Toll-like receptor 3 deficiency decreases epileptogenesis in a pilocarpine model of SE-induced epilepsy in mice
Epilepsy affects 60 million people worldwide. Despite the development of antiepileptic drugs, up to 35% of patients are drug refractory with uncontrollable seizures. Toll-like receptors (TLRs) are central components of the nonspecific innate inflammatory response. Because TLR3 was recently implicated in neuronal plasticity, we hypothesized that it may contribute to the development of epilepsy after status epilepticus (SE).Methods
To test the involvement of TLR3 in epileptogenesis, we used the pilocarpine model for SE in TLR3-deficient mice and their respective wild-type controls. In this model, a single SE event leads to spontaneous recurrent seizures (SRS). Two weeks after SE, mice were implanted with wireless electroencephalography (EEG) transmitters for up to 1 month. The impact of TLR3 deficiency on SE was assessed using separate cohorts of mice regarding EEG activity, seizure progression, hippocampal microglial distribution, and expression of the proinflammatory cytokines tumor necrosis factor (TNF)α and interferon (IFN)β.Results
Our data indicate that TLR3 deficiency reduced SRS, microglial activation, and the levels of the proinflammatory cytokines TNFα and IFNβ, and increased survival following SE.Significance
This study reveals novel insights into the pathophysiology of epilepsy and the contribution of TLR3 to disease progression. Our results identify the TLR3 pathway as a potential future therapeutic target in SE.
Interrater agreement in the interpretation of neonatal electroencephalography in hypoxic-ischemic encephalopathy
Research using neonatal electroencephalography (EEG) has been limited by a lack of a standardized classification system and interpretation terminology. In 2013, the American Clinical Neurophysiology Society (ACNS) published a guideline for standardized terminology and categorization in the description of continuous EEG in neonates. We sought to assess interrater agreement for this neonatal EEG categorization system as applied by a group of pediatric neurophysiologists.Methods
A total of 60 neonatal EEG studies were collected from three institutions. All EEG segments were from term neonates with hypoxic-ischemic encephalopathy. Three pediatric neurophysiologists independently reviewed each record using the ACNS standardized scoring system. Unweighted kappa values were calculated for interrater agreement of categorical data across multiple observers.Results
Interrater agreement was very good for identification of seizures (κ = 0.93, p < 0.001), with perfect agreement in 95% of records (57 of 60). Interrater agreement was moderate for classifying records as normal or having any abnormality (κ = 0.49, p < 0.001), with perfect agreement in 78% of records (47 of 60). Interrater agreement was good in classifying EEG backgrounds on a 5-category scale (normal, excessively discontinuous, burst suppression, status epilepticus, or electrocerebral inactivity) (κ = 0.70, p < 0.001), with perfect agreement in 72% of records (43 of 60). Other specific background features had lower agreement, including voltage (κ = 0.41, p < 0.001), variability (κ = 0.35, p < 0.001), symmetry (κ = 0.18, p = 0.01), presence of abnormal sharp waves (κ < 0.20, p < 0.05), and presence of brief rhythmic discharges (κ < 0.20, p < 0.05).Significance
We found good or very good interrater agreement applying the ACNS system for identification of seizures and classification of EEG background. Other specific EEG features showed limited interrater agreement. Of importance to both clinicians and researchers, our findings support using the ACNS system in identifying seizures and classifying backgrounds of neonatal EEG recordings, but also suggest limited reproducibility for certain other EEG features.
Efficacy of mGlu2-positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures
The metabotropic glutamate receptor subtype 2 (mGlu2) possesses both orthosteric and allosteric modulatory sites, are expressed in the frontal cortex and limbic structures, and can affect excitatory synaptic transmission. Therefore, mGlu2 is a potential therapeutic target in the treatment of epilepsy. The present study seeks to evaluate the anticonvulsant potential of mGlu2-acting compounds.Methods
The anticonvulsant efficacy of two selective mGlu2-positive allosteric modulators (PAMs) (JNJ-42153605 and JNJ-40411813/ADX71149) and one mGlu2/3 receptor agonist (LY404039) were evaluated alone and in combination with the antiseizure drug levetiracetam (LEV) in the mouse 6 Hz model.Results
In the 6 Hz (32 mA stimulus intensity) model, median effective dose (ED50) values were determined for JNJ-42153605 (3.8 mg/kg), JNJ-40411813 (12.2 mg/kg), and LY404039 (10.9 mg/kg). At the 44 mA stimulus intensity, ED50 values were determined for JNJ-42153605 (5.9 mg/kg), JNJ-40411813 (21.0 mg/kg), LY404039 (14.1 mg/kg), and LEV (345 mg/kg). In addition, subprotective doses of each mGlu2-acting compound, administered in combination with various doses of LEV, were able to shift the 6 Hz 44 mA ED50 for LEV by >25-fold. When JNJ-42153605 was administered at varying doses in combination with a single dose of LEV (10 mg/kg), the potency of JNJ-42153605 was increased 3.7-fold. Similarly, when a moderately effective dose of LEV (350 mg/kg) was administered in combination with varying doses of JNJ-40411813, the potency of JNJ-40411813 was increased approximately 14-fold. Plasma levels of JNJ-40411813 and LEV were not different when administered alone or in combination, suggesting that increases in potency are not due to pharmacokinetic effects.Significance
These studies suggest a potential positive pharmacodynamic effect of mGlu2-acting compounds in combination with LEV. If this effect is translated in a clinical setting, it can support a rational polypharmacy concept in treatment of epilepsy patients.
This event is the first of its kind in Glasgow, held at the University of Glasgow, on the 28th February 2017. The day has a neurological / genetics theme with a number of local speakers with a specialism in epilepsy.
The event is open to the public and is free to attend but registration is essential. Policy makers, researchers, clinicians, charities or anyone with an interest in the area are also welcome.
Lunch, tea and coffee will be provided. Click here for more information.