Cortical Regional Hyperperfusion in Nonconvulsive Status Epilepticus Measured by Dynamic Brain Perfusion CT

Study Population

We retrospectively studied 19 patients admitted to the emergency department or the Department of Neurology of our institution. All patients presented with a witnessed preceding clinical epileptic seizure and persistent altered mental status. Unenhanced contrast-enhanced brain CT and PCT were performed during the routine diagnostic work-up of these patients at the request of the referring physician to rule out an acute stroke or structural brain lesions as the cause of the seizure and altered mental status and/or neurologic deficit. In all patients, EEG was performed within 2 hours after the CT scanning. For analysis, patient data were identified by using the Department of Radiology admission log. Medical records were reviewed after patient discharge. We recorded demographic data (sex, age), medical history (epilepsy, neurologic comorbidities), and the clinical characteristics (seizure classification, focal neurologic deficits, worst Glasgow Coma Scale [GCS] score, respiratory deficits leading to mechanical ventilation); survival was assessed by evaluation of the discharge logs. The study was approved by the local ethics committee.

CT

Data Analysis

Segmentation and Quantitative Analysis.

To establish a quantitative basis for evaluation, we used a semiautomatic segmentation program (Perfusion Evaluation, Version 3.6) to separate the cortex and white matter. The segmentation was performed by a threshold algorithm, for which the user predefined the minimum and maximum pixel-intensity threshold value. To obtain a sufficient signal-intensity-to-noise ratio for accurate discrimination of cortical tissue from deep white matter, the first 6 acquisitions of the PCT series before contrast agent arrival were averaged. Regions of interest (ROIs) covering the symptomatic cortical region were defined as contralateral to the side of the clinical symptoms and/or adjacent to a structural lesion if present; in cases with no lesions, the frontal cortical region was selected (ROI_symp). A corresponding region of interest in the unaffected cortical region of the other hemisphere was defined (ROI_ref) (Fig 1). For each ROI, the rCBV, rCBF, and MTT values were calculated. Asymmetry indices (AI) for rCBV, rCBF, and MTT of each individual perfusion were defined as follows: Calculation of AI provides results independent of interindividual perfusion differences and intraindividual differences of perfusion in different vascular territories. Hyperperfusion was defined as AI > 10 in rCBF; and hypoperfusion, as AI < −10.^19,20

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Fig 1.

Semiautomatic segmentation of the cortical region.

The AI values for rCBF, rCBV, and MTT of the different patient groups were compared by using an unpaired Mann-Whitney U test. The significance of group differences of patient data was analyzed by using nonparametric statistical analysis (Fisher exact test, 2-sided; Mann-Whitney U test) with the commercial statistics software Statistical Package for the Social Sciences, Version 14.0 (SPSS, Chicago, Ill).

EEG

EEG was recorded via 19 surface electrodes placed according to the international 10–20 system within 2 hours after the CT scanning by using a standard software package (NicOne, Nicolet Biomedical; Viasys Healthcare, Madison, Wis). The EEG recordings were independently analyzed by a certified electroencephalographer (A.N.), who was unaware of the PCT results.

Definitions of NCSE and Postictal State

Episodes were classified as NCSE if the subject exhibited changes in behavior and/or mental processes lasting longer than 30 minutes without clinical signs of overt convulsive activity and if the EEG showed continuous or intermittent ictal activity consisting of rhythmic discharges (spikes, sharp waves, or slow wave discharges).⁵ A classification as NCSE allowed the presence of subtle movements and isolated jerks.²¹ Patients in NCSE with initial GTCS were classified as having SSE; patients without GTCS, as having complex partial status epilepticus; and patients with coma due to central nervous system disorder with NCSE, as having coma with NCSE.¹

Episodes were classified as postictal if after a preceding seizure, the subject did not present with persistent ictal semiology (eg, myoclonus) and no ictal activity was present on EEG.

NCSE

In 9 patients, the diagnosis of NCSE was based on clinical criteria and EEG findings.

Quantitative analysis of PCT showed regional cortical hyperperfusion corresponding to the patients’ neurologic deficits or jerks in 8/9 patients. The lateralization was confirmed by EEG in all patients. In patient 1.6 with chronic left parietal hemorrhage, symmetric rCBF values were obtained outside the insult. EEG recordings revealed focal seizure activity in the left frontal lobe.

Visual analysis allowed the identification and lateralization of a regional hyperperfusion in 8/9 patients. The inter-rater concordance was 100% among the 3 independent readers. Perfusion maps revealed hyperperfusion in the gray matter, sparing the adjacent deep white matter and outlying boundaries of vascular territories (Fig 3). In patient 1.9, the insular hyperperfusion identified by quantitative analysis was not visible during ad hoc visual analysis of the parametric maps. In accordance with the quantitative analysis, the hyperperfusion of patient 1.6 could not be identified visually, either.

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Fig 3.

Cortical hyperperfusion frontal right during NCSE. Bottom left: EEG shows right frontal spike-and-wave activity (patient 1.3).

Postictal State

All 10 patients in the postictal group presented with initial GTCS. At admission, jerks were not a feature, and EEG did not show seizure activity in any of the subjects. Quantitative analysis revealed a regional hypoperfusion in 3/10 patients. In these patients (2.1, 2.2, and 2.3), the lateralization fit their respective clinical deficits and EEG. The remaining 7 patients showed symmetric brain perfusion values. In the visual analysis, none of the 10 patients showed signs of regional hyperperfusion. Reduced regional perfusion was detected in the 3 patients (2.1, 2.2, and 2.3) with lateralizing signs. The distribution of the regional hypoperfusion differed from that of the NCSE in that both cortical and subcortical regions were involved (Fig 4). Again, the inter-rater concordance was 100% among the 3 independent readers.

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Fig 4.

Widespread hypoperfusion over the right hemisphere in a postictal state encompassing carotid and basilar vascular territories. Bottom left: EEG shows a diffuse right hemispheric slowing (patient 2.3).

Quantitative Analysis

Quantitative post hoc analysis of PCT was concordant with the clinical and EEG data in all except 1 patient in our cohort. These results indicate that PCT-derived cortical perfusion maps discriminate NCSE and a postictal state. Thus, we have confirmed our previous results²² and the findings of a recent case study²³ that investigated cortical hyperperfusion as a discriminating feature of NCSE. Some reports have found a persistence of cortical hyperperfusion after EEG cessation of epileptic seizures,^24,25 but such effects tend to switch rapidly (within 90 seconds of seizure end) into neocortical hypoperfusion²⁶ and have been excluded in our series because the time from cessation of convulsions to PCT ranged from 30 to 90 minutes.

Visual Analysis in NCSE

PCT provides instantaneous results on altered brain perfusion in emergency situations. In our study, ad hoc qualitative analysis performed by visual inspection of the parametric perfusion maps identified regional hyperperfusion in 78% of patients with NCSE. In 2 patients with NCSE, visual analysis did not detect any perfusion changes in favor of ongoing seizure activity: In patient 1.9, quantitative analysis showed regional hyperperfusion in the left perisylvian regions, which was not confirmed by visual inspection, probably due to the overlap of cortical hyperperfusion and of abundant arteries in the adjacent Sylvian fissure. In patient 1.6, despite a clearly lateralized and focal frontal status epilepticus on EEG, no perfusion changes were detected. This might reflect the fact that NCSE is a highly dynamic process including periods with generalized or without active ongoing seizure activity, indicating a limitation of the PCT technique mapping only 45 seconds of cerebral perfusion. Although the PCT approach presented here is limited by the anatomic coverage along the craniocaudal axis of, at maximum, 40 mm, new CT scanners are capable of covering ≥100 mm. The use of MR perfusion measurements, offering coverage of the entire brain parenchyma, is limited due to safety issues in patient monitoring in the scanner and by a limited availability in emergency conditions.

Visual Analysis in Postictal States

In our series, PCT demonstrated hypoperfusion, mainly visible on MTT maps, during a postictal state in 3 patients with a focal neurologic deficit (Todd paresis), which is in keeping with previous results.^22,27 Beyond hypoperfusion, the pattern of perfusion alterations differed from those of NCSE in that both cortical and subcortical regions were involved. Subcortical hypoperfusion is in agreement with previous single-photon emission CT (SPECT) studies.^26,28 The absence of regional postictal hypoperfusion in 7 patients without lateralizing signs might reflect the fact that the altered mental state in these patients was caused by a diffuse functional impairment of the associated cortex in postictal states after a primary generalized seizure²⁹ or due to the sedation effects of antiepileptic drugs, but not to focal postictal brain exhaustion. Similar observations have been confirmed by SPECT studies, in which visual inspection of postictal hypoperfusion has a very low sensitivity^12,24 and is not helpful in delineating the irritative zone. Although the results of PCT in the setting of patients with epilepsy seem to be most valuable in identifying whether there is a regional hyperperfusion indicating ongoing seizure activity, a regional hypoperfusion may still be of diagnostic relevance in patients with lateralizing clinical signs.

Comparison with PCT in Other Pathologies

In this series, we evaluated a new indication for PCT for the differentiation of NCSE and postictal states. In clinical routine, PCT is already a highly valuable and standardized tool in other conditions (eg, in stroke). Comparing the findings of PCT in epilepsy and stroke, however, reveals some well-defined differences. First, the quantity of focal perfusion changes differs between NCSE and stroke: In NCSE, mean focal rCBF change accounts for an AI of 23% (SD, 11.6; max, 37%) and, in a postictal state with lateralizing signs, for 21% (SD, 2.55; max, 23%; Fig 2), which is in keeping with previous SPECT studies.^12,24 In contrast, in stroke, the core of an infarction shows an rCBF reduction exceeding 80% compared with the other hemisphere,³⁰ and the defined threshold for a penumbra requires a minimal rCBF reduction of 34%.³¹

Second, the distribution of focal perfusion changes differs between NCSE and stroke: Concordant with the concept of cortical generation of epileptic activity and with previous MR imaging and CBF-SPECT studies,^13,14 ictal hyperperfusion is predominantly present in the cortex and may encompass multiple vascular territories (Fig 3).^32,33 Acute stroke presenting with epileptic seizures or status epilepticus at onset has been reported,³⁴ but we did not encounter such etiologies in our series. Furthermore, PCT has been used for prognostic issues in traumatic brain injury.³⁵ Typically, its corticosubcortical decrease in rCBF^35,36 allows a differentiation between traumatic brain injury and NCSE. Several other studies have demonstrated the correlation between microvessel attenuation and increased rCBV and blood flow in high-grade tumors with PCT.³⁷ The different morphologies and perfusion patterns of NCSE and brain tumors, however, should not provide any diagnostic problem apart from subjects in whom perfusion changes due to epileptic seizures and neovascularized brain tumors coincide. Hyperperfusion in other pathologies, such as encephalitis³⁸ and abscesses,³⁹ has been sporadically reported but did not omit the adjacent white matter.