Sharp wave ripples (SPW-Rs) represent the most synchronous population pattern in the mammalian brain. Their excitatory output affects a wide area of the cortex and several subcortical nuclei. SPW-Rs occur during "off-line" states of the brain, associated with consummatory behaviors and non-REM sleep, and are influenced by numerous neurotransmitters and neuromodulators. They arise from the excitatory recurrent system of the CA3 region and the SPW-induced excitation brings about a fast network oscillation (ripple) in CA1. The spike content of SPW-Rs is temporally and spatially coordinated by a consortium of interneurons to replay fragments of waking neuronal sequences in a compressed format. SPW-Rs assist in transferring this compressed hippocampal representation to distributed circuits to support memory consolidation; selective disruption of SPW-Rs interferes with memory. Recently acquired and pre-existing information are combined during SPW-R replay to influence decisions, plan actions and, potentially, allow for creative thoughts. In addition to the widely studied contribution to memory, SPW-Rs may also affect endocrine function via activation of hypothalamic circuits. Alteration of the physiological mechanisms supporting SPW-Rs leads to their pathological conversion, "p-ripples," which are a marker of epileptogenic tissue and can be observed in rodent models of schizophrenia and Alzheimer's Disease. Mechanisms for SPW-R genesis and function are discussed in this review.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/hipo.22488

Hippocampal sharp wave‐ripple: A cognitive biomarker for episodic memory and planning

The kainic acid model of temporal lobe epilepsy

Diverse brain insults, including traumatic brain injury, stroke, infections, tumors, neurodegenerative diseases, and prolonged acute symptomatic seizures, such as complex febrile seizures or status epilepticus (SE), can induce “epileptogenesis,” a process by which normal brain tissue is transformed into tissue capable of generating spontaneous recurrent seizures. Furthermore, epileptogenesis operates in cryptogenic causes of epilepsy. In view of the accumulating information about cellular and molecular mechanisms of epileptogenesis, it should be possible to intervene in this process before the onset of seizures and thereby either prevent the development of epilepsy in patients at risk or increase the potential for better long-term outcome, which constitutes a major clinical need. For identifying pharmacological interventions that prevent, interrupt or reverse the epileptogenic process in people at risk, two groups of animal models, kindling and SE-induced recurrent seizures, have been recommended as potentially useful tools. Furthermore, genetic rodent models of epileptogenesis are increasingly used in assessing antiepileptogenic treatments. Two approaches have been used in these different model categories: screening of clinically established antiepileptic drugs (AEDs) for antiepileptogenic or disease-modifying potential, and targeting the key causal mechanisms that underlie epileptogenesis. The first approach indicated that among various AEDs, topiramate, levetiracetam, carisbamate, and valproate may be the most promising. On the basis of these experimental findings, two ongoing clinical trials will address the antiepileptogenic potential of topiramate and levetiracetam in patients with traumatic brain injury, hopefully translating laboratory discoveries into successful therapies. The second approach has highlighted neurodegeneration, inflammation and up-regulation of immune responses, and neuronal hyperexcitability as potential targets for antiepileptogenesis or disease modification. This article reviews these areas of progress and discusses the challenges associated with discovery of antiepileptogenic therapies.

/pdf/prevention-or-modification-of-epileptogenesis-after-brain-1bds3qdt9p.pdf

Prevention or Modification of Epileptogenesis after Brain Insults: Experimental Approaches and Translational Research

https://research.birmingham.ac.uk/portal/files/5102835/2012PROGNEU.pdf

Mechanisms of physiological and epileptic HFO generation.

The mechanisms involved in the transition to an epileptic seizure remain unclear. To examine them, we used tissue slices from human subjects with mesial temporal lobe epilepsies. Ictal-like discharges were induced in the subiculum by increasing excitability along with alkalinization or low Mg(2+). During the transition, distinct pre-ictal discharges emerged concurrently with interictal events. Intracranial recordings from the mesial temporal cortex of subjects with epilepsy revealed that similar discharges before seizures were restricted to seizure onset sites. In vitro, pre-ictal events spread faster and had larger amplitudes than interictal discharges and had a distinct initiation site. These events depended on glutamatergic mechanisms and were preceded by pyramidal cell firing, whereas interneuron firing preceded interictal events that depended on both glutamatergic and depolarizing GABAergic transmission. Once established, recurrence of these pre-ictal discharges triggered seizures. Thus, the subiculum supports seizure generation, and the transition to seizure involves an emergent glutamatergic population activity.

/pdf/glutamatergic-pre-ictal-discharges-emerge-at-the-transition-4bw7w4ztir.pdf

Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy.

Interictal spikes: harbingers or causes of epilepsy?

Summary


Purpose: Chronic epilepsy frequently develops after brain injury, but prediction of which individual patient will develop spontaneous recurrent seizures (i.e., epilepsy) is not currently possible. Here, we use continuous radiotelemetric electroencephalography (EEG) and video monitoring along with automated computer detection of EEG spikes and seizures to test the hypothesis that EEG spikes precede and are correlated with subsequent spontaneous recurrent seizures.



Methods:  The presence and pattern of EEG spikes was studied during long recording epochs between the end of status epilepticus (SE) induced by three different doses of kainate and the onset of chronic epilepsy.



Results:  The presence of spikes, and later spike clusters, over several days after SE before the first spontaneous seizure, was consistently associated with the development of chronic epilepsy. The rate of development of epilepsy (i.e., increase in seizure frequency) was strongly correlated with the frequency of EEG spikes and the cumulative number of EEG spikes after SE.



Conclusions:  The temporal features of EEG spikes (i.e., their presence, frequency, and pattern [clusters]) when analyzed over prolonged periods, may be a predictive biomarker for the development of chronic epilepsy after brain injury. Future clinical trials using prolonged EEG recordings may reveal the diagnostic utility of EEG spikes as predictors of subsequent epilepsy in brain-injured humans.

EEG spike activity precedes epilepsy after kainate-induced status epilepticus

Background and Purpose: Acute central retinal artery occlusion (CRAO) is a serious ophthalmologic emergency that may result in monocular blindness. To date, studies evaluating intra-arterial thrombolysis (IAT) have not shown a definitive clinical benefit. We have conducted a systematic review with a meta-analysis to effectively evaluate this treatment option. Methods: A systematic literature search was focused on studies containing five or more patients undergoing intra-arterial thrombolysis that included a control group treated with standard therapy. Pooled meta-analysis was performed. Results: Five retrospective controlled studies and one randomized clinical trial were identified satisfying all inclusion criteria resulting in the analysis of 236 patients treated with intra-arterial thrombolysis and 255 patients treated with standard therapy. A pooled fixed effects analysis resulted in an estimated odds ratio of 2.52, 95% CI [1.69, 3.77], (P<0.0001) favoring intra-arterial thrombolysis. Conclusion: IAT is a promising therapeutic option for CRAO with great potential. Further randomized trials are needed to establish a significant benefit and ensure the safety of the intervention.

/pdf/intra-arterial-thrombolysis-for-acute-central-retinal-artery-4ugl914oh4.pdf

Intra-Arterial Thrombolysis for Acute Central Retinal Artery Occlusion: A Systematic Review and Meta-Analysis.

Corpus callosotomy is a viable treatment for patients with refractory generalized or multifocal epilepsy, particularly those who have drop attacks. Laser interstitial thermal therapy (LITT) is a minimally invasive surgical option for various intracranial lesions. In this report, we present a 2-trajectory thermal ablation using the NeuroBlate® system (Monteris Medical, MN, USA) for an anterior two-thirds callosotomy in a patient with refractory epilepsy and frequent drop attacks. Adequate ablation of the corpus callosum was confirmed by MRI during the procedure. At the 1-month follow-up, the frequency had decreased from multiple seizures per day to only 3 over the course of 1 month. In addition, he had not suffered any drop attacks or tonic-clonic movements since the procedure. Five months after surgery, seizures had decreased to 1 per month with no drop attacks or loss of consciousness, consistent with an Engel class II outcome. In conclusion, LITT ablation of the corpus callosum is a safe, feasible, and minimally invasive treatment option for patients with refractory epilepsy, and it may be an attractive alternative for patients unwilling or unable to undergo open surgery.

Anterior Corpus Callosotomy Using Laser Interstitial Thermal Therapy for Refractory Epilepsy.

Aneurysmal subarachnoid hemorrhage (aSAH) remains a significant cause of stroke disability despite gradual reductions in physical morbidity and mortality. Heparin is an effective anti-inflammatory agent and may potentially prevent delayed neurological injury in the days to weeks after the hemorrhage. Various human studies have shown the safety of a continuous infusion of low-dose unfractionated heparin in the setting of subarachnoid hemorrhage as well as its efficacy in minimizing delayed neurological deficits including symptomatic cerebral vasospasm, vasospasm-related infarction, and cognitive dysfunction. Studies have also shown mixed results with low-molecular-weight heparin usage in this patient population. Heparin treatment is not associated with significant hemorrhagic complications; however, vigilance is essential for early detection of heparin-induced thrombocytopenia in order to prevent devastating sequelae. Multicenter randomized controlled trials are necessary for objective characterization of the effects of heparin.

Andrew C White

Papers

Interictal spikes: harbingers or causes of epilepsy?

EEG spike activity precedes epilepsy after kainate-induced status epilepticus

Intra-Arterial Thrombolysis for Acute Central Retinal Artery Occlusion: A Systematic Review and Meta-Analysis.

Anterior Corpus Callosotomy Using Laser Interstitial Thermal Therapy for Refractory Epilepsy.

Heparin Treatment in Aneurysmal Subarachnoid Hemorrhage: A Review of Human Studies.