Personalized Medicine and Disorders of Consciousness: An Alternate Convergence of Knowledge Towards a New Clinical Nosology
When scholars write about personalized medicine, most refer to the interpretation of molecular biomarkers for the development of therapeutics tailored to an individual’s disease. By moving beyond pathological phenotypes to better characterize disease and guide treatment, next generation personalized medicine moves more deeply into the biology of the malady to refine diagnostics at a genotypic, or molecular level. By understanding the unique biology of an individual’s disease, in most cases a malignancy, personalized therapies can be directed against specific biological targets. This focus maximizes therapeutic effect, decreases the variance of therapeutic response through more accurate diagnostic classification, and minimize side effects.
I will suggest another domain where the metaphor of personalized medicine is apt and consider its application in the realm of neuropsychiatric disorders. To do this I will invoke the example of emerging diagnostics, therapeutics and neuroethics informing the care of patients with disorders of consciousness., These conditions comprise a range of brain states that span coma, the vegetative, and minimally conscious states. Each of these states have behavioral and biological characteristics that warrant review and consideration for our discussion of personalized medicine.
With disorders of consciousness, as with cancer biology, overt presentation and underlying biological mechanisms may be discordant. Patients presenting similarly at the bedside may meaningful differences in their underlying neural circuitry. These distinctions, or the discordance between observed phenomenology and unobserved neurobiology can have normative implications for the diagnosis and treatment of these conditions.
To begin, let us review the prevailing nosology attendant to these brain states. When a patient loses consciousness, it can return without incident as after fainting or anesthesia. But in the cases of severe trauma, metabolic, or anoxic brain injury the duration and nature of impairment can linger. Notably for our consideration of personalized medicine, these conditions have historically been characterized diagnostically by their overt behavioral manifestations, that is responsiveness and neurological findings seen on bedside examination. To introduce a metaphor from genetics, so important to personalized medicine and cancer care therapeutics, what is seen at the bedside might be best thought of as a neurological phenotype.
This phenotype varies by brain state. For coma, it is characterized by an eyes-closed state of unresponsiveness. Coma which is a transient and self-limited state of about 10-14 days, unless it is prolonged and/or induced by medication, either resolves or progresses to the vegetative state. The vegetative state, first described by Jennett and Plum in The Lancet in 1972, is a state of wakeful unresponsiveness in which the eyes are open but there is no awareness of self, other or the environment. These patients have sleep-wake cycles and even a startle reflex but are unconscious. Depending upon the duration of the vegetative state it has been characterized as persistent or permanent. If it lasts for a month it is described as persistent. If it lasts over three months following anoxic injury and twelve following traumatic injury it was designated as permanent based on 1994 criteria published in the New England Journal of Medicine.
In 2018 these criteria were revised by the American Academy of Neurology, the American College of Rehabilitation Medicine as well as the National Institute on Disability, Independent Living, and Rehabilitation Research. These guidelines notably altered the designation from the permanent vegetative state to the chronic vegetative state because upwards of 20% of patients once thought to be permanently vegetative have the potential to migrate into the minimally conscious state (MCS).,[†]
MCS as a diagnostic condition was codified in 2002 as a state of consciousness in which patients show behavioral evidence of self, others or the environment. They will say their name, reach for objects, respond when someone comes in the room but only do so episodically and intermittently. The variability of the MCS patient’s phenotypic presentation of consciousness causes significant diagnostic challenges. When behavioral manifestations of consciousness are not demonstrated the patient appears vegetative. A notable paper found that 41% of patients in chronic care following traumatic brain injury and thought to be in the vegetative state were actually in the minimally conscious state.
We now appreciate from neuroimaging data that the underlying biology of the vegetative and minimally conscious states is neurophysiologically distinct. Patients in the vegetative state have autonomic functions grounded in the brain stem without higher integrative function. If properly diagnosed, vegetative patients do not have intact distributed neural networks in their brains. When presented with stimuli, the usual processing networks that handle and interpret this input are not activated beyond the primary sensory areas. Further integrative activity does not occur. This contrasts with the MCS patient where network responses, similar to unaffected individuals, can be sustained. Notably, this allows MCS patients to experience pain or process language in a manner impossible for vegetative patients.
A failure to properly assess these patients can have profound ethical implications. If a patient is diagnostically mischaracterized by phenotype as vegetative when they are in fact minimally conscious, they can either be thought to be insensate and in the vegetative state or non-communicative. While these presumptions would adhere to vegetative patients, they would not to patients in MCS. Thus mischaracterized, MCS could be deprived pain medication and/or deprived of communication, compounding untreated pain with the tragedy of an isolation known only to them and not suspected by family or friends who believe them incapable of responsiveness. This has implications for what I have described as the neuro-palliative care of these patients.
And herein lies the problem for a phenotypic characterization of patients with disorders of consciousness. It may be inaccurate and thus biologically misrepresentative. While a vegetative and minimally conscious patient may have similar phenotypes, their neurologic genotype – grounded in the circuitry of their distinct underlying neural networks – can be quite distinct. Because MCS patients have intact neural networks, these patients are biologically different from vegetative patients with whom they can too easily, and sometimes ideologically, be conflated.
I described this disconnect between observed phenotype observed and neurologic genotype in patients with intact neural networks on neuroimaging and a vegetative examination, as evidence of a non-behavioral minimally conscious state. If a patient activated appropriate regions in response to stimuli on neuroimaging, they could not logically fit the vegetative criteria of wakeful unresponsiveness. They were responsive, albeit at a level not observable by clinical examination. More recently, this phenomena has been described as cognitive motor dissociation (CMD), where what is manifested motorically or behaviorally is not commensurate with the cognitive capabilities within the brain.
The challenge of the discordance represented by CMD is akin to that seen between phenotype and genotype in conventional discussions of personalized medicine. Those of us who have treated patients with cancer, with seemingly the same disease have had patients with variable outcomes. This has made prognostication difficult. Why are these patients responding so differently to the same treatment? With the advent of genetic arrays, we now appreciate that what appeared to be the same diseases histologically were in fact biologically distinct. Considering cancer genetics, these conditions were distinct. They responded differently to treatment because they were different. With this realization, prognosis and treatment has evolved with each informed by a more sophisticated biomarkers.
In cancer biology precision medicine is an emerging success story. As a resident in medicine at Memorial Sloan Kettering Cancer Center I recall treating patients with the dreaded acute pro-myelocytic leukemia who did worse than their peers. They had horrific bleeding diatheses and were paradoxically treated with heparin to quell this complication. Of all the AML subtypes this was the one to avoid. But today with a deeper understanding of APL’s biology, and the advent of targeted therapy with all-trans retinoic acid, this is one of the AML subtypes with the best prognosis. There are, of course, other examples.
The challenge with disorders of consciousness is that we are several decades behind the progress made in cancer biology and personalized medicine. We are in a transition phase between behavioral criteria and a fuller understanding of the circuitry which might better characterize these conditions. With the advent of functional imaging, it almost is as if we had just discovered the microscope.
This presents a problem for prognostication and speaking with families as we make a transition between established behavioral metrics used at the bedside like the Coma Recovery Scale-Revised CRS-R) to neuroimaging criteria. While a physiologic approach to understanding will be useful in the longer term, the CRS-R still has the best test characteristics of any diagnostic modality. The challenge is how to use this behavioral (phenotypic) tool in conjunction with new technologies like neuroimaging and EEG. In the long run, this combination will yield a powerful synergy although it can produce confusion and mixed signals in the short term, making conversations with families especially challenging.
Knowledge is power and our knowledge base is expanding dramatically. The challenge is that we still know less than what we need to know. Today, we have a whole new suite of questions with which we did not need to grapple. Here scientific advance presents us with a paradox: new knowledge can lead to increased uncertainty and be disempowering. Consider the example of covert consciousness... Before we had neuroimaging, we had no knowledge of its possibility. Our assessment was based on what we saw at the bedside and we believed what we saw. Now we are not so sure. Neuroimaging has expanded our knowledge and presented us with a normative problem for which we still do not have a reliable solution.
An associated challenge posed by our advance in knowledge is presented by the newly designated chronic vegetative state. If 20% of patients once thought to be permanently vegetative have the prospect for additional recovery, how long is it prudent to wait? At what emotional costs for families and economic ones for society? We are in a period of tremendous intellectual advance but with this progress come new ethical challenges of which we were once perhaps blissfully unaware. Where once clinicians thought they knew unconscious when they saw it, now they can’t be sure. Consciousness might lurk beneath the surface unrecognized. Or it could reappear with the tincture of time, and/or novel therapeutics.
And this leads to personalized medicine and emerging therapeutics for this population. Like personalized medicine in cancer biology which is grounded in generalizable pathways, neuromodulation is based on an emerging knowledge of the circuitry of consciousness and its disruptions. As certain molecular-based illnesses are caused by discrete pathologic abnormalities that operate within known pathways, neuropsychiatric conditions have dislocations within constituent circuits. Recently, the mesocircuit has been identified as a key circuit that plays a key role in consciousness and its disruption.
Simply depicted, the mesocircuit links the thalamus with the brain stem below and the cortex above with the additional mediation of the basal ganglia. The brainstem provides arousal necessary but still insufficient for the achievement of consciousness. This requires the involvement of the integrative functions of the thalamus which brings in the cerebral cortex. It is a widely projected modular system with cortico-thalmo-cortical pathways whose disruption provides physiologic opportunities for personalized therapeutic engagement.
In 2007 our group pioneered the manipulation of this system with the first use of deep brain stimulation (DBS) in the minimally conscious state. Our work, published in Nature, demonstrated the ability of intralaminar thalamic DBS to improve cognitive function in a severely brain injured patient. In this proof of principle, first in human study, double blind, cross-over study, a patient who had been in a stable MCS for four years with an inability to communicate, eat by mouth and with impaired motor and postural control was able, with deep brain stimulation, to say six or seven word sentences and the first 16 words of the American Pledge of Allegiance. He could go shopping with his mother and voice preferences for clothing. He could eat by mouth for the first time in six years, manage his secretions and had improved motor and postural tone. From a normative point of view, his improved functionality led to what I have described as the restoration of agency ex machina, the ability to participate in decisions about his care at the level of assent and dissent. This was in some degree the restoration of his personhood lost beneath the shadows of a disorder of consciousness through the therapeutic capabilities of DBS.
Like molecular-based medicine, the provision of emerging therapeutics – most still in the investigational stage – requires skilled diagnostic assessment that transcends bedside examination and which is conversant with circuit-based derangements. Like molecular-based personalized medicine, we envision that a new nosology will emerge based on the therapeutic targets offered by distinct injuries. This would represent a transformational change in how these conditions are categorized and move robustly from a behavioral to circuit-based classification.
Until that occurs, and before we can assert generalizable patterns from a collected experience of engaging in this probative biology, itself a product of therapeutic investigations such as our work using deep brain stimulation in the injured brain, we will be in a state of personalized medicine by default. We will try to apply incomplete data sets in a particularistic way to individual patients with unique injury patterns. This will lead to interventions that appear as N=1 cohorts until data can be aggregated into predictable patterns.
This methodology, as essential as it is at the frontiers of knowledge, makes the traditional metrics (and ethics) of randomized clinical trials impossible. It calls for a different regulatory approach and what the philosopher of science, Miriam Solomon, has described as a pluralistic way of knowing. She suggests that we need both methodological rigor as well knowledge of mechanism and the integration of personal narratives., This has bearing on ethical and regulatory questions about informed consent, disclosure and discussions of proportionality.
And of course there is the additional epistemic complication when considering neuropsychiatric conditions. Whether one is attempting to restore or give voice to consciousness as my colleagues and I have tried to do, treat drug resistant depression, as the neurologist Helen Mayberg has done also using deep brain stimulation, or live with Parkinson’s Disease the question arises about the personal nature of the outcome., What are the goals and who decides them is perhaps the ultimate question of personalized medicine and the continuity of the true self.
Fundamentally then, what we are witnessing in the demarcated clinical landscape of disorders of consciousness is an epistemic transition between what is observed and what is understood. This transition represents a move away from well-worn patterns of practice informed by decades, if not centuries of diligent clinical observation, into a state of personalized care informed by the particularities of a patient’s injuries. In time, these responses to “personalized” therapeutics will be aggregated into generalizable findings applicable to groups of patients.
When this occurs, investigators will come up with a new nosology that replaces the descriptive one upon which we have long relied. This new diagnostic classification will not solely be grounded in what is observed but the responsiveness of circuit derangements to neuromodulation. In this way we will improve diagnostics, prognostication, and refine therapeutics for this population.
If we achieve this objective, traversing the perils of an intervening period of indeterminacy, we will have fulfilled an ancient mandate of medical inquiry as described by the great physician Sir William Osler, a founder of Johns Hopkins School of Medicine and late Regius Professor of Medicine at Oxford. In his classic The Leaven of Science, Osler observed that, “The determination of structure with a view to the discovery of function has been the foundation of progress”.
I believe that this period of so-called personalized medicine is part of this Oslerian journey. It only seems personal because we need to make our discoveries one patient at a time. But this quest is in a long tradition of medical inquiry pushing back the shrouds of ignorance so that patients individually, and then collectively, will benefit from the foundation of progress that has sprung from our careful interrogation of function and its variance in disease and injury.
[*] The E. William Davis, Jr., M.D. Professor of Medical Ethics, Chief, Division of Medical Ethics, Professor of Medicine, Professor of Medicine in Psychiatry, Professor of Medical Ethics in Neurology, Professor of Medical Ethics in Rehabilitation Medicine, Professor of Health Care Policy and Research, Weill Medical College of Cornell University; Co-Director, CASBI, The Consortium for the Advanced Study of Brain Injury, Weill Cornell Medical College and The Rockefeller University & Solomon Center Distinguished Scholar in Medicine, Bioethics and the Law, Solomon Center for Health Law and Policy, Yale Law School
[†] This change in designation, as yet not fully appreciated by the bioethics or religious communities, could well have bearing on how society reflects upon the right to die, in large part predicated upon the presumed futility and irreversibility of the vegetative state [See: Fins JJ. A Palliative Ethic of Care: Clinical Wisdom at Life’s End. Sudbury, MA: Jones and Bartlett. 2006]. While this is true for the majority of the patients in the chronic vegetative state, because the right to die began in the vegetative state in cases like Quinlan and was later contested in cases involving other patients in the vegetative state (Cruzan and Schiavo) [See: Fins JJ. Affirming the Right to Care, Preserving the Right to Die: Disorders of Consciousness and Neuroethics after Schiavo. Supportive & Palliative Care 2006;4(2): 169-178] the consequences of this change in designation from permanent to chronic could well have consequences in society outside of the house of medicine [See also: Fins JJ and Bernat JL. Ethical, Palliative, and Policy Considerations in Disorders of Consciousness. Arch Phys Med Rehabil. 2018; 99(9): 1927-1931].
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