Assessment of the Potential of Modern Diagnostic Tools in Differentiation of Minimum Conscious State from the Vegetative State

Abstract

Background

The problem of treatment of patients in coma and persistent disturbances of consciousness is difficult and often neglected.

Purpose

The study validated the effectiveness of functional magnetic resonance imaging, electroencephalography and isotopic brain perfusion in differentiating vegetative state from minimal conscious state.

Methods

The study was performed in a group of 61 patients with persistent disturbances of consciousness. All patients underwent CRS-R differentiation of consciousness and functional magnetic resonance imaging, EEG, and SPECT/CT studies according to a uniform diagnostic protocol.

Results

Analysis has shown that functional magnetic resonance imaging is an effective tool for detecting of consciousness. Analysis of the EEG showed that the occurrence of primary alpha rhythm in patients with impaired consciousness coincides with the state of minimal conscious and may indicate a favourable prognosis. Sector analysis of isotopic cerebral perfusion allowed to put forward the thesis that the key role in the maintenance of consciousness plays a medial part of the left parietal lobe.

Conclusion

On the basis of these results, diagnostic protocol was developed for patients with disturbances of consciousness.

Keywords

Diagnostic tool minimally conscious state fMRI EEG SPECT/CT

Introduction

The problem of treating patients with persistent disturbances of consciousness is a difficult and neglected topic. Continually growing development of emergency medicine and intensive care significantly increased the number of survivors so-called acute cerebral incident.

Paradoxically, along with the increase in the effectiveness of life saving therapies. the number of people with chronic consciousness disorders increases. Unfortunately. the increase in incidence does not go hand in hand with more interest in the subject of coma. Following the fate of patients with persistent disturbances of consciousness, a clear lack of comprehensive treatment and care of these patients is noticed. For effective treatment of patients with major consciousness disorders, it is important to distinguish potentially reversible from irreversible disturbances of consciousness. This fact is particularly important due to the limited number of centres specialising in the comprehensive treatment of these patients and the frequent discontinuation of treatment of patients with reversible consciousness disorders.

At present, the only tool dedicated to differentiating the vegetative state from the state of minimal consciousness is the Coma Recovery Scale-Revised (CRS-R). Unfortunately, this scale is characterised by low diagnostic sensitivity. It is estimated that as many as 40% of patients with diagnosed vegetative state are aware of reality. For this reason, an attempt was made to develop an objective and effective method of diagnosis of patients enabling verification of the diagnosis. The aim of the study is to validate the effectiveness of methods: functional magnetic resonance, electroencephalography and isotopic analysis of cerebral perfusion in differentiating the vegetative state from the minimal consciousness state.

Methods

Data Availability Statement

The study has been conducted at the Department of Neurology and Neurosurgery, Faculty of Medicine, University of Warmia and Mazury in Olsztyn, Poland and the University Clinical Hospital in Olsztyn, Poland. The study was approved by the Bioethical Committee of the Faculty of Medicine, University of Warmia and Mazury in Olsztyn, Poland (2013–2017) (ethical approval No. 7/2013, and No. 46/2013). The study was carried out in accordance with the provisions of the Declaration of Helsinki. The analysis involved 61 patients diagnosed because of persistent disturbances of consciousness. The study group consisted of 39 (63.93%) men and 22 (36.06%) women. The average age of men was 33.8 years and women 30.36 years.

The group of patients was very diverse in terms of the duration of disturbances of consciousness. In the study group were patients with disorders of consciousness from 2 months to 14 years. The standard deviations of the duration of consciousness disturbances in the studied population was 40.05 ± 44.00 months (Table 1).

Table 1.

Age and Duration of Disturbances of Consciousness.

	General (N = 60)	Sex		P
	General (N = 60)	M (n = 38)	W (n = 22)	P
Age (mean ± SD)	32.57 ± 12.77	33.84 ± 10.87	30.36 ± 15.54	.080
Time from injury (mean ± SD)	40.05 ± 44.00	37.51 ± 40.52	44.55 ± 50.28	.735

Due to the generally accepted data in the literature on the more favourable prognosis of patients with central nervous system injuries and the need to maintain a 12-month period to meet the criterion of permanent vegetative state, the patients were divided into a group in which the cause of consciousness disorders is an injury and a group in which another was found the cause of disturbing consciousness. The non-traumatic causes of disturbances of consciousness included:

cardiac arrest

hypoxia

ischemic stroke

haemorrhagic stroke

subarachnoid haemorrhage

poisoning

electric shock.

Among the 61 patients examined, 34 (55.74%) representing the group to which the cause of disturbance of consciousness were completed head injuries, and 27 (44.26%) were group atraumatic. All patients were rated according to a uniform research protocol that included neurological examination, evaluation specialist in internal medicine and cardiology, evaluation anaesthetist, ENT assessment, physician assessment of rehabilitation and speech therapy and psychological testing. These studies were supplemented by:

assessment of the state of consciousness according to the CRS-R scale;

study of regional cerebral blood flow (rCBF) using 99mTc HMPAO - SPECT-CT;

functional magnetic resonance imaging – fMRI.

Evaluation of the state of consciousness using the scale CRS – R

The CRS-R scale was selected for the assessment of patients. The scale, according to the current literature, best reflects the clinical condition, is currently the most recommended scale for differentiating the states of consciousness and monitoring the progress of treatment.¹ For the purpose of the study (due to the lack of a Polish edition), the English-language CRS-R scale form was used. Assessment of the patient on the CRS-R scale became the basis for making the diagnosis and at the same time a reference point for comparing the effectiveness of other research methods. Due to the differences in the prognosis and clinical picture highlighted in the literature, the existing medical records were analysed to separate patients with traumatic and an atraumatic cause of consciousness disorders.^{2, 3} All 61 subjects were evaluated according to the CSR-R scale in order to recognise the vegetative state or the state of minimal consciousness and in terms of the point value of this assessment.⁴

As criteria for diagnosing the vegetative state in the CRS-R point scale, all values were accepted:

in the assessment of the auditory response ≤2

in the assessment of the visual response ≤1

in the assessment of motor response ≤2

in the assessment of verbal skills ≤2

in the assessment of communication ability = 0

level of arousal ≤2.

As the criteria for recognising the state of minimum consciousness in the CRS-R point scale. at least one of the following values was accepted:

in the assessment of the auditory response = 3–4

in the assessment of the visual response = 2–5

in the assessment of motor response = 3–5

in the assessment of verbal abilities = 3

in the assessment of communication ability = 1.

In 36 patients, the vegetative state was diagnosed, which constituted 59.02% of the studied population, and the level of consciousness was diagnosed by 25 patients, which constituted 40.98% of the studied population (Table 2).

Table 2.

The Results of fMRI Positive Tests Depending on the Diagnosis Based on the CRS-R Scale.

	In all	Diagnosis		p
	In all	VS	MCS	p
negative fMRI (%)	14/61 (22.95%)	14/36 (38.89%)	0/25 (0.00%)	.000
positive fMRI (%)	36/61 (59.02%)	17/36 (47.22%)	19/25 (76.00%)	.047
nonodiagniostic (%)	11/61 (18.03%)	5/36 (13.89%)	6/25 (24.00%)	.502
In all	61/61 (100.00%)	36/61 (59.02%)	25/61 (40.98%)

The standard deviation of the number of points on the CRS-R total was 8.51 ± 2.26. The standard deviation of the scores in patients diagnosed with a vegetative state was 7.14 ± 1.50 and the standard bending of the patients with a minimum consciousness (MCS) level was 10.48 ± 1.61. confirming the significant difference in the average CRS-R score in depending on the diagnosis.

At the same time, it was found that in the subjects in the vegetative state the score ranged from 3 to 9 points. On the other hand, in subjects in the State of minimal consciousness, the score ranged from 9 to 13 points. Thus, it is possible to distinguish a group of patients VS and MCS that obtain the same point value.

Methodology of fMRI Examination

fMRI studies were performed on a 3T MRI scanner for Trio Magnetos (Siemens. Germany); using the fMRI stimulation system (NordicNeuroLab) and software (NordicAktiva by NNL). The stimulation system consisted of visual stimulation goggles equipped with an eye tracker and audio stimulation kit. All tests were carried out according to a uniform test protocol with constant physical parameters and the same stimulation paradigm.

The fMRI study was divided into two stages. In the first stage, standard protocols of visual stimulation were performed by displaying chessboard points moving synchronously, auditory stimulation by non-synchronous stimulation with variable frequency sounds and motor-sensory stimulation by moving the patient’s foot or hand by a person from outside. This phase of the study aimed to assess the behaviour of the efferent pathway from the receptor to the cerebral cortex and to assess the overall brain cortex potential for activation.^{5, 6}

In the second stage of the research, a specific paradigm designed specifically for this purpose was designed to differentiate the vegetative state from the state of minimal consciousness. This study focused on linguistic stimulation as well as visual and auditory emotional tests. Through the system of goggles to fMRI. pictures and videos of the people closest to him were displayed to the patient and, depending on their previous interests, various scenes from his life. The pictures appeared in various configurations and juxtapositions with the faces of strangers. Attention focus was monitored by eyetracking.⁷ Through the audio stimulation set, auditory stimulation was carried out by playing back a previously recorded audio recording by the family with the name of the patient. favourite music or favourite sounds recognised by the closest to be the strongest stimulants.

Stimulation was carried out according to the protocol of stimulation block 30 seconds of stimulation, a 30-second interval following the 120 measurements.

Due to the fact that the paradigm used in the paradigm of stimulation having an almost exclusively emotional character, it was assumed that for this kind of stimulation the answer can only be conscious. Based on this thesis patients were suspected of having a state of consciousness in patients who received activation areas during stimulation. This result was compared at a later stage with the diagnosis based on the CRS-R scale.

SPECT/CT Scintigraphic Study of Regional Cerebral Flow Using 99mTc-HMPAO

The scintigraphic study of regional cerebral flow was performed after intravenous administration of 99mTc-HMPAO 480MBq (370MBq-555MBq). mean (range of activity). The SPECT/CT study was performed using a two-head gamma camera SPECT/CT Discovery NM/CT 670 pro (GE Healthcare; WI; USA). The patient was given and waiting for the examination in a darkened room, reducing the stimulation of the visual cortex. In each case, the collimation was used LEHR (Low Energy High Resolution), with a single energy peak for 99mTc of 140keV (± 15%). Images acquisition was obtained from 60 projections using a standard matrix 128 × 128. rotation of 360 25s per projection.

Reconstruction of images was made using the OSEM algorithm using 10 subsets and 4 iterations and a standard Gaussian filter, made at the post-processing station Xeleris. GE Healthcare, USA. The analysis of scintigraphic images was performed in the qualitative assessment, based on the obtained SPECT images.

The evaluation of obtained images was performed manually by a nuclear medicine doctor and then subjected to automatic analysis of parametric parametric mapping (SPM) of 26 brain regions carried out using the company’s Q.Brain software (GE Healthcare; WI; USA).

As a parameter to the further statistical analysis selected resolution Z-score, which is the indicator of the number of normalised standard deviations of regional blood flow in a subject relative to the population of the same sex and the same age (normative base).

In the automatic analysis (Q.Brain) of radiopharmaceutical uptake within the CNS of the studied patients. they were compared to the normative value of the database. Quantitative assessment of rCBF in the scintigraphic study was presented using the volume of interest (VOIs), the value of the radio tag acquisition parameter in the voxel, and three-dimensional stereotaxic projection maps. Analysis of the scintigraphic image obtained was carried out by standardising the individual shape of the brain of the examined patient based on the CT (SPECT/CT) examination to the standard atlas, while maintaining full information obtained from the SPECT study.

The results of the Z-score distribution were analysed in combination with the diagnosis based on the CRS-R scale and after verification of the diagnosis based on fMRI. Then, the distribution of Z-score was analysed depending on the cause of the disturbance of consciousness.

The results of the distribution of the Z-score distribution were analysed in combination with the diagnosis based on the CRS-R scale and verification of the diagnosis based on fMRI. Then, the distribution of Z-score was analysed depending on the cause of the disturbance of consciousness.

EEG Research Methodology

The EEG test has been used in the diagnosis of the central nervous system since 1875. Admittedly, the first report of the recording of the brain’s electrical activity belongs to the English scientist Richard Caton.

Despite the development of numerous neuroimaging techniques, EEG still plays an important role in the diagnosis of the central nervous system. The most important advantage of this test is the fact that it can be repeatedly performed directly at the patient’s bedside. It also enables long-term monitoring of brain functions while maintaining the patient’s comfort.

Electroencephalographic studies in patients with impaired consciousness were carried out in the EEG laboratory and in the Department of Neurosurgery. The recording was carried out on a 16-channel computer apparatus Digi Track of the Polish brand Elmiko. The mobile registration station allowed for the examination to be carried out outside the laboratory. Cup electrodes and an electrolyte gel were used for recording. The electrodes were placed in the 10/20 system. Registration was conducted for at least 20 minutes.

In accordance with the test protocol, photostimulation with strobe flashes of white light with frequencies ranging from 1 to 32 Hz was also performed. The tests were recorded by certified technicians and described by an electroencephalographer certified by the Polish Society of Clinical Neurophysiology. The leading basic rhythm obtained was analysed in each of the studied patients in the EEG study, which was the basis for the classification of patients into appropriate groups and for further comparison with other modalities.

Data Analysis

Statistical analysis was done using several tests. All the values in this study were expressed as a mean ± standard deviation (SD). Differences within and between groups were assessed by applying one-way ANOVA or t-Student’s test. Differences were also assessed by Mann-Whitney U test.

Results

fMRI Results

MRI examination in patients with impaired consciousness is difficult and time-consuming. This study requires very precise application of a geometric map of the cerebral function on the morphological image, so that even small movements may prevent the execution of diagnostics. Important reasons for the inability to perform the test in patients with impaired consciousness there is agitation, increased reflexes as a result of increased spasticity. anxiety related to the retention of secretions in the airways, and respiratory failure during long-term horizontal position.

In the group of 61 patients, the aforementioned reasons made it impossible to carry out the study in 11 cases, which constituted 18.03% of the respondents. A fully diagnostic examination was completed in the remaining patients, which accounted for 82.92% of the study group.

In order to validate the usefulness of the fMRI study in differentiating the state of consciousness, the obtained results were compared with the diagnosis of the vegetative state or the state of minimal awareness based on the patient’s assessment in the CRS-R scale. In the fMRI study, a research paradigm designed specifically for this purpose focused exclusively on stimulation requiring conscious mating. Based on this assumption, it has been assumed that obtaining stable activation in BOLD sequences is evidence of the preservation of consciousness.

The analysis showed that none of the patients diagnosed with the state of minimal consciousness on the basis of the CRS-R scale obtained a false negative result in the fMRI study. In 76% of patients in the MCS group a positive activation result was obtained confirming the state of consciousness. while in the remaining 24% it was not possible to perform fully diagnostic examination. In the VS patients group, 38.89% of the subjects did not receive activation. However, in 13.89%, no diagnostic examination was obtained and as many as 46.22% of patients achieved stable activation that could be a sign of retained consciousness.

In order to accurately assess the effectiveness of the fMRI technique in differentiating the states of consciousness relative to the CRS-R scale, a correction of the analysis was performed comparing only the groups of patients in whom the fMRI diagnostic test was possible. Based on this analysis. it was found that in all patients who were diagnosed with the state of minimal consciousness based on the CRS-R scale, this diagnosis was confirmed in the fMRI study.

Analysing the group of patients diagnosed with vegetative state, it was found that as much as 54.84% of patients had cortical response to stimulation in fMRI, which led to the need to change the diagnosis and to the thesis that more than half of patients classified as CRS-R the vegetative one in fact shows signs of awareness.

fMRI to obtain a positive result confirming the diagnosis of MCS in 100% of patients. and no false negative results, confirms the high specificity of fMRI to detect states of consciousness.

However, the high sensitivity of the fMRI test is indirectly supported by the fact that in 54.84% of patients diagnosed with a vegetative state in CRS-R in the fMRI study, stable activation was obtained which may lead to a change in the diagnosis (Table 3).

Table 3.

List of fMRI Results with the CRS-R Scale.

	In all	Diagnosis		p
	In all	VS	MCS	p
negative fMRI (%)	14/50 (28.00%)	14/31 (45.16%)	0/19 (0.00%)	.002
positive fMRI (%)	36/50 (72.00%)	17/31 (54.84%)	19/19 (100.00%)	.002
In all	50/50 (100.00%)	31/50 (62.00%)	19/50 (38.00%)

These data clearly demonstrate that fMRI is a very useful tool for detecting consciousness. While maintaining the appropriate stimulation paradigm, fMRI is the solution to the problem of low-sensitivity CRS-R and should be included in the standard diagnostic package of patients with consciousness disorders.

EEG Test Results

Resting EEG recording was performed in all 61 patients. Despite the difficulties encountered during the examination, often resulting from bone defects after craniotomy, and the heterogeneous record of the cerebral cortex damaged many places, a diagnostic EEG was obtained in all patients. The EEG was analysed to establish the leading basal rhythm. Basal alpha was achieved in 37.7%, beta in 34.43% and theta in 26.23% of patients. The delta rhythm was encountered in only one patient of the study group. In order to assess the usefulness of the resting EEG in differentiating states of consciousness, the distribution of basic rhythms in groups of patients diagnosed with the vegetative state and minimal state of consciousness based on the CRS-R scale and the diagnosis based on fMRI was analysed.

Analysing the data of the group of patients diagnosed on the basis of the CRS-R scale, it was found that basic alpha activity, that is, activities within the frequency range from 8 to 13 Hz, occurred in 64% of cases, together with the diagnosis of minimal consciousness. However, only 19.44% of patients in a vegetative state had an alpha rhythm.

Basic activity beta is a desynchronised rhythm with low amplitude and frequencies from 12 to 28 Hz, it occurred in as many as 47.22% of patients in a vegetative state, and only in 16% of patients in the state of minimal consciousness. The above results are presented in Table 4.

Table 4.

Occurrence of Particular Types of EEG Activity.

Rhythm

Type of diagnosis

Diagnosis of CRS-R

Diagnosis of fMRI

the cause of consciousness disorders

Total

diagnosis

Total

Diagnosis

Total

cause

MCS

negative

positive

trauma

no trauma

Rhythm alfa

23/61 (37.7%)

7/36 (19.44%)

16/25 (64%)

.000

18/50 (36.00%)

2/14 (14.29%)

16/36 (44.44%)

.048

23/61 (37.7%)

17/34 (50.00%)

6/27 (22.22%)

.028

Rhythm beta

21/61 (34.43%)

17/36 (47.22%)

4/25 (16%)

.013

19/50 (38.00%)

10/14 (71.43%)

9/36 (25.00%)

.003

21/61 (34.43%)

6/34 (17.65%)

15/27 (55.56%)

.002

Rhythm theta

16/61 (26.23%)

11/36 (30.56%)

5/25 (20%)

.361

12/50 (24.00%)

2/14 (14.29%)

10/36 (27.78%)

.526

16/61 (26.23%)

10/34 (29.41%)

6/27 (22.22%)

.530

Rhythm delta

1/61 (1.64%)

1/36 (2.78%)

0/25 (0.00%)

.853

1/50 (2.00%)

0/14 (0,00%)

1/36 (2.78%)

.621

1/61 (1.64%)

1/34 (2.94%)

0/27 (0.00%)

.907

Total

61/61 (100%)

36/61 (59.02%)

25/61 (40.98%)

50/50 (100%)

14/50 (28.00%)

36/50 (72.00%)

61/61 (100%)

34/61 (55.74%)

27/61 (44.26%)

Based on the results, there is a statistically significant correlation between the occurrence of the alpha rhythm with the state of minimal consciousness and the beta rhythm with the vegetative state. Comparing the occurrence of the leading EEG rhythms with the diagnosis made in the fMRI study, as many as 71.43% of patients in a vegetative state achieved basic beta activity, and only 14.29% achieved alpha activity. In a state of minimal consciousness, 44.44% of patients had the primary activity of the afla rhythm and 25% of the patients had beta rhythm. The occurrence of leading rhythms depending on the diagnosis made on the basis of fMRI is presented in Table 4.

These comparisons clearly show the coexistence of basic beta activity with the vegetative state, and alpha activity with the state of minimal consciousness. An analysis of the coexistence of the underlying EEG function was also performed depending on the cause of the disturbed consciousness. This comparison showed that alpha activity occurs in patients with craniocerebral trauma in 50% of respondents, and beta activity only in 17.65%. In contrast, in patients with non-traumatic causes of consciousness disorders, beta activity was present in 55.56%, and alpha activity in 22.22% (Table 4).

The analysis of theta rhythm, both in the differentiation of states of consciousness and in the analysis of the causes of consciousness disorders, gives a statistically questionable result, without giving a clear answer. Due to the small group, the occurrence of the delta rhythm could not be statistically analysed.

The obtained results clearly indicate that basic beta activity is a negative prognostic factor in the diagnosis of patients with disturbed consciousness. The beta rhythm is characterised by coexistence with the vegetative state and another negative prognostic factor, which is the non-traumatic cause of consciousness disorders. The alpha activity, on the other hand, is a factor with a relatively good prognosis, showing coexistence with the state of minimal consciousness and a prognostic positive factor, which is the traumatic cause of consciousness disorders.

The study of basic EEG rhythms has thus confirmed its usefulness in diagnosing patients with impaired consciousness. However, despite the enormous advantages of EEG, which is universal availability and the possibility of performing at the patient’s bedside, it must not be forgotten that due to the low sensitivity and limited specificity of the test, it cannot be used as the only tool confirming the diagnosis. This examination should be treated as a diagnostic tool that can be performed at the bedside, and should be included in the standard diagnostic protocol of consciousness disorders as a complementary tool.

SPECT/CT Results

The scintigraphic study of regional cerebral blood flow using 99mTc-HMPAO is a study that has been well-established for many years in diagnosing central nervous system dysfunctions. It is a test that allows comprehensive and reproducible assessment of the brain with no restrictions typical of magnetic resonance imaging (such as movement artifacts). The study analysed the flow value determined by the Z-score index and compared the averaged values with the diagnosis of the vegetative state or the state of minimum consciousness based on the CRS-R scale. The standard deviation of Z-scores in the general group was –3.26 (± 5.12). The standard deviation of Z-score values in patients diagnosed with vegetative condition based on the CRS-R scale was –3.79 (± 5.24), and in patients in the State of minimal consciousness –2.5 (± 5.12) (Table 5).

Table 5.

Distribution of the Z-score Distribution in the Study Population and Diagnosis Based on the CRS-R Scale.

	In all (n = 854)	Diagnosis		p
		VS (n = 504)	MCS (n = 350)
Z score	–3.26 ± 5.12	–3.79 ± 5.24	–2.50 ± 5.12	.000

The averaged distribution of Z-score clearly indicates differences in global cerebral perfusion, with a significant decrease in its value in the vegetative state in relation to the state of minimal consciousness.

Analysis of the examined group showed that none of the patients diagnosed with vegetative condition on the basis of the CRS-R scale did not reach the Z-score above –2.2, and none of the patients in the State of minimal consciousness scored Z-score below –2.42. These data may indicate that the average Z-score above –2.2 is an indicator of minimum consciousness. while values below –2.42 may indicate a vegetative state. In the –2.42 range –2.20 the test result should be considered doubtful.

Then, the value of the Z-score distribution was analysed in patients with a diagnosis of the minimum level of consciousness confirmed by a positive result of the fMRI study. The standard deviation of Z-score in the group of patients in which both the CRS-R and fMRI scale confirmed the state of consciousness was –1.94 (± 3.97). Standard deviation Z-score in patients who changed their diagnosis from a vegetative state diagnosed on the basis of the CRS-R scale to the state of minimal awareness based on the obtained activation in fMRI was –2.86 (± 5.15). With these values Z-score should be sought for patients in whom the CRS-R scale may give a false negative result.

Assuming correction of diagnosis based on fMRI in none of the patients with the diagnosis of vegetative state. no Z-score was found above –3.9. while in patients diagnosed with minimal consciousness below –3.5. The difference in Z-score is clearly visible for the group in which the diagnosis was changed.

On this basis, it can be concluded that the fMRI study shows excellent sensitivity in detecting states of consciousness. and SPECT/CT after standardisation is extremely useful in differentiating VS and MCS. In order to further validate the CRS-R scale. A comparison of the distribution of the Z-score index value was performed. depending on the obtained score. Standard deviations of the Z-score values for the respective point values were tested. The results are presented in Figure 1. The obtained data indicate that despite the increase in Z-score. with the increase in CRS-R scores. these results are characterised by high variability and the point value is only applicable to monitoring the progress of treatment. It is not possible to determine the point value of the differentiating VS and MCS.

Figure 1.

Z-score Depending on fMRI and CRS-R Diagnosis.

Another analysis was made to examine the value of the Z-score indicator depending on the cause of the disturbance of consciousness. The standard deviation of global cerebral perfusion in patients after CNS injury was –3.15 (± 5.42). and in the group of patients with non-traumatic cause of disturbances of consciousness the level of global cerebral perfusion was –3.4 (± 4.73) (Table 6).

Table 6.

Value of Z-score Depending on the Cause of the Disturbance of Consciousness.

	In all (n = 854)	Cause		p
		Injury (n = 476)	No injury (n = 378)
Z score	–3,26 ± 5,12	–3,15 ± 5,42	–3,40 ± 4,73	.055

Sector Analysis of Cerebral Perfusion

SPECT perfusion examination as one of the few modalities allows detailed analysis of the brain regions. Using the SPS automatic analysis system using the Q.Brain software. the distribution of averaged Z-score values of brain regions in the whole group of patients with consciousness disorders was assessed. The aim was to search for areas responsible for the occurrence of these disorders. As a result of the analysis. it was found that the largest decrease in perfusion concerned the frontal lobes, and the standard deviation Z-score for these areas was –6.64 (± 5.54). For the other analysed areas, successively: gyrus cinguli –2.06 (± 3.43), parietal lobes –2.96 (± 4.87), precuneus 0.5 (± 3.43), occiputs 0.9 (± 1.6), temporal lobes –3.64 (± 2.12).

The highest decrease in perfusion was observed in the area of the frontal lobes, and especially their peripheral parts. This proves the fact that this is the area most sensitive to damage. Regardless of the diagnosis of VS or MSC, the reduction of perfusion values in the frontal lobes did not show statistically significant differences. On this basis. it should be concluded that the frontal lobes do not play a leading role in maintaining consciousness (Table 7).

Table 7.

Perfusion Z-score in the Sectoral Analysis.

Location	In all (n = 854)	Location				p
Location	In all (n = 854)	Cingulate (n = 244)	Parietal (n = 244)	Precuneus (n = 122)	Frontal (n = 244)	p
Z score	–3.26 ± 5.12	–2.06 ± 3.43	–2.96 ± 4.87	0.50 ± 3.43	–6.64 ± 5.54	.000

In order to confirm this assertion was carried out further examination of the brain in order to seek a sector gap Z-score based on the diagnosis VS and MCS posed by scale CRS-R. As a result of the analysis. the differences of the highest statistical significance were found in the area of: left gyrus cingula, left precuneus, the lower part of the left parietal lobe, right gyrus cingula, upper part of the left parietal lobe, right precuneus (Table 8).

Table 8.

List of Z-score Values with the Location of the Examined Part of the Brain and Diagnosis of CRS-R and Values of Z-score of the Location of the Test Piece and the Diagnosis of Brain Fmri.

Place of measurement	In all	Diagnosis		p
Place of measurement	In all	VS	MCS	p
G - Anterior Cingulate L-Z score	–3,22 ± 2,78 (n = 61)	–3,34 ± 3,04 (n = 36)	–3,04 ± 2,41 (n = 25)	0,613
G - Parietal Superior R - Z score	–1,46 ± 2,58 (n = 61)	–1,4 ± 2,53 (n = 36)	–1,56 ± 2,69 (n = 25)	0,997
G - Anterior Cingulate R - Z score	–2,9 ± 3,2 (n = 61)	–2,91 ± 3,68 (n = 36)	–2,88 ± 2,42 (n = 25)	0,889
G - Parietal Inferior L - Z score	–4,28 ± 6,02 (n = 61)	–5,96 ± 6,34 (n = 36)	–1,88 ± 4,66 (n = 25)	0,006
G - Parietal Inferior R - Z score	–4,36 ± 6,05 (n = 61)	–4,23 ± 4,68 (n = 36)	–4,55 ± 7,71 (n = 25)	0,420
G - Parietal Superior L - Z score	–1,74 ± 2,98 (n = 61)	–2,52 ± 3,23 (n = 36)	–0,61 ± 2,17 (n = 25)	0,011
G - Posterior Cingulate L - Z score	–1,33 ± 3,48 (n = 61)	–2,54 ± 3,49 (n = 36)	0,42 ± 2,68 (n = 25)	0,000
G - Posterior Cingulate R - Z score	–0,78 ± 3,64 (n = 61)	–1,69 ± 3,97 (n = 36)	0,52 ± 2,68 (n = 25)	0,007
G - Precuneus L - Z score	0,02 ± 2,89 (n = 61)	–0,82 ± 3,04 (n = 36)	1,22 ± 2,2 (n = 25)	0,005
G - Precuneus R - Z score	0,98 ± 3,86 (n = 61)	0,00 ± 4,47 (n = 36)	2,38 ± 2,15 (n = 25)	0,017
G - Prefrontal Lateral L - Z score	–10,37 ± 6,46 (n = 61)	–11,62 ± 7 (n = 36)	–8,57 ± 5,21 (n = 25)	0,021
G - Prefrontal Lateral P - Z score	–8,11 ± 5,44 (n = 61)	–8,03 ± 5,75 (n = 36)	–8,23 ± 5,07 (n = 25)	0,971
G - Prefrontal Medial L Z score	–3,94 ± 3,32 (n = 61)	–3,7 ± 3,54 (n = 36)	–4,3 ± 3 (n = 25)	0,709
G - Prefrontal Medial R Z score	–4,12 ± 3,43 (n = 61)	–4,3 ± 4,03 (n = 36)	–3,87 ± 2,37 (n = 25)	0,528
In all	–3,26 ± 5,12 (n = 854)	–3,79 ± 5,24 (n = 504)	–2,5 ± 4,85 (n = 350)	0,000

Place of measurement	In all	fMRI		p
Place of measurement	In all	negative fMRI	positive fMRI	p
G - Anterior Cingulate L-Z score	–2,92 ± 2,81 (n = 50)	–3,38 ± 3,65 (n = 14)	–2,74 ± 2,44 (n = 36)	0,567
G - Parietal Superior R - Z score	–1,18 ± 2,49 (n = 50)	–2,22 ± 2,5 (n = 14)	–0,78 ± 2,41 (n = 36)	0,048
G - Anterior Cingulate R - Z score	–2,53 ± 3,26 (n = 50)	–2,79 ± 4,35 (n = 14)	–2,43 ± 2,8 (n = 36)	0,531
G - Parietal Inferior L - Z score	–4,17 ± 6,21 (n = 50)	–7,79 ± 4,73 (n = 14)	–2,76 ± 6,2 (n = 36)	0,000
G - Parietal Inferior R - Z score	–3,87 ± 5,36 (n = 50)	–5,7 ± 4,95 (n = 14)	–3,16 ± 5,41 (n = 36)	0,059
G - Parietal Superior L - Z score	–1,78 ± 3,14 (n = 50)	–3,61 ± 2,18 (n = 14)	–1,07 ± 3,19 (n = 36)	0,000
G - Posterior Cingulate L - Z score	–1,22 ± 3,25 (n = 50)	–3,95 ± 4,09 (n = 14)	–0,15 ± 2,1 (n = 36)	0,001
G - Posterior Cingulate R - Z score	–0,67 ± 3,55 (n = 50)	–3,42 ± 5,24 (n = 14)	0,4 ± 1,81 (n = 36)	0,005
G - Precuneus L - Z score	–0,15 ± 2,91 (n = 50)	–1,86 ± 3,67 (n = 14)	0,52 ± 2,29 (n = 36)	0,023
G - Precuneus R - Z score	0,92 ± 4,02 (n = 50)	–1,02 ± 5,45 (n = 14)	1,67 ± 3,08 (n = 36)	0,053
G - Prefrontal Lateral L - Z score	–9,61 ± 6,43 (n = 50)	–12,26 ± 7,16 (n = 14)	–8,58 ± 5,91 (n = 36)	0,073
G - Prefrontal Lateral P - Z score	–7,06 ± 5,04 (n = 50)	–8,68 ± 5,16 (n = 14)	–6,43 ± 4,92 (n = 36)	0,248
G - Prefrontal Medial L Z score	–3,73 ± 3,52 (n = 50)	–3,58 ± 4,61 (n = 14)	–3,79 ± 3,08 (n = 36)	0,582
G - Prefrontal Medial R Z score	–4,05 ± 3,66 (n = 50)	–4,39 ± 5,17 (n = 14)	–3,92 ± 2,96 (n = 36)	0,804
In all	–3 ± 4,92 (n = 700)	–4,62 ± 5,38 (n = 196)	–2,37 ± 4,58 (n = 504)	0,000

In order to verify the analysis. another comparison was made comparing the differences between the Z-scores and the diagnosis based on fMRI. In the analysis again the most significant differences in the VS and MCS groups occurred in the area of: parietal lobe, left gyrus cingula, left precuneus, right gyrus cinguli (Table 8).

This study drew attention to the hypothetically significant importance of the left parietal lobe and left cingulate cusp in maintaining the state of consciousness. Again and in this case the difference in perfusion in the frontal lobes did not show statistically significant differences in the VS and MCS groups. which may indicate that the frontal lobes do not play a leading role in maintaining consciousness.

SPECT/CT scintigraphic study of regional cerebral flow using 99mTc-HMPAO turns out to be an extremely useful tool in diagnosing patients with consciousness disorders. The averaged Z-score value of the brain flow after proper standardisation can become an excellent tool confirming the diagnosis based on fMRI. The sector analysis of local cerebral perfusion indicates that the assessment of the degree of damage to the medial part of the left parietal lobe plays a key role in diagnosing the state of consciousness. The 99mTc-HMPAO SPECT/CT cerebral perfusion study along with fMRI should become the standard for diagnosing patients in the vegetative state and minimal consciousness state.

Discussion

A study conducted in 1996 by Payne and his coworkers on the attitude of American doctors to patients in a state of minimal consciousness showed that⁸: 13% of doctors said that patients diagnosed with a persistent vegetative state (PVS) are conscious and experience hunger and thirst. Thirty per cent thought that patients with PVS felt pain. Eighty-nine per cent said it was ethically permissible to withdraw the feeding and rehydration of the sick. Ninety-one per cent of respondents said that it was acceptable not to undertake the treatment of respiratory disorders, cardiovascular disorders and acute renal failure. Sixty-six per cent of respondents claimed that organs should be taken for transplantation from patients in persistent vegetative state.⁸

Approaching critically this type of stimulation, a new fMRI diagnostic protocol was developed for the purpose of the study. This protocol is designed to stimulate the cerebral cortex response by a stimulation with simple emotional stimuli that do not require complex stimulus analysis. The use of images and the voice of the loved ones, clearly saying the patient’s name, was adopted as the strongest stimulus that can be used. In order to compare this method with the CRS-R scale, it was necessary to adopt a certain simplification in that obtaining areas of stable fMRI activation indicates awareness and qualifies patients for the MCS group.

Our own material confirms that over 40% (according to Giacino’s theorem^{4, 9}), and exactly 54.84% of patients with a diagnosed vegetative state on the CRS-R scale, in fact show reactivity that supports a certain degree of consciousness.

Obtaining a positive fMRI result confirming the diagnosis of MCS in 100% of the subjects, and lack of false negative results, confirms a high specificity of the fMRI examination in detecting states of consciousness.

However, the high sensitivity of the fMRI examination is indirectly evidenced by the fact that in 54.84% of patients diagnosed with a vegetative state in CRS-R, in the fMRI study there was a stable activation obtained, which may lead to a change in the diagnosis. To date, it has been estimated that the sensitivity of fMRI in detecting states of consciousness is 44% and the specificity is 59%.¹⁰ However, it should be taken into account that these differences may be due to the differences in the stimulation paradigm. The number of non-diagnostic fMRI tests has also a significant impact on the obtained results. In the world literature, only one article mentions the difficulties that may occur during MRI examination. Despite the diagnostic difficulties described, the fMRI was obtained in 70 out of 72 subjects, which constituted 97% of the diagnosed population.¹⁰ In own material, 17.08% of patients could not have been tested due to motor artifacts. These differences may result from the diversity of the studied population, or from methodological differences not described in the article.

In the world literature, the CRS-R scale is always treated as the gold standard in differentiating the vegetative state and the state of minimal consciousness. Other proposed diagnostic methods such as fMRI, EEG, SPECT/CT, PET are validated against each other. Assuming high sensitivity and specificity of the fMRI test, the validation of the CRS-R scale against fMRI seems to be an interesting suggestion.

Despite various research assumptions and a different group of patients, the author’s own results show some data that could indicate the usefulness of EEG in diagnosing patients with consciousness disorders. Analysing the data of a group of patients, who were diagnosed according to the CRS-R scale, it was found that the reactive basic alpha function occurred in 64% of cases together with the diagnosis of a state of minimal consciousness. In the group of patients in the vegetative state, alpha occurred only in 19.44% of patients. Beta rhythm in the examined group occurred in 47.22% of patients in a vegetative state and only in 16% of patients in a state of minimal consciousness. Comparing the leading EEG rhythms with the diagnosis made in the fMRI study, 71.43% of patients in the vegetative state achieved basal beta function and only 14.29% alpha. In minimal consciousness, 44.44% of patients exhibited a baseline alpha rhythm and 25% of patients had a beta rhythm. The fact that alpha coexists with a traumatic cause of the consciousness disorder and is a favourable prognostic factor in patients with disturbed consciousness may indicate a favourable prognosis in patients with a reactive alpha rhythm.¹¹

When analysing the results, one should be aware of the multitude of EEG recordings, the variability of the record over time, and numerous reports of uncertain usefulness in drawing conclusions about patients with impaired consciousness. Despite widespread scepticism regarding resting EEG in coma, there are reasons to use electroencephalography as a complementary study in differentiating states of minimal consciousness. It should also be expected that a clear change in the perception of the EEG examination in the diagnosis of consciousness disorders may be brought by the analysis of a functional EEG performed simultaneously with the fMRI examination.¹²

Scintigraphic examination of the regional cerebral flow using 99mTc-HMPAO has been widely used in the diagnostics of the central nervous system for many years.^13–15 Unfortunately, it has been systematically supplanted by the functional FDG-PET examination for several years now.^{10, 16} However, one cannot underestimate the fact that SPEC-CT is definitely cheaper and more available in our country. Because of the cost, it is impossible to use PET for screening diagnostics of consciousness disorders. The 99mTc-HMPAO SPECT-CT study, despite the low spatial resolution, is a complementary study to MRI techniques and brings data of an inestimable value.^{13, 17, 18}

Analysing the world literature, there is observed an increasing interest in research in which the main goal is to find prognostic factors for the disappearance of consciousness disorders. Unfortunately, only isolated studies focusing on the use of nuclear medicine in differentiating states of consciousness can be found.¹⁰ Only one report can be found in the literature on the use of isotope techniques in the search for areas responsible for consciousness.¹⁰

Similar analyses were also made in the own material in accordance with the global trends. As expected, the study confirmed a statistically significant difference in the reduction of global cerebral perfusion in vegetative patients compared to patients in the state of minimal consciousness. As expected, a similar relationship could be found by analysing the cause of consciousness disorders finding a lower decrease in perfusion in patients after injuries of the central nervous system.

A sectoral analysis of a decrease in cerebral perfusion proved that the largest decrease in perfusion concerned frontal lobes. Based on this diagnosis, some authors have argued that the causes of disturbed consciousness should be seen in particular in the frontal lobes.

However, the latest FDG-PET research has challenged this hypothesis by seeing the causes of consciousness disorders not only in the frontal lobes but also in the parietal lobes and especially the precuneus.¹⁰

A detailed analysis of own material showed that the decrease in perfusion in the frontal lobes statistically did not affect the recording of consciousness. However, the obtained data indicate a significant relationship between VS and MCS groups regards the perfusion in the parietal lobes and the gyrus of the left hemisphere.

Conclusion

Based on the results obtained, it should be concluded that the functional magnetic resonance technique is a great tool for detecting even minimal states of consciousness. Despite the technical difficulties encountered with the optimally refined diagnostic paradigm, this technique definitely exceeds the tools recommended so far. It is also necessary to re-evaluate the CRS-R scale on a larger group of patients regarding the fMRI technique as the gold standard in detecting minimal consciousness states.

Footnotes

Authors’ Contribution

Lukasz Grabarczyk is the sole author of the article who contributed to the study’s conception/design and approved the final manuscript.

Declaration of Conflicting Interests

The author declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The author received no financial support for the research, authorship and/or publication of this article.

Informed Consent

Consent to the diagnostics was obtained by a Polish court in accordance with applicable Polish law.

Statement of Ethics

Not applicable.

ORCID iD

Lukasz Grabarczyk

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