Patterns of single-neuron activity during associative recognition memory in the human medial temporal lobe.

Electrophysiological activity in medial temporal lobe (MTL) structures is pivotal for declarative long-term memory. Single-neuron and microcircuit findings capitalizing on human microwire recordings from the medial temporal lobe are still fragmentary. In particular, it is an open question whether identical or different groups of neurons participate in different memory functions. Here, we investigated category-specific responses in the human MTL based on single-neuron recordings in presurgical epilepsy patients performing an associative long-term memory task. Additionally, auditory beat stimuli were presented during encoding and retrieval to modulate memory performance. We describe the proportion of neurons in amygdala, entorhinal cortex, hippocampus and parahippocampal cortex belonging to different response classes. These entail neurons coding stimulus-familiarity, neurons coding successful item memory, and neurons coding associated source memory, as well as the overlap between these classes. As major results we demonstrate that neurons responding to stimulus familiarity (old/new effect) can be identified in the MTL even when using previously known rather than entirely novel stimulus material (words). We observed a significant overlap between familiarity-related neurons and neurons coding item retrieval (remembered/forgotten effect). The largest fraction of familiarity-related neurons was found in the parahippocampal cortex, and a considerable fraction of all parahippocampal neurons was related to successful item retrieval. Neurons related to successful source retrieval were different from the neurons coding the associated information. Most importantly, there was no overlap between neurons coding item memory and those coding associated source memory strongly suggesting that these functions are facilitated by different sets of neurons.

[Laboratory diagnostics in transient loss of consciousness : Serum lactate compared to serum creatine kinase as diagnostic indicator for generalized tonic-clonic seizures]. / Labordiagnostik bei transienten Bewusstseinsstörungen : Serumlaktatwert im Vergleich zur Serumkreatinkinase als diagnostischer Indikator für generalisierte tonisch-klonische Anfälle.

BACKGROUND: Laboratory parameters can help in the differential diagnostics of acute episodes of transient loss of consciousness. Especially serum lactate and serum creatine kinase (CK) levels may provide valuable hints to distinguish generalized tonic-clonic seizures (GTCS) from syncope. MATERIAL AND METHODS: Serum lactate levels at admission and CK levels 10-48 h after the episodes that led to admission were compared between patients with GTCS (n = 30) and those with syncope (n = 15). In addition, sensitivity and specificity of lactate and CK as diagnostic markers for syncope and GTCS were determined. RESULTS: The serum lactate and serum CK levels were significantly increased in patients with GTCS as compared to syncope patients (serum lactate: p < 0.001; CK: p < 0.005). The area under the curve (AUC) for serum lactate as an indicator for GTCS was 0.94 (95% confidence interval [CI] 0.88-1.0). For CK the receiver operating characteristics (ROC) analysis produced an AUC of only 0.77 (95% CI: 0.63-0.9). CONCLUSION: The determination of the lactate value as point-of-care diagnostics appears to be highly relevant in the rapid clarification of unclear episodes with transient loss of consciousness. The CK level at follow-up is also suitable for distinguishing GTCS from syncope but is inferior to the serum lactate value.

Adjunctive retigabine in refractory focal epilepsy: Postmarketing experience at four tertiary epilepsy care centers in Germany.

PURPOSE: Retigabine (RTG, ezogabine) is the first potassium channel-opening anticonvulsant drug approved for adjunctive treatment of focal epilepsies. We report on the postmarketing clinical efficacy, adverse events, and retention rates of RTG in adult patients with refractory focal epilepsy. METHODS: Clinical features before and during RTG treatment were retrospectively collected from patients treated at four German epilepsy centers in 2011 and 2012. RESULTS: A total of 195 patients were included. Daily RTG doses ranged from 100 to 1500 mg. Retigabine reduced seizure frequency or severity for 24.6% and led to seizure-freedom in 2.1% of the patients but had no apparent effect in 43.1% of the patients. Seizure aggravation occurred in 14.9%. The one-, two-, and three-year retention rates amounted to 32.6%, 7.2%, and 5.7%, respectively. Adverse events were reported by 76% of the patients and were mostly CNS-related. Blue discolorations were noted in three long-term responders. Three possible SUDEP cases occurred during the observation period, equalling an incidence rate of about 20 per 1000 patient years. CONCLUSIONS: Our results are similar to other pivotal trials with respect to the long-term, open-label extensions and recent postmarketing studies. Despite the limitations of the retrospective design, our observational study suggests that RTG leads to good seizure control in a small number of patients with treatment-refractory seizures. However, because of the rather high percentage of patients who experienced significant adverse events, we consider RTG as a drug of reserve.

Hippocampal involvement in secondarily generalised seizures of extrahippocampal origin.

BACKGROUND AND AIMS: Recent data have revealed that clinically generalised tonic-clonic seizures do not involve all brain regions electrophysiologically. The hippocampus in particular could be protected from epileptic activity by putative filtering properties of the dentate gyrus. Here we investigated if simple or complex focal seizures (SFS/CFS) and in particular secondarily generalised tonic-clonic seizures (SGS) of extrahippocampal onset (EHO) spare the hippocampus and if there are promotive factors. METHODS: We retrospectively assessed clinical, electrophysiological, imaging and histopathological data from patients undergoing presurgical evaluation of focal epilepsy with hippocampal depth and extrahippocampal subdural electrodes and selected those suffering from SGS of EHO. We further subdivided this patient sample according to qualitative MRI criteria into a HL(-) group, with an extrahippocampal lesion only, and a HL(+) group, displaying an extrahippocampal and additional hippocampal lesion. RESULTS: 14 patients (seven in each group) fulfilling the inclusion criteria had a total of 43 SGS, of which 35 were of EHO. Whereas only 68% of SFS/CFS of EHO propagated into the hippocampus, all SGS of EHO invaded the hippocampi independently of the ictal propagation pattern or degree of hippocampal pathology. All hippocampi in the HL(-) group displayed interictal epileptiform activity and even seizure onset in two patients. CONCLUSIONS: In our patient sample, the human hippocampus was not spared during SGS of EHO, but was invariably invaded by epileptic activity. The presence of spontaneous epileptic activity in the HL(-) group revealed persistent modifications in hippocampal excitability that might be due to secondary epileptogenesis in the hippocampus following repeated seizures of EHO.

The discriminative value of blood gas analysis parameters in the differential diagnosis of transient disorders of consciousness.

AIM: The differentiation between epileptic and non-epileptic episodes can be challenging. Our aim was to compare lactate, anion gap (AG), bicarbonate and the Denver Seizure Score (DSS) as point-of-care test (POCT) markers for episodes of transient alterations of consciousness. METHODS: The blood serum parameters were drawn at arrival in the emergency department (ED) within 2 h of the episode. After calculating AG and DSS values, the four parameters were compared retrospectively between patients with generalized tonic-clonic seizures (GTCS) (n = 165) and patients with other disorders of consciousness [syncopes (n = 43), and psychogenic non-epileptic seizures (n = 15)]. Additionally, we compared all values among men and women. RESULTS: In GTCS patients, all four parameters differed significantly compared to non-epileptic episode patients (p < 0.001). Serum lactate showed significant additional benefit over the remaining values, with an AUC of 0.947 (95% CI 0.92-0.975) and a high sensitivity and specificity for an optimal cut-off value of 2.45 mmol/l. For DSS, the AUC was 0.857 (95% CI 0.808-0.906; cut-off: 0.35), and for AG 0.836 (95% CI 0.783-0.889; cut-off: 12.45 mmol/l). In the case of serum bicarbonate, the AUC was 0.831 (95% CI 0.775-0.886; cut-off: 22.75 mmol/l). In the sex-dependent comparison, the results were similar. Men showed more significant differences in the compared values than women. CONCLUSIONS: Serum lactate is best suited as POCT marker in the differential diagnosis of epileptic and non-epileptic episodes and is superior to AG, DSS and bicarbonate. The differences among sexes may pose a challenge in their implementation and interpretation.

Treatment of immune-mediated temporal lobe epilepsy with GAD antibodies.

PURPOSE: Temporal lobe epilepsy with antibodies (abs) against the glutamic acid decarboxylase 65 isoform (GAD-TLE) is known as an immune-mediated neurological syndrome. Here we evaluate the therapy response to various immunotherapies and epilepsy surgery in this syndrome. METHOD: All patients with GAD-TLE and follow-up data and stored serum and CSF samples, identified and treated at the Bonn centre from 2002 to 2010, were studied retrospectively. Seizure freedom for ≥1 year and reduction of ≥50%, i.e. therapy response, were assessed. GAD-ab titres and neuropsychological performances were documented prior and after individual interventions. RESULTS: Thirteen patients with GAD-TLE were identified with the following seizure responses: corticosteroids (5 responders out of 11 treated patients); i.v. immunoglobulins (1/5), apheresis therapy (1/8); and natalizumab (1/1), selective amygdala-hippocampectomy (2/3). None of the patients achieved sustained seizure freedom apart from one patient. This patient was on antiepileptic drug treatment after discontinuation of immunotherapy. CONCLUSION: The seizure response to immunotherapies in patients with GAD-TLE was poor. Corticosteroids were the most effective regarding seizure response. Especially the poor effects of apheresis therapies support the idea that GAD-abs are not directly pathogenic. None of three patients was seizure-free after temporal lobe surgery suggesting that GAD-TLE patients respond worse than others to this type of intervention. Our results reflect the chronic course of the disease with low likelihood for patients with GAD-TLE to attain long-term seizure freedom.

Outcome of limbic encephalitis with VGKC-complex antibodies: relation to antigenic specificity.

In limbic encephalitis (LE) with antibodies (Abs) to the voltage-gated potassium channel complex (VGKC), the Abs are mainly directed to the VGKC-complex proteins, leucine-rich, glioma inactivated 1 protein (LGI1) or contactin-associated protein-like 2 (CASPR-2) or neither. Here, we relate the outcomes of VGKC-LE patients to the presence of Abs to LGI1, CASPR-2 or neither antigen (LGI1/CASPR-2-Ab(-)). Clinical, neuropsychology and MRI data were obtained from patient records for all LE patients from the Bonn Epilepsy Centre positive for VGKC-Abs by radioimmunoprecipitation assay between 2002 and 2011. Eighteen VGKC-LE patients were identified: nine patients (50 %) had LGI1-Abs, three (16 %) had CASPR-2-Abs; and six (33 %) were negative for both LGI1- and CASPR-2-Abs. At first assessment, the groups did not differ clinically or radiologically, but faciobrachial dystonic seizures were only observed in two LGI1-Ab(+) patients. All patients received monthly intravenous methylprednisolone (MP) pulses. At the most recent follow up (median 26 months), thirteen (72 %) were seizure-free, and seizure-freedom rates did not differ between the Ab groups. Hippocampal atrophy had developed in 7/9 LGI1-Ab(+) patients, but in none of the CASPR-2-Ab(+) or LGI/CASPR-2-Ab(-) patients (p = 0.003). While all subgroups improved, memory scores only normalized in six patients (33 %) and LGI1-Ab(+) patients were left with significantly poorer memory than the other two subgroups. Most VGKC-LE patients become seizure-free with pulsed monthly MP, but memory outcome is less favourable. Hippocampal atrophy and poor memory recovery is common in patients with LGI1-Abs and suggests permanent functional damage. More intense immunotherapies could improve outcomes in LGI1-Ab(+)-LE.

Do alterations in inter-ictal heart rate variability predict sudden unexpected death in epilepsy?

Reduced heart rate variability (HRV) may predispose to sudden unexpected death in epilepsy (SUDEP). We ascertained whether HRV predicts SUDEP in chronic epilepsy using a case-control design and investigated parameters of inter-ictal HRV in 14 patients (7 had died from SUDEP). No HRV parameter was associated with SUDEP. Thus, although altered HRV might be involved in SUDEP, HRV parameters are not clear-cut predictors for SUDEP.

Rapid modulation of L-type calcium current by acutely applied oestrogens in isolated cardiac myocytes from human, guinea-pig and rat.

Gender-based differences in cardiovascular mortality may be due to a cardio-protective effect of oestrogens on the myocardium. However, mRNA expression of oestrogen receptors in myocardial tissue of the adult heart has yet to be demonstrated. Furthermore, a calcium antagonistic action of 17beta-oestradiol on myocardial tissue has been discussed. Therefore, two subjects were investigated in atrial myocytes of the human, and ventricular myocytes of guinea-pig and rat in this study. (1) Are oestrogen receptors expressed in adult myocardial cells? (2) Is there an influence of oestrogens on the L-type calcium current of cardiac myocytes? Expression of oestrogen receptors was investigated by reverse polymerase chain reaction. L-type calcium current was usually measured by the patch-clamp technique in whole-cell recording mode under selective recording conditions, i.e. overlapping currents were blocked. One series of experiments was performed in perforated patch configuration to avoid internal perfusion. 17beta-oestradiol inhibited L-type calcium current reversibly in all three species. At 10(-5) M, the inhibition was 15-20%. This inhibition was independent of the sex and the species. A full concentration response curve of 17beta-oestradiol on basal L-type current was recorded from female guinea-pig myocytes. The inhibition increased from 2% at 10(-7) M to about 30% at 10(-4) M 17beta-oestradiol. The values could be fitted by a sum of two sigmoidal functions with log EC50 values of -6.5 and -4.9 M and Hill slopes of 2.5 for both. The specificity of the 17beta-oestradiol action was tested by recording the L-type current in the presence of 17alpha-oestradiol and oestrone. 17alpha-oestradiol also inhibited the current, but with a maximal inhibition of only 17%. The concentration-response curve could be fitted by a single sigmoidal function (log EC50 -6-3 M; Hill slope 0.55). Oestrone did not influence the current at all. The decrease in L-type current after the application of 17beta-oestradiol via a rapid perfusion system developed with a time constant of 3-4 s, which was in the same range as that for the influence of isoprenaline. The isoprenaline-stimulated L-type current was much more susceptible to the inhibition by 17beta-oestradiol, i.e. in pre-stimulated cells (1) the inhibitory effect is significantly higher (e.g. at 10(-5) M, inhibition was 36.3% compared with 11.2% in untreated cells) and (2) an inhibitory effect can be seen with oestradiol concentrations as low as 10(-9) M. Although the concentrations needed to gain a calcium antagonistic influence on the basal current were much too high to explain a cardio-protective influence of oestrogens, the presence of oestrogen receptors in cardiac myocytes of all three species, together with the shift in concentration dependence following pre-stimulation by isoprenaline, suggest that myocytes are a potential target for oestrogen.