Abstract
Bonduelle T, Ollivier M, Trin K, Thomas B, Daubigney A, Michel V, De Montaudouin M, Marchal C, Aupy J. Neurology. 2022. doi:10.1212/WNL.0000000000201599. Online ahead of print. Status epilepticus (SE) is a life-threatening emergency requiring a prompt assessment of patient prognosis to guide management. Magnetic resonance imaging (MRI) allows the identification of peri-ictal MRI abnormalities (PMA) and provides insight into brain structural modifications induced by SE. However, little is known about the significance of PMA in SE prognosis. The aim of this study was to determine whether PMA are associated with an increased mortality in SE, and to establish the association between PMA and refractoriness to antiseizure medications, complications encountered and induced morbidity. We conducted a retrospective observational cohort study including all eligible consecutive patients over 15 years-old and hospitalized with SE at Bordeaux University Hospital (France), between January 2015 and December 2019. The primary endpoint was in-hospital mortality. Together with a dedicated neuroradiological reassessment, baseline characteristics, in-hospital death, SE characterization, drug refractoriness and following outcome in survivors were assessed by comprehensive medical review. Of 307 patients included, 79 (26%) showed PMA related to SE. Demographic, functional status at baseline and median delay between SE onset and MRI exam were similar in PMA-positive and PMA-negative group. In-hospital death occurred in 15% (45/307) patients and was significantly higher in the PMA-positive group (27%, 21/79 vs 11%, 24/228; p<0.001). In multivariate analysis, the presence of PMA (odds ratio [OR] 2.86, 95% confidence interval [CI] 1.02-8.18; p=0.045), together with SE duration ([OR] 1.01, 95% CI 1.01-1.02; p=0.007), older age at SE onset ([OR] 1.05, 95% CI 1.01-1.09; p=0.013), preexisting ultimately fatal comorbidity ([OR] 4.01, 95% CI 1.56-10.6; p=0.004) and acute lesional SE etiology ([OR] 3.74, 95% CI 1.45-10.2; p=0.007) were independent predictors associated with in-hospital death. Patients with PMA had a higher risk of refractory SE (71 vs 33%, p<0.001). Among survivors, delayed onset epilepsy (40% vs 21%, p=0.009) occurred more frequently in the PMA-positive group. PMA-positive cases had a higher mortality rate in the largest cohort so far to assess the prognosis value of PMA in SE. As a non-invasive and easily available tool, PMA represents a promising structural biomarker for developing a personalized approach to prognostication in SE patients receiving MRI.
Cornwall CD, Dahl SM, Nguyen N, Roberg LE, Monsson O, Krøigård T, Beier CP. Epilepsia. 2022;63(11):2970-2980. doi:10.1111/epi.17404 In patients with status epilepticus (SE), the clinical significance of ictal changes on magnetic resonance imaging (MRI) is insufficiently understood. We here studied whether the presence of ictal MRI changes was associated with neurological deterioration at discharge. The retrospective cohort comprised all identifiable patients treated at Odense University Hospital in the period 2008-2017. All amenable MRIs were systemically screened for ictal changes. Patient demographics, electroencephalography, seizure characteristics, treatment, and SE duration were assessed. Neurological status was estimated before and after SE. The predefined endpoint was the association of neurological deterioration and ictal MRI changes. Of 261 eligible patients, 101 received at least one MRI during SE or within 7 days after cessation; 43.6% (44/101) had SE due to non- or less brain-damaging etiologies. Patients who received MRI had a longer duration of SE, less frequently had a history of epilepsy, and were more likely to have SE due to unknown causes. Basic characteristics (including electroencephalographic features defined by the Salzburg criteria) did not differ between patients with (n = 20) and without (n = 81) ictal MRI changes. Timing of MRI was important; postictal changes were rare within the first 24 h and hardly seen >5 days after cessation of SE. Ictal MRI changes were associated with a higher risk of neurological deterioration at discharge irrespective of etiology. Furthermore, they were associated with a longer duration of SE and higher long-term mortality that reached statistical significance in patients with non- or less brain-damaging etiologies. In this retrospective cohort, ictal changes on MRI were associated with a higher risk of neurological deterioration at discharge and, possibly, with a longer duration of SE and poorer survival.Background and objectives:
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Commentary
Imaging plays an important role in the management of status epilepticus (SE). While computed tomography (CT) scans are sometimes sufficient, magnetic resonance imaging (MRI) scans are often necessary to identify the cause of SE. In addition to etiology-specific abnormalities, MR imaging can reveal the presence of changes that are induced by seizures themselves. These changes are variably referred to as peri-ictal MRI abnormalities (PMA), seizure-induced reversible MRI abnormalities. 1,2 While the imaging features of PMAs are well described, their evolution and clinical significance are not as well understood. The most common appearance of PMA is increased diffusion-weighted imaging (DWI) signal with decreased or normal apparent diffusion coefficient (ADC) and increased T2/fluid-attenuated recovery (FLAIR) signal. Contrast enhancement is occasionally seen as well. These abnormalities often localize to the cortical region that is involved in the seizures but remote, possibly network-related, abnormalities can often be observed in the pulvinar of the thalamus, the splenium of the corpus callosum or the ipsilateral hippocampus. It is hypothesized that they represent transient vasogenic and cytotoxic edema and breakdown of the blood–brain barrier, but they can also evolve to irreversible abnormalities, including cortical laminar necrosis and atrophy. From a clinical standpoint, they are associated with recurring and prolonged focal seizures. Recent large series found a variable prevalence, between 12% and 46% of these changes in SE, 2 -4 possibly owing to the nonsystematic use of MRI and to the overlap between PMA and MRI changes attributable to the underlying etiology of SE.
A recent study by Bonduelle et al 5 brings important new insights on the prevalence and clinical implications of PMAs. In this large retrospective series, the authors reviewed the MRI scans performed in 307 patients admitted at their institution with non-anoxic SE over a 5-year period. Of note, almost 80% of patients with SE received an MRI during the study period. I think this proportion is higher than what would have occurred in many other institutions, especially since 31% patients had a history of prior epilepsy and another 35% had an acute lesional etiology, which is often visible on CT scans. The demographic, clinical and SE characteristics, including etiology, semiology, duration and degree of refractoriness, of the sample were similar to prior large SE series, so the results are likely generalizable. The authors used the International League Against Epilepsy (ILAE) definitions and classification of SE, again ensuring generalizability and comparability. Overall, PMA were observed in 79 (26%) patients, likely an accurate estimate of the prevalence of PMA in SE, given the high proportion of patients who underwent an MRI. In line with the literature, DWI changes were the most frequent (94%), most often with normal (54%) or decreased (30%) ADC, followed by increased T2/FLAIR abnormalities (81%) and contrast enhancement (18%). Again similar to previous reports, PMA were mostly located in neocortical (75%), hippocampal (43%), and thalamic regions (61%). In the 35 available follow-up MRI scans, after a median of 14 days, most PMA had partially or completely resolved but cortical atrophy developed in 10 (29%) cases.
Compared to patients without PMA, patients with PMA had a more severe course, with a longer duration of SE, a higher risk of transition to refractory and super-refractory SE. They required more anti-seizure medications and more endotracheal intubation. They had longer intensive care unit and hospital stays and experienced more complications, including pneumonia. Ultimately, in-hospital mortality was almost 3 times higher (27% vs 11%) in patients with PMA and this association remained significant in multivariate analysis, together with age, etiology, and duration of SE. In the subgroup of patients (n = 205) with long-term follow-up available, PMA were associated with mortality, worse functional outcome and delayed-onset epilepsy (40% vs 20%), all in univariate analysis.
Another recent study by Cornwall et al 6 confirms these findings. Following a similar retrospective design, the authors reviewed the acute MRI scans performed in 101 patients, among the 261 who were admitted for SE during a 10-year study period. The cohort features differed from the first study, with a much higher proportion of nonconvulsive (82%) and refractory (71%) SE. Overall, PMA were seen in 20 (20%) patients, mostly in cortical and hippocampal regions, and could be observed up to 5 days after SE cessation. The PMA were associated with SE duration and a higher risk of functional decline, refractoriness, and mortality, but not in the subgroup of patients with no or less damaging acute brain injury for the latter two.
Altogether, these findings suggest that PMA is an imaging biomarker of severity of SE that could be used as a prognostic factor and to tailor the intensity of SE management to each individual situation. Neurological prognostication remains a challenge, including in the field of SE. Currently available clinical scores lack accuracy. 7 In Bonduelle et al, the presence of PMA was not associated with higher status epilepticus severity scores, the most frequently used score, but it was associated with mortality, even when accounting for age and etiology, two components of most SE severity scores. In Cornwall et al, the association of PMA with mortality was significant, even when adjusting for the epidemiology-based mortality in SE score. It thus seems that the presence of PMA marks a crucial turn in the course of SE.
In animal models, neurons and glia in seizure foci swell before and during ictal activity as a consequence of the influx and intracellular accumulation of ions, especially chloride, caused by the severe persistent electrical activity of action potentials and gap junctions. 8,9 Other mechanisms, such as energy failure and cortical spreading depression, might also be involved. 10 Extracellular edema is the result of increased blood–brain barrier permeability, which typically takes several hours or days to appear. 11 In line with these mechanisms, DWI and ADC changes in animal models occur within 1 hour of a prolonged seizure, while T2 changes take several hours to appear. 12 -14 Both are reversible but the intensity of the transient T2 changes correlates with the degree of neuronal injury, as measured by histology. 13
What determines the presence of PMA in some patients but not all remains partly unknown. Surely, the duration of ictal activity prior to imaging is of importance. In both Bonduelle et al and Cornwall et al, PMA were associated with a longer total duration of SE. Whether this was also the case with pre-MRI SE duration is unclear. Time from SE to MRI was not different between patients with PMA and those without PMA, but that does not imply that both groups spent the same amount of time seizing prior to the MRI. In Bonduelle et al, most patients had intermittent EEG recordings and 107 (35%) patients had documented ongoing electrographic ictal activity while 110 (36%) had interictal epileptic findings, including 21 with lateralized periodic discharges. Both ictal and interictal findings were more frequent in the PMA group, which would support the hypothesis that PMA reflect the amount of time spent seizing. Interestingly, patients with PMA also had higher admission lactate and creatine kinase levels, suggesting that they might have had more prolonged convulsions prior to admission and MRI. Finally, time from SE onset to EEG and accurate burden of ictal and interictal abnormalities were not reported and would deserve further investigation. This will require acute continuous EEG monitoring, which, until the development and implementation of fast EEG solutions, remains a challenge for many places. As confirmed by the authors, ongoing ictal and periodic activities are also associated with outcome in patients SE. Whether they provide additional information to PMA is still mostly unclear as they did not remain associated as a whole with mortality in the multivariate analysis.
Do these studies change how MRI fits in the management algorithm of SE? Should it now be performed in all cases or should it be reserved to specific subgroups only? There is no question that MRI remains the brain imaging modality of choice to determine the etiology of SE if it is not known from history or other easily accessible ancillary tests (CT scan, lumbar puncture, blood tests). I would also think that it might be of interest in refractory cases, regardless of the underlying etiology, as an indicator of the damage that has already be sustained by the brain to be included in the overall assessment to guide the intensity of future therapy. Will it replace EEG? I think not, as EEG still remains our only way to monitor ongoing nonconvulsive SE and adjust treatment in a timely manner.
