Status epilepticus models: imaging

In epilepsy, the role of imaging in the evaluation of accurate or onset seizure is critical to exclude lesional causes, such as traumatic, vascular, tumoral, malformations, inflammatory or infectious. In the absence of preceding events, there is supporting evidence for MRI as the neuroimaging technique of choice due to better sensibility and specificity [86,87].

However, computerized tomography scan (CT) can be preferred due to more widespread availability, rapidity of acquisition, and limited contraindications. In [86], authors indicated, however, that 8-12 % of patients with initial negative CT scans, present positive findings in MRI. Still, it is also possible for patients to have negative MRI. Classically, MRI is used to qualitatively assess for an atrophic hippocampus with hyperintense T2

signals (described in the subsequent section2.2.2.1), which is a defining trait of advanced hippocampal sclerosis [88, 89]. Although qualitative imaging remains the gold standard for diagnosis, there is a constant need to develop quantitative and automated methods to identify hippocampal and extra-hippocampal damages. MRI can provide a precise characterization of the internal architecture of the hippocampus, which allows better detection of more subtle changes. One of the main targeted development is the detection of the epileptogenic foci but one can also study the epileptic condition following the status epilepticus in experimental model to identify biomarkers of the development of a chronic condition. Of course, a robust method to reduce the number of negative MRI scans is also very valuable.

A step forward is the use of more complex MRI acquisitions such as functional, diffusion, perfusion with or without contrast agent administration among others. These MRI techniques are described in section 2.3 but we propose to summarize here the important findings associated with epilepsy. In fact, some parameters are very well documented while others are sometimes completely absent from the picture. We propose to report most of the last quantitative MRI findings in experimental status epilepticus models summarized in table2.1. We also propose to interpolate from few longitudinal studies, the variations of the most documented MRI parameter values during the month following the status epilepticus in figure 2.13. This duration includes the entire epileptogenesis that ends with the establishment of a favorable environment for epileptic seizures. Note that the graph was produced from several models/scanners.

Regarding cellular related MRI parameters, several works reported hyperintensity in T2-weighted images after status epilepticus [90], which matches increased T2 values reported in quantitative studies [91]. In this work, authors also reported increased T₁ values. Usually, these parameters return to their initial values after 1-2 weeks [91].

Diffusion parameters are the most documented MRI parameters in epilepsy. Early diffusion decreased first days after status epilepticus is followed by an increase in diffusion at the chronic period [92–94]. Regarding vascular related MRI parameters, the blood flow first increases and then, decreases at one week [91, 95]. Finally, several works have shown a significant increase in BBB permeability [96–98].

MRI

[90] - Hyperintensity in T2-weighted images Rats / KA (in striatum) 1 day

[88]

[99] - Hyperintensity in T2-weighted images (40-70% in ipsilateral hippocampus and 20-50% in ipsilateral amygdala) from first hours to 7 days and reduced hyperinten-sity (30% in hippocampus and 0-10% in amygdala) at 21 to 120 days

Mice / KA

[91] - Increase T1 (5-12% in hippocampus) at 1 to 3 days and normal after 2 weeks

Rats / pilocarpine 0 to 21 days

[100]

[91] - Increase T2 (15-20% in pyriform cortex, 20-35% in piriform cortex, 5-20% in hip-pocampus) at 1 to 3 days and normal after 1 week

Diffusion [92] - Decrease diffusion (ADC) (30% in piri-form cortex and 7% in hippocampus)

Rats / KA 1 day

[89]

[93] - Early increase ADC (10-30% in pyriform cortex, amygdala and hippocampus) at 3-5 minutes and decrease (9-30% in the same regions) at 15 to 120 minutes

Rats / pilocarpine

Perfusion [95] - Increase cerebral blood flow (CBF) at 14 days in amygdala, no changes before

Rats / pilocarpine 2 and 14 days

[102]

[91] - Increase CBF (45-65% in hippocampus), at 1 to 2 days) and normal after

- Decrease CBF (15-25% in parietal cortex and 5-30% in piriform cortex) at 3 to 14 days

Rats / pilocarpine 0 to 21 days

Susceptibility-weighted [103] - Increase cerebral blood volume (rCBV) (100% in deep layers, to 200% in super-ficial layers in cingulate/parietal cortex, 106% in hippocampus, 150-500% in cau-doputamen and thalamic nuclei)

[98] - BBB breakdown only in the thalamus at 2 hours; it had disappeared by 6 hours. At 24 hours, edema was present in the amyg-dala, the piriform and entorhinal cortices;

it disappeared over a 5-day period. In the hippocampus, the T2-weighted signal un-derscored the progressive constitution of atrophy and sclerosis, starting at 2 days

Rats / pilocarpine 2 hours to 9 weeks

[107]

MRI

[97] - Damaged BBB in piriform, enthorhi-nal cortex, hippocampus and amygdala (gadolinium leakage is 1.5-4 times higher at 1 day than at 6 weeks)

Rats / KA 1 day to 6 weeks

[96] - Increase volume with damaged BBB at 2/7 days in amygdala, cortex and piriform and reduction of the increase volume dam-aged BBB at 1 month

Rats / paraoxon 2 days to 1 month

Table 2.1 – Overview of MRI findings in murine experimental models of epilepsy from status epilepticus to the establishment of the chronic condition favorable to the occurrence of spontaneous seizures .

When the injection site is not specified, the injection was not intracerebral. When the values were not provided in the text, they were manually measured in figures.

1 2 3 5 7 10 14 21 28 35 50

Figure 2.13 – Cellular and vascular MRI parameter evolutions after status epilepticus until chronic period.

Curves represent the evolution of cellular and vascular MRI parameters induced by status epilep-ticus: blue (T₁), red (T₂), yellow (apparent diffusion coefficient, ADC), purple (cerebral blood flow, CBF), and green (damaged blood-brain-barrier, BBB). Four longitudinal/multiparametric studies were used to interpolate these curves [91, 94, 95, 97] by modified Akima cubic Her-mite interpolation after smoothing. Each marker represents a study: circle [91], triangle [94], cross [95], and asterisk [97].