Chin Wei Huang

Influence of seizures on stroke outcomes A large multicenter study

Objective: We compared clinical characteristics of seizures at ischemic stroke presentation (SSP) to seizures during hospitalization post ischemic stroke (SDH), and their impacts on stroke outcome, using the Registry of the Canadian Stroke Network (RCSN) database. Methods: This cohort study included consecutive patients from the RCSN who had an acute ischemic stroke between July 2003 and March 2008. Outcome measures included morbidity, mortality, length of hospital stay, and discharge disposition. Clinical variables for either SSP or SDH were investigated and the stroke outcome was stratified by stroke severity. Results: The study included 10,261 patients with ischemic strokes: 157 patients (1.53%) had SSP and 208 patients (2.03%) had SDH. Compared to stroke patients without seizures, patients with SSP and SDH were younger, had more severe strokes (p < 0.001), a higher admission rate to the intensive care unit (p < 0.001), higher morbidity, and higher mortality (p < 0.05). SSP was associated with female sex and less limb weakness, while SDH was associated with pneumonia and the presence of hemineglect. Importantly, patients with less severe strokes had higher morbidity and mortality (p < 0.005) if SDH occurred. Variables predicting overall mortality were SDH, older age, higher Charlson-Deyo index, more severe strokes, and nonalert status on arrival (all p < 0.001). Conclusions: SSP and SDH have different characteristics. SDH indicates a poorer prognosis in patients. Increased awareness of SSP and efforts to prevent SDH may be important in improving outcomes following clinical stroke care.

Terminating prolonged refractory status epilepticus using ketamine.

Refractory status epilepticus (RSE) is an emergent and difficult neurologic problem that is not uncommon in clinical practice. In this report, we describe a 23-year-old man whose RSE was refractory to standard antiepileptic drugs and barbiturates; it was successfully terminated only with intravenous ketamine. In this report, we evaluated and discuss the clinical and electroencephalographic effects under ketamine. This case and the rare cases of ketamine experience in RSE reported in the literature show that ketamine is potentially effective to use when treating patients with RSE. Further clinical trials are warranted, however.

The synergistic inhibitory actions of oxcarbazepine on voltage-gated sodium and potassium currents in differentiated NG108-15 neuronal cells and model neurons

Oxcarbazepine (OXC), one of the newer anti-epileptic drugs, has been demonstrating its efficacy on wide-spectrum neuropsychiatric disorders. However, the ionic mechanism of OXC actions in neurons remains incompletely understood. With the aid of patch-clamp technology, we first investigated the effects of OXC on ion currents in NG108-15 neuronal cells differentiated with cyclic AMP. We found OXC (0.3-30 microm) caused a reversible reduction in the amplitude of voltage-gated Na+ current (INa). The IC50 value required for the inhibition of INa by OXC was 3.1 microm. OXC (3 microm) could shift the steady-state inactivation of INa to a more negative membrane potential by approximately -9 mV with no effect on the slope of the inactivation curve, and produce a significant prolongation in the recovery of INa inactivation. Additionally, OXC was effective in suppressing persistent INa (INa(P)) elicited by long ramp pulses. The blockade of INa by OXC does not simply reduce current magnitude, but alters current kinetics. Moreover, OXC could suppress the amplitude of delayed rectifier K+ current (IK(DR)), with no effect on M-type K+ current (IK(M)). In current-clamp configuration, OXC could reduce the amplitude of action potentials and prolong action-potential duration. Furthermore, the simulations, based on hippocampal pyramidal neurons (Pinsky-Rinzel model) and a network of the Hodgkin-Huxley model, were analysed to investigate the effect of OXC on action potentials. Taken together, our results suggest that the synergistic blocking effects on INa and IK(DR) may contribute to the underlying mechanisms through which OXC affects neuronal function in vivo.

Diabetic hyperglycemia is associated with the severity of epileptic seizures in adults.

Epileptic seizures in diabetic hyperglycemia (DH) patients are not uncommon in clinical practice. Although there have been reports suggesting an association, most were limited case studies. The role of DH in the severity and recurrence of epileptic seizures remains unclear. We thus conducted a prospective comparative study of newly diagnosed unprovoked seizures in adult patients, with and without DH, from 2000 to 2004. Seizure semiology and severity were studied and all subjects were followed-up for 2 years to evaluate seizure recurrence. Forty-one patients in the DH and 70 patients in the non-DH group were recruited. Seizure clustering in initial presentation (63%) and in recurrence (78.6%) in the DH group was significantly higher than that in the non-DH group (38.5 and 41.4%) (p<0.05). In the DH group, the HbA1c at first seizure was significantly higher in patients with seizure recurrence than in those without (11.8% vs. 8.6%, p<0.05). Patients with poor glycemic control (HbA1c >9%) had significantly higher risk of seizure recurrence (44.8% vs. 8.3%) and clustering (79.3% vs. 25%) (p<0.05). In conclusion, DH might aggravate epileptic seizures. Severe seizures might be associated with recurrent seizures in patients with DH. DH should be investigated in adult patients with newly diagnosed epileptic seizures and aggressive blood sugar control might benefit seizure management in patients with DH.

Glucose and hippocampal neuronal excitability: Role of ATP-sensitive potassium channels

Hyperglycemia‐related neuronal excitability and epileptic seizures are not uncommon in clinical practice. However, their underlying mechanism remains elusive. ATP‐sensitive K+ (KATP) channels are found in many excitable cells, including cardiac myocytes, pancreatic β cells, and neurons. These channels provide a link between the electrical activity of cell membranes and cellular metabolism. We investigated the effects of higher extracellular glucose on hippocampal KATP channel activities and neuronal excitability. The cell‐attached patch‐clamp configuration on cultured hippocampal cells and a novel multielectrode recording system on hippocampal slices were employed. In addition, a simulation modeling hippocampal CA3 pyramidal neurons (Pinsky‐Rinzel model) was analyzed to investigate the role of KATP channels in the firing of simulated action potentials. We found that incremental extracellular glucose could attenuate the activities of hippocampal KATP channels. The effect was concentration dependent and involved mainly in open probabilities, not single‐channel conductance. Additionally, higher levels of extracellular glucose could enhance neuropropagation; this could be attenuated by diazoxide, a KATP channel agonist. In simulations, high levels of intracellular ATP, used to mimic increased extracellular glucose or reduced conductance of KATP channels, enhanced the firing of action potentials in model neurons. The stochastic increases in intracellular ATP levels also demonstrated an irregular and clustered neuronal firing pattern. This phenomenon of KATP channel attenuation could be one of the underlying mechanisms of glucose‐related neuronal hyperexcitability and propagation.

Inhibitory effect of lamotrigine on A-type potassium current in hippocampal neuron-derived H19-7 cells

Summary:  Purpose: We investigated the effects of lamotrigine (LTG) on the rapidly inactivating A‐type K+ current (IA) in embryonal hippocampal neurons.

The Opening Effect of Pregabalin on ATP‐Sensitive Potassium Channels in Differentiated Hippocampal Neuron–derived H19‐7 Cells

Summary:  Purpose: Adenosine triphosphate (ATP)‐sensitive K+ (KATP) channels can couple an intracellular metabolic state to an electrical activity, which is important in the control of neuronal excitability and seizure propagation. We investigated whether the newer antiepileptic drug, pregabalin (PGB), could exert effects on KATP channels in differentiated hippocampal neuron–derived H19‐7 cells.

Comparative cognitive effects of levetiracetam and topiramate in intractable epilepsy

Aim:  Anti‐epileptic drugs (AED) may cause cognitive impairment. Because intractable epilepsy (IE) represents a distinct group, the purpose of the present study was to study the comparative cognitive effects of the two efficacious AED, levetiracetam (LEV) and topiramate (TPM), on IE.

Activation by Zonisamide, a Newer Antiepileptic Drug, of Large-Conductance Calcium-Activated Potassium Channel in Differentiated Hippocampal Neuron-Derived H19-7 Cells

Zonisamide (ZNS; 3-sulfamoylmethyl-1,2-benzisoxazole), as one of the newer antiepileptic drugs, has been demonstrated its broad-spectrum clinical efficacy on various neuropsychiatric disorders. However, little is known regarding the mechanism of ZNS actions on ion currents in neurons. We thus investigated its effect on ion currents in differentiated hippocampal 19-7 cells. In whole-cell configuration of patch-clamp technology, the ZNS (30 μM) reversibly increased the amplitude of K+ outward currents, and paxilline (1 μM) was effective in suppressing the ZNS-induced increase of K+ outward currents. In inside-out configuration, ZNS (30 μM) applied to the intracellular face of the membrane did not alter single-channel conductance; however, it did enhance the activity of large-conductance Ca2+-activated K+ (BKCa) channels primarily by decreasing mean closed time. In addition, the EC50 value for ZNS-stimulated BKCa channels was 34 μM. This drug caused a left shift in the activation curve of BKCa channels, with no change in the gating charge of these channels. Moreover, ZNS at a concentration greater than 100 μM also reduced the amplitude of A-type K+ current in these cells. A simulation modeling based on hippocampal CA3 pyramidal neurons (Pinsky-Rinzel model) was also analyzed to investigate the inhibitory effect of ZNS on the firing of simulated action potentials. Taken together, this study suggests that, in hippocampal neurons during the exposure to ZNS, the ZNS-mediated effects on BKCa channels and A-type K+ current could be potential mechanisms through which it affects neuronal excitability.

Characterizing the effects of Eugenol on neuronal ionic currents and hyperexcitability

RationaleEugenol (EUG, 4-allyl-2-methoxyphenol), the main component of essential oil extracted from cloves, has various uses in medicine because of its potential to modulate neuronal excitability. However, its effects on the ionic mechanisms remains incompletely understood.ObjectivesWe aimed to investigate EUG’s effects on neuronal ionic currents and excitability, especially on voltage-gated ion currents, and to verify the effects on a hyperexcitability-temporal lobe seizure model.MethodsWith the aid of patch-clamp technology, we first investigated the effects of EUG on ionic currents in NG108-15 neuronal cells differentiated with cyclic AMP. We then used modified Pinsky–Rinzel simulation modeling to evaluate its effects on spontaneous action potentials (APs). Finally, we investigated its effects on pilocarpine-induced seizures in rats.ResultsEUG depressed the transient and late components of INa in the neurons. It not only increased the degree of INa inactivation, but specifically suppressed the non-inactivating INa (INa(NI)). Its inhibition of INa(NI) was reversed by tefluthrin. In addition, EUG diminished L-type Ca2+ current and delayed rectifier K+ current only at higher concentrations. EUG’s effects on APs frequency reduction was verified by the simulation modeling. In pilocarpine-induced seizures, the EUG-treated rats showed no shorter seizure latency but a lower seizure severity and mortality than the control rats. The EUG’s effect on seizure severity was occluded by the INa(NI) antagonist riluzole.ConclusionThe synergistic blocking effects of INa and INa(NI) contributes to the main mechanism through which EUG affects the firing of neuronal APs and modulate neuronal hyperexcitability such as pilocarpine-induced temporal lobe seizures.