Advances in medical knowledge and technologies have made it possible for many patients
who had traumatic or nontraumatic severe brain injuries to survive, and, consequently,
transition into or remain in what are now referred to as disorders of consciousness
(DoC). Over one million people are affected by DoC each year worldwide.[1]
[2] Among DoC patients, withdrawal of life-sustaining therapy is a frequent cause of
death.[3]
[4]
[5]
[6] However, the lack of knowledge about patients' consciousness level and their potential
for long-term recovery remains a challenge throughout this decision-making process.
Thus, correct diagnosis and outcome prediction of this vulnerable patient population
have tremendous clinical and ethical implications for patients, their caregivers,
and clinicians.
DoC are categorized on a spectrum of diagnostic entities, ranging from the most severe
state, coma, to vegetative state/unresponsive wakefulness syndrome (VS/UWS), minimally
conscious state minus (MCS − ), minimally conscious state plus (MCS + ), and emergence
from MCS (eMCS). The acute period of DoC is defined as the first 28 days after the
brain injury, and subacute-to-chronic (or “prolonged” DoC) as longer than 28 days.[7] Coma is defined as the complete absence of arousal and awareness.[8] VS/UWS is defined as preserved arousal (eye opening spontaneously or upon stimulation)
without awareness, the patient showing only reflexive behaviors.[9]
[10]
[11] MCS is defined as minimal, reproducible but inconsistent behavioral signs of awareness.[12] MCS− patients show nonreflex movements such as localization of noxious stimuli,
visual pursuit or fixation, localization of objects, and movement or affective behaviors
in a contextual manner to relevant environmental stimuli. MCS+ patients display behaviors
related to language expression and comprehension, including command-following, intelligible
verbalization, and intentional communication.[13] When patients demonstrate functional object use or functional communication, they
are considered eMCS.[12] Cognitive motor dissociation (CMD),[14] functional locked-in syndrome,[13] MCS*,[15]
[16] and covert cognition[17] are terms suggested by different research teams to define behaviorally unresponsive
patients who show brain activity compatible with (minimal) consciousness detected
by functional magnetic resonance imaging (fMRI), electroencephalography (EEG), or
positron emission tomography (PET). CMD is specifically used for patients who show
no (VS/UWS) or little (MCS − ) behavioral evidence of consciousness at the bedside
but have cortical responses related to language processing in fMRI or EEG active paradigms.[14] MCS* encompasses VS/UWS patients with CMD as well as VS/UWS patients who have residual
brain activation in neuroimaging compatible with diagnosis of MCS even in the absence
of active paradigms.[15]
[16]
Accurate diagnosis of DoC patients is highly challenging. Indeed, over one-third of
DoC patients previously diagnosed with VS/UWS by clinical consensus (based on behavioral
observations and clinical experience) had evidence of consciousness when they were
later evaluated based on standardized behavioral assessments using the Coma Recovery
Scale-Revised (CRS-R).[18]
[19]
[20] However, it is important to note that, if performed only once, standardized behavioral
assessment with the CRS-R can also lead to a 35% rate of misdiagnosis (compared with
five CRS-R assessments).[21] Thus, repeated assessment (at least five times in a short period, e.g., 10 days)
is of critical importance. The high misdiagnosis rates in DoC patients may be related
to the lack of a proper gold standard to assess the presence of consciousness, and
the need to integrate neuroimaging and new potential behavioral signs of consciousness
into diagnostic guidelines. All these warrant the urgent need for improvement in diagnostic
methods.
Currently available standardized behavioral scales to assess patients with DoC include,
among others, the Glasgow Coma Scale (GCS),[8] the Full Outline of UnResponsiveness,[22] the Simplified Evaluation of CONsciousness Disorders (SECONDs),[23]
[24] and the CRS-R.[25] The American Congress of Rehabilitation Medicine Task Force and European Academy
of Neurology recommends the use of repeated CRS-R in the assessment of patients with
subacute-to-chronic DoC.[26]
[27]
The CRS-R consists of 23 items composed of six subscales assessing auditory, visual,
motor, oromotor/verbal functions, communication, and arousal. Among these items, 11
indicate an MCS diagnosis (six for MCS− and five for MCS + ). From these items, visual
pursuit, reproducible command-following, and automatic motor response (e.g., nose
scratching, grasping bedrail, grabbing tubes) were found to be the first three most
common signs of MCS to reemerge after brain injury.[28] The five most frequently observed items detecting 99% of chronic MCS patients were
visual fixation, visual pursuit, reproducible movement to command, automatic motor
response, and localization to noxious stimulation.[29] When transitioning into MCS, chronic VS/UWS patients were found to show mostly only
one behavioral sign (73%): visual fixation, visual pursuit, localization to noxious
stimulation, reproducible movement to command, or functional communication.[30] Similarly, chronic MCS patients were also found to show mostly only one behavioral
sign (64%) while transitioning into eMCS, either functional communication or functional
object use[30] ([Fig. 1]).
Fig. 1 Prevalence of 11 minimally conscious state (MCS) items from the Coma Recovery Scale-Revised
(CRS-R) in disorders of consciousness (DoC) patients from four different studies.
Black, the prevalence of MCS items in the CRS-R in patients who transition from vegetative
state/unresponsive wakefulness syndrome (VS/UWS) to MCS (adapted from Carrière et
al[30]). Dark gray, the prevalence of MCS items in the CRS-R taking into account all MCS items observed
in the whole cohort of MCS patients, and (light gray) when taking into account MCS items observed in patients who show only one sign of
consciousness (adapted from Wannez et al[29]; in this study they included the first CRS-R where all MCS items were tested for
every patient). In white, the frequency of CRS-R items is shown as temporally first
ones to emerge in MCS patients (adapted from Martens et al[28]; evidence of transition to consciousness was defined as 2 consecutive complete CRS-R
within 7 days indicating new MCS or emergence from MCS). Given the prevalence of MCS
items in this figure from different studies, we highly encourage paying attention
to these five most prevalent items (visual fixation, visual pursuit, reproducible
movement to command, automatic motor response, and localization to noxious stimulation).
In addition to the already available items that denote MCS in the CRS-R, recent studies
suggest that other behaviors may be considered as signs of consciousness in DoC patients.
The objective of this article is to summarize and review these new behavioral findings:
resistance to eye opening, spontaneous eye blink rate, auditory localization, habituation
of auditory startle reflex, olfactory sniffing, swallowing/oral feeding, facial expressions
to noxious stimulation, subtle motor behavior assessed by Motor Behavioral Tool-revised
(MBT-r), and leg crossing ([Table 1] and [Fig. 2]).
Fig. 2 Potential new behavioral signs of consciousness. All the new behavioral signs of
consciousness reviewed in this article have feasible, practical, and affordable assessment
methods in clinical practice. In this illustration, the signs are displayed according
to the complexity of the assessment and the need for expertise and/or equipment to
carry out examinations. Depending on the resources of each center, we recommend using
as many items as possible to improve the diagnostic accuracy.
Table 1
Summary of results from studies reviewed in this article
|
Author (year)
|
Behavior
|
No. of patients and sex
|
Age (mean±SD or median, IQR or range)
|
Onset (mean±SD or median, IQR or range)
|
Etiology
|
Behavioral tool
|
Diagnosis
|
Brain imaging
|
Main findings
|
Sign of C
|
Prognosis
|
Bias/Limitations
|
|
van Ommen et al[35] (2018)
|
Resistance to eye opening
|
79
36 F
43 M
|
37, IQR: 28–52
|
15 mo, IQR: 1–41 mo
|
42 TBI
25 post-anoxic encephalopathy due to cardiac arrest
6 stroke
5 SAH
2 encephalitis
1 hypoglycemia
|
CRS-R
|
23 VS/UWS
15 MCS−
41 MCS+
|
PET
MRI
|
Significant relationship between REO and the level of consciousness.
Higher REO repeatability in MCS.
Atypical neuroimaging findings similar to MCS in VS/UWS patients with REO.
|
Yes
|
No correlation
|
Heterogeneity in time since onset, etiologies, and brain damage.
|
|
Magliacano et al[39] (2021)
|
Spontaneous eye blink rate
|
24
6 F
18 M
|
50 ± 18 VS/UWS
53 ± 18 MCS
|
6 ± 16 mo
|
7 TBI
9 ABI
8 vascular
|
CRS-R
|
10 VS/UWS
14 MCS
|
EEG
|
Eye blink rate was significantly higher in MCS patients compared with VS/UWS patients.
A significant positive correlation was found between CRS-R index and eye blink rate.
|
Yes
|
n/a
|
Researcher who evaluated eye blink rates was not blinded to patients' diagnosis.
Only investigating eye blink rate, but not other blink characteristics.
Not recording all sessions for all patients at the same time of the day.
Some patients were assessed less than 5 times by CRS-R for diagnosis.
Small sample size.
|
|
Carrière et al[41] (2020)
|
Auditory localization
|
186
66 F
120 M
|
39 ± 16
|
9 mo, range: 1mo–29y
|
100 TBI
86 non-TBI
|
CRS-R
|
64 VS/UWS
28 MCS−
71 MCS+
|
PET
fMRI
hdEEG
|
Auditory localization increased with level of consciousness.
Higher survival rates after 2-y follow-up in patients with auditory localization compared
with patients without auditory localization.
Higher fMRI functional connectivity between frontoparietal network and secondary occipital
regions in VS/UWS patients with auditory localization.
Higher participant coefficient in α band in VS/UWS patients with auditory localization.
|
Yes
|
Increased survival rate
|
Small sample size of VS/UWS with localization (auditory localization as the only “sign
of consciousness” is rare).
Subgroups not matched for age and time since injury.
Missing clinical outcome data.
Some patients had light sedation for fMRI.
Lack of auditory evoked potentials or otoacoustic emissions to rule out deafness in
the absence of auditory response.
|
|
Hermann et al[45] (2020)
|
Habituation to auditory startle reflex
|
96
M/F ratio: 1.8
|
44 ± 16
|
58 d, IQR: 31–236d
|
39 ABI
27 TBI
12 vascular
18 other
|
CRS-R
|
48 VS/UWS
48 MCS
|
PET
DTI MRI
hdEEG
|
More habituation in MCS compared with VS/UWS.
Higher CRS-R scores in all subscales except communication in patients with habituation.
Highest prevalence and sensitivity for habituation compared with the performance of
all MCS items of the CRS-R to discriminate MCS.
PET activity in salience and default mode networks correlated with habituation.
Higher θ and α power, with higher prefrontal-temporal connectivity in patients with habituation.
Higher recovery of command-following after 6-mo follow-up in VS/UWS with habituation.
|
Yes
|
Yes (recovery of command-following after six-mo follow up)
|
None reported.
|
|
Sattin et al[46] (2019)
|
Olfactory discrimination
|
11
6 F
5 M
|
57, IQR: 14
|
3–146 mo
|
6 ABI
3 hemorrhagic brain injury
1 ischemic and hemorrhagic brain injury
1 TBI + ABI
|
CRS-R
|
9 VS/UWS
2 MCS
|
fMRI
|
All MCS and 33% of VS/UWS had a discriminatory olfactory response.
All VS/UWS with discriminatory olfactory response had olfactory-related activity in
olfactory cortices in fMRI.
|
Yes
|
n/a
|
Small sample size.
Lack of quantitative analysis of nasal airflow.
Using only 4 odors could underestimate the real olfactory functions due to chance
of specific anosmia.
4 patients excluded due to head movements in fMRI.
|
|
Nigri et al[47] (2016)
|
Olfactory processing
|
42
19 F
23 M[*]
|
57, IQR: 23–77 for VS/UWS; 44, IQR: 20–71 for MCS
|
26mo, IQR: 3–146 for VS/UWS; 41mo, IQR: 11–170 for MCS
|
17 ABI
7 hemorrhagic brain injury
6 TBI
2 ischemic and hemorrhagic brain injury
1 TBI + ABI
|
CRS-R
|
26 VS/UWS
7 MCS
|
fMRI
|
58% of VS/UWS, 100% of MCS showed odor-induced activity in primary olfactory areas.
39% of VS/UWS and 71% of MCS showed activation within a higher-order olfactory processing
area.
Most patients with anoxic brain injury had no activation in primary olfactory areas.
|
n/a
|
n/a
|
Small sample size.
The excluded populations (due to movement in fMRI) were majorly MCS, and thus might
have skewed the results.
|
|
Arzi et al[48] (2020)
|
Olfactory sniffing
|
43
8 F
35 M
|
43 ± 17
|
1mo–10mo
|
27 TBI
5 ABI
10 cerebrovascular accident
1 infection
|
CRS-R
CNC
|
21 VS/UWS
22 MCS
|
n/a
|
Reduction of nasal airflow in response to odorants and empty jar presentation in MCS
sessions, but not in VS/UWS sessions.
Sniff response had 64.5% sensitivity to determine MCS.
On individual level, VS/UWS patients who showed sniff response in at least one session
later transitioned to MCS.
Sniff response had 100% specificity and 62.5% sensitivity in predicting transition
from VS/UWS to MCS.
Sniff response had sensitivity of 91.7% in predicting survival after >3 y.
|
Yes
|
Recovery of consciousness (transition to MCS) and predicting survival after >3 y
|
Data using two different behavioral assessment protocols (this was alleviated by having
a third tool applied equally to all participants).
Not being able to test more frequently due to clinical schedule (possible observation
of advance detection with more frequent testing).
This method requires uninflated tracheostomy balloons and would not work with inflated
tracheostomy balloons.
|
|
Wang et al[49] (2022)
|
Behavioral response to olfactory stimuli
|
23
7 F
16 M
|
22–69
|
1–11 mo
|
10 TBI
13 non-TBI
|
CRS-R
|
8 VS/UWS
15 MCS
|
n/a
|
Behavioral response to odorant stimuli compared with nonodorant stimuli (water) was
higher among all patients.
In response to the neutral odor presentation (1-Octen-3-ol), MCS patients had higher
behavioral response compared with VS/UWS patients.
|
Yes
|
No correlation
|
No neuroimaging.
Small sample size.
|
|
Mélotte et al[54] (2020)
|
Oral feeding
|
92
39 F
53 M
|
41 ± 12 VS/UWS
38 ± 12 MCS
|
30mo±22 for VS/UWS; 4mo±34 for MCS
|
60 focal
32 global
|
CRS-R
PET
|
26 VS/UWS
66 MCS
|
PET
|
Presence of tracheostomy, cough reflex, and oral phase efficacy related to consciousness.
0 VS/UWS with oral feeding or efficient oral phase.
0 MCS with complete feeding.
|
Yes
|
n/a
|
Missing data for cough reflex criterion.
Limited number of available criteria due to retrospective nature of the study.
|
|
Chatelle et al[55] (2018)
|
Facial expression to noxious stimuli
|
85
28 F
57 M
|
48 ± 17 VS/UWS
43 ± 17 MCS
|
142d, IQR: 88–396 for VS/UWS; 133d, IQR: 78–350 for MCS
|
35 TBI
25 ABI
25 other
|
CRS-R
|
28 VS/UWS
57 MCS
|
n/a
|
MCS had higher NCS-R scores compared with VS/UWS.
Grimace observed more frequently in painful stimulation compared with nonpainful stimulation
in all patients.
Grimacing frequency more frequent in MCS compared with VS/UWS.
|
Yes
|
n/a
|
High overlap of the items in NCS-R and CRS-R.
In group analyses, single CRS-R assessment was used for diagnosis.
Lack of blinding, same raters carrying out both assessments.
|
|
Gélinas et al[56] (2019)
|
Behavioral response to noxious stimulation
|
147
51 F
96 M
|
56 ± 20
|
> 4 wk after brain injury
|
94 TBI
33 aneurysm
13 stroke
1 brain abscess
|
GCS
|
26 not conscious
56 altered
65 conscious
|
n/a
|
Higher number of active behaviors during nociceptive procedures in conscious patients.
Grimace was a strong indicator for pain intensity in conscious patients.
|
Yes
|
n/a
|
Raters not blinded.
Checklist ratings included both bedside observation and videos which may have led
to differences.
Only 35 patients were able to self-report their pain (limiting power of analyses).
|
|
Pincherle et al[58] (2019)
|
Subtle motor behavior
|
30
13 F
17 M
|
64 ± 16
|
10±5d
|
16 hemorrhage
3 metabolic
7 trauma
1 stroke
3 ABI
|
CRS-R
MBT-r
|
13 coma
10 VS/UWS
5 MCS
2 eMCS
|
n/a
|
75% of coma and VS/UWS diagnosed by CRS-R showed signs of residual cognition with
MBT-r.
66.7% of patients showing residual cognition by MBT-r had favorable outcome.
|
Yes
|
Yes, favorable outcome (discharge, 3 and 6 mo)
|
Small and heterogenous cohort.
|
|
Jöhr et al[59] (2020)
|
Subtle motor behavior
|
141
54 F
87 M
|
53 ± 17
|
35±107d for clinical CMD; 55±19d for DoC; 25±20d for non-DoC
|
55 severe traumatic
63 vascular
12 ABI
7 encephalopathy
4 neoplasm
|
CRS-R
MBT-r
|
105 clinical CMD
19 DoC
17 non-DoC
|
n/a
|
Strong improvement trajectory of functional/cognitive recovery from admission to discharge
in patients with residual cognition based on MBT-r assessment.
|
Yes
|
Yes, functional, and cognitive recovery from admission to discharge.
|
Categorizing patients into clinical CMD solely based on MBT-r, and not performing
active mental-imagery tasks stated in the definition of CMD. No differentiation of
subtypes of CMD.
Potential measurement error and reliability issues due to nonstandardized assessment
of outcome measures retrospectively.
Medical complications and their possible impact on outcomes not taken into consideration.
Data collection only at two time points, which limited information about recovery
course during hospitalization.
|
Abbreviations: ABI, anoxic brain injury; CNC, Coma/Near Coma Scale; CMD, cognitive
motor dissociation; CRS-R, Coma Recovery Scale-Revised; DoC, disorders of consciousness;
DTI, diffusion tensor imaging; eMCS, emerging from minimally conscious state; F, female;
fMRI, functional magnetic resonance imaging; hdEEG, high-density electroencephalography;
IQR, interquartile range; M, male; MBT-r, Motor Behavioral Tool-revised; MCS, minimally
conscious state; n/a, not available; NCR-R, Nociception Coma Scale-Revised; REO, resistance
to eye opening; SAH, subarachnoid hemorrhage; SD, standard deviation; TBI, traumatic
brain injury; VS/UWS, vegetative state/unresponsive wakefulness syndrome.
* 9 patients were discarded in data analysis due to excessive movements. The columns
of etiology, diagnosis and main findings take into account only analyzed patients.
New Potential Behavioral Signs of Consciousness in DoC Patients
Resistance to Eye Opening
Resistance to eye opening, a firm closure of already closed eyelids when an examiner
touches or tries to open the eyes, is evident in multiple neurological disorders.[31]
[32]
[33]
[34] The presence of resistance to eye opening and its correlation with different levels
of consciousness were assessed in 79 prolonged DoC patients (TBI and non-TBI).[35] The diagnosis of patients was based on repeated CRS-R assessments. The examiners
considered resistance to eye opening present when there was forceful closure of one
or both eyes upon manually opening the patients' upper eyelids bilaterally. Resistance
to eye opening was present in 24% of patients (19/79): 26% of VS/UWS (6/23), 53% of
MCS− (8/15), and 12% of MCS+ (5/41). Although MCS+ patients had the lowest rate of
resistance to eye opening, a statistically significant relationship was present between
resistance to eye opening and the level of consciousness. In addition, the repeatability
of resistance to eye opening was the highest in patients with MCS + , suggestive of
a correlation between the level of consciousness and the number of times resistance
to eye opening was seen. MCS+ patients having the lowest rate but the highest repeatability
seem contradictory. One possible explanation might be that as patients recover their
consciousness, they might be able to understand the instructions of the examiner and
inhibit their resistance to eye opening. To replicate, validate, and better understand
the relationship between resistance to eye opening and the level of consciousness,
future studies could include eMCS patients and healthy controls.
Furthermore, atypical neuroimaging findings (brain activity consistent with MCS diagnosis)
were more likely to be seen in VS/UWS patients with resistance to eye opening (83%)
than without (29%). Indeed, five out of six patients diagnosed with VS/UWS and with
resistance to eye opening had neuroimaging results more compatible with MCS. Four
showed relatively preserved PET metabolism in the frontoparietal network (similar
to MCS patients), and one showed response to command during a motor imagery task assessed
with fMRI, suggesting that these patients were MCS*/CMD.[14]
[16] After 6 months of follow-up, only one of these patients showing resistance to eye
opening recovered from VS/UWS, two passed away, and three remained in VS/UWS. Thus,
there was no correlation between this behavior and the prognosis of these patients.
Collectively, these results suggest that assessing resistance to eye opening repeatedly
in prolonged DoC patients can help clinicians gain insight into patients' levels of
consciousness. However, this study population had heterogeneity of etiologies and
locations of brain injury. Since there might be voluntary and reflexive presentations
of resistance to eye opening, future studies localizing brain lesions and correlating
this with resistance to eye opening might provide more information regarding the cortical
mediation of this behavior.
Spontaneous Eye Blink Rate
Several research teams have shown that eye blink rate is modulated by fatigue, vigilance,
task demand, and cognitive load.[36]
[37]
[38] To test whether there was a difference in the spontaneous eye blink rate between
MCS and VS/UWS patients, 24 chronic DoC patients (TBI and non-TBI) were enrolled in
a recent study.[39] Ten patients were diagnosed as VS/UWS and 14 as MCS according to the CRS-R. There
were two experimental sessions for each patient, at least 24 hours apart, where patients'
eye blink rate was observed at rest for 3 minutes. The examiners stood next to the
patients' bed, out of patients' visual field, where they could observe and count the
eye blinks. All patients were encouraged to stay relaxed with their eyes open, and
not move (they were not informed about the eye blink counting to avoid potential bias).
Spontaneous eye blink rate at rest (the final agreement on the rate was reached after
also taking into account EEG and EOG recordings) was found to be significantly higher
in MCS compared with VS/UWS patients (first session: mean of 8 ± 3 blinks for UWS
and 18 ± 3 for MCS; second session: mean of 6 ± 2 blinks for UWS and 26 ± 4 for MCS
patients). CRS-R index (a modified linear score taking into account the highest item
in each subscale)[40] was calculated and found to significantly correlate with the mean eye blink rate
at rest. Due to small sample size and fluctuations in the arousal of DoC patients
in this study, more studies with larger sample sizes and more standardized assessment
protocols (blinding examiners to patients' diagnosis and applying consistent timing
of experimental sessions across patients) are recommended to further test the spontaneous
eye blink rate as a potential indicator for the level of consciousness.
Auditory Localization
In the CRS-R, spatial localization in visual and motor domains (visual pursuit and
localization to noxious stimulation, respectively) is considered signs of MCS, whereas
in the auditory subscale this is not the case, and localization to auditory stimulus
is considered a reflex. In the CRS-R, auditory localization is evaluated by presenting
auditory stimuli (patients' name, voice, noise, etc.) behind the patient, out of view,
for 5 seconds twice on each side (right and left). When there is a clear head or eye
movement toward the auditory stimuli on both trials in at least one direction within
10 seconds of stimulus presentation, the patient is considered to have auditory localization.[25] In a multimodal study, 186 patients with prolonged DoC (TBI and non-TBI) were assessed
to examine whether auditory localization could be considered as a sign of MCS.[41] The probability of auditory localization increased with the level of consciousness:
13% of VS/UWS, 46% of MCS − , 62% of MCS + , and 78% of eMCS patients had auditory
localization ([Fig. 3A]). Notably, regardless of the diagnosis, patients with auditory localization had
higher survival rates after 2 years of follow-up (despite no significant differences
in clinical improvement). According to the results obtained with PET, there were no
significant differences in brain metabolism between VS/UWS patients with and without
auditory localization. However, fMRI analysis showed higher functional connectivity
between frontoparietal network and secondary occipital regions during rest in VS/UWS
patients with localization compared with those without localization. High-density
EEG results showed that VS/UWS patients with localization also had a higher participation
coefficient in the α-band compared with VS/UWS patients without localization. The
participant coefficient is a connectivity measure that has been shown to correlate
with the level of consciousness in previous studies on DoC patients.[42]
[43]
[44] Taking all these results into consideration, auditory localization might be a more
complex behavior than a reflex, and with the need for additional confirmation of further
studies, it could be reconsidered as a potential sign of MCS.
Fig. 3 Evidence from different studies showing how behavioral, neuroimaging, and prognosis
data can be used to validate signs of consciousness in disorders of consciousness
(DoC) patients. (A) Behavioral results: auditory localization in DoC patients (reproduced from Carrière
et al[41]). The percentage of auditory localization increases with the level of consciousness,
with significant differences between vegetative state/unresponsive wakefulness syndrome
(VS/UWS) and minimally conscious state minus (MCS − ), VS/UWS and MCS + , and VS/UWS
and eMCS. (B) Neuroimaging results: a. FDG-PET whole brain voxel-based analysis of metabolic index showing higher values
in patients who had habituation to auditory startle reflex (EX) compared with patients
who did not have habituation (IN), in parietal and medial frontal regions (top row),
with significant differences in precuneus/posterior cingulate, premotor area, and
anterior cingulate (bottom row) (adapted from Hermann et al[45]). b. ANOVA showing an independent main effect of the habituation of auditory startle
reflex in posterior and anterior cingulate and supplementary motor area. (C) Prognosis result: patients showing sniff response had better prognosis than patients
who did not (adapted from Arzi et al[48]): the red lines indicate a previously published sniff-response threshold,[90] dots within the boxed area (white background; bottom right) reflect sessions without
a sniff response; dots outside the boxed area (shaded background) reflect sessions
with a sniff response. a–c, Each dot represents a VS/UWS session. Unfilled dots indicate sessions of patients
who recovered later and transitioned to MCS and filled dots indicate sessions of patients
who did not recover consciousness during the study. a, Pleasant odorant. b, Unpleasant odorant. c, Blank. d, Percentage of VS/UWS patients who later transitioned to MCS (left, “Recovered”)
or remain unconscious (right, “Unrecovered”) with sniff responses (white; recovered,
62.5%; unrecovered, 0%) and without sniff responses (red; recovered, 37.5%; unrecovered,
100%) across pleasant, unpleasant, and blank conditions.
Habituation of Auditory Startle Reflex
In the auditory subscale of the CRS-R, auditory startle reflex is the lowest score
item above zero (no response). To test its validity as a sign of MCS, habituation
of auditory startle reflex was examined in 98 patients with prolonged DoC (TBI and
non-TBI).[45] Habituation was assessed by presenting a loud handclap noise directly above the
patients' head (out of view) 10 times consecutively (∼120 bpm), administering four
trials. If patients had eyelid flutter or blink immediately after the stimulus in
at least two trials, this was considered as auditory startle being present. If patients
had eyelid flutter or blink after each and every clap, this was considered as inextinguishable
auditory startle reflex; otherwise, patients were considered as having habituation
of auditory startle reflex. Habituation was observed in 55% (53/96) of the patients.
Patients who had habituation were significantly younger than patients who did not
have habituation (which may have introduced a bias to the results). Habituation was
present in 75% (36/48) of MCS patients, whereas it was only observed in 35% (17/48)
of VS/UWS patients. Additionally, on the group level analysis, patients with habituation
had higher scores in every CRS-R subscale except the communication subscale. The performance
of each MCS item in the CRS-R and the habituation of auditory startle reflex in discriminating
MCS patients were compared. Habituation had the highest prevalence and sensitivity,
55 and 75% [60–86], respectively, among all MCS items. The accuracy of habituation
was 70%, second highest after visual pursuit (75% [65–83]). The mechanism of habituation
of auditory startle reflex could be of cortical origin, as shown with FDG-PET and
high-density EEG data. PET metabolic activity in multiple networks including the salience
network and the default mode network correlated with the presence of habituation of
auditory startle reflex ([Fig. 3B]). Higher θ- and α-power, together with higher values of cortico-cortical functional
connectivity (especially, higher prefrontal–temporal connectivity), were observed
in patients with habituation compared with patients without habituation. The recovery
of command-following at 6 months was significantly higher in VS/UWS patients who showed
habituation compared with those who did not show habituation. This new behavioral
item could be considered as another sign of consciousness for MCS diagnosis and could
be implemented in the CRS-R auditory scale.
Olfactory Sniffing
The sense of smell in DoC patients has been scarcely studied; yet, accumulating findings
suggest a link between olfactory abilities and the level of consciousness. A pilot
study in 11 DoC patients (nine VS/UWS and two MCS) examined olfactory discrimination
abilities based on patients' behavior.[46] A discriminatory olfactory response was defined by a behavioral response (eyes closure,
grimace, avoiding head movement, or vocalization) to an unpleasant odor (stuffy socks-like
or rancid-like) and trigeminal-irritating odor (ammonia) but not to a pleasant odor
(rose-like). All MCS patients and three VS/UWS patients (33.3%) showed a discriminatory
olfactory response. Notably, the three patients diagnosed with VS/UWS who showed a
discriminatory olfactory response had olfactory-related activity in olfactory cortices
when assessed with fMRI, suggesting that these patients might be MCS*. The six VS/UWS
patients (66.7%) with no discriminatory olfactory response had no olfactory-related
activity in either the primary or secondary olfactory cortices. These findings align
with an fMRI study that examined olfactory neural processing in 26 VS/UWS and 7 MCS
patients.[47] Odor-induced activity in primary olfactory areas was evident in 58% of VS/UWS patients
(15/26) and all MCS patients (100%, 7/7). Brain activation also varied with the etiology
of the lesion, where most patients with anoxic brain injury had no activation in primary
olfactory areas.
A recent study investigated olfactory sniffing in 43 patients with chronic DoC (TBI
and non-TBI).[48] Sensory-driven sniffing (level 1, odorant detection; level 2, odorant discrimination)
reflected automatic odorant-driven response, whereas cognitive-driven sniffing reflected
situational understanding and/or learning (when subjects were told they will be presented
with an odorant, but they were instead presented with an empty jar; nevertheless they
modified their nasal inflow). Patients were presented with pleasant (shampoo) and
unpleasant (rotten fish) odors, or clean air (empty jar); their nasal inhalation volume
in response to the stimuli was examined via a nasal cannula directly connected to
a spirometer, and an instrumentation amplifier. Patients' level of consciousness was
assessed with CRS-R and/or Coma/Near Coma Scale after each session (in addition, the
Loewenstein Communication Scale was used in some cases). In total, 73 sessions were
conducted in 31 MCS patients, and 73 sessions were conducted in 24 VS/UWS patients.
At the group level analysis (for sessions), they observed a 10% reduction of nasal
airflow from baseline in response to the odorants' presentation (regardless of pleasant
or unpleasant, indicating sensory-driven level 1 sniffing response) in MCS sessions,
but not in VS/UWS sessions. A similar difference was also recorded for cognitive-driven
sniffing, with a 5% nasal airflow reduction in response to clean air presentation
(empty jar) compared with baseline among MCS patients only. When reanalyzing the data
to reflect individual level differences (of clinical importance at the patient level),
sniff response had a sensitivity of 64.5% to determine MCS. Surprisingly, 10 out of
24 VS/UWS patients showed sniff response in at least one session, and all 10 patients
later transitioned into MCS (during the study, 16 out of 24 VS/UWS patients transitioned
to MCS). In this sample, the sniff response in VS/UWS patients therefore demonstrated
100% specificity and 62.5% sensitivity (10 out of 16 VS/UWS patients who transitioned
to MCS) to predict a transition to MCS. All the patients were followed up to see how
their sniff response related to long-term outcome ([Fig. 3C]). A sensitivity of 91.7% was measured for the sniff response in predicting survival
at 3.1 ± 1.2 years after brain injury.
A more recent study evaluated DoC patients' behavioral responses to different olfactory
stimuli, with a more qualitative approach compared with the aforementioned olfactory
sniffing studies.[49] Twenty-three DoC patients (TBI and non-TBI) were enrolled in this study. Eight patients
were diagnosed as VS/UWS and 15 as MCS according to repeated CRS-R. Videos were recorded
while patients were being presented with one of three different olfactory stimuli:
1-Octen-3-ol (familiar neutral odor), pyridine (unpleasant fish-like smell), and water
(odorless). Each odor was presented once for 3 seconds, with 15 seconds between different
stimuli. The behavioral responses such as pouting, shaking head, pushing things away
with hands, frowning, and twisting head in avoidance were scored by two independent
and blinded (to the stimuli and diagnosis) raters. Among all patients, the behavioral
responses to olfactory stimuli (1-Octen-3-ol and pyridine) were higher than nonolfactory
(water) stimuli. During the familiar neutral odor session, 93% of MCS and none of
the VS/UWS patients showed behavioral responses, and this difference was significant.
During unpleasant fish-like smell session, 60% of MCS and 13% of VS/UWS patients showed
behavioral responses, although this difference was not significant. During the odorless
session, 13% of MCS and none of the VS/UWS patients showed behavioral responses. The
patients were followed up after 1, 3, and 6 months with CRS-R evaluations. There was
no significant correlation between behavioral response to olfactory stimuli and the
prognosis.
Altogether, these findings suggest that olfactory stimuli are valuable additions to
the current assessment protocols and that olfactory sniff response is a powerful and
easily accessible tool which can be used in the assessment, diagnosis, and prognosis
of DoC patients, further decreasing misdiagnosis rates.
Swallowing/Oral Feeding
Previous neuropathological studies suggest that a correlation may exist between the
level of consciousness and swallowing function.[50]
[51]
[52] The presence of oral feeding was investigated in 68 chronic VS/UWS patients (TBI
and non-TBI) by reviewing their clinical information. These patients also underwent
multimodal assessments.[53] Only 3% (2/68) of these VS/UWS patients could be fed orally. The first patient received
liquid and semi liquid oral feeding in combination with gastrostomy feeding. Otorhinolaryngological
exam and fiberoptic endoscopic evaluation demonstrated intact laryngeal mobility and
cough reflex, and no salivary or secretions stasis. Even though no inhalation occurred,
the initiation of the swallowing reflex was delayed. Clinical evaluation and neuroimaging
assessments were suggestive of VS/UWS diagnosis. The second patient received full
oral feeding, with solid food. Behavioral evaluations were suggestive of VS/UWS diagnosis
as well, but neuroimaging and electrophysiologic assessments showed atypical findings
(relative preservation of metabolism within frontal and occipital cortices, relatively
preserved white matter integrity on diffusion tensor imaging, and theta activity on
EEG, despite the absence of resting-state fMRI networks). Due to dissociation between
behavioral and neuroimaging findings, this patient could be considered as MCS* rather
than VS/UWS. This study suggests that full oral feeding and a complex oral phase of
swallowing might be considered as a sign of consciousness.
A more recent study collected information regarding respiratory status, nutritional
status, and otolaryngological swallowing examination from 92 patients with prolonged
DoC (TBI and non-TBI).[54] Ten criteria were established: respiratory status (tracheostomy), nutritional status
(feeding type), oral phase of swallowing (hypertonia of the jaw muscles, oral phase,
efficacy of the oral phase), and pharyngeal phase of swallowing (pharyngo-laryngeal
secretions, saliva aspiration, cough reflex, cream aspiration, liquid aspiration).
The presence of a tracheostomy, cough reflex, and oral phase efficacy were found to
be related to consciousness. None of the VS/UWS patients (diagnosed with multiple
CRS-Rs and confirmed with hypometabolism in the frontoparietal network bilaterally
using PET) had an efficient oral phase, and none could be fed orally. Additionally,
none of the MCS patients received ordinary oral food. Since VS/UWS patients more frequently
had a tracheostomy at the time of assessment than MCS patients, their ability to correctly
manage saliva differed significantly. Taken together, these results suggested that
objective and systematic assessment of swallowing should also be performed in all
DoC patients, which could provide additional clinical data on the level of consciousness.
Facial Expressions to Nociception
Pain assessment and management in DoC patients have long been an important ethical
issue, since these patients cannot communicate their needs explicitly. Whether the
level of responsiveness to painful stimuli could reflect the level of consciousness
was investigated in a study enrolling 85 acute and prolonged DoC patients (TBI and
non-TBI).[55] The levels of consciousness assessed by CRS-R total scores correlated with responses
to the Nociception Coma Scale-Revised (NCS-R). Specifically, MCS patients had higher
NCS-R scores compared with VS/UWS patients. CRS-R oromotor/verbal and motor subscores
after noxious stimulation correlated with total NCS-R scores during noxious stimulation,
and the NCS-R was not found to be more sensitive than CRS-R in assessing nociception.
However, the importance of observing facial expressions to nociception was emphasized,
with the results showing that grimace was observed more frequently in all patients
during painful stimulation compared with nonpainful stimulation. Furthermore, there
was a difference in grimacing frequency between MCS and VS/UWS patients during noxious
stimulation, less frequent in the latter group. This difference may be due to the
presence of tracheostomy (more frequently present in VS/UWS patients) having a possible
effect on decreased lower face expression of patients. Nonetheless, observation of
the facial expressions in the DoC patient population could add valuable information
to the assessment.
Another study including 147 brain-injured patients (TBI and non-TBI) assessed behaviors
related to standard ICU care procedures (nociceptive and non-nociceptive) in patients
with different levels of consciousness.[56] Patients were classified as unconscious (GCS: 3–8), altered (GCS: 9–12), or conscious
(GCS: 13–15). A behavioral checklist consisting of 30 active (grimace, tube biting,
brow lowering, mouth opening, etc.) and 10 neutral (open mouth, open eyes, smile,
etc.) behaviors was used for scoring. A higher number of active behaviors were observed
during nociceptive procedures in conscious patients. In addition, grimace was found
to be a strong indicator for pain intensity in conscious patients. The results of
this study, again, emphasize that the standardized observation of facial expressions
during noxious stimulation could help better classify patients.
Subtle Motor Behavior Assessed by the Motor Behavioral Tool
The Motor Behavioral Tool-revised (MBT-r)[57]
[58] was developed to capture subtle motor behaviors possibly overlooked by the CRS-R.
MBT-r includes seven positive signs and two negative signs ([Table 2]). Patients were considered to have residual cognition if at least one positive item
was present. The presence of a negative item suggested brainstem dysfunction and potentially
abnormal automatic responses, in which case patients were not scored with MBT-r. The
tool also took into consideration the inter-rater agreement of each item, eliminating
reliance on an isolated item with a low inter-rater agreement. MBT-r was administered
to a cohort of 30 patients with acute DoC (TBI and non-TBI) as a complementary tool
to the CRS-R.[58] The authors followed up patients at discharge, after 3 months, and after 6 months,
with the Glasgow Outcome Scale score, grouping them into favorable and unfavorable
outcome according to their consciousness recovery (unfavorable: remaining in VS/UWS
or death). Out of 24 patients classified as unconscious (coma, VS/UWS) by the CRS-R
(best score out of three assessments), 18 (75%) showed signs of residual cognition
with MBT-r. Also, 66.7% of patients showing residual cognition by the MBT-r had a
favorable outcome. Thus, MBT-r could be a useful clinical tool to detect signs of
residual cognition (subtle motor behavior) underestimated by the CRS-R, and predict
recovery in acute DoC patients.
Table 2
The Motor Behavioral Tool-revised (MBT-r) items[58]
[59]
|
The Motor Behavioral Tool-revised (MBT-r) items
|
|
Positive signs
|
Spontaneous nonreflexive movements
|
|
Response to command
|
|
Visual fixation or visual pursuit
|
|
Responses in a motivational context
|
|
Defensive nonreflexive response to a noxious stimulation: nipple
|
|
Defensive nonreflexive response to a noxious stimulation: nail bed
|
|
Response to a noxious stimulation: grimace
|
|
Negative signs
|
Abnormal motor or neurovegetative responses to stimulation
|
|
Signs of roving eyes or absence of oculocephalic reflex
|
Note: MBT-r consists of seven positive signs and two negative signs to assess patients
with DoC for subtle motor behaviors and residual cognition.
This tool was also used in a study of 140 patients (TBI and non-TBI), where the patients
were grouped into DoC (coma, VS/UWS, and MCS), non-DoC (patients who were able to
interact adequately), and potential clinical CMD (patients who have residual cognition
according to MBT-r assessment).[59] The latter group showed a strong improvement trajectory of functional/cognitive
recovery from admission to discharge, where outcomes were measured by GOS and other
outcome scales (e.g., Disability Rating Scale).[59] Collectively, these results emphasize that the combination of MBT-r and CRS-R in
DoC patients could help detect covert consciousness in a substantial fraction of patients.
Leg Crossing
Crossing legs is considered an automatic motor response in the CRS-R, one of the eleven
signs that denotes MCS − . In one study, 34 patients with severe stroke who crossed
their legs during their hospitalization (“crossers”) were matched with 34 severe stroke
patients who did not cross their legs (“non-crossers”).[60] Patients were evaluated at admission, upon discharge, and 1 year after discharge,
with GCS, NIH Stroke Scale (NIHSS), modified Rankin scale (mRS), and Barthel Index
(BI). No significant differences were observed between the two groups at the time
of admission, but upon discharge NIHSS and mRS were lower and BI was higher for crossers,
indicating less severe neurologic deficits, less disability, and higher functional
independence, respectively. After 1-year follow-up, these differences were even larger.
Also, mortality was significantly lower in the “crossers” group. Leg crossing within
the first 15 days after severe stroke favored better outcome in patients, and could
be used as a prognostic tool. It is a sign that any healthcare provider could easily
assess and needs further attention and validation by larger studies. This behavior
has not been assessed in patients with DoC, but further attention is warranted in
clinical practice, and further studies should assess the validity of this sign in
patients with DoC.
Discussion
In this review, we summarized recent findings regarding newly proposed behaviors denoting
consciousness in patients with DoC, which could help improve the accuracy of detecting
and predicting recovery of consciousness. A summary of the findings is presented in
[Table 1]. While they may not all reliably reflect the presence of conscious processing, the
use of these behaviors can be justified based on their safe and affordable evaluation.
We therefore advocate a careful observation of these new behavioral signs (resistance
to eye opening, spontaneous eye blink rate, auditory localization, habituation to
auditory startle reflex, olfactory sniffing, swallowing/oral feeding, facial expressions
to noxious stimulation, subtle motor behavior, and leg crossing) among DoC patients
when clinically appropriate ([Fig. 2]). Raising awareness about these behaviors among caregivers, families, and all the
responsible healthcare personnel might drive the development of validation studies
and encourage a thorough multimodal assessment of patients presenting these clinical
signs.
Beyond repeated assessments with CRS-R, we encourage the use of additional standardized
tools in patients with DoC to test specific functions, such as the MBT-r or the SWADOC
(SWallowing Assessment in Disorders of Consciousness—a standardized swallowing tool
under validation[61]). However, we acknowledge the challenges of time management when assessing patients
in ICU settings. In this context, a new validated scale (SECONDs) has been developed
to provide a faster and more practical tool to administer than the CRS-R in time-constrained
clinical settings.[23]
[24] We also encourage continuous observation and reporting by healthcare personnel of
other spontaneous motor behaviors such as tube pulling, nose scratching, and grabbing
sheets. As more potential new behaviors of consciousness emerge from these observations,
we recommend evaluating these behaviors in future studies in three ways: by comparing
these behaviors between different states of consciousness (VS/UWS, MCS, MCS*, CMD,
eMCS), by correlating each behavior with long-term outcome measures, and finally supporting
these studies with neuroimaging techniques ([Fig. 3]).
Despite established criteria for the diagnosis of MCS in standardized behavioral assessments,
some of the items in the CRS-R denoting MCS are still controversial, such as visual
fixation. In a study comparing the cerebral metabolism of five patients with chronic
anoxic VS/UWS (therefore without visual fixation) with five patients with chronic
anoxic MCS in whom the only sign of consciousness was visual fixation, no significant
difference was found in cortical metabolism or cortico-cortical connectivity between
the two groups.[62] Although this study used a small sample size limited to anoxic brain injury, it
stresses the need to further validate some of the controversial signs of consciousness,
such as visual fixation, with multimodal neuroimaging studies and larger sample sizes
to elucidate the neural mechanisms supporting behavior and relate it to conscious
processing.
Recent studies, beyond the scope of this article, suggest that electrophysiological
findings,[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73] neuroimaging findings,[16]
[43]
[74] pupil responses,[75]
[76] and autonomic nervous system correlates[77]
[78] might also reflect the level of consciousness in patients with DoC. Thus, we emphasize
the need to further investigate and validate these parameters within the framework
of a multimodal assessment (behavioral and neuroimaging) in DoC patients. There have
been studies also suggesting that using salient stimuli, assessing behaviors within
a context relevant to the patients, or performing individually tailored motivational
assessments might further enhance arousal and patient participation when diagnosing
patients with DoC.[59]
[79]
[80]
[81]
[82]
[83]
[84] Thus, we encourage further validation studies about the effects of implementing
emotional context and salient stimuli in the assessment of DoC patients.
Regarding the diagnosis of DoC patients, some of the recommendations by the 2020 European
Academy of Neurology guideline[27] are as follows: (1) passively opening patients' eyes who have no spontaneous or
stimulation-triggered eye opening, and assess for both horizontal and vertical eye
movements (patients with locked-in syndrome have preserved vertical eye movements)
(strong recommendation); (2) using a mirror for visual pursuit, and if not elicited
by a mirror, the use of pictures showing the patient's or relatives' faces or personal
objects (strong recommendation); and (3) using repeated CRS-R (at least five times)
assessments in the subacute–chronic setting and the Full Outline of UnResponsiveness
scale in the acute setting instead of the GCS (strong recommendation). Also, the need
for multicenter collaborations is highly stressed in this guideline, as well as the
need for more studies investigating resistance to eye opening,[35] pupillary dilation assessment following mental arithmetic with automated pupillometry,[75]
[85] quantitative assessment of visual tracking,[86]
[87] standardized rating of spontaneous motor behavior,[58] the possibility of oral feeding,[53] evidence of circadian rhythms,[88] vegetative responses to salient stimuli,[89] and modulations of cardiac cycle (heart rate, heart rate variability, cardiac cycle
phase shifts).[69]
[70]
The diagnostic assessment of DoC patients is associated with major clinical and ethical
implications. Feasible solutions to improve diagnostic accuracy are urgently needed
in clinical practice, which should be addressed in a multidisciplinary approach. Further
formal validation studies for the proposed new behavioral signs of consciousness summarized
in this article are needed for implementation in clinical practice, although we acknowledge
the challenge of lacking a gold standard reference for consciousness. Currently, very
few specialized centers perform an up-to-date multimodal assessment of these patients.
As a result, there is a distinct gap between scientific research and clinical practice.
We encourage ICU and rehabilitation healthcare workers to collaborate with translational
research teams worldwide and adopt a multidisciplinary approach in their assessment
of patients with DoC, which may help bridge the gap between research and clinical
practice in this field.
