The Neuroethics of Disorders of Consciousness

A Brief History of Evolving Ideas

Michael J. Young; Yelena G. Bodien; Joseph T. Giacino; Joseph J. Fins; Robert D. Truog; Leigh R. Hochberg; Brian L. Edlow

Disclosures

Brain. 2021;144(11):3291-3310. 

In This Article

The Search for Covert Consciousness and Genesis of new Guidelines

Recognizing undue pessimism that the previous terminology of permanence invited, recent practice guideline recommendations from the AAN, ACRM and NIDILRR suggest eliminating the term permanent and replacing it with chronic vegetative state.[88] The AAN guideline additionally provides as a level A recommendation that when discussing prognosis with caregivers during the first 28 days post injury, 'clinicians must avoid statements that suggest a universally poor prognosis'.[88] It is important to recognize that this statement does not imply that it is never permissible to prognosticate or limit aggressive treatments for a patient with DoC before 28 days; rather, it encourages clinicians to avoid, during the first 28 days, statements suggesting that one can definitively know that the prognosis for functional recovery is poor. Echoing perceived pitfalls of current diagnostic procedures and prognostic standards for DoC, a 2020 European Academy of Neurology (EAN) guideline encourages 'repeated multimodal evaluations for evidence of preserved consciousness in patients with DoC' rather than predicating clinical decisions or prognostication on isolated assessments.[215] Similarly, the 2020 Royal College of Physicians National Clinical Guidelines for prolonged DoC emphasize that 'the diagnosis of VS (vegetative state) or MCS should only be made by an appropriately experienced assessor, using formal diagnostic tools applied on repeated occasions over an appropriate period of time in conjunction with a detailed clinical neurological assessment' and details that in comparison to the US health system, 'NHS (National Health Service) care allows for a considerably longer period of time over which to evaluate and monitor patients'.[216] In even stronger terms, Norwegian Neurological Society guidelines concerning DoC, updated in 2020, recommend that 'it might be appropriate to consider limitations of LST (life-sustaining therapy) but often not before at least after 1 year observation time for traumatic injuries' and 3 months for non-traumatic brain injuries, echoing the need for rigorous and repeated assessments over time.[209,217]

Ethical and logistical challenges to these guidelines have highlighted the potential resource strain that would likely ensue in intensive care units that choose to continue aggressive therapies for a longer period of time for more patients with severe brain injury.[134,218] Resource constraints during the COVID-19 pandemic magnified these difficulties worldwide.[3,219–222] These challenges are amplified in contexts where intensive care unit beds, ventilators and rehabilitation beds are already scarce, with clinicians facing tragic decisions about how to prioritize and equitably triage patients. Similar situations occur in specialized intensive care units (ICUs) located in tertiary care centres that can provide advanced services not available in community hospital ICUs, but only to the extent that beds in the specialized ICUs remain available. Therefore, increases in ICU and rehabilitation capacities will likely be needed before clinicians can universally meet this need; such increases should be considered in the context of other unmet medical needs and how limited resources should be best allocated. Furthermore, processes to support decision-making after 28 days have not been standardized, and supports to facilitate revisiting individualized goals-of-care decisions longitudinally are limited after discharge from acute or subacute care settings where such processes are increasingly emphasized.[214] Logistical challenges may be compounded by possible psychosocial risks of prolonging patient and family suffering in situations where survival without meaningful recovery is likely yet uncertain.[223]

Where do we go from here? The answer starts with a landmark case report published in 2006, which sparked a paradigm shift in approaches to DoC.[224] This landmark case report described a 23 year-old female who sustained severe brain injury after a motor vehicle accident. Repeated multidisciplinary assessments detected no typical behavioural evidence of responsiveness, and she thus received the diagnosis of vegetative state. However, a functional MRI was performed and when asked to imagine playing tennis, the blood oxygen level-dependent (BOLD) functional MRI signal increased in the premotor cortex, and when asked to relax, the BOLD signal in this region diminished. The patient was then asked to imagine moving from room to room in her house and a different pattern of functional MRI activity emerged that included the parietal cortex and part of the parahippocampal gyrus, two regions known to be involved in spatial navigation. Her pattern of functional MRI activity closely resembled that seen in healthy controls. Based on these findings, it was concluded that she in fact was not vegetative, but rather covertly conscious, even though the paper was entitled 'Detecting awareness in the vegetative state'.[102,224,225] This study opened up a wide area of investigation over the next decade, where investigators started to identify covert awareness in the behaviourally unresponsive. In a follow-up functional MRI study in 2010, 4 of 23 patients who received vegetative state diagnoses on admission appeared covertly aware and able to generate reliable responses on functional MRI.[120] One patient was even able to produce yes/no responses by alternating corresponding spatial or motor imagery tasks,[120] a finding that was subsequently replicated in one additional patient using different language paradigms.[121] These findings indicated that the motor capacity of some patients can be so compromised that bedside evaluations may fail to identify awareness, regardless of how meticulously they are administered.[226] More recently, EEG paradigms have been used to detect command-following in the absence of overt behaviour. Leveraging differences in EEG power spectra during performance of motor and spatial imaging tasks, quantitative analysis of high-density EEG may provide evidence of reliable command-following in patients who are otherwise behaviourally unresponsive through detected changes in the EEG power spectra or other patterns.[128,227,228]

The emerging role of EEG in aiding the diagnosis and prognosis of patients with DoC was emphasized by an International Federation of Clinical Neurophysiology (IFCN) Expert Group opinion statement in August 2020 that proposed a scheme for the integrated neurophysiological assessment of patients with prolonged DoC. The scheme envisions proceeding stepwise from traditional neurophysiological measures including standard EEG and somatosensory evoked potentials to gradually more complex measures including event related potentials, quantitative EEG and paired transcranial magnetic stimulation-EEG to enhance the capture and characterization of covert cognitive abilities not discernible by bedside examination.[229] The IFCN Expert Group suggests that embedding these techniques into multimodal assessments of patients with prolonged DoC 'might help direct behaviourally unresponsive patients towards different lines of evaluation based on objective markers of thalamo-cortical integrity'.[229]

What about in the acute stage? In a cohort of 16 DoC patients with acute traumatic brain injury admitted to the neurointensive care unit, covert consciousness was identified in four patients using functional MRI and EEG paradigms, including three whose behavioural diagnosis suggested a vegetative state.[127] A subsequent study examined a consecutive series of patients in the Neuro-ICU who were unresponsive to spoken commands. Machine learning was applied to EEG recordings to detect brain activation in response to commands for patients to move their hands. Brain activation was detected in 15% of those who were unresponsive to commands and predicted functional independence at 12 months,[130] suggesting that people with covert consciousness carry better prognoses. More recently, passive responses to an EEG protocol probing language function were found to be associated with improved outcomes at 3 and 6 months as measured by the Glasgow Outcome Scale-Extended,[132] adding to a growing body of evidence supporting the clinical role of advanced neurotechnologies in the diagnosis and prognosis of patients with DoC.[132,133,230]

Many groups around the world have used techniques like these to detect covert awareness in patients who appear clinically to be in a vegetative state. A meta-analysis of 37 published studies and over 1000 patients found that in aggregate approximately 20% were misclassified as vegetative when in fact they displayed covert awareness by functional MRI or EEG.[231] These findings raise the daunting possibility that a substantial percentage of patients diagnosed as vegetative worldwide might not be vegetative at all, but simply physically non-responsive with retained awareness. However, the phenomenological nature of the disordered states of consciousness uncovered by these advanced techniques remains unclear and requires further study. Conceivably, the category of cognitive motor dissociation encapsulates a heterogeneous group of states, ranging from complete locked-in awareness to merely reflexive or rudimentary cognitive processing.[232,233] Abundant caution is therefore necessary when counselling surrogates about the significance of these states, particularly what it might be like to be in the state reflected by functional MRI or EEG responsiveness, which is currently unknown.

Recognizing the fundamental diagnostic ambiguity that may be left due to the shortcomings of the bedside exam, the recent AAN DoC Guideline suggested a role for multimodal evaluations including functional imaging or EEG to assess awareness not identified at the bedside, but the guideline does not detail when and how these tools should be optimally used or integrated into clinical decision making. A subsequent 2020 EAN DoC Guideline amplified these sentiments, recommending that '[m]ultimodal assessment and neuroimaging is necessary to avoid misdiagnosis,' and that 'EEG-based techniques and functional neuroimaging (fMRI, PET) should be integrated into a composite reference standard' (Figure 2) but like the AAN guideline does not clarify at what time point(s) or in which particular clinical contexts these should be used.[215] Each of the paradigms used, including EEG, functional MRI, PET and transcranial magnetic stimulation-EEG, have strengths and limitations, ranging from spatial resolution, temporal resolution, cost, safety and experience required to use them.[226,229] When there is discordance between the level of consciousness detected by different paradigms, the EAN guideline recommends that a patient should be diagnosed with the 'highest level of consciousness' suggested by any of the approaches.[215] This important recommendation implies that in contexts where neuroimaging or neurophysiological measures have not (or cannot) been obtained, the workup remains incomplete, as assessment of the highest level of consciousness relies on knowledge of each of these measures. For the recipients of such incomplete or conflicting information (including surrogates and clinicians) there is potential for greater confusion and compromised decision-making. Possible reasons for discordance between the level of consciousness suggested by different diagnostic modalities include temporal fluctuations in consciousness, evolution of functional status, as well as the inherent limitations of each approach.

Figure 2.

Expanding the detection of consciousness. Multimodal assessments, including neurophysiological and neuroimaging techniques such as EEG and functional MRI, can augment the sensitivity of bedside behavioural examinations and aid in the diagnosis and prognosis of DoC. A patient may be diagnosed with the highest level of consciousness assessed by each of these measures. Adapted with permission.234

Norwegian Neurological Society DoC guidelines also recognize the potential supplementary role of advanced neuroimaging including functional MRI and electrophysiological techniques in the diagnosis and prognosis of patients with DoC.[217] The 2020 Royal College of Physicians National Clinical Guidelines have emphasized that 'advanced brain imaging and electrophysiology techniques have provided valuable insights into this patient group, and will continue to provide an important focus for research' but do not yet recommend their use in routine clinical practice, a position that has recently been critically evaluated.[235] These Royal College of Physicians guidelines also importantly note that 'while it is acknowledged that there is a small cohort of patients who present behaviourally as being in vegetative state but demonstrate covert responses within an fMRI scanner, the prognostic significance of these findings is as yet unclear [and this] raises the ethical dilemma of whether or not and how to disclose this information to clinicians and patients' families'.[235] Of note, it is explicitly specified that 'these UK guidelines do not apply until patients have been in PDOC (persistent DoC) for at least 4 weeks' and thus are not meant to provide guidance during acute stages of DoC or recommendations surrounding the use of advanced neuroimaging or electrophysiological techniques for acute neuroprognostication.[216]

Innovations in detecting consciousness come at an especially exciting time as we are learning more about opportunities to promote neurorecovery in DoC.[236,237] Therapeutic candidates include amantadine, methylphenidate, modafinil, apomorphine, zolpidem, transcranial direct current stimulation, transcranial magnetic stimulation, low intensity focused ultrasound pulsation, deep brain stimulation, vagal nerve stimulation, vestibular stimulation, music stimulation and brain–computer interfaces.[131,236–240] Most available data for these interventions derive from open-label studies and case reports, with the exception of amantadine which shows class I evidence for patients with traumatic brain injury during rehabilitation and is currently the only pharmacological intervention recommended by AAN guidelines for patients with DoC.[88,241] The mechanisms of many of these interventions are thought to converge on the central thalamus[98] and key brainstem networks.[242]

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