Abstract
Focal non-convulsive status epilepticus (fNCSE) is a neurological condition characterized by a prolonged seizure that may lead to the development of epilepsy. Emerging experimental evidence implicates neuronal death, microglial activation and alterations in the excitatory and inhibitory synaptic balance as key features in the pathophysiology following fNCSE. We have previously reported alterations in the excitatory adhesion molecule N-cadherin in rats with fNCSE originating from the hippocampus that subsequently also develop spontaneous seizures. In this study, fNCSE rats were treated intraperitoneally with the conventional anti-epileptic drug levetiracetam in combination with intraparenchymal infusion of N-cadherin antibodies (Ab) for 4 weeks post-fNCSE. The N-cadherin Ab was infused into the fornix and immunohistochemically N-cadherin Ab-stained neurons were detected within the dorsal hippocampal structures as well as in superjacent somatosensory cortex. Continuous levetiracetam treatment for 4 weeks post-fNCSE reduced microglia activation, including cell numbers and morphological changes, partly decreased neuronal cell loss, and excitatory post-synaptic scaffold protein PSD-95 expression in selective hippocampal structures. The additional treatment with N-cadherin Ab did not reverse neuronal loss, but moderately reduced microglial activation, and further reduced PSD-95 levels in the dentate hilus of the hippocampus. Despite the effects on brain pathology within the epileptic focus, neither monotherapy with systemic levetiracetam nor levetiracetam in combination with local N-cadherin Ab administration, reduced the amount of focal or focal evolving into bilateral convulsive seizures, seizure duration, or interictal epileptiform activity during 1 month of continuous electroenephalogram recordings within the hippocampus after fNCSE. Behavioral tests for spatial memory, anxiety, social interaction and anhedonia did not detect gross behavioral differences between fNCSE rats with or without treatment. The results reveal the refractory features of the present rodent model of temporal lobe epilepsy following fNCSE, which supports its clinical value for further therapeutic studies. We identify the persistent development of epilepsy following fNCSE, in spite of partly reduced brain pathology within the epileptic focus.
Highlights
Status epilepticus can be a serious medical condition and life threatening if not interrupted
We further explored whether N-cadherin Ab and levetiracetam treatment would affect common pathophysiological changes associated with focal NCSE (fNCSE) [19] including neuronal cell death and inflammation
Within the inner ML (iML), an area where the hippocampal granule cells mainly receive inhibitory afferents from interneurons in addition to excitatory input, and where we have previously shown seizure-related changes [4, 41], we observed an increased expression of PSD-95 clusters in fNCSE compared to Ctrls (Supplementary Table 1.20)
Summary
Status epilepticus can be a serious medical condition and life threatening if not interrupted. Convulsive features are typically observed in most patients, where seizures lasting for more than 30 min can be fatal and need immediate medical attention. 20–40% of all SE cases manifest with more subtle symptoms including altered consciousness, automatism, chewing, and minor motor movement, commonly referred to as non-convulsive status epilepticus (NCSE). When NCSE involves only parts of the brain it is called focal NCSE (fNCSE). The subtle presentations of fNCSE pose clinical challenges in terms of diagnosis and treatment. The pathophysiological events that follow can over time result in epilepsy development with recurrent spontaneous seizures
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