Coma or Vegetative State and Vagus Nerve Stimulation

Recently, emerging data from a pilot study conducted by a group of French investigators, has suggested that a patient in a state of extended coma, could partially recover from it. This striking discovery is joining the long list of progress made these past years in the field of neuroscience, challenging along the way, major existing theories on coma recovery, and bringing with it an array of medical, legal and ethical issues, including consent and withdrawal of life sustaining treatment.

For more than 50 years, "neurological interventions for coma have included primarily deep brain stimulation (DBS)", which has not proved to be conclusive in terms of restoring consciousness and communication in comatose patients.

In this paper, we will attempt to assess the impact of Vagus Nerve Stimulation (VNS) on the basis of our hypothesis that data accumulated over a short period would strongly support the assumption of causality or correlation in spite of a lack of evaluation methodologies spanning the course of time, or gold standard epidemiological studies, or peer-reviewed publications.

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This assumption seems justified in light of the apparent endorsement of VNS procedures by respected domain stakeholders such as the U.S FDA and NIH.

We will additionally take a look at some of the ethical considerations that might arise from these findings, such as patient's rights, or questions pertaining to the withdrawal of life sustaining treatment in cases in which consciousness could be regained.

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INTRODUCTION AND BACKGROUND

According to several sources, among which the World Health Organization, coma is defined as "a state of deep unconsciousness that lasts for a prolonged or indefinite period, caused especially by severe injury or illness.

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From a clinical perspective, comatose patients are unable to consistently follow basic commands, and most of the time their Glasgow Coma Scale (GCS) score is ? 8 for a duration of 6 hours, or more. A patient is deemed conscious, if he or she can maintain both awareness and wakefulness. Awareness pertains to the "qualitative aspects of the functions mediated by the cortex, including cognitive abilities such as attention, sensory perception, explicit memory, language, the execution of tasks, temporal and spatial orientation and reality judgment", while wakefulness relates to the quantitative extent of consciousness.

Neurologically speaking, consciousness is preserved through the stimulation of the cerebral cortex "the gray matter that forms the outer layer of the brain and by the reticular activating system (RAS), a structure located within the brainstem."

There is a difference between coma and vegetative state. According to Angela Sirigu of the Institut des Sciences Cognitives Marc Jeannerod in Lyon, France, people in vegetative states "don't have a presence in the world." However, they are able to breathe on their own, have moments of wakefulness, and this in spite of the fact that they are unconscious of their surroundings, or unable to react to external stimuli.

Patients in a coma, on the other hand, are totally unresponsive, with no movements, or reaction to sound or light, and are said not to be able to feel pain. Usually, their eyes remain closed.

On September 2017, several French and international newspapers released the story of a 35-year-old patient who incurred brain damage following a car accident, and spent, consecutively, 15 years in a vegetative state. By stimulating the vagus nerve - which runs from the abdomen to the brain - the French researchers significantly "restored" consciousness in the man.

This event may alter the conventional way of thinking about coma and vegetative states, according to which a vegetative state that exceeds a year, is deemed non-reversible.

In the case of the French patient, a nerve stimulator was implanted into his chest, and for a month, his vagus nerve was stimulated. The vagus nerve is an essential link between the brain and the body and contributes to a series of vital functions, including awareness and awakening. "After one month of vagal nerve stimulation (VNS), the patient's attention, movements and brain activity significantly improved," stated Angela Sirigu. The patient moved from vegetative to "minimally conscious" state. In that new state, he could answer simple orders (which he could not before), such as turning his head once prompted, or following an object with his eyes.

In the next section of our paper, we will briefly discuss the traditional neurological interventions that were used for coma - Deep Brain Stimulation (DBS), and understand why their use has been inconclusive for more than fifty years.

Then, we will appraise the impact of Vagus Nerve Stimulation (VNS) on comatose patients based on the current technology and explain why the data accumulated over a short period of time, would strongly suggest causality or correlation between an increase in consciousness and the use of Vagus Nerve Stimulation. What arguments sustain our hypothesis? Are there any counterarguments to our theory?

Finally, we will take a look at some of the ethical issues and challenges that could result from Vagus Nerve Stimulation in case of successful interventions on patients who regain partial or full consciousness.

DISCUSSION

Traumatic brain injury (TBI), defined as "a blow to the head or a penetrating head injury that disrupts the normal function of the brain," is an impending epidemic, resulting most of the times in devastating sequaelae such as "coma, minimally conscious state, or deficits in executive functions."

Main intervention procedures for persons with disorders of consciousness include various forms of environmental stimulation, transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS), deep brain stimulation, and learning-based intervention programs (Daveson 2010; Lancioni et al. 2014a; Magee et al. 2016; Pape et al. 2009, 2012; Piccione et al. 2011; Schnakers et al. 2016).

Deep brain stimulation (DBS), described as "a functional neurosurgery procedure being performed by inserting two specific pace-making probes into specific deep brain nuclei and sending electrical stimulations in order to suppress or stimulate different nerve groups in the nuclei", has been used for many years in neurological interventions for coma, but has not proved to be conclusive in terms of restoring consciousness and communication in patients, despite the fact that it is FDA-approved, and recognized as an efficient treatment for individuals with movement disorders, such as dystonia, Parkinson's disease, or people suffering from psychiatric conditions, such as obsessive-compulsive disorder, or hard to treat epileptic seizures.

More recently, in 2017, a group of French researchers from different institutions, explored a more promising technology called Vagus Nerve Stimulation (VNS), which could restore consciousness in patients suffering from persistent vegetative state (PVS). The case we are discussing here is that of a 35-year-old patient who went through vagus nerve stimulation after having spent 15 years in a persistent vegetative state, following traumatic brain injury caused by a car crash collision.

The procedure involved an "implanted vagal nerve stimulator" the intensity of which was gradually increased to an electrical current of "1.5 mA over a period of 6 months." Following the stimulation, the Coma Recovery Scale-Revised (CRS-R) scores were "improved with increased VNS intensity, from 5 at baseline to 10 at 1.00-1.25 mA," which led the investigators to state that there was a notable transition from a persistent vegetative state (PVS) to a minimally conscious state (MCS).

Yet, despite such progress, the patient did not reach a "new level of function". He retrieved his ability to track an object with his eyes and turn his head upon request. "Perhaps most tellingly," said Sirigu, one of the French investigators, "the man's brain began producing stronger theta waves, electrical brain rhythms correlated with consciousness."

Following the vagal nerve stimulation, the patient's progress was monitored. Although, nine months later, his level of consciousness had not really improved, it did not revert to a vegetative state.

Consequently, the team of researchers reached the conclusion that "VNS in this patient appeared to promote the spread of cortical signals and caused an increase in metabolic activity leading to behavioral improvement as measured by the CRS-R scale and as reported by clinicians and family members."

Such discovery raised hopes that even comatose patients who remained in a vegetative state for years could one day regain "some basic level of consciousness". In so doing, it challenged the belief that loss of consciousness persisting beyond twelve months was "irreversible."

Our hypothesis is that the data accumulated over such a short period of time, would strongly suggest causality or correlation between an increase in consciousness and the use of Vagus Nerve Stimulation (VNS).

This first experiment was conducted on "a patient having received a pessimistic outcome on his chances to recover consciousness." According to the French team, if after fifteen years of vegetative state, no response was recorded "to any kind of stimulation or no improvements following clinical rehabilitation or pharmacological intervention," it was right to believe that such an experiment, if successful, "constitutes compelling arguments in favor of a causal effect of VNS as this is the only procedure that improved the patient's state."

Additionally, the experimenters explained how one could have argued that the beneficial effect was not the resultant of VNS, but rather, of the "surgical intervention per se." Their response was that "there was a delay of one month between the surgical implantation and the time when the stimulator was switched on. During this off period no significant changes were observed. Yet, after stimulation, one month was a sufficient delay to induce changes and to observe patient's behavior recovering."

In light of these explanations, our hypothesis according to which VNS is responsible for the patient's progress and regaining of consciousness, does make sense. Furthermore, because such type of study takes about seven years to be completed, "a single case investigation remains an important step to demonstrate the feasibility and the benefits, along the possible side effects, of VNS."

Several neuroscientists, including Nicholas Schiff of Weill Cornell Medicine in New York City stated that "a study of a single patient is not enough to make sweeping conclusions about the therapy," but that they were "optimistic about the treatment's promise."

They added that neuroscientists would need "to treat multiple patients with VNS under a variety of stimulation durations and strengths" to confirm the articulated conclusions.

To this position, however, we would respond that it could be extremely costly and time-consuming in light of the resources to deploy to do so.

Another potential roadblock to VNS, might be the difficulty to convince insurance companies to cover costs related to patients in a vegetative state who could potentially revert to awareness, or to explain to them, that minor progress in consciousness "counts as rehabilitation." According to Nicholas Schiff, "it has been an uphill battle."

These potential counterarguments against our hypothesis, may be completed by additional ethical challenges related to the administration of VNS, as discussed in a 2017 review by Vanhoecke and Hariz, which suggested that VNS administration resulted in more damage than good by creating a "self-awareness paradox, in which upon awakening, a patient becomes aware of the limitations imposed by incomplete recovery from the initial injury."

One could therefore wonder to what degree such interventions release suppressed thoughts or self-consciousness, while leaving the patient incapacitated and hampered with significant damage?

This would run against the very purpose of therapy for coma or minimally conscious states, which should be to retrieve consciousness and be able to communicate and interact with one's environment.

Vanhoecke and Hariz additionally questioned "the psychological impact" of such procedures, and further stated that "patients needed to retain the right to refuse continued treatment and to engage support for end-of-life considerations."

This brings us to another challenge directly related to vagus nerve stimulation (VNS) - questions pertaining to the withdrawal of life sustaining treatment in cases in which consciousness could be regained. How to handle such situations?

In an article written by Ofra G. Golan, and Esther-Lee Marcus, M.D. about Life-Sustaining Treatments to Patients with Permanent Loss of Cognitive Capacities, it is wisely stated that "the preliminary guiding principle of any ethical deliberation is that good ethics starts with good facts." In our current discussion, however, the line between the "known" and the "unknown" is still blurred, especially once newer procedures like VNS might prove us wrong regarding the irreversible nature of loss of consciousness.

The issue that we often encounter with patients like our French subject is that the facts pertaining to their actual well-being, lived experiences and wishes are unknown. This makes the framework of the four ethical principles - autonomy, beneficence, non-maleficence, and justice - hardly applicable.

Patients in such cases seem to lack a great deal of consciousness and awareness. Do they truly? To which extent? What about their feelings? How aware are they of their situation and lost abilities? Do they have, deep inside, untold wishes? Would they want to be kept alive, or let to die? Spiritually speaking, where is what could be considered to be their soul? Free or locked-in? What if the loss of self-consciousness spared them from being afraid to die? Was there ever, any such conscious fear in them in the first place?

As stated by Ofra Golan, "these uncertainties create an epistemic gap." Thus, before making any withdrawal of life sustaining treatment decision on minimally conscious patients we must be very cautious, especially in light of the weight attached to the slightest cognitive awareness recovery that VNS procedures may trigger. Such potential "miracle recovery" makes it worth examining the question of life sustaining treatment withdrawal with "great humbleness."

Although the respective fields of medicine and neuroscience have been evolving rapidly with new procedures such as VNS, which offers the potential of bringing back consciousness in persistent vegetative cases like our French patient, it would be wise, when considering issues such as the termination of treatment, to start by recognizing our ignorance in the face of our lack of "real understanding of the mechanisms of consciousness and the potential consequences of awakening on quality of life over the longer-term, which provide the basis for such decisions."

CONCLUSION

From this discussion, we would conclude that even though unprecedented and extremely promising and supported by strong indicators of causality, the VNS methodology will still need additional proof points over the coming years to gain the status of treatment, widely recognized as such by the main stakeholders in this field.

Moreover, the possibilities this procedure offers in terms of increased patient consciousness, raise significant ethical issues that will need to be addressed as this methodology gains wider adoption