 years after surgery and who underwent routine EEG recordings 5.6 +/- 3 months (range 3-12) postoperatively. Interictal epileptiform activity (IEA) on the EEG was compared in 17 seizure-free patients to 9 patients with recurrent seizures. The two groups were similar in gender, age, febrile convulsions, trauma, family history, seizure frequency prior to surgery, epilepsy duration and number of antiepileptic drugs. Following surgery, 17 study patients (65%) became seizure free; 9 (35%) had seizure recurrence. Post-operative EEG recordings showed IEA in 8/26 study patients (31%), 3 of whom were from the seizure-free group (3/17, 18%); 5 had seizure recurrence (5/9, 56%) (p=0.078). IEAs in postoperative EEGs were less frequently demonstrated in patients who were seizure free, but the presence of postoperative IEAs does not preclude successful surgical outcome.     

Comparison of short-term outcome between surgical and clinical treatment in temporal lobe epilepsy: a prospective study.

OBJECTIVE: To compare the efficacy of medical and surgical treatment for refractory mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE). METHODS: A prospective controlled non-randomized study of 26 patients with MTLE who underwent surgical treatment and 75 patients with MTLE who underwent medical treatment between August 2002 and October 2004. All patients failed to achieve seizure control with at least two first line antiepileptic drugs (AED) for partial seizures before entering the study. We used Kaplan-Meier survival analyses as a function of time of seizure recurrence to obtain estimates of 95% confident interval of seizure freedom and log-rank test to compare the status of seizure control between the two groups. RESULTS: The cumulative proportion of patients free of all seizures (Engel's class IA) was higher in the surgical group (73%) compared to the clinical group (12%) (p<0.0001). In the surgical group, 2 of 26 patients (7.7%) had transient adverse effects and 2 of 26 patients (7.7%) had a permanent deficit related to the surgical procedure. In the clinical group 7 patients (9.3%) major adverse events during follow-up, including burns and status epilepticus. CONCLUSIONS: Surgical treatment for patients with MTLE who failed to achieve seizure control with two previous AED regimens was more efficient than medical treatment with further trials of AED.     

Temporal lobe epilepsy causes selective changes in mu opioid and nociceptin receptor binding and functional coupling to G-proteins in human temporal neocortex

There is no information concerning signal transduction mechanisms downstream of the opioid/nociceptin receptors in the human epileptic brain. The aim of this work was to evaluate the level of G-proteins activation mediated by DAMGO (a mu receptor selective peptide) and nociceptin, and the binding to mu and nociceptin (NOP) receptors and adenylyl cyclase (AC) in neocortex of patients with pharmacoresistant temporal lobe epilepsy. Patients with temporal lobe epilepsy associated with mesial sclerosis (MTLE) or secondary to tumor or vascular lesion showed enhanced [³H]DAMGO and [³H]forskolin binding, lower DAMGO-stimulated [³⁵S]GTPγS binding and no significant changes in nociceptin-stimulated G-protein. [³H]Nociceptin binding was lower in patients with MTLE. Age of seizure onset correlated positively with [³H]DAMGO binding and DAMGO-stimulated [³⁵S]GTPγS binding, whereas epilepsy duration correlated negatively with [³H]DAMGO and [³H]nociceptin binding, and positively with [³H]forskolin binding. In conclusion, our present data obtained from neocortex of epileptic patients provide strong evidence that a) temporal lobe epilepsy is associated with alterations in mu opioid and NOP receptor binding and signal transduction mechanisms downstream of these receptors, and b) clinical aspects may play an important role on these receptor changes.     

The antiepileptic drug levetiracetam stabilizes the human epileptic GABAA receptors upon repetitive activation

PURPOSE: GABAA receptors from the brain of patients afflicted with mesial temporal lobe epilepsy (MTLE) become less efficient (run-down) when repetitively activated by GABA. Experiments were designed to investigate whether the antiepileptic drug, levetiracetam (LEV), which is used as an adjunctive treatment for medically intractable MTLE, counteracts the GABAA receptor run-down. METHODS: GABAA receptors were microtransplanted from the brains of patients afflicted with MTLE into Xenopus oocytes. The GABA-current run-down, caused by repetitive applications of GABA, was investigated using the standard two-microelectrode voltage-clamp technique. Additionally, the GABA-current run-down was investigated directly on pyramidal neurons in human MTLE cortical slices. RESULTS: It was found that, in oocytes injected with membranes isolated from the MTLE neocortex, the GABA-current run-down was inhibited by a 3-h pretreatment with 0.5-100 microM LEV. Moreover, the GABAA receptors of pyramidal neurons in human neocortical slices exhibited a current run-down that was significantly reduced by 1 microM LEV. Interestingly, the run-down in oocytes injected with membranes isolated from the MTLE hippocampal subiculum was not affected by LEV. CONCLUSIONS: We report that the antiepileptic LEV strengthens GABA inhibition of neuronal circuits by blocking the receptor run-down in the cortex whilst leaving the run-down of GABAA receptors in the hippocampal subiculum unaltered. These findings point to the GABAA receptor run-down as an important event in epileptogenesis and as a possible target for testing and screening antiepileptic drugs.     

Seizure outcome and hippocampal atrophy in familial mesial temporal lobe epilepsy

OBJECTIVE: To describe the clinical, genetic and MR characteristics of patients with familial mesial temporal lobe epilepsy (MTLE). DESIGN/METHODS: The familial occurrence of MTLE was identified by a systematic search of family history of seizures in patients followed in the authors' epilepsy clinic. All probands and, whenever possible, other affected family members underwent EEG and MR investigations. RESULTS: Twenty-two unrelated families with at least two individuals with MTLE were identified by clinical and EEG findings. Ninety-eight individuals with history of seizures were evaluated. Sixty-eight patients fulfilled the diagnostic criteria for MTLE. MRI was performed in 84 patients, and showed hippocampal atrophy with increased T2 signal in 48 (57%). The distribution of hippocampal atrophy according to the seizure outcome groups was 6 of 13 patients (46%) with seizure remission, 16 of 31 (51%) with good seizure control under medication, and all 16 patients with refractory MTLE. Hippocampal atrophy was found also in patients that did not fulfill the criteria for MTLE: 3 of 10 (30%) patients with febrile seizure alone, 6 of 10 (60%) patients with recurrent generalized tonic-clonic seizures, and 1 of 4 (25%) patients with a single partial seizure. CONCLUSION: Familial MTLE is a clinically heterogeneous syndrome. Hippocampal atrophy was observed in 57% of patients, including those with benign course or seizure remission, indicating that the relationship between hippocampal atrophy and severity of epilepsy might be more complex than previously suspected. In addition, these findings indicate the presence of a strong genetic component determining the development of mesial temporal sclerosis in these families.     

Autoradiography reveals selective changes in serotonin binding in neocortex of patients with temporal lobe epilepsy

The main goal of the present study was to evaluate binding to serotonin in the neocortex surrounding the epileptic focus of patients with mesial temporal lobe epilepsy (MTLE). Binding to 5-HT, 5-HT(1A), 5-HT(4), 5-HT(7) receptors and serotonin transporter (5-HTT) in T1-T2 gyri of 15 patients with MTLE and their correlations with clinical data, neuronal count and volume were determined. Autopsy material acquired from subjects without epilepsy (n=6) was used as control. The neocortex from MTLE patients demonstrated decreased cell count in layers III-IV (21%). No significant changes were detected on the neuronal volume. Autoradiography experiments showed the following results: reduced 5-HT and 5-HT(1A) binding in layers I-II (24% and 92%, respectively); enhanced 5-HT(4) binding in layers V-VI (32%); no significant changes in 5-HT(7) binding; reduced 5-HTT binding in all layers (I-II, 90.3%; III-IV, 90.3%, V-VI, 86.9%). Significant correlations were found between binding to 5-HT(4) and 5-HT(7) receptors and age of seizure onset, duration of epilepsy and duration of antiepileptic treatment. The present results support an impaired serotoninergic transmission in the neocortex surrounding the epileptic focus of patients with MTLE, a situation that could be involved in the initiation and propagation of seizure activity.     

Benefits of the laryngeal mask for airway management during electroconvulsive therapy

Accumulation of carbon dioxide (CO2) can disturb systemic hemodynamics and increase the seizure threshold in patients receiving electroconvulsive therapy (ECT). The purpose of this study was to investigate the effects of the laryngeal mask on blood gas, hemodynamics, and seizure duration during ECT under propofol anesthesia. Ventilation was assisted using either a face mask (n=23) or laryngeal mask (n=23) and 100% oxygen. There was no significant difference in PaO2 between the two groups. PaCO2 was greater in the face mask group than the laryngeal mask group at 3 minutes (54 +/- 11 mm Hg, 41 +/- 8 mm Hg, respectively) and 5 minutes (52 +/- 11 mm Hg, 43 +/- 15 mm Hg, respectively) after electrical stimulation (p<0.01). Mean blood pressure was higher than the corresponding preanesthesia value at 1 to 5 minutes after electrical stimulation in the face mask group and at 1 to 3 minutes after electrical stimulation in the laryngeal mask group. Mean seizure duration in the face mask group was significantly shorter than that in the laryngeal mask group (33 +/- 11 seconds, 42 +/- 10 seconds, respectively p<0.01). The change in PaCO2 was minor in the laryngeal mask group compared with the face mask group and seizure duration was longer in the laryngeal mask group. Laryngeal mask may be suitable for airway management during ECT anesthesia, especially when fitting a face mask is difficult.     

Accuracy of ictal SPECT in mesial temporal lobe epilepsy with bilateral interictal spikes

OBJECTIVE: In mesial temporal lobe epilepsy (MTLE), the rate of correct seizure lateralization of ictal semiology and ictal EEG is better for patients with unilateral interictal spikes (UIS) than for patients with bilateral interictal spikes (BIS), possibly due to rapid seizure propagation patterns associated with bilateral epileptogenesis. In this study, the authors investigated if ictal SPECT is a reliable diagnostic test for both UIS and BIS patients. METHODS: Video-EEG recording was used as the gold standard to examine the accuracy of ictal SPECT and its relationship with interictal and ictal EEG. Ninety-three consecutive patients with MTLE associated with hippocampal sclerosis were included in the analysis. Ictal SPECT was considered accurate if two blinded observers independently lateralized the scan correctly. RESULTS: Ictal SPECT correctly lateralized 75 (80.6%) of 93 scans. The rate of correct seizure lateralization was 87.6% for the UIS group and only 55.0% for the BIS group (p = 0.0027). In the EEG epochs, 66.7% of BIS patients vs 43.4% of UIS patients had nonlateralized ictal EEG (p < 0.001). CONCLUSION: The authors conclude that the accuracy of ictal SPECT is worse for MTLE patients with BIS than for those with UIS. The role of ictal SPECT in presurgical evaluation of patients with BIS must be reviewed.     

mu-opioid receptor and alpha2-adrenoceptor agonist stimulation of [35S]GTPgammaS binding to G-proteins in postmortem brains of opioid addicts

Repeated opioid administration has been associated in human brain with unaltered density of mu-opioid receptors (agonist radioligand binding sites and immunodetected receptor protein). These receptors are coupled to Gi/Go-proteins, which are increased in brain of heroin addicts. To assess the activity of G-proteins and their coupling to receptors after chronic opioid abuse, [35S]GTPgammaS binding was quantified in postmortem prefrontal cortices of 15 opioid-dependent subjects and 15 matched controls. The stimulation of [35S]GTPgammaS binding by the mu-opioid receptor agonist DAMGO or the alpha2-adrenoceptor agonist UK14304 was used as a functional measure of the status of the receptor-G-protein coupling. [35S]GTPgammaS binding basal values were similar in opioid addicts (819+/-83 fmol mg-1 of protein) and controls (918+/-106 fmol mg(-1) of protein). In opioid addicts, [35S]GTPgammaS binding stimulation by DAMGO showed a maximal effect (62+/-8%) and a potency (EC50 = 1.09+/-0.26 microM) that did not differ from the maximal effect (60+/-12%) and potency (EC50 = 2.01+/-0.58 microM) in controls. In opioid addicts, [35S]GTPgammaS binding stimulation by UK14304 was not different in maximal effect (28+/-3%) from controls (32+/-8%), but the potency of the agonist was decreased (EC50 = 4.36+/-1.81 microM) when compared with controls (EC50 = 0.41+/-0.15 microM). The results provide a direct evidence of an apparent normal functional activity of brain mu-opioid receptors (Gi/Go-protein coupling) during the opioid dependence process in humans. The data also demonstrate a functional uncoupling of alpha2-adrenoceptors from G-proteins, which indicates a heterologous desensitization of these receptors. This finding could represent an adaptive mechanism against the decreased noradrenergic activity induced by the chronic presence of opioid drugs.     

Hippocampal atrophy and neurocysticercosis calcifications.

OBJECTIVE: To determine the relationship between hippocampal atrophy (HA), neurocysticercosis calcifications (NC) and seizure semiology in patients with partial epilepsy. METHODS: We identified two groups of patients: mesial temporal lobe epilepsy (MTLE) and extra-temporal epilepsy (ETE) patients. Each group was subdivided according to CT findings: normal, NC in the temporal regions, and NC in extra-temporal regions. MRI was obtained in a 2-T scanner and hippocampal volumetry was performed using 3-mm coronal T1-IR images. Hippocampal volumes below 2 standard deviations from the mean of the control group determined the presence of HA. RESULTS: We studied 89 consecutive patients: 63 with MTLE and 26 with ETE. HA was found in 43/89 (49.5 %) patients, 42 of them with MTLE. There was no difference in frequency of HA in the comparison between patients with (25/50) and without NC (18/39) (chi(2), p=0.71). Furthermore, there was no relationship between localization of NC (temporal or extra-temporal) and seizure semiology (MTLE or ETE). CONCLUSIONS: HA was more frequent and more severe in patients with MTLE, with no differences regarding the presence and localization of NC. These findings further support the concept that NC on CT not necessarily indicate the etiology of epilepsy and may represent only a co-existent pathology.     

Coherence between the hippocampus and anterior thalamic nucleus as a tool to improve the effect of neurostimulation in temporal lobe epilepsy: An experimental study

BackgroundAlthough the mechanisms by which deep brain stimulation (DBS) modifies the activity of the ictal network are mostly undefined, recent studies have suggested that DBS of the anterior nucleus of the thalamus (ANT) can be an effective treatment for mesial temporal lobe epilepsy (MTLE) when resective surgery cannot be performed. In a nonhuman primate (NHP) model of MTL seizures, we showed that the ANT was actively involved during interictal and ictal periods through different patterns and that the hippocampus (HPC) and ANT synchronously oscillate in the high beta-band during seizures.ObjectiveBased on those findings, we evaluated whether the frequency of stimulation is an important parameter that interferes with seizures and how to adapt stimulation protocols to it.MethodsWe investigated the effects of low-frequency (40 Hz - determined as the ictal frequency of correlation between structures) and high-frequency (130 Hz - as commonly used in clinic) ANT stimulation in three monkeys in which MTLE seizures were initiated.ResultsLow-frequency stimulation had a strong effect on the number of seizures and the total time spent in seizure, whereas high-frequency stimulation had no effect. The coherence of oscillations between the HPC and the ANT was significantly correlated with the success of low-frequency stimulation: the greater the coherence was, the greater the antiepileptic effect of ANT-DBS.ConclusionOur results suggest that low-frequency stimulation is efficient in treating seizures in a nonhuman primate model. More importantly, the study of the coherence between the ANT and HPC during seizures can help to predict the anti-epileptic effects of ANT stimulation. Furthermore, the DBS paradigm could be customized in frequency for each patient on the basis of the coherence spectral pattern.     

Prognostic factors in patients with mesial temporal lobe epilepsy

Purpose:   To disclose clinical, electrophysiologic, and neuroradiologic factors correlated to prognosis in patients with mesial temporal lobe epilepsy (MTLE).
Methods:   One hundred thirty-six MTLE patients were studied for family history, clinical characteristics, instrumental data [electroencephalography (EEG), video-EEG, neuroimaging], and outcome. The population was divided into drug-resistant (DR: 108 patients, 79.4%) and non–drug-resistant (NDR: 28 patients, 20.6%) groups; all variables were analyzed in the two groups.
Results:   The comparison between the two groups shows a relation between resistance to therapy and febrile seizures (FS) (DR 43.5% vs. NDR 17.8%, p = 0.008), mesial temporal sclerosis (MTS) (DR 64.8% vs. NDR 32.1%, p = 0.0025), early age at seizure onset (DR 23.1% vs. NDR 3.6% p = 0.0160), and epileptiform interictal abnormalities (DR 89.7% vs. NDR 68%, p = 0.010). FS were more frequent in patients with MTS than in patients without (46.28% vs. 26.3%, p = 0.0199). Sixty-nine patients underwent surgery and 85.3% of them had a good outcome.
Conclusion:   MTLE is a heterogeneous syndrome. Establishing the factors responsible for and associated with drug resistance is important for therapeutic purposes, as prompt diagnosis of drug resistance must lead to early surgical management. This study shows that FS, MTS, early age at seizure onset, and epileptiform interictal abnormalities are negative prognostic factors and that FS are related to MTS.     

Factors contributing to clinical seizure lateralization in patients with mesial temporal lobe epilepsy

Clinical seizure semiology can provide important information on the lateralization of the epileptogenic zone. We investigated factors associated with clinical seizure lateralization in patients with pathologically proven mesial temporal sclerosis. We reviewed 243 seizures of 58 patients. Clinical lateralization was possible in 155 (63.8%) of 243 seizures. Lateralization was correct in 144 (92.9%) of 155 lateralized seizures. Logistic regression analysis showed that age at onset (p = 0.001; odds ra tio = 1.089, 95% confidence interval = 1.035-1.145) and the contralateral propagation pattern of ictal discharges (p = 0.001; odds ratio = 3.544, 95% confidence interval = 1.723-7.289) correlated with clinical seizure lateralization. The patient group with clinically lateralized seizures had a younger age at onset of habitual seizures compared to the clinically nonlateralized group (11.1 +/- 6.3 vs. 15.6 +/- 8.4 years; p < 0.001). Of seizures without bitemporal asynchrony or switch of lateralization, 70.7% were clinically lateralized compared with only 46.4% of seizures with asynchrony or lateralization switch. The present results suggest that the age of epilepsy onset and the ictal scalp EEG propagation pattern affect clinical seizure lateralization in patients with mesial temporal sclerosis.     

Factors related to successful antiepileptic drug withdrawal after anterior temporal lobectomy for medial temporal lobe epilepsy.

OBJECTIVE: To assess the rate of successful antiepileptic drug (AED) discontinuation, prognostic factors and proper time of AED withdrawal after surgery for medial temporal lobe epilepsy (MTLE). METHODS: We reviewed 171 consecutive patients who underwent resective surgery for MTLE. All patients were followed up for more than two postoperative years. AEDs were slowly tapered with an individualized schedule for each patient. Outcome status was determined from medical records and telephone interviews. RESULTS: 41.2% of patients experienced no seizure recurrence. 34.5% discontinued medication without seizure recurrence for more than 2 years at final assessment. Multivariate analysis revealed that an age greater than 30 years at surgery and postoperative AED reduction before 10 months increased the risk of recurrence [hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.1-3.9 and HR 2.5, CI 1.1-5.8]. CONCLUSIONS: Resective surgery for MTLE brings seizure remission without AED to one-third of patients. Postoperative AED tapering is recommended after at least 10 months. Younger age at surgery is a good predictive factor of remission after MTLE surgery.     

Sex differences in patients with mesial temporal lobe epilepsy

Possible sex differences in the pattern of interictalhypometabolism were investigated, and also seizure spread in patients with mesial temporal lobe epilepsy (n=48) and hippocampal sclerosis (MTLE). Male patients (n=21) more often had a frontal lobehypometabolism ipsilateral to the seizure onset (p<0.0001) and aspread of epileptiform activity to this region (p=0.001). By contrast,female patients more often exhibited hypometabolism (p=0.0052) and anictal spread to the contralateral temporal lobe (p=0.0097). Thesefindings suggest sex differences in spatial distribution of braindysfunction in MTLE, perhaps reflecting sexual dimorphism in regionalcerebral connectivity.

     

Clinical and neuroimaging features of good and poor seizure control patients with mesial temporal lobe epilepsy and hippocampal atrophy

Summary: Purpose: Hippocampal atrophy (HA) and signal changes, detected at magnetic resonance imaging, have been associated with intractable seizures. Such a relation has been established by tertiary centers, where the prevalence of more severe cases tends to be higher. We evaluated the clinical and imaging variables that may have relevance to seizure control in patients with mesial temporal lobe epilepsy (MTLE) and HA. Methods: MTLE patients from the outpatient clinic of University of São Paulo School of Medicine at Ribeirão Preto were evaluated with protocols for the temporal lobe. Patients were considered to have good seizure control (GC; n = 42 ) if they had three of fewer seizures per year. Patients with pharmacoresistance and who did not fit the criteria for GC were considered to have poor seizure control (PC; n = 44 ). We made group comparisons and correlations of clinical data and hippocampal volume (HV) with seizure frequency. Results: No statistical differences were observed between the GC and PC groups in the following parameters: age at the time of study, age at the time of the initial precipitating injury (IPI) or first epileptic seizure, epilepsy duration and follow‐up, and family history of epilepsy. No differences were found in HV between GC (male, 2.04 ± 0.60 cc ; female, 2.00 ± 0.70 cc ) and PC (male, 2.26 ± 0.47 cc ; female, 2.15 ± 0.48 cc ) groups. Regression analysis indicated no correlation between seizure frequency and HV (p = 0.33) . Conclusions:These findings suggest that the intensity of HA does not have a direct correlation with seizure frequency in patients with MTLE with HA and that the detection of HA in MTLE patients does not mean an unequivocal indication of intractability.     

Antiepileptic drugs combined with high‐frequency electrical stimulation in the ventral hippocampus modify pilocarpine‐induced status epilepticus in rats

Purpose: To evaluate the effects of high‐frequency electrical stimulation (HFS) in both ventral hippocampi, alone and combined with a subeffective dose of antiepileptic drugs, during the status epilepticus (SE) induced by lithium‐pilocarpine (LP). Methods: Male Wistar rats, stereotactically implanted in both ventral hippocampi, were injected with pilocarpine (30 mg/kg, i.p.) 24 h after lithium (3 mEq/kg) administration. One minute following pilocarpine injection, HFS (pulses of 60 μs width at 130 Hz at subthreshold intensities and applied during 3 h) was applied alone or combined with subeffective doses of antiepileptic drugs. Results: HFS alone reduced the incidence of severe generalized seizures. This effect was not evident when HFS was combined with phenytoin (33.3 mg/kg, i.p.). HFS combined with diazepam (0.41 mg/kg, i.p.) or phenobarbital (10 mg/kg, i.p.) reduced the incidence of severe generalized seizures and mortality rate, and augmented the latency to first forelimb clonus, generalized seizure, and status epilepticus (SE). When combined with gabapentin (46 mg/kg, i.p.), HFS reduced the incidence of severe generalized seizures, enhanced latency to SE, and decreased mortality rate. Discussion: Subeffective doses of antiepileptic drugs that increase the γ‐aminobutyric acid (GABA)ergic neurotransmission may represent a therapeutic tool to augment the HFS‐induced anticonvulsant effects.     

Parasympathetic dysfunction is associated with baroreflex and chemoreflex impairment in streptozotocin-induced diabetes in rats

This study explored physiological mechanisms of diabetic dysfunction in baroreceptors and chemoreceptors-mediated hemodynamic responses, and cholinergic neurotransmission in 30-day diabetic rats (n = 14) and controls (n = 14). Basal hemodynamic data and vagal response to electrical stimulation and methacholine injection were also evaluated. Muscarinic receptors were characterized using a radioligand receptor binding assay ([3H]N methylscopolamine). Experimental diabetes (50 mg/kg of STZ, i.v.) decreased systolic, diastolic, and mean arterial pressure and basal heart rate. Heart rate (HR) responses to vagal electrical stimulation (16, 32, and 64 Hz) were 15%, 11%, and 14% higher in diabetics vs non-diabetics, as were HR responses to methacholine injection (-130+/-24, -172+/-18, -206+/-15 bpm vs. -48+/-15, -116+/-12, -151+/-18 bpm, P < 0.05). Muscarinic receptor density was higher (267.4+/-11 vs 193.5+/-22 fmol/mg/prot, P < 0.05) in the atria of diabetic rats than in those of controls; the affinity was similar between groups. Diabetes-induced reduction of reflex responses to baro- (reflex bradycardia: -3.4+/-0.3 and -2.7+/-0.2 bpm/mm Hg; reflex tachycardia: -1.6+/-0.1 and -1.4+/-0.07 bpm/mm Hg, in control and diabetics, P < 0.05) and chemoreceptor stimulation, enhancement of HR responsiveness to cardiac vagal electrical stimulation and methacholine stimulation, plus an increase in the number of atrial muscarinic receptors indicates reduced parasympathetic activity, which is probably derived from central nervous system derangement.