May 2018—Trenton McKinley: ‘Brain-Dead’ Boy Wakes Up Hours Before Organ Donation (The Week)
September 2017—Jahi McMath, Girl Declared Brain Dead Three Years Ago, Might Still be Technically Alive, Judge Says (LA Times)
July 2017—Brain Dead Mother Gives Birth to Twins After Being Kept on Life Support for 123 Days (Inside Edition)
An increasing number of headlines reporting the awakening of people declared brain-dead raises the question, “Are brain-dead patients actually alive?” Until 1968, physicians defined death as “a total stoppage of the circulation of the blood, and a cessation of the animal and vital functions consequent thereupon, such as respiration, pulsation” and related cardiopulmonary functions . Then, a redefinition, drafted by the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death, incorporated “irreversible coma” as a new criterion for death . While this definition was well-intentioned, a neurological and ethical dilemma arises today when we find people with “permanently nonfunctioning” brains who later regain the very characteristics that render them alive. As we straddle the gray area between life and death, a closer inspection of the brain’s mechanisms for potentially recovering from a state resembling brain death can help revise criteria for accurately assessing irreversible coma and reveal novel targets for restoring consciousness through biomedical research innovations.
Diagnosing Brain Death
The President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research considered and incorporated ideas of “irreversible coma” from the definition drafted by a Harvard Medical School ad hoc committee, and in 1981, the Commission defined death in the Uniform Determination of Death Act as follows: “An individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem, is dead. A determination of death must be made in accordance with accepted medical standards .” To identify such accepted standards, the American Academy of Neurology (AAN) published updated guidelines for diagnosing brain death in 2010 . The protocol begins with the establishment of the cause of coma and exclusion of confounding factors, followed by determining the futility of interventions, and finally, the complete neurologic assessment that includes examining brainstem reflexes and apnea [5, 6].
Confirmatory tests, such as electroencephalography (EEG) and cerebral angiography, are optional for adults and children at least one year old and are recommended for children under one year of age. While some U.S. states require two neurologic examinations, the AAN guidelines suggest that one should be sufficient given that a “certain period of time has passed since the onset of the brain insult to exclude the possibility of recovery (in practice, usually several hours)” . Assuming the neurologic assessments are properly performed, some questionable points are whether the brain can mask its possibility of recovery in the hours or even days post-trauma and whether certain parts of the brain can remain functional despite passing the neurologic exam for brain death. What if even the confirmatory tests do not conclusively indicate whole-brain death?
Regaining Partial to Complete Brain Function
Once a physician has followed the AAN guidelines and declared that a brain is irreparably damaged (perhaps even having conducted an optional confirmatory test), could it be possible for the brain to recover to the point of, in some cases, full functionality? While the precise answer is still unknown and may differ case by case, there are several explanations that may account for these seemingly miraculous revivals. Brazilian neurologist Dr. Cicero Coimbra posited that a phenomenon called “ischemic penumbra” may be at play . Soon after traumatic brain injury, the brain may be receiving a minimal amount of blood such that cerebral blood flow is undetectable. Hence, current diagnostic criteria may lead physicians to conclude, on this basis, that the brain has no chance of recovery. Coimbra hypothesized that if blood was still flowing to parts of the brain, then some degree of recovery could be possible. Interestingly, physician Dr. Jean-Didier Vincent of the Institut Universitaire in France emphasized that although a brain-dead person has suffered destruction of the brain, there could be partial brain activity , as evidenced by hormonal production observed in the pregnant woman and Jahi McMath from the aforementioned headlines [7, 9]. When any such activity of the pituitary gland is observed, it becomes apparent that the patient should not be declared brain dead but rather in a state of coma. Even if these patients exhibit an absence of brainstem reflexes, they do not fit the criteria for whole-brain death, as part of their brains is still functional. As a result, diagnostic criteria may need revision to test for the possibility of subcortical forebrain structures retaining functionality.
Another plausible explanation for physicians being unable to detect vital signs after brain injury is catalepsy. Manifesting occasionally as a symptom of epilepsy, catalepsy is characterized by unresponsiveness, loss of muscle control, and slowing of vital signs such as respiration and pulse. In fact, a man who snored back to life minutes before autopsy was found to have epilepsy, and he presumably experienced a cataleptic episode, which might explain why three physicians declared him to be dead . To avoid this type of misdiagnosis, the physicians could have carefully examined the patient’s medical history to determine that he may have catalepsy, which would explain the unresponsiveness of his brain associated with brain death.
For Trenton McKinley, the 13-year-old boy who was misdiagnosed as brain-dead, awoke hours before his organs were donated; neural plasticity and ν-complexes (nu-complexes) may explain his quick recovery that took under three days . By neuroplasticity, the brain has the innate potential to heal itself after injury, and younger brains like Trenton’s may exhibit greater plasticity than more mature brains. Assuming that Trenton’s brainstem reflexes were absent and that his EEG flat-lined (i.e., he had no cortical activity), recovery may still have been possible due to ν-complexes (Figure 1). These quasi-rhythmic sharp-wave EEG waveforms are thought to form through the hippocampus’s ripple activity, which is high-frequency electrical activity of hippocampal neurons . Even when a patient has an isoelectric EEG that means no cortical activity is detected, the subcortical ν-complexes could be present and ultimately give rise to a functional cortex and — potentially — brainstem. Considering these possibilities for partial to complete brain recovery, criteria for establishing that a patient is brain dead may need to be revised to incorporate this potential for recovery. Furthermore, cutting-edge research is paving the way for regenerating brain activity in cases that were traditionally thought to be irreversible coma.
In 2016, a research team in Germany successfully transplanted embryonic neurons into the damaged brains of mice . If such findings in the mouse model could soon be translated into human medicine, then millions of stroke patients around the world, maybe even those deemed brain dead by current standards, could potentially be saved each year. We might be closer to that reality than imagined: Pittsburgh-based company Bioquark has recently planned clinical trials to inject a brain-dead patient’s own stem cells into the spinal cord to hypothetically regenerate neurons and essentially restore consciousness . Still other research groups are seeking inspiration from the brain’s natural recovery mechanisms that have yielded novel insights. A cocktail of molecules that can convert glial cells—one type of cell in the nervous system—into neural cells is among the latest advances in neurology . These exciting discoveries lend support to the seemingly radical idea that any brain-dead patient may one day regain consciousness and a fully functional brain.
Research into reviving people deemed brain dead by today’s standards can, in the future, help individuals with similarly damaged brains undergo a treatment to step out of a merely temporary state of coma. At the very least, more extensively studying phenomena such as ischemic penumbra, catalepsy, and neural plasticity that may initially veil brains with reversible coma can help physicians identify patients who do, indeed, have chances of recovery. If we soon discover a reliable method of clinically reviving “irreversibly” damaged brains or allow their natural course of recovery, then perhaps the most ethical option, with which ethicist Christian Brugger agrees, would be to consider brain death not as actual death but as a temporary state of lapsed consciousness that can potentially be cured .
The brain is undoubtedly a complex organ, with its mysteries still being solved today. Just as the quotidian cardiac defibrillator resuscitates those whose hearts have stopped beating, our era of rapid scientific progress may soon permit the regeneration of brain-dead patients’ consciousness. Considering this tremendous potential and to prevent cases like Jahi McMath’s and Trenton McKinley’s, it is in the best interest of the biomedical ethics community to further study the brain’s various mechanisms of recovery from comatose states. Consequently, revising the criteria for properly identifying irreversible coma may save countless lives. By better understanding how to treat patients in these types of cases, modern medicine and research can continue to revive both brains and hope for millions of patients and families.
Rohan Tummala is a student in the Departments of Molecular Biology and Neuroscience at Princeton University, Class of 2019. Upon graduating from Princeton this spring, he hopes to pursue a medical degree with a specialization in neurosurgery.