Subjects

We studied a prospectively enrolled series of patients with ICH that underwent MRI including fluid attenuated inversion recovery (FLAIR) and diffusion weighted imaging (DWI) within one week of the ICH between March 2009 and November 2015. MRIs were obtained as part of our clinical management protocol whenever feasible. Inclusion criteria were: (1) spontaneous ICH, and (2) MRI obtained within 7 days of the hemorrhage. Exclusion criteria were: (1) age < 18 years, (2) pregnancy, (3) ICH due to tumor, trauma, or hemorrhagic conversion of an ischemic stroke, and (4) patients or families who declined to participate in the study. Patient management was in accordance with current guidelines (Supplementary Material). Data were collected as part of a prospective observational cohort study approved by the local institutional review board (Columbia University Medical Center IRB). Written informed consent was obtained from patients and/or legal surrogates on admission to the ICU, patients that recovered consciousness were given the opportunity to withdraw from the study. All experiments were performed in accordance with relevant guidelines and regulations.

Clinical variables

We collected baseline demographic and medical history (e.g., age, gender, race), and admission characteristics of the ICH (e.g., ICH volume and location, presumed etiology, intraventricular hemorrhage, primary ICH-score)15. We calculated the admission Functional Outcome in Patients With Primary Intracerebral Hemorrhage (FUNC) score by quantifying ICH volume and location, age, Glasgow Coma Scale, and pre-ICH cognitive impairment16. Daily assessments included documentation of seizures (as per hospital protocol all unconscious patients undergo continuous EEG monitoring for at least 24 hours)17,18, metabolic abnormalities (e.g., renal function and liver failure), and fever. Doses of all sedatives and laboratory values were recorded at the time of all behavioral assessments.

Behavioral assessment

We assessed level of consciousness daily from ICU admission to ICU discharge, whichever was sooner. As described previously19, behavioral assessments of consciousness were performed during morning rounds. These consisted of protocolized, hierarchical assessments categorizing consciousness into three levels of behavioral states: (1) “comatose” (no response to stimulation), (2) “arousable” (opening eyes and/or attending to stimulation), or (3) “conscious” (following simple commands; e.g., “show me two fingers”). To overcome language impairment or aphasia while testing for consciousness, we used in addition to verbal commands, non-verbal cues to induce mimicking (e.g., holding up two fingers and then gesturing to subject’s supported hand). For the classification approach described below, we dichotomized patients into “conscious” (category 3, following verbal and/or non-verbal commands) and “unconscious” (categories 1 and 2; see details in Supplementary Material). According to our ICU protocol daily assessments were performed during interruption of sedation.

MR acquisition

As part of our clinical protocol we acquired MR images within 7 days of hemorrhage whenever deemed safe by the attending neurointensivist using a 3 T scanner (GE Signa HDx MRI scanner; HD23 software). Total acquisition time did not exceed 45 minutes. We obtained FLAIR, T1-weighted, and DWI sequences (for details please refer to the Supplementary Material).

Categorization of lesions

Anatomical regions of interest (ROIs) were predefined based on established neuroanatomical atlases20 with a focus on subcortical brain regions (henceforth referred to as “subcortical ROIs”) previously implicated in consciousness1,2,3,4,5,6,7,12. A board-certified neurologist (AR) categorized the presence of blood and perihematomal FLAIR hyperintensity (henceforth referred to as “edema”) for each ROI based on a 3D visualization of FLAIR, T1 and DWI sequences. The following ROIs were included in the models: pontine tegmentum, midbrain (central and peduncles), hypothalamus, basal forebrain, thalamus, pallidum, putamen, and caudate nuclei (see Fig. S1). For purposes of analysis, lesion laterality was reclassified from right/left into ipsi/contralateral using the following approach. The side of the brain with the larger amount of blood was labelled as ipsilateral. The side with the smaller amount was labelled as contralateral. Intraventricular hemorrhage (IVH) was assessed in the 3rd, 4th, and each lateral ventricle and classified as present or absent. Any challenging cases with bilateral hemorrhage were classified by consensus between three board certified neurologists (AR, JC, BR). A board-certified neurologist (DR) coded the same imaging parameters on a random 20% sample of MRIs blinded to the first coder’s results. Interrater agreement was assessed using kappa statistics.

Volumetric measurements and midline shift

Hemorrhage, perilesional edema, and brain volumes were quantified based on FLAIR sequences using a semi-automatized method. Briefly, a gross region-of-interest was identified that encapsulated the affected region (ICH or edema) to automatically compute a 3D image that were visually inspected and manually corrected if necessary (KI, see Supplementary Material and Fig. 1A). Midline shift (MLS) was measured both at the level of the septum pellucidum as well as at the pineal gland, and the larger number was recorded21.

Figure 1 Hemorrhage and edema volumes and midline shift. Panel A. Illustrates the volume on MRIs of one exemplary case. Panel B. Measurements according to consciousness level at time of MRI (normalized values; for details please refer to methods). ICH: Intracerebral Hemorrhage; MLS: midline shift. Full size image

Main outcome

Main outcomes were the level of consciousness observed at time of ICU discharge and the Glasgow Outcome Scale-Extended (GOS-E) obtained 3 months following the hemorrhage via phone interviews22. As an additional outcome measure, we recorded the best level of consciousness observed at any time during hospitalization following MRI acquisition.

Confounders

All patients were clinically evaluated for the presence of seizures, hypo- or hyperglycemia (70 and 200 mg/dL, respectively), hypo- and hypernatremia (133 and 150 mmol/L, respectively), and renal and fulminant liver failure at the time of behavioral assessments. All analyses were directly controlled for potential metabolic confounders (including blood urea nitrogen, creatinine, serum glucose level). In addition to the above outlined protocol of stopping sedation for all behavioral assessments we collected the cumulative doses of all sedative medications administered within the two elimination half-lives preceding clinical assessments19.

Statistical analysis

A machine learning approach using logistic regressions with elastic net regularization was applied to identify the parameters that best predicted consciousness at time of MRI and at time of ICU discharge23. This method allows a robust data-driven analysis when there are a large number of features compared to the number of observed events and/or when features are highly correlated. Models were trained on the clinical labels (conscious vs unconscious) obtained either at the time of MRI or at the time of ICU discharge. In order asses robustness of the model, we performed 5-fold cross validations repeated 500 times24. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) with 95% confidence intervals (95% CI). Logistic regression using elastic net regularization were computed with the Glmnet R package (for details please refer to the Supplementary Material).

Differences in baseline features between patients that fulfilled inclusion criteria and those that did not were explored using Fisher’s exact test for categorical and Wilcoxon–Mann–Whitney test for quantitative variables as appropriate. All statistical tests were two-sided. Categorical variables are reported as percentage (number) and quantitative variables as median (interquartile range). Significance was set at P < 0.05. All analyses were performed using the R statistical software version 3.4.125.