Generalized periodic discharges: Pathophysiology and clinical considerations

Generalized periodic discharges (GPDs) are commonly encountered in metabolic encephalopathy and cerebral hypoxia/ischemia. The clinical significance of this EEG pattern is indistinct, and it is unclear whether treatment with antiepileptic drugs is beneficial. In this study, we discuss potential pathophysiological mechanisms. Based on the literature, supplemented with simulations in a minimal computational model, we conclude that selective synaptic failure or neuronal damage of inhibitory interneurons, leading to disinhibition of excitatory pyramidal cells, presumably plays a critical role. Reversibility probably depends on the potential for functional recovery of these interneurons. Whether antiepileptic drugs are helpful for regaining function is unclea

Reduced Synaptic Vesicle Recycling during Hypoxia in Cultured Cortical Neurons

Improvement of neuronal recovery in the ischemic penumbra, an area around the core of a brain infarct with some remaining perfusion, has a large potential for the development of therapy against acute ischemic stroke. However, mechanisms that lead to either recovery or secondary damage in the penumbra largely remain unclear. Recent studies in cultured networks of cortical neurons showed that failure of synaptic transmission (referred to as synaptic failure) is a critical factor in the penumbral area, but the mechanisms that lead to synaptic failure are still under investigation. Here we used a Styryl dye, FM1-43, to quantify endocytosis and exocytosis in cultures of rat cortical neurons under normoxic and hypoxic conditions. Hypoxia in cultured cortical networks rapidly depressed endocytosis and, to a lesser extent, exocytosis. These findings support electrophysiological findings that synaptic failure occurs quickly after the induction of hypoxia, and confirms that the failing processes are at least in part presynaptic

Early EEG contributes to multimodal outcome prediction of postanoxic coma

Objectives:\ud Early identification of potential recovery of postanoxic coma is a major challenge. We studied the additional predictive value of EEG. \ud \ud Methods:\ud Two hundred seventy-seven consecutive comatose patients after cardiac arrest were included in a prospective cohort study on 2 intensive care units. Continuous EEG was measured during the first 3 days. EEGs were classified as unfavorable (isoelectric, low-voltage, burst-suppression with identical bursts), intermediate, or favorable (continuous patterns), at 12, 24, 48, and 72 hours. Outcome was dichotomized as good or poor. Resuscitation, demographic, clinical, somatosensory evoked potential, and EEG measures were related to outcome at 6 months using logistic regression analysis. Analyses of diagnostic accuracy included receiver operating characteristics and calculation of predictive values. \ud \ud Results:\ud Poor outcome occurred in 149 patients (54%). Single measures unequivocally predicting poor outcome were an unfavorable EEG pattern at 24 hours, absent pupillary light responses at 48 hours, and absent somatosensory evoked potentials at 72 hours. Together, these had a specificity of 100% and a sensitivity of 50%. For the remaining 203 patients, who were still in the “gray zone” at 72 hours, a predictive model including unfavorable EEG patterns at 12 hours, absent or extensor motor response to pain at 72 hours, and higher age had an area under the curve of 0.90 (95% confidence interval 0.84–0.96). Favorable EEG patterns at 12 hours were strongly associated with good outcome. EEG beyond 24 hours had no additional predictive value. \ud \ud Conclusions:\ud EEG within 24 hours is a robust contributor to prediction of poor or good outcome of comatose patients after cardiac arrest

Preservation of thalamocortical circuitry is essential for good recovery after cardiac arrest

Continuous electroencephalographam (EEG) monitoring contributes to prediction of neurological outcome in comatose cardiac arrest survivors. While the phenomenology of EEG abnormalities in postanoxic encephalopathy is well known, the pathophysiology, especially the presumed role of selective synaptic failure, is less understood. To further this understanding, we estimate biophysical model parameters from the EEG power spectra from individual patients with a good or poor recovery from a postanoxic encephalopathy. This biophysical model includes intracortical, intrathalamic, and corticothalamic synaptic strengths, as well as synaptic time constants and axonal conduction delays. We used continuous EEG measurements from hundred comatose patients recorded during the first 48 h postcardiac arrest, 50 with a poor neurological outcome [cerebral performance category (CPC = 5)] and 50 with a good neurological outcome (CPC = 1). We only included patients that developed (dis-)continuous EEG activity within 48 h postcardiac arrest. For patients with a good outcome, we observed an initial relative excitation in the corticothalamic loop and corticothalamic propagation that subsequently evolved towards values observed in healthy controls. For patients with a poor outcome, we observed an initial increase in the cortical excitation-inhibition ratio, increased relative inhibition in the corticothalamic loop, delayed corticothalamic propagation of neuronal activity, and severely prolonged synaptic time constants that did not return to physiological values. We conclude that the abnormal EEG evolution in patients with a poor neurological recovery after cardiac arrest may result from persistent and selective synaptic failure that includes corticothalamic circuitry and also delayed corticothalamic propagation.</p

Unstandardized Treatment of Electroencephalographic Status Epilepticus Does Not Improve Outcome of Comatose Patients after Cardiac Arrest

Objective: Electroencephalographic status epilepticus occurs in 9–35% of comatose patients after cardiac arrest. Mortality is 90–100%. It is unclear whether (some) seizure patterns represent a condition in which anti-epileptic treatment may improve outcome, or severe ischemic damage, in which treatment is futile. We explored current treatment practice and its effect on patients’ outcome. Methods: We retrospectively identified patients that were treated with anti-epileptic drugs from our prospective cohort study on the value of continuous electroencephalography (EEG) in comatose patients after cardiac arrest. Outcome at 6 months was dichotomized between “good” [cerebral performance category (CPC) 1 or 2] and “poor” (CPC 3, 4, or 5). EEG analyses were done at 24 h after cardiac arrest and during anti-epileptic treatment. Unequivocal seizures and generalized periodic discharges during more than 30 min were classified as status epilepticus. Results: Thirty-one (22%) out of 139 patients were treated with anti-epileptic drugs (phenytoin, levetiracetam, valproate, clonazepam, propofol, midazolam), of whom 24 had status epilepticus. Dosages were moderate, barbiturates were not used, medication induced burst-suppression not achieved, and treatment improved electroencephalographic status epilepticus patterns temporarily (<6 h). Twenty-three patients treated for status epilepticus (96%) died. In patients with status epilepticus at 24 h, there was no difference in outcome between those treated with and without anti-epileptic drugs. Conclusion: In comatose patients after cardiac arrest complicated by electroencephalographic status epilepticus, current practice includes unstandardized, moderate treatment with anti-epileptic drugs. Although widely used, this does probably not improve patients’ outcome. A randomized controlled trial to estimate the effect of standardized, aggressive treatment, directed at complete suppression of epileptiform activity during at least 24 h, is needed and in preparation

Evolution of Excitation–Inhibition Ratio in Cortical Cultures Exposed to Hypoxia

In the core of a brain infarct, neuronal death occurs within minutes after loss of perfusion. In the penumbra, a surrounding area with some residual perfusion, neurons initially remain structurally intact, but hypoxia-induced synaptic failure impedes neuronal activity. Penumbral activity may recover or further deteriorate, reflecting cell death. Mechanisms leading to either outcome remain ill-understood, but may involve changes in the excitation to inhibition (E/I) ratio. The E/I ratio is determined by structural (relative densities of excitatory and inhibitory synapses) and functional factors (synaptic strengths). Clinical studies demonstrated excitability alterations in regions surrounding the infarct core. These may be related to structural E/I changes, but the effects of hypoxia /ischemia on structural connectivity have not yet been investigated, and the role of structural connectivity changes in excitability alterations remains unclear. We investigated the evolution of the structural E/I ratio and associated network excitability in cortical cultures exposed to severe hypoxia of varying duration. 6–12 h of hypoxia reduced the total synaptic density. In particular, the inhibitory synaptic density dropped significantly, resulting in an elevated E/I ratio. Initially, this does not lead to increased excitability due to hypoxia-induced synaptic failure. Increased excitability becomes apparent upon reoxygenation after 6 or 12 h, but not after 24 h. After 24 h of hypoxia, structural patterns of vesicular glutamate stainings change. This possibly reflects disassembly of excitatory synapses, and may account for the irreversible reduction of activity and stimulus responses seen after 24 h

A Biophysical Model for Cytotoxic Cell Swelling

We present a dynamic biophysical model to explain neuronal swelling underlying cytotoxic edema in conditions of low energy supply, as observed in cerebral ischemia. Our model contains Hodgkin—Huxley-type ion currents, a recently discovered voltage-gated chloride flux through the ion exchanger SLC26A11, active KCC2-mediated chloride extrusion, and ATP-dependent pumps. The model predicts changes in ion gradients and cell swelling during ischemia of various severity or channel blockage with realistic timescales. We theoretically substantiate experimental observations of chloride influx generating cytotoxic edema, while sodium entry alone does not. We show a tipping point of Na+/K+-ATPase functioning, where below cell volume rapidly increases as a function of the remaining pump activity, and a Gibbs–Donnan-like equilibrium state is reached. This precludes a return to physiological conditions even when pump strength returns to baseline. However, when voltage-gated sodium channels are temporarily blocked, cell volume and membrane potential normalize, yielding a potential therapeutic strategy