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).