Diagnostic precision of PET imaging and functional MRI in disorders of consciousness: a clinical validation study

Summary

Background

Bedside clinical examinations can have high rates of misdiagnosis of unresponsive wakefulness syndrome (vegetative state) or minimally conscious state. The diagnostic and prognostic usefulness of neuroimaging-based approaches has not been established in a clinical setting. We did a validation study of two neuroimaging-based diagnostic methods: PET imaging and functional MRI (fMRI).

Methods

For this clinical validation study, we included patients referred to the University Hospital of Liège, Belgium, between January, 2008, and June, 2012, who were diagnosed by our unit with unresponsive wakefulness syndrome, locked-in syndrome, or minimally conscious state with traumatic or non-traumatic causes. We did repeated standardised clinical assessments with the Coma Recovery Scale–Revised (CRS–R), cerebral ¹⁸F-fluorodeoxyglucose (FDG) PET, and fMRI during mental activation tasks. We calculated the diagnostic accuracy of both imaging methods with CRS–R diagnosis as reference. We assessed outcome after 12 months with the Glasgow Outcome Scale–Extended.

Findings

We included 41 patients with unresponsive wakefulness syndrome, four with locked-in syndrome, and 81 in a minimally conscious state (48=traumatic, 78=non-traumatic; 110=chronic, 16=subacute). ¹⁸F-FDG PET had high sensitivity for identification of patients in a minimally conscious state (93%, 95% CI 85–98) and high congruence (85%, 77–90) with behavioural CRS–R scores. The active fMRI method was less sensitive at diagnosis of a minimally conscious state (45%, 30–61) and had lower overall congruence with behavioural scores (63%, 51–73) than PET imaging. ¹⁸F-FDG PET correctly predicted outcome in 75 of 102 patients (74%, 64–81), and fMRI in 36 of 65 patients (56%, 43–67). 13 of 41 (32%) of the behaviourally unresponsive patients (ie, diagnosed as unresponsive with CRS–R) showed brain activity compatible with (minimal) consciousness (ie, activity associated with consciousness, but diminished compared with fully conscious individuals) on at least one neuroimaging test; 69% of these (9 of 13) patients subsequently recovered consciousness.

Interpretation

Cerebral ¹⁸F-FDG PET could be used to complement bedside examinations and predict long-term recovery of patients with unresponsive wakefulness syndrome. Active fMRI might also be useful for differential diagnosis, but seems to be less accurate.

Funding

The Belgian National Funds for Scientific Research (FNRS), Fonds Léon Fredericq, the European Commission, the James McDonnell Foundation, the Mind Science Foundation, the French Speaking Community Concerted Research Action, the University of Copenhagen, and the University of Liège.

Introduction

Many studies have been done on the differential diagnosis of disorders of consciousness.¹ The term covers several pathological states, characterised by diminished consciousness and responsiveness. Among these, patients with unresponsive wakefulness syndrome, also known as a vegetative state,1, 2 retain arousal but show no behavioural signs of awareness.3, 4 Patients in a minimally conscious state show fluctuating awareness, and can respond appropriately to some stimuli.⁵ By convention, emergence from minimally conscious state arises when the patient regains a capacity for functional communication or object use.⁵ Because these states occupy a border zone between awareness and unconsciousness, the distinction between them has important ethical and therapeutic implications.³ For example, patients in minimally conscious states are more likely to have pain or suffer, and might benefit from analgesic treatment or other interventions aimed to improve quality of life.6, 7 Patients in a minimally conscious state are also more likely to recover higher levels of consciousness than are patients with unresponsive wakefulness syndrome.3, 8 Several countries have established the legal right of physicians to withdraw artificial life support from patients with unresponsive wakefulness syndrome9, 10, 11 but not from patients in a minimally conscious state.¹²

The detection of unambiguous signs of consciousness in severely brain-damaged patients is challenging. The frequency of misdiagnoses of patients with unresponsive wakefulness syndrome by clinical consensus methods is up to 40%.13, 14, 15 This error rate can be attenuated by the use of standardised scoring systems, such as the Coma Recovery Scale–Revised (CRS–R).16, 17, 18 However, misdiagnosis can still arise even with rigorous behavioural testing.¹⁹ Neuroimaging methods are being developed to complement the bedside examinations to investigate whether a patient has cerebral activity compatible with consciousness. These tests can assess spontaneous brain activity in the so-called resting brain, or specific responses to mental tasks. For example, findings of recent neuroimaging studies19, 20, 21 show that some patients diagnosed with unresponsive wakefulness syndrome probably can modulate their thoughts voluntarily, which suggests at least minimal awareness. The existence of locked-in syndrome22, 23, 24 proves that even behaviourally unresponsive patients can be conscious. This knowledge of a patient otherwise perceived as unconscious fundamentally alters his or her ethical, legal, and possibly social and therapeutic standing.

Consciousness is supported by internally and externally related awareness networks encompassing the frontoparietal associative cortices, cingulate gyrus, precuneus, and thalamus.24, 25, 26, 27, 28 Neural activity in these areas can be examined by ¹⁸F-fluorodeoxyglucose (FDG) PET, which allows visualisation of glucose metabolism at a whole brain level. Generally, the rate of cerebral energy turnover is proportional to the rate of synaptic firing. Therefore, lowered glucose metabolic rates suggest dysfunctional or dormant brain areas.²⁹ Specific metabolic decreases of the frontoparietal associative cortices are seen in patients with unresponsive wakefulness syndrome and those in a minimally conscious state. Patients in a minimally conscious state maintain partial metabolism in the frontoparietal networks, whereas patients with unresponsive wakefulness syndrome show a broad bilateral frontoparietal dysfunction.24, 30, 31, 32 Similar findings of extensive frontoparietal hypometabolism are seen in deep sleep³³ and general anaesthesia,²⁷ suggesting that this pattern is associated with unawareness.

Activity in neuronal populations also triggers fluctuations in capillary deoxyhaemoglobin concentrations. Such increases can be seen with functional MRI (fMRI), and form the basis of maps of the functional architecture of brain activity.³⁴ When asked to do mental tasks, such as motor or visuospatial imagery tasks, healthy patients generate reproducible and specific patterns of brain activation.³⁵ Some patients with unresponsive wakefulness syndrome or those in a minimally conscious state can do similar mental tasks on request.19, 20, 21 Assuming that such brain activations constitute mental parallels of outward communication, fMRI testing might enable detection of consciousness in cases in which severe paralysis or spasticity makes regular communication impossible.

On the basis of these studies, FDG PET and fMRI might, in theory, distinguish patients in a minimally conscious state from those with unresponsive wakefulness syndrome. Because patients in a minimally conscious state, compared with patients with unresponsive wakefulness syndrome, have better outcomes, neuroimaging tests could also provide prognostic predictions. However, the diagnostic utility of these tests needs validation in clinical practice.

We aimed to test the hypothesis that neuroimaging with ¹⁸F-FDG PET at rest and fMRI during mental tasks can complement bedside clinical detection of consciousness and prediction of recovery. Inclusion of patients with locked-in syndrome (ie, a brain-damaged yet conscious control group)²⁴ allows internal validity to be controlled by verifying the ability of the tests to detect awareness in fully conscious but physically incapacitated patients.