Dexamethasone exacerbates cerebral edema and brain injury following lithium-pilocarpine induced status epilepticus

Abstract

Anti-inflammatory therapies are the current most plausible drug candidates for anti-epileptogenesis and neuroprotection following prolonged seizures. Given that vasogenic edema is widely considered to be detrimental for outcome following status epilepticus, the anti-inflammatory agent dexamethasone is sometimes used in clinic for alleviating cerebral edema. In this study we perform longitudinal magnetic resonance imaging in order to assess the contribution of dexamethasone on cerebral edema and subsequent neuroprotection following status epilepticus. Lithium-pilocarpine was used to induce status epilepticus in rats. Following status epilepticus, rats were either post-treated with saline or with dexamethasone sodium phosphate (10mg/kg or 2mg/kg). Brain edema was assessed by means of magnetic resonance imaging (T2 relaxometry) and hippocampal volumetry was used as a marker of neuronal injury. T2 relaxometry was performed prior to, 48 h and 96 h following status epilepticus. Volume measurements were performed between 18 and 21 days after status epilepticus. Unexpectedly, cerebral edema was worse in rats that were treated with dexamethasone compared to controls. Furthermore, dexamethasone treated rats had lower hippocampal volumes compared to controls 3 weeks after the initial insult. The T2 measurements at 2 days and 4 days in the hippocampus correlated with hippocampal volumes at 3 weeks. Finally, the mortality rate in the first week following status epilepticus increased from 14% in untreated rats to 33% and 46% in rats treated with 2mg/kg and 10mg/kg dexamethasone respectively. These findings suggest that dexamethasone can exacerbate the acute cerebral edema and brain injury associated with status epilepticus.

Keywords: BBB; Biomarker; COX-2; CSE; Corticosteroids; DEX; Epilepsy; FOV; Inflammation; IκB; MRI; NSAIDs; ROIs; SE; T(2); TE; TEeff; TR; blood–brain barrier; convulsive status epilepticus; cyclooxygenase-2; dexamethasone; echo time; echo-train length; effective echo time; etl; fast spin-echo; field of view; fse; inhibitor of kappa-B; magnetic resonance imaging; non-steroidal anti-inflammatory drugs; rHCV; regions of interest; relative hippocampal volume; repetition time; status epilepticus; transverse magnetisation relaxation time constant.

Fig. 1

Behavioral assessment of status epilepticus in SE and SE-DEX rats. (a): Latency to onset of status epilepticus. (b): Behavioral assessment of seizure severity throughout status epilepticus. (a) and (b): SE (n = 21), SE-DEX 10 mg/kg (n = 13), SE-DEX 2 mg/kg (n = 6). Data are displayed as mean ± standard deviation.

Fig. 2

Automatic segmentation of MRI images used for quantitative T₂ measurements. Automated segmentation was performed via affine coregistration to a rat brain template. Regions were transformed to the image space and are shown here on coronal MRI images with a slice thickness of 1 mm. For display purposes, the image shown is the image averaged across all echo times in the multi-echo sequence. Images are shown for alternate slices.

Fig. 3

T₂ relaxation times measured pre, 48 h and 96 h following lithium-pilocarpine induced status epilepticus. (a) hippocampus, (b) piriform cortex, (c) thalamus, (d) caudate putamen, (e) primary somatosensory cortex, (f) cingulate cortex. Treatment groups: CTL (n = 4), SE (n = 20), SE-DEX10 (n = 10), SE-DEX2 (n = 4).

Fig. 4

Coronal MRI images of the rat brain following status epilepticus demonstrating early edema and later hippocampal injury. First column: Control. Second column: post status epilepticus. (a) and (b): low resolution images acquired at 48 h following administration of saline or pilocarpine respectively. (c) and (d): high resolution images acquired 3 weeks after saline or pilocarpine respectively. (b) Illustrates marked bilateral edema in the hippocampus and unilateral edema in the neocortex. (d) shows significant atrophy of the hippocampus leading to enlargement of the lateral ventricles. Hypointense regions in the CA1,CA3 and dentate gyrus of the hippocampus are evident and hyperintense regions in the right neocortex correspond to the regions of hyperintensity that occurred at 2 days following SE.

Fig. 5

Total brain volume and relative hippocampal volume at 3 weeks after status epilepticus. (a) Total brain volume vs. treatment group. (b) Relative hippocampal volume vs. treatment group. (c) Example image showing automated segmentation of the hippocampus in a control rat. (d) Example image demonstrating automated segmentation of the hippocampus in a post-status epilepticus rat, 3 weeks after the initial insult. Treatment groups: CTL (n = 4), SE (n = 16), SE-DEX10 (n = 5), SE-DEX2 (n = 4).

Fig. 6

Scatter plots showing the relationship between early T₂ measurements and relative hippocampal volume (rHCV) measured 3 weeks after SE. (a) and (b): Hippocampus and cingulate ctx T₂ measured 2 days after SE vs. rHCV. (c) rHCV vs. rHCV modelled using a linear mixed-effects model for the data shown in (a) and (b). (d) Hippocampus T₂ measured 4 days after SE vs. rHCV. (e) rHCV vs. rHCV modelled using a linear mixed-effects model for the data shown in (d).