- Email: [email protected]
Covert Consciousness in the Intensive Care Unit
TINS 1544 No. of Pages 3
Trends in Neurosciences
Spotlight
Covert Consciousness in the Intensive Care Unit Joseph T. Giacino1,2,5,* and Brian L. Edlow3,4,5
bedside measures such as the Glasgow Coma Scale [3–5]. More comprehensive standardized assessment instruments like the Coma Recovery Scale-Revised (CRS-R) yield better detection rates [6] (Figure 1), but do not eliminate false neg-
ative errors. Task-based fMRI and EEG can be used to complement the CRS-R assessment of consciousness in the ICU [7], but the prognostic utility of fMRI and EEG during the acute period has not been demonstrated.
Claassen et al. performed taskbased electroencephalography (EEG) in patients with disorders of consciousness in the intensive care unit (ICU) and found that covert consciousness detected by EEG is associated with better longterm outcomes. The diagnostic and prognostic uncertainty raised by these findings lead to pressing ethical questions concerning clinical management.
For clinicians caring for patients with severe brain injuries in the ICU, the bedside behavioral examination is an essential diagnostic and prognostic tool. Early emergence of consciousness on the behavioral exam impacts time-sensitive decisions about continuation of life-sustaining therapy and predicts long-term functional recovery [1]. But what if clinicians’ bedside examinations fail to detect signs of consciousness in patients who actually retain awareness yet are unable to express their sentience due to underlying sensory, motor, cognitive, or language impairments? There is consistent evidence that this is a common problem affecting approximately 40% of patients with loss of consciousness after severe brain injury [2]. The consequences can be dire, including the decision to withdraw life-sustaining therapy (WoLST) in those otherwise destined to eventually achieve meaningful recovery. Over the past decade, task-based functional magnetic resonance imaging (fMRI) and EEG studies have shown that ‘covert consciousness’ can be detected in up to 20% of patients with severe brain injury who appear behaviorally unresponsive on
Trends in Neurosciences
Figure 1. Detection of Covert Consciousness Using Task-Based Electroencephalography (EEG). The gold-standard for behavioral assessment of consciousness is the Coma Recovery Scale-Revised (CRS-R) [6]. The CRS-R is comprised of standardized behavioral assessment procedures, such as the use of a mirror to detect visual pursuit (left panel), which provide higher sensitivity for detection of consciousness in comparison with the Glasgow Coma Scale. In the study by Claassen and colleagues [8], task-based EEG detected covert consciousness in 15% of acutely brain-injured patients who appeared unconscious on the CRS-R assessment. In the task-based EEG protocol, the patient is verbally instructed to perform a movement. A machine learning algorithm is then applied to determine if the patient’s cortical rhythms are significantly different during periods of instructed movement than during periods of rest (right panel). Adapted, with permission, from Edlow and Fins [10]. Artwork by Kimberly Main Knoper.
Trends in Neurosciences, Month 2019, Vol. xx, No. xx
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Trends in Neurosciences
The CMD group underwent a median of three EEG studies [interquartile range (IQR) = 1–4] while patients who did not demonstrate CMD completed a median of two studies (IQR = 1–3). Because the number of studies performed between groups was unequal, non-CMD patients who underwent fewer studies may have shown activation on a subsequent exam, potentially impacting between-group differences in 12-month outcome. Second, because a patient control group was not included, the sensitivity and specificity of the EEG procedure is unknown among the general DoC population. For example, patients diagnosed with minimally conscious state (MCS) ‘plus’ (not included in the sample studied), are frequently found to have negative results on fMRI and EEG studies of covert consciousness, despite behaviorally confirmed evidence of The observation that early diagnosis of command-following [4,7]. covert consciousness in the ICU predicts 1-year outcome has the potential to The findings by Claassen et al. raise funchange clinical practice. EEG is relatively damental questions about the neuroinexpensive, portable, and safe to perform physiology of consciousness and should at the bedside. Although the machine- spark a new dialogue about the current learning analytic methods require exper- approach to clinical practice. The investitise and computing infrastructure, EEG gators identified evidence of covert condata acquisition could be performed sciousness in 8 of 56 (14%) patients today in many ICUs around the world, who were comatose on bedside examieven in resource-limited settings. More- nation. Unlike the many behaviorally over, the growing commitment to dissem- vegetative and minimally conscious ination of methods and open-source data patients with CMD reported since the sharing by investigators in the disorders seminal 2006 study by Owen et al. [3], of consciousness (DoC) research commu- comatose patients show no signs of nity lays a foundation for rapid dissemina- arousal (i.e., wakefulness). These newly tion of the analytic methods. One can reported CMD findings suggest that also imagine a future in which task-based cognition is not only dissociable from overt EEG data are acquired locally and sent to expression of awareness [9], but also from remote specialty centers that perform the arousal, one of the most fundamental funcanalysis, then return the results to the tions of the brain. If replicated, these results suggest that bedside behavioral examinareferring clinician or center. tion, even when standardized, may be unThere are, however, some important reliable across the full spectrum of DoC, caveats to consider when evaluating the from coma through MCS. results of the study by Claassen et al. The investigators assigned patients to The increased diagnostic and prognostic the CMD group if brain activation was uncertainty raised by these findings lead observed on at least one assessment. to pressing ethical questions about the The recently published paper by Claassen et al. [8] is a bellwether that reaffirms the complexity associated with assessment of consciousness in the ICU and, more importantly, highlights the importance of diagnostic accuracy in prognostication and planning goals of care. The investigators performed task-based EEG in the largest cohort of acutely brain-injured ICU patients to date (104 patients) and found covert consciousness in 16 patients (15%). They also demonstrated, for the first time, that very early detection of covert consciousness is associated with favorable functional outcome at 1 year. Patients with EEG evidence of cognitive motor dissociation (CMD) in the ICU were more likely to be able to live without supervision for up to 8 hours a day by 12 months postinjury (odds ratio = 4.6).
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Trends in Neurosciences, Month 2019, Vol. xx, No. xx
clinical management of patients with DoC. Under what conditions should task-based EEG paradigms be employed: anytime behavioral findings are negative, only when behavioral findings are ambiguous, only when WoLST is being considered, or always? What level of cognitive processing should be inferred from functional EEG activation: simple discrimination of words from nonwords, recognition of word meaning, or conceptual understanding? If CMD is a possible cause of unresponsiveness in all DoC cases, is there an obligation to delay WoLST decisions for a prespecified period of time or until studies of covert consciousness can be obtained? The stakes for detecting early signs of consciousness in the ICU could not be higher. Time-sensitive decisions about continuation of life-sustaining therapy hang in the balance. The study by Claassen et al. [8] highlights the potential for covert consciousness in acutely brain-injured patients and underscores the perfidy of the behavioral examination. The new evidence that early detection of covert consciousness may presage subsequent functional recovery raises substantive ethical questions about the current approach to clinical management of this population and suggests the need for new lines of research in this area. Acknowledgments The authors wish to thank the agencies and organizations who have supported our work and helped frame our approach to clinical practice and research on disorders of consciousness, including the James S. McDonnell Foundation, National Institute on Disability, Independent Living and Rehabilitation Research, National Institute of Neurological Disorders and Stroke, American Academy of Neurology/American Brain Foundation, Center for Integration of Medicine and Innovative Technology, Barbara Epstein Foundation, Rappaport Foundation, Tiny Blue Dot Foundation, Spaulding Rehabilitation Hospital Disorders of Consciousness Program, and Massachusetts General Hospital Department of Neurology and Division of Neurocritical Care and Emergency Neurology. We also wish to thank all the patients and families who we have had the great pleasure of working with and continue to inspire us.
Trends in Neurosciences
1
Spaulding Rehabilitation Hospital, 300 First Ave, Charlestown, MA 02129, USA 2 Department of Physical Medicine and Rehabilitation and Center for Bioethics, Harvard Medical School, 25 Shattuck St, Boston, MA 02115, USA 3 Department of Neurology, Center for Neurotechnology and Neurorecovery, Massachusetts General Hospital, 175 Cambridge Street – Suite 300, Boston, MA 02114, USA 4 Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129, USA 5 These authors contributed equally to the conceptualization and drafting of this manuscript. *Correspondence: [email protected] (J.T. Giacino). https://doi.org/10.1016/j.tins.2019.08.011 © 2019 Elsevier Ltd. All rights reserved.
References 1. Giacino, J.T. and Kalmar, K. (1997) The vegetative and minimally conscious states: a comparison of clinical features and functional outcome. J. Head Trauma Rehabil. 12, 36–51 2. Schnakers, C. et al. (2009) Diagnostic accuracy of the vegetative and minimally conscious state: clinical consensus versus standardized neurobehavioral assessment. BMC Neurol. 9, 35 3. Owen, A.M. et al. (2006) Detecting awareness in the vegetative state. Science 313, 1402 4. Monti, M.M. et al. (2010) Willful modulation of brain activity in disorders of consciousness. N. Engl. J. Med. 362, 579–589 5. Giacino, J.T. et al. (2014) Disorders of consciousness after acquired brain injury: the state of the science. Nat. Rev. Neurol. 10, 99–114 6. Giacino, J.T. et al. (2004) The JFK Coma Recovery ScaleRevised: measurement characteristics and diagnostic utility. Arch. Phys. Med. Rehabil. 85, 2020–2029
7.
Edlow, B.L. et al. (2017) Early detection of consciousness in patients with acute severe traumatic brain injury. Brain 140, 2399–2414 8. Claassen, J. et al. (2019) Detection of brain activation in unresponsive patients with acute brain injury. N. Engl. J. Med. 380, 2497–2505 9. Schiff, N.D. (2015) Cognitive motor dissociation following severe brain injuries. JAMA Neurol. 72, 1413–1415 10. Edlow, B.L. and Fins, J.J. (2018) Assessment of covert consciousness in the intensive care unit: clinical and ethical considerations. J. Head Trauma Rehabil. 33, 424–434
Trends in Neurosciences, Month 2019, Vol. xx, No. xx
3
Trends in Neurosciences
Spotlight
Covert Consciousness in the Intensive Care Unit Joseph T. Giacino1,2,5,* and Brian L. Edlow3,4,5
bedside measures such as the Glasgow Coma Scale [3–5]. More comprehensive standardized assessment instruments like the Coma Recovery Scale-Revised (CRS-R) yield better detection rates [6] (Figure 1), but do not eliminate false neg-
ative errors. Task-based fMRI and EEG can be used to complement the CRS-R assessment of consciousness in the ICU [7], but the prognostic utility of fMRI and EEG during the acute period has not been demonstrated.
Claassen et al. performed taskbased electroencephalography (EEG) in patients with disorders of consciousness in the intensive care unit (ICU) and found that covert consciousness detected by EEG is associated with better longterm outcomes. The diagnostic and prognostic uncertainty raised by these findings lead to pressing ethical questions concerning clinical management.
For clinicians caring for patients with severe brain injuries in the ICU, the bedside behavioral examination is an essential diagnostic and prognostic tool. Early emergence of consciousness on the behavioral exam impacts time-sensitive decisions about continuation of life-sustaining therapy and predicts long-term functional recovery [1]. But what if clinicians’ bedside examinations fail to detect signs of consciousness in patients who actually retain awareness yet are unable to express their sentience due to underlying sensory, motor, cognitive, or language impairments? There is consistent evidence that this is a common problem affecting approximately 40% of patients with loss of consciousness after severe brain injury [2]. The consequences can be dire, including the decision to withdraw life-sustaining therapy (WoLST) in those otherwise destined to eventually achieve meaningful recovery. Over the past decade, task-based functional magnetic resonance imaging (fMRI) and EEG studies have shown that ‘covert consciousness’ can be detected in up to 20% of patients with severe brain injury who appear behaviorally unresponsive on
Trends in Neurosciences
Figure 1. Detection of Covert Consciousness Using Task-Based Electroencephalography (EEG). The gold-standard for behavioral assessment of consciousness is the Coma Recovery Scale-Revised (CRS-R) [6]. The CRS-R is comprised of standardized behavioral assessment procedures, such as the use of a mirror to detect visual pursuit (left panel), which provide higher sensitivity for detection of consciousness in comparison with the Glasgow Coma Scale. In the study by Claassen and colleagues [8], task-based EEG detected covert consciousness in 15% of acutely brain-injured patients who appeared unconscious on the CRS-R assessment. In the task-based EEG protocol, the patient is verbally instructed to perform a movement. A machine learning algorithm is then applied to determine if the patient’s cortical rhythms are significantly different during periods of instructed movement than during periods of rest (right panel). Adapted, with permission, from Edlow and Fins [10]. Artwork by Kimberly Main Knoper.
Trends in Neurosciences, Month 2019, Vol. xx, No. xx
1
Trends in Neurosciences
The CMD group underwent a median of three EEG studies [interquartile range (IQR) = 1–4] while patients who did not demonstrate CMD completed a median of two studies (IQR = 1–3). Because the number of studies performed between groups was unequal, non-CMD patients who underwent fewer studies may have shown activation on a subsequent exam, potentially impacting between-group differences in 12-month outcome. Second, because a patient control group was not included, the sensitivity and specificity of the EEG procedure is unknown among the general DoC population. For example, patients diagnosed with minimally conscious state (MCS) ‘plus’ (not included in the sample studied), are frequently found to have negative results on fMRI and EEG studies of covert consciousness, despite behaviorally confirmed evidence of The observation that early diagnosis of command-following [4,7]. covert consciousness in the ICU predicts 1-year outcome has the potential to The findings by Claassen et al. raise funchange clinical practice. EEG is relatively damental questions about the neuroinexpensive, portable, and safe to perform physiology of consciousness and should at the bedside. Although the machine- spark a new dialogue about the current learning analytic methods require exper- approach to clinical practice. The investitise and computing infrastructure, EEG gators identified evidence of covert condata acquisition could be performed sciousness in 8 of 56 (14%) patients today in many ICUs around the world, who were comatose on bedside examieven in resource-limited settings. More- nation. Unlike the many behaviorally over, the growing commitment to dissem- vegetative and minimally conscious ination of methods and open-source data patients with CMD reported since the sharing by investigators in the disorders seminal 2006 study by Owen et al. [3], of consciousness (DoC) research commu- comatose patients show no signs of nity lays a foundation for rapid dissemina- arousal (i.e., wakefulness). These newly tion of the analytic methods. One can reported CMD findings suggest that also imagine a future in which task-based cognition is not only dissociable from overt EEG data are acquired locally and sent to expression of awareness [9], but also from remote specialty centers that perform the arousal, one of the most fundamental funcanalysis, then return the results to the tions of the brain. If replicated, these results suggest that bedside behavioral examinareferring clinician or center. tion, even when standardized, may be unThere are, however, some important reliable across the full spectrum of DoC, caveats to consider when evaluating the from coma through MCS. results of the study by Claassen et al. The investigators assigned patients to The increased diagnostic and prognostic the CMD group if brain activation was uncertainty raised by these findings lead observed on at least one assessment. to pressing ethical questions about the The recently published paper by Claassen et al. [8] is a bellwether that reaffirms the complexity associated with assessment of consciousness in the ICU and, more importantly, highlights the importance of diagnostic accuracy in prognostication and planning goals of care. The investigators performed task-based EEG in the largest cohort of acutely brain-injured ICU patients to date (104 patients) and found covert consciousness in 16 patients (15%). They also demonstrated, for the first time, that very early detection of covert consciousness is associated with favorable functional outcome at 1 year. Patients with EEG evidence of cognitive motor dissociation (CMD) in the ICU were more likely to be able to live without supervision for up to 8 hours a day by 12 months postinjury (odds ratio = 4.6).
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Trends in Neurosciences, Month 2019, Vol. xx, No. xx
clinical management of patients with DoC. Under what conditions should task-based EEG paradigms be employed: anytime behavioral findings are negative, only when behavioral findings are ambiguous, only when WoLST is being considered, or always? What level of cognitive processing should be inferred from functional EEG activation: simple discrimination of words from nonwords, recognition of word meaning, or conceptual understanding? If CMD is a possible cause of unresponsiveness in all DoC cases, is there an obligation to delay WoLST decisions for a prespecified period of time or until studies of covert consciousness can be obtained? The stakes for detecting early signs of consciousness in the ICU could not be higher. Time-sensitive decisions about continuation of life-sustaining therapy hang in the balance. The study by Claassen et al. [8] highlights the potential for covert consciousness in acutely brain-injured patients and underscores the perfidy of the behavioral examination. The new evidence that early detection of covert consciousness may presage subsequent functional recovery raises substantive ethical questions about the current approach to clinical management of this population and suggests the need for new lines of research in this area. Acknowledgments The authors wish to thank the agencies and organizations who have supported our work and helped frame our approach to clinical practice and research on disorders of consciousness, including the James S. McDonnell Foundation, National Institute on Disability, Independent Living and Rehabilitation Research, National Institute of Neurological Disorders and Stroke, American Academy of Neurology/American Brain Foundation, Center for Integration of Medicine and Innovative Technology, Barbara Epstein Foundation, Rappaport Foundation, Tiny Blue Dot Foundation, Spaulding Rehabilitation Hospital Disorders of Consciousness Program, and Massachusetts General Hospital Department of Neurology and Division of Neurocritical Care and Emergency Neurology. We also wish to thank all the patients and families who we have had the great pleasure of working with and continue to inspire us.
Trends in Neurosciences
1
Spaulding Rehabilitation Hospital, 300 First Ave, Charlestown, MA 02129, USA 2 Department of Physical Medicine and Rehabilitation and Center for Bioethics, Harvard Medical School, 25 Shattuck St, Boston, MA 02115, USA 3 Department of Neurology, Center for Neurotechnology and Neurorecovery, Massachusetts General Hospital, 175 Cambridge Street – Suite 300, Boston, MA 02114, USA 4 Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129, USA 5 These authors contributed equally to the conceptualization and drafting of this manuscript. *Correspondence: [email protected] (J.T. Giacino). https://doi.org/10.1016/j.tins.2019.08.011 © 2019 Elsevier Ltd. All rights reserved.
References 1. Giacino, J.T. and Kalmar, K. (1997) The vegetative and minimally conscious states: a comparison of clinical features and functional outcome. J. Head Trauma Rehabil. 12, 36–51 2. Schnakers, C. et al. (2009) Diagnostic accuracy of the vegetative and minimally conscious state: clinical consensus versus standardized neurobehavioral assessment. BMC Neurol. 9, 35 3. Owen, A.M. et al. (2006) Detecting awareness in the vegetative state. Science 313, 1402 4. Monti, M.M. et al. (2010) Willful modulation of brain activity in disorders of consciousness. N. Engl. J. Med. 362, 579–589 5. Giacino, J.T. et al. (2014) Disorders of consciousness after acquired brain injury: the state of the science. Nat. Rev. Neurol. 10, 99–114 6. Giacino, J.T. et al. (2004) The JFK Coma Recovery ScaleRevised: measurement characteristics and diagnostic utility. Arch. Phys. Med. Rehabil. 85, 2020–2029
7.
Edlow, B.L. et al. (2017) Early detection of consciousness in patients with acute severe traumatic brain injury. Brain 140, 2399–2414 8. Claassen, J. et al. (2019) Detection of brain activation in unresponsive patients with acute brain injury. N. Engl. J. Med. 380, 2497–2505 9. Schiff, N.D. (2015) Cognitive motor dissociation following severe brain injuries. JAMA Neurol. 72, 1413–1415 10. Edlow, B.L. and Fins, J.J. (2018) Assessment of covert consciousness in the intensive care unit: clinical and ethical considerations. J. Head Trauma Rehabil. 33, 424–434
Trends in Neurosciences, Month 2019, Vol. xx, No. xx
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