'Landmark' Study Pushed Detection of Covert Consciousness in TBI

Compelling advances in the ability to detect signs of consciousness in unconscious patients who have experienced traumatic brain injury (TBI) are leading to unprecedented changes in the field. There is now hope of improving outcomes and even sparing lives of patients who may otherwise have been mistakenly assessed as having no chance of recovery.

A recent key study represents a tipping point in the mounting evidence of the ability to detect "covert consciousness" in patients with TBI who are in an unconscious state. That research, published in The New England Journal of Medicine (NEJM) in June 2019, linked the promising signals of consciousness in comatose patients, detected only on imaging, with remarkable outcomes a year later.

"This was a landmark study," said Brian L. Edlow, MD, in a presentation on the issue of covert consciousness during the American Neurological Association's 2020 virtual annual meeting.

"Importantly, it is the first compelling evidence that early detection of covert consciousness also predicts 1-year outcomes in the Glasgow Outcome Scale Extended (GOSE), showing that covert consciousness in the ICU appears to be relevant for predicting long-term outcomes," said Edlow, who is associate director of the Center for Neurotechnology and Neurorecovery, Massachusetts General Hospital, in Boston.

The researchers showed that 15% of unconscious patients with acute brain injury in the study exhibited significant brain activity on EEG in response to stimuli that included verbal commands such as envisioning that they are playing tennis.

Although other studies have shown similar effects with task-based stimuli, the NEJM study further showed that a year later, the patients who had shown signs of covert consciousness, also called "cognitive motor dissociation" (CMD), were significantly more likely to have a good functional outcome, said the study's senior author, Jan Claassen, MD, director of critical care neurology at Columbia University, in New York City, who also presented during the ANA session.

"Importantly, a year later after injury, we found that 44% of patients with CMD and only 14% of non-CMD patients had a good functional outcome, defined as a GOSE score indicating a state where they can at least take care of themselves for 8 hours in a day," he said.

"[Whether] these patients in a CMD state represent a parallel state or a transitory state on the road to recovery remains to be shown," he said.

Jennifer Frontera, MD, a professor in the Department of Neurology at NYU Langone in New York City and co-moderator of the session, agreed that the research is "remarkable."

"Also, it is practical, since many could potentially apply and validate his algorithms, since EEG technology is portable and widely available," she told Medscape Medical News.

Research Has Ushered in a "Sea Change" in Neuro-Critical Care

The research has helped push forward recommendations on the treatment of unconscious patients, Edlow said.

"This has led to a sea change in our field just over the last 2 years, with multiple guidelines published suggesting that it may be time for us to consider incorporating task-based fMRI and EEG techniques into our clinical assessment of patients with disorders of consciousness," Edlow said.

Among those updating their recommendations was the American Academy of Neurology, which revised guidelines on practice parameters for patients in a persistent vegetative state. Those guidelines had not been updated since 1995.

Although concluding that "no diagnostic assessment procedure had moderate or strong evidence for use," the guidelines acknowledge that "it is possible that a positive electromyographic (EMG) response to command, EEG reactivity to sensory stimuli, laser-evoked potentials, and the Perturbational Complexity Index can distinguish a minimally conscious state from vegetative state/unresponsive wakefulness syndrome (VS/UWS)."

Earlier this year, the European Academy of Neurology (EAN) followed suit with updated guidelines of its own.

In the EAN guideline, the academy's Panel on Coma, Disorders of Consciousness, recommends that task-based fMRI, EEG, and other advanced assessments be performed as part of a composite assessment of consciousness and that a patient's best performance or highest level of consciousness on any of those tests should be a reflection of their diagnosis, Edlow explained.

"What this means is that our field is moving toward a multimodal assessment of consciousness in the ICU as well as beyond, in the subacute to chronic setting, whereby the behavioral exam, advanced DG, and advanced MRI methods all also contribute to the diagnosis of consciousness," he said.

The gold standard for assessment of disorders of consciousness is the Coma Recovery Scale – Revised, with 25-item scale for diagnosis, prediction of outcome, and assess potential treatment efficacy.

But much uncertainty can remain despite the assessment, Claassen said.

"Behavioral assessments of patients with acute brain injury are challenging because examinations fluctuate, and there's variability between assessors," he said. "Nevertheless, patients and their families demand guidance from us."

Edlow pointed out that the largest study to date of the causes of death among patients with TBI in the ICU underscores the need for better assessments.

The study of more than 600 patients at six level l trauma centers in Canada showed that 70% of patients who died in the ICU from TBI did so as the result of the withdrawal of life-sustaining therapy.

However, only about a half (57%) had an unreactive pupil, and only about a quarter (23.7%) had evidence of herniation on CT, findings that are commonly associated with a poor prognosis.

"What emerges from this is that the manner in which the clinicians communicated the prognosis to families was a primary determinant of decisions to withdraw life-sustaining therapy," Edlow said.

Negative Response Not Necessarily Conclusive

Edlow added a word of caution that the science is still far from perfect. He noted that for 25% of healthy patients who are given a motor imagery task, neuroimaging might not show a response, implying that the lack of a signal may not be conclusive.

He described the case of a patient who was comatose at the time she was scanned on day 3 after injury and who showed no responses to language, music, or motor imagery during the MRI, yet a year later, she was functionally independent, back in the workforce, and had very few residual symptoms from her trauma.

"So if a patient does not show a response, that does not prove the patient is not conscious, and it does not prove that the patient is likely to have a poor outcome," Edlow said.

Such cases underscore the need for more advances in understanding the inner workings of brain injury.

Heeding that call, Edlow and his colleagues are embarking on a trial of the effects of intravenous methylphenidate in targeting the stimulation of dopaminergic circuits within the subcortical ascending arousal network in patients with severe brain injuries.

"The scientific premise of the trial is that personalized brain network mapping in the ICU can identify patients whose connectomes are amenable to neuromodulation," Edlow and his colleague report in an article in Neurocritical Care.

The trial, called STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness), is part of the newly launched Connectome-based Clinical Trial Platform, which the authors describe as "a new paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU."

Such efforts are essential, given the high stakes of TBI outcomes, Edlow said.

"Let's be clear about the stakes of an incorrect prognosis," he said. "If we're overly pessimistic, then a patient who could have potential for meaningful recovery will likely die in our ICU. On the other hand, if we are overly optimistic, then a patient could end up in a vegetative or minimally conscious state that he or she may never have found to be acceptable," he said.

Access to Technologies a "Civil Right?"

Some ethicists in the field are recommending that patients be given access to the advanced techniques as a civil right, similar to the rights described in the Convention on the Rights of Persons With Disabilities, which was adopted by the United Nations in 2008, Edlow noted.

"So the question that we as clinicians are going to face moving forward from an ethical standpoint is, if we have access to these techniques, is it an ethical obligation to offer them now?" he said.

Edlow underscored the need to consider the reality that "there are profound issues relating to resource allocation and access to these advanced techniques, but we're going to have to consider this together as we move forward."

Edlow has received funding from the National Institutes of Health. Claassen is a minority shareholder with ICE Neurosystems. Frontera has disclosed no relevant financial relationships.

ANA 2020: 145th Annual Meeting of the American Neurological Association: Abstract 535, presented October 9, 2020.

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