1. Phase 1: from ICU to prolonged unresponsiveness in IRU (week 1 to 5)
1.1 Clinical history and structural neuroimaging
Eight weeks prior to admission at our IRU, the patient (female, 65 years old, right-handed, without relevant medical history) was hospitalized due to a sudden series of seizures associated with an altered state of consciousness. Head computed tomography (CT) scan and angiography revealed a bi-hemispheric subarachnoid hemorrhage with intraventricular hemorrhage and severe brain swelling due to the rupture of an aneurysm of the anterior communicating artery (ACoA). The patient soon became comatose (with a Glasgow Coma Scale, GCS, of 6) and an urgent endovascular coiling treatment was performed on the same day. In a few days, the neurological status further deteriorated (GCS decreased from 6 to 4) in ICU due to a re-bleeding of the ACoA aneurysm, requiring an additional endovascular treatment. A left cortical-subcortical parieto-occipital infarct due to diffuse cerebral vasospasm was also revealed by serial CT-scans. Apart from the GCS, no clinical or paraclinical assessments of consciousness were collected during the patient’s ICU stay.
Upon sufficient stabilization of vital signs, the patient was admitted at our IRU with a diagnosis of a prolonged VS/UWS requiring artificial hydration and feeding, as well as total nursing care (Figure 1). Here, a first neurological examination showed spontaneous eye opening, a severe diffuse hypertonia with combined extrapyramidal and pyramidal features (rigidity and spasticity were predominant in both lower limb and the left upper limb), grasp and palmo-mental reflexes, Myerson’s sign (not-extinguishable glabellar tap reflex), hypomimia after painful stimuli and a lack of any consistent command following, visual fixation or tracking. She did not initiate any spontaneous motor behavior.
A multimodal investigation was conducted within the multicentric “Perbrain” project (Willacker et al. , 2022), approved by the ethics section ”IRCCS Fondazione Don Carlo Gnocchi ” of ethics committee IRCCS Regione Lombardia (Prot. n. 32/2021/CE FdG/FC/SA) and a written informed consent was provided by the patient’s legal guardian at admission.
On week 1, sMRI protocol was acquired on a 3 Tesla Siemens Prisma scanner equipped with a 64channels head/neck coil. The MRI protocol included a 3D sagittal magnetization-prepared rapid acquisition with gradient echo (MPRAGE) as anatomical reference (1mm3; 256x256;TR/TE: 2300/2,98ms; TI:919ms), a 3D sagittal fluid-attenuated inversion recovery (FLAIR) for lesion detection (0,8x0,8x1mm; 320x320; TR/TE:5000/394ms; TI:1800ms) and a diffusion weighted imaging (DWI) sequence for quantifying the white matter microstructural status (2mm3; 104x104; including short and long phase-encoding reversed data; TR/TE:3600/92ms 5 b0 images, 50 diffusion-encoding directions with b = 1000 s/mm2 and 50 diffusion directions with b = 2000s/mm2).
Neuroradiologist’s visual analysis of sMRI sequences revealed extensive bilateral cortico-subcortical encephalomalacia (associated with hemosiderin deposits) at frontal and parietal median parasagittal locations and corpus callosum thinning throughout its extent (Figure 2). In addition, there was a cortico-subcortical ischemia at the left parieto-occipital region as well as a bilateral enlargement of the ventricles at the frontal and temporal horns. Due to the aneurysm clip in the anterior communicating artery territory, a partial magnetic distortion in the median fronto-basal area and in the region of the basal nuclei was also observed.
The lesions were segmented on the FLAIR images by an expert radiologist using the Jim software package (http://www.xinapse.com). Then, in order to map which gray matter (GM) and white matter (WM) areas were involved by the lesion, the lesion mask was non-linearly registered to the MNI space (resolution 1x1x1mm3) using FMRIB’s Software Library (FSL,http://www.fmrib.ox.ac.uk/fsl).
1.2 Serial standardized behavioral assessment is consistent with a VS/UWS
In view of the clinical presentation and of the pattern of anatomical injury, involving the bilateral mesial frontal territory of the anterior cerebral arteries, a differential diagnosis between a complete AM and a VS/UWS was considered (Freemon, 1971). To minimize the possibility of missing minimal signs of volitional motor activity such as gaze tracking or reproducible responses to stimuli, a standardized clinical assessment with serial CRS-R was applied weekly, along the IRU stay (at least 3-5 times/week for 20 weeks). Multiple behavioral evaluations were performed by expert examiners (neurologist and neuropsychologist) at different times of the day, with similar environmental conditions. The clinical trajectory as well as the best CRS-R total score per week is detailed in Figure 1. During the first five weeks of standardized clinical monitoring, the patient was repeatedly diagnosed as VS/UWS since only reflexive responses (such as auditory startle, visual startle, abnormal posturing, and oral reflexive movement) could be detected in the absence of any reproducible behavioral sign of minimal consciousness. During this period, the patient appeared fully awake, but she was not able to consistently follow moving objects with the gaze or fixate. No verbal contact was possible and no motor response on request was produced (CRS-R total score ranging from 5 to 7).