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The MRI of Jahi McMath and Its Implications for the Global Ischemic Penumbra Hypothesis
Abstract
Jahi McMath was diagnosed brain dead on 12/12/2013 in strict accordance with both the pediatric and adult Guidelines, reinforced by 4 isoelectric electroencephalograms and a radionuclide scan showing intracranial circulatory arrest. Her magnetic resonance imaging scan 9 1/2 months later surprisingly showed gross integrity of cortex, basal ganglia, thalamus, and upper brainstem. The greatest damage was in the white matter, which was extensively demyelinated and cystic, and in the lower brainstem, most likely from partial herniation that resolved. The apparent integrity of gray matter and the ascending reticular activating system may have provided a potential structural basis for the reemergence of some limited brain functions, while the white matter and lower brainstem lesions would have caused severe motor disability, brainstem areflexia and apnea. The findings indicate that there could never have been a period of sustained intracranial circulatory arrest. Rather, at the time of brain death diagnosis, low blood flow below the detection threshold of the radionuclide scan was sufficient to maintain widespread neuronal viability, though insufficient to support synaptic function. Her case represents the first indirect confirmation of the reality and clinical relevance of global ischemic penumbra, hypothesized in 1999 as a generally unacknowledged and possibly common brain death mimic.
... The clinical case data are published (13,14). Briefly, Ms McMath underwent a tonsillectomy at age 13 years, followed V C The Author(s) ...
... [12]). The clinical course of this extraordinary patient was reported in detail by one of us (DAS) who was involved directly in her case, along with neuroimaging findings 9 months after brain death declaration (13,14). After final cardiopulmonary arrest, she underwent autopsy examination. ...
... Maintained on ventilatory and other complementary support, she eventually was able to be cared for at home, with occasional hospitalizations for infections and metabolic derangements. Neuroimaging studies were performed 9 months after brain death declaration (i.e. 3 years and 9 months prior to "somatic" death), and reported by one of us (DAS) (14). Following a final hospital admission more than 4 years after brain death declaration, she succumbed to septic and abdominal complications. ...
Brain death (death by neurologic criteria) is declared in 2% of all in-hospital deaths in the United States. Published neuropathology studies of individuals maintained on cardiorespiratory support are generally decades old, and notably include only 3 cases with long intervals between brain and "somatic" death (68 days, 101 days, 20 years). Here, we share our observations in a young woman supported for nearly 4½ years following declaration of brain death after oropharyngeal surgery. While limited by tissue availability and condition, we found evidence of at least partial perfusion of the superficial cerebral and cerebellar cortices by external carotid and vertebral arteries (via meningeal and posterior pharyngeal branches), characterized by focal cellular reaction and organization. Dural venous sinuses had thrombosis and recanalization, as well as iron deposition. In nonperfused brain areas, tissue "mummification," akin to that seen in certain postmortem conditions, including macerated stillbirths and saponification (adipocere formation), was identified, and are reviewed herein. Unfortunately, correlation with years-earlier clinical and radiographic observations was not possible. Nevertheless, we feel that our careful neuropathologic inspection of this case expands the understanding of the spectrum of human brain tissue alterations possible in a very rarely seen set of conditions.
... Nearly 10 months later, her MRI scan showed surprising gross integrity of cortex, basil ganglia, and upper brainstem. 20 These findings supported that there was minimal blood flow (below the threshold to detect on a radionucleotide scan) sufficient to maintain widespread neuronal viability. ...
Since the beginning of time, man has been intrigued with the question of when a person is considered dead. Traditionally, death has been considered the cessation of all cardiorespiratory function. At the end of the last century a new definition was introduced into the lexicon surrounding death in addition to cessation of cardiac and respiratory function: Brain Death/Death by Neurologic Criteria (BD/DNC). There are medical, legal, ethical, and even theological controversies that surround this diagnosis. In addition, there is no small amount of confusion among medical practitioners regarding the diagnosis of BD/DNC. For families enduring the devastating development of BD/DNC in their loved one, it is the duty of the principal caregiver to provide a transparent presentation of the clinical situation and clear definitive explanation of what constitutes BD/DNC. In this report, we present a historical outline of the development of BD/DNC as a clinical entity, specifically how one goes about making a determination of BD/DNC, what steps are taken once a diagnosis of BD/DNC is made, a brief discussion of some of the ethical/moral issues surrounding this diagnosis, and finally the caregiver approach to the family of a patient who had been declared with BD/DNC. It is our humble hope that with a greater understanding of the myriad of complicated issues surrounding the diagnosis of BD/DNC that the bedside caregiver can provide needed closure for both the patient and the family enduring this critical time in their life.
... This phenomenon may explain the preservation of substantial (MRI-confirmed) brain tissue in the case of Jahi McMath, a child appropriately declared dead by clinical neurologic criteria and supportive ancillary testing, who, nonetheless, was maintained on ventilator support for several years and subsequently demonstrated motor responses to commands. 8 Conducting apnea testing in a neurologically devastated patient risks hypercarbia and cerebral ischemia that could be the coupe de grace in the progression from severe (but not irreversible) brain damage to permanent brain death. We find evidence for these concerns to be lacking. ...
... Several medical personnel, including a prominent pediatric neurologist, came to believe that Jahi could intermittently respond in a purposeful manner to verbal commands (such as "move your arm") (2). Additionally, the MRI examination performed 10 mo after the initial cardiac arrest unexpectedly demonstrated large regions of grossly intact brain, including cortex, basal ganglia, thalamus, upper brain stem, and cerebellum, which could serve as a structural basis for intermittent consciousness (8). Return of minimal responsiveness, if present, would directly challenge the presumption that BD is definitive and permanent. ...
The concept of brain death was introduced in the late 1960s and continues to develop. The article presents a brief history of the evolution of the idea of death by neurologic criteria. The concept is accepted worldwide, but there is still considerable variability in brain death determination protocols. New treatments for critical patients change the preconditions for brain death testing. The refinement of diagnostic techniques improves the capabilities of confirmatory tests. Controversial cases of determination of brain death cause public resonance and justified criticism of opponents of the concept. All these factors lead to review of some concept statements, terminology and update diagnostic protocols. In 2020, an international expert working group presented the minimum clinical standards for determination of brain death/death by neurologic criteria with guidance for various clinical circumstances. Some countries have already started to implement international recommendations and revise national diagnostic protocols. The extensive debate accompanying this process is an important contribution to the improvement of the concept of brain death.
The World Brain Death Project (WBDP) is a 2020 international consensus statement that provides historical background and recommendations on brain death/death by neurologic criteria (BD/DNC) determination. It addresses 13 topics including: (1) worldwide variance in BD/DNC, (2) the science of BD/DNC, (3) the concept of BD/DNC, (4) minimum clinical criteria for BD/DNC determination, (5) beyond minimum clinical BD/DNC determination, (6) pediatric and neonatal BD/DNC determination, (7) BD/DNC determination in patients on ECMO, (8) BD/DNC determination after treatment with targeted temperature management, (9) BD/DNC documentation, (10) qualification for and education on BD/DNC determination, (11) somatic support after BD/DNC for organ donation and other special circumstances, (12) religion and BD/DNC: managing requests to forego a BD/DNC evaluation or continue somatic support after BD/DNC, and (13) BD/DNC and the law. This review summarizes the WBDP content on each of these topics and highlights relevant work published from 2020 to 2023, including both the 192 citing publications and other publications on BD/DNC. Finally, it reviews questions for future research related to BD/DNC and emphasizes the need for national efforts to ensure the minimum standards for BD/DNC determination described in the WBDP are included in national BD/DNC guidelines and due consideration is given to the recommendations about social and legal aspects of BD/DNC determination.
Purpose of review
The adoption of brain death played a crucial role in the development of organ transplantation, but the concept has become increasingly controversial. This essay will explore the current state of the controversy and its implications for the field.
Recent developments
The brain death debate, long limited to the bioethics community, has in recent years burst into the public consciousness following several high-profile cases. This has culminated in the reevaluation of the Uniform Determination of Death Act (UDDA), which is in the process of being updated. Any change to the UDDA has the potential to significantly impact the availability of organs.
Summary
The current update to the UDDA introduces an element of uncertainty, one the brain death debate had not previously had.
When the Uniform Law Commission (ULC) was recently in the process of revising the Uniform Determination of Death Act (UDDA), Neurology® ran a series of debates over certain controversial issues being deliberated. Omitted was a debate over the fundamental concept underlying brain death. In his introductory article, Bernat offered reasons for this omission: "It is not directly relevant to practicing neurologists who largely accept brain death, do not question its conceptual basis, …." In this article I argue the opposite: the fundamental concept of death is highly relevant to the clinical criteria and tests used to diagnose it. Moreover, most neurologists in fact disagree with the conceptual basis articulated by Bernat. Basically, there are 3 competing concepts of death: (1) biological: cessation of the integrative unity of the organism as a whole (endorsed by Bernat and the 1981 President's Commission), (2) psychological: cessation of the person, equated with a self-conscious mind (endorsed by half of neurologists), and (3) the vital work concept proposed by the 2008 President's Council on Bioethics. The first actually corresponds to a circulatory, not a neurologic, criterion. The second corresponds to a "higher brain" criterion. The third corresponds loosely to the UK's "brainstem death" criterion. In terms of the biological concept, current diagnostic guidelines entail a high rate of false-positive declarations of death, whereas in terms of the psychological concept, the same guidelines entail a high rate of false-negative declarations. Brainstem reflexes have nothing to do with any death concept (their role is putatively to guarantee irreversibility). By shining a spotlight on the deficiencies of the UDDA through attempting to revise it, the ULC may have unwittingly opened a Pandora's box of fresh scrutiny of the concept of death underlying the neurologic criterion-particularly on the part of state legislatures with irreconcilably opposed worldviews.
This Element considers current legal, ethical, metaphysical, and medical controversies concerning brain death. It examines the implicit metaphysical and moral commitments and dualism implied by neurological criteria for death. When these commitments and worldview are not shared by patients and surrogates, they give rise to distrust in healthcare providers and systems, and to injustice, particularly when medicolegal definitions of death are coercively imposed on those who reject them. Ethical obligations to respect persons and patient autonomy, promote patient-centered care, foster and maintain trust, and respond to the demands of justice provide compelling ethical reasons for recognizing reasonable objections. Each section illustrates how seemingly academic debates about brain death have real, on-the-ground implications for patients and their families.
This chapter examines concepts and criteria of death and the coherence of their associations. Concepts of death fall into two broad categories: non-ontological and ontological. Non-ontological concepts include death as a cluster kind and death as a process; the corresponding criteria are stipulative, based on pragmatic concerns. Ontological concepts are essentially either psychological (cessation of “personhood,” equated with capacity for thinking and self-awareness) or biological (cessation of the human organism). The psychological concept corresponds to a “higher brain” criterion, namely irreversible, permanent nonfunction (destruction) of bilateral thalami (the sufficiency of neocortical destruction alone being uncertain); anatomically broader criteria are sufficient but not necessary. The biological concept corresponds to a criterion of irreversible, permanent cessation of circulation of oxygenated blood (irreversible cessation of brain function being necessary but not sufficient). Irreversible apneic unconsciousness is best understood not as a concept of death but as a stipulative criterion. Concepts of life and death and their corresponding criteria derive from fundamental worldviews, on which there has been no consensus for over two millennia, nor is there likely ever to be. Respect for deeply held fundamental worldviews requires allowance for personal specification of circulatory or brain-based criteria.
Irreversible loss of all functions of the entire brain must be confirmed in order to determine death by neurologic criteria (i.e. brain death). However, in many cases the accepted medical standards for determination of death by neurologic criteria cannot absolutely confirm either irreversibility or the loss of all functions of the entire brain. One way to reconcile this discrepancy is to require the absence of brain circulation to determine death by neurologic criteria. Prolonged absent brain circulation guarantees neuronal death, and is thus the only way to assure both irreversibility and loss of all functions of the entire brain. In this chapter, I discuss how the accepted medical standards for determination of death by neurologic criteria fail to determine death by neurologic criteria. I then discuss several benefits that will emerge if these accepted medical standards are amended to require the absence of brain circulation: (1) more accurate determination of loss of all functions of the entire brain, (2) more accurate determination of irreversibility, and (3) improved congruity with the determination of death by circulatory-respiratory criteria.
In this chapter, we discuss whether death requires permanent or irreversible cessation of function. We argue that death requires only permanent cessation of function, ultimately focusing on the application of this argument to determining death by neurologic criteria. Throughout history, we have relied on permanent cessation of function. The genuine possibility of reversing the cessation of function became real only from about the 1700s. The gradual introduction of the requirement of irreversibility reflects the ethical norm that everything should be done to revive a patient where this is possible and appropriate. However, this norm does not apply to patients for whom resuscitation is not appropriate. Since permanence covers both patient cohorts, it is a sound criterion for declaring death. Influential defenses of irreversibility, such as that of Don Marquis, are subjected to critical scrutiny.
Although death is irreversible, we present a few published reports of alleged “recovery” from death by neurologic criteria. We discuss the implications of these false-positive determinations and the concept of both (1) absence of brain circulation as the pathophysiological mechanism that leads to cellular death and (2) legal status.
Importance
There are inconsistencies in concept, criteria, practice, and documentation of brain death/death by neurologic criteria (BD/DNC) both internationally and within countries.
Objective
To formulate a consensus statement of recommendations on determination of BD/DNC based on review of the literature and expert opinion of a large multidisciplinary, international panel.
Process
Relevant international professional societies were recruited to develop recommendations regarding determination of BD/DNC. Literature searches of the Cochrane, Embase, and MEDLINE databases included January 1, 1992, through April 2020 identified pertinent articles for review. Because of the lack of high-quality data from randomized clinical trials or large observational studies, recommendations were formulated based on consensus of contributors and medical societies that represented relevant disciplines, including critical care, neurology, and neurosurgery.
Evidence Synthesis
Based on review of the literature and consensus from a large multidisciplinary, international panel, minimum clinical criteria needed to determine BD/DNC in various circumstances were developed.
Recommendations
Prior to evaluating a patient for BD/DNC, the patient should have an established neurologic diagnosis that can lead to the complete and irreversible loss of all brain function, and conditions that may confound the clinical examination and diseases that may mimic BD/DNC should be excluded. Determination of BD/DNC can be done with a clinical examination that demonstrates coma, brainstem areflexia, and apnea. This is seen when (1) there is no evidence of arousal or awareness to maximal external stimulation, including noxious visual, auditory, and tactile stimulation; (2) pupils are fixed in a midsize or dilated position and are nonreactive to light; (3) corneal, oculocephalic, and oculovestibular reflexes are absent; (4) there is no facial movement to noxious stimulation; (5) the gag reflex is absent to bilateral posterior pharyngeal stimulation; (6) the cough reflex is absent to deep tracheal suctioning; (7) there is no brain-mediated motor response to noxious stimulation of the limbs; and (8) spontaneous respirations are not observed when apnea test targets reach pH <7.30 and Paco2 ≥60 mm Hg. If the clinical examination cannot be completed, ancillary testing may be considered with blood flow studies or electrophysiologic testing. Special consideration is needed for children, for persons receiving extracorporeal membrane oxygenation, and for those receiving therapeutic hypothermia, as well as for factors such as religious, societal, and cultural perspectives; legal requirements; and resource availability.
Conclusions and Relevance
This report provides recommendations for the minimum clinical standards for determination of brain death/death by neurologic criteria in adults and children with clear guidance for various clinical circumstances. The recommendations have widespread international society endorsement and can serve to guide professional societies and countries in the revision or development of protocols and procedures for determination of brain death/death by neurologic criteria, leading to greater consistency within and between countries.
In this paper, I reviewed the case of Jahi McMath who was diagnosed as being in brain death (BD). Nonetheless, ancillary tests, performed 9 months after initial brain insult, showed conservation of intracranial structures, EEG activity, and autonomic reactivity to “Mother Talks” stimulus. She was clinically in a state of unarousable and unresponsiveness, without evidence of awareness of self or environment, but full absence of brainstem reflexes, and partial responsiveness rejected the possibility of being in coma. Jahi was not a UWS, because she was not in a wakefulness state, and showed partial responsiveness. LIS patients are wakeful and aware, and although these cases are quadriplegic, they fully or partially preserve brainstem reflexes, vertical eye movements, and/or blinking, and respire by their own, rejecting the possibility of classifying her as a LIS patient. She was not a MCS because she did not preserve arousal, and only partially preserved awareness. The CRS-R resulted in a very low score, not corresponding with MCS patients. MCS patients fully or partially preserve brainstem reflexes, and usually breathe by their own. MCS has been always described as a transitional state between coma, UWS, but MCS has never been reported in a patient who has all clinical BD findings. This case doesn’t contradict the concept of BD, but brings again to discussion the needs of using ancillary tests in BD. I concluded that Jahi represented a new state of disorder of consciousness, non-previously described, that I have termed: “responsive unawake syndrome” (RUS).
Delayed post-hypoxic leukoencephalopathy (DPHL) is an uncommon, potentially under-recognized, cause of hypoxia induced white matter injury. It characteristically follows a biphasic course: After an initial phase of altered neurologic status a recovery occurs which is then followed by a recurring phase of neurologic deterioration, typically 2–4 weeks after the initial event. At this time white matter changes can be identified on MRI, which are the hallmark of DPHL. The characteristics and the typical MR-imaging signs of DPHL are discussed in this case report.
The whole-brain criterion of death provides that a person who has irreversibly lost all clinical functions of the brain is dead. Bedside brain death (BD) tests permit physicians to determine BD by showing that the whole-brain criterion of death has been fulfilled. In a nonsystematic literature review, we identified and analyzed case reports of a mismatch between the whole-brain criterion of death and bedside BD tests. We found examples of patients diagnosed as BD who showed (1) neurologic signs compatible with retained brain functions, (2) neurologic signs of uncertain origin, and (3) an inconsistency between standard BD tests and ancillary tests for BD. Two actions can resolve the mismatch between the whole-brain criterion of death and BD tests: (1) loosen the whole-brain criterion of death by requiring only the irreversible cessation of relevant brain functions and (2) tighten BD tests by requiring an ancillary test proving the cessation of intracranial blood flow. Because no one knows the precise brain functions whose loss is necessary to fulfill the whole-brain criterion of death, we advocate tightening BD tests by requiring the absence of intracranial blood flow.
We compare and discuss three cases including: a clearly brain-dead patient, a vegetative state/unresponsive wakefulness syndrome (VS/UWS) patient and a patient diagnosed as brain-dead (BD) demonstrating some but not all clinical features of a BD state. Two of the patients demonstrated clear presentation allowing for an effective determination of state of death or consciousness. One patient, in comparison to the other two, presented with a complete absence of brainstem reflexes, absence of spontaneous driving to breath, and required permanent mechanical ventilation. Nonetheless, preservation of intracranial structures, remaining brain function in both brainstem and cerebral hemispheres was evidenced in the third case similar to the reported VS/UWS patient. Moreover, autonomic reactivity to mother's voice stimulation precluded the diagnosis of a BD in the latter case. This third patient was not comatose. The clinical examination demonstrated complete absence of brainstem reflexes, and no spontaneous driving to breath. This patient did not appear to be a VS/UWS, as she had not shown intermittent wakefulness with measurable sleep-wake cycles, and variably preserved cranial nerve reflexes. Therefore, the possibility of a responsive wakefulness state-minimally conscious state (MCS), or MCS emergence state was also excluded. This third patient in contradistinction to the other two demonstrates features similar to BD states, without being brain-dead, comatose, or VS/UWS or MCS states, and therefore rests somewhere on the spectrum of clinical consciousness. The importance of this paper is in that it highlights some of the difficulties in the clinical classification of states of consciousness, when the evaluation is categorized, showing that one of the patients presented rests somewhere else on the spectrum of clinical consciousness. Keywords: Brain death (BD); persistent vegetative state, unresponsive wakefulness syndrome (PVS/UWS), minimally conscious state (MCS), EEG, magnetic resonance imaging (MRI), autonomic nervous system (ANS), heart rate variability (HRV).
Introduction:
Delayed posthypoxic leukoencephalopathy (DPHL) may result from a variety of hypoxic insults, including respiratory depression from an opiate overdose. The underlying pathophysiological mechanism of DPHL remains uncertain. We describe a patient with a typical case of DPHL who responded clinically to antioxidant treatment.
Methods:
Clinical, serological, and radiographic investigations were undertaken in the evaluation of the patient.
Results:
A 63-year-old man developed altered mental status 10 days following recovery from an opiate overdose and aspiration pneumonia that required intubation. The clinical course and brain imaging were consistent with DPHL. Initiation of antioxidant therapy with vitamin E, vitamin C, B-complex vitamins, and coenzyme Q10 coincided with the prompt reversal of clinical deterioration.
Conclusions:
The potential therapeutic effect of antioxidants on DPHL needs to be explored in future cases. If this relationship indeed holds true, it would be consistent with the hypothesis that formation of reactive oxygen species during reperfusion plays a role in the pathophysiology of this disorder.
The absence of cerebral blood flow is presently considered the most reliable ancillary test in diagnosing brain death. A patient with an open skull fracture who met all criteria for brain death, including confirmatory postmortem studies, had a cerebral angiogram that showed unilateral preservation of cerebral circulation with diffuse extravasation of contrast material. We conclude that a skull defect may result in pressure reduction within the cranial cavity and persistent ipsilateral cerebral circulation, even after brain death. In this setting, diffuse extravasation of contrast material on angiography may reflect diffuse autolysis and suggest the diagnosis of brain death.
The data reviewed here suggest the possibility that a global reduction of blood supply to the whole brain or solely to the infratentorial structures down to the range of ischemic penumbra for several hours or a few days may lead to misdiagnosis of irreversible brain or brain stem damage in a subset of deeply comatose patients with cephalic areflexia. The following proposals are advanced: 1) the lack of any set of clinically detectable brain functions does not provide a safe diagnosis of brain or brain stem death; 2) apnea testing may induce irreversible brain damage and should be abandoned; 3) moderate hypothermia, antipyresis, prevention of arterial hypotension, and occasionally intra-arterial thrombolysis may contribute to good recovery of a possibly large subset of cases of brain injury currently regarded as irreversible; 4) confirmatory tests for brain death should not replace or delay the administration of potentially effective therapeutic measures; 5) in order to validate confirmatory tests, further research is needed to relate their results to specific levels of blood supply to the brain. The current criteria for the diagnosis of brain death should be revised.
Jahi McMath was a 13-year-old girl who was declared brain dead on December 12, 2013, after a hemorrhagic complication following complex oropharyngeal surgery. Her case gained international attention as her mother fought a legal battle to keep her on life support. Upon issuance of a death certificate shortly after the declaration of brain death, Jahi was transferred from California to New Jersey, where the law includes a religious exemption from the neurologic determination of death. There she became statutorily resurrected and was treated as a comatose, living patient for the next four and a half years. During that time, she underwent menarche and other aspects of puberty and developed intermittent responsiveness to commands, documented by eyewitness attestations and multiple home videos. Jahi died on June 18, 2018, from abdominal complications. This article summarizes her clinical history over those intervening years, taken directly from her medical records and personal observation. Her case represents an instance of a false-positive diagnosis of brain death, unquestionably made according to both the pediatric and adult guidelines, reinforced by four false-positive EEGs and a false-positive radionuclide blood flow test. The bioethical consequences of a nonnegligible risk of false-positive declaration of death are profound.
Death can be defined as the permanent cessation of the organism as a whole. Although the organism as a whole is a century-old concept, it remains better intuited than analyzed. Recent concepts in theoretical biology including hierarchies of organization, emergent functions, and mereology have informed the idea that the organism as a whole is the organism’s critical emergent functions. Because the brain conducts the critical emergent functions including conscious awareness and control of respiration and circulation, the cessation of brain functions is death of the organism. A newer concept, the brain as a whole, may offer a superior criterion of death to the whole-brain criterion, because it more closely matches accepted clinical brain death tests and confirms the cessation of the organism’s emergent functions. Although the concepts of organism as a whole and brain as a whole remain vague and in need of rigorous biophilosophical analysis, their future precision will be restricted by the categorical limitations intrinsic to theoretical biological models.
Background and purpose:
Prior studies regarding acute toxic leukoencephalopathy (ATL) are either small, or preliminary. Our aim was to evaluate etiologies of and differences in imaging severity and outcomes among various etiologies of ATL.
Materials and methods:
MRIs of patients with suspected ATL over 15 years were retrospectively reviewed; inclusion criteria were: MRI <3 weeks of presentation with both DWI and FLAIR. These were jointly graded by two neuroradiologists via a previously described score of severity. Clinical outcome was evaluated via both modified Rankin (mRS) and ATL outcome (ATLOS) scores, each being correlated with the DWI and FLAIR scores. Etiologic subgroups of n > 6 patients were statistically compared.
Results:
Of 101 included patients, the 4 subgroups of n > 6 were the following: chemotherapy (n = 35), opiates (n = 19), acute hepatic encephalopathy (n = 14), and immunosuppressants (n = 11). Other causes (n = 22 total) notably included carbon monoxide (n = 3) metronidazole (n = 2), and uremia (n = 1). The mean DWI/FLAIR severity scores were 2.6/2.3, 3.3/3.3, 2.1/2.1 and 2.0/2.5 for chemotherapeutics, opiates, AHE and immunosuppressants, respectively, with significant differences in both imaging severity and outcome (P = .003-.032) among subgroups, particularly immunosuppressant versus chemotherapy-related ATL and immunosuppressants versus opiates (P = .004-.032) related ATL. DWI and FLAIR severity weakly correlated with outcome (ρ = 0.289-.349, P < .005) but correlated stronger in the chemotherapy (ρ = 0.460-.586, P < .010) and opiate (ρ =.472-.608, P < .05) subgroups, which had the worst outcomes. ATL clinically resolved in 36%, with severe outcomes in 23% (coma or death, 9/16 deaths from fludarabine). Notable laboratory results were elevated CSF myelin basic protein levels in 8/9 patients and serum blood urea nitrogen levels in 24/91.
Conclusions:
Clinical outcomes of ATL vary on the basis of etiology, being worse in chemotherapeutic- and opiate-related ATL. Uremia may be a predisposing or exacerbating factor.
At its inception, “brain death” was proposed not as a coherent concept but as a useful one. The 1968 Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death gave no reason that “irreversible coma” should be death itself, but simply asserted that the time had come for it to be declared so. Subsequent writings by chairman Henry Beecher made clear that, to him at least, death was essentially a social construct, and society could define it however it pleased. The first widely endorsed attempt at a philosophical justification appeared thirteen years later, with a report from the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research and a seminal paper by James Bernat, Charles Culver, and Bernard Gert, which introduced the insightful tripartite scheme of concept, criterion, and tests for death. Their paper proposed that the correct concept of death is the “permanent cessation of functioning of the organism as a whole,” which tenuously remains the mainstream concept to this day. In this essay, I focus on this mainstream concept, arguing that equating brain death with death involves several levels of incoherence: between concept and criterion, between criterion and tests, between tests and concept, and between all of these and actual brain death praxis.
From the start, I followed the case of Jahi McMath with great interest. In December 2013, she clearly fulfilled the diagnostic criteria for brain death. As a neurologist with a special interest in chronic brain death, I was not surprised that, after she was flown to New Jersey, where she became statutorily resurrected and was treated as a comatose patient, Jahi's condition quickly improved. In 2014, her family reported that she sometimes responded to simple motor commands. I shared the general skepticism regarding these reports, assuming that the family was in denial and was misinterpreting spinal myoclonus (a rapid, involuntary twitch generated by the spinal cord) as volitional. The family had noticed that when Jahi's heart rate was above eighty beats per minute, she was more likely to respond, as though the heart rate reflected some sort of inner level of arousal. So they began to make video recordings. I have been privileged to be entrusted with copies of these recordings, forty‐eight of which proved suitable for assessing alleged responsiveness. All have been certified by a forensic video expert as unaltered. The first thing that struck me was that the great majority of the alleged responses were not spinal myoclonus. In fact, they did not resemble any type of spontaneous, involuntary movement described in patients paralyzed from high spinal cord lesions.
Among the old and new controversies over brain death, none is more fundamental than whether brain death is equivalent to the biological phenomenon of human death. Here, I defend this equivalency by offering a brief conceptual justification for this view of brain death, a subject that Andrew Huang and I recently analyzed elsewhere in greater detail. My defense of the concept of brain death has evolved since Bernard Gert, Charles Culver, and I first addressed it in 1981, a development that paralleled advances in intensive care unit treatment. The century‐old concept of the organism as a whole provides the fundamental justification for the equivalency of brain death and human death. In our technological age, in which increasing numbers of components and systems of an organism can be kept alive, and for longer intervals, the permanent cessation of functioning of the organism as a whole is the phenomenon that best corresponds to its death.
The widely accepted concept of brain death (BD) comprises the demonstration of irreversible coma in combination with the loss of brainstem reflexes and irreversible apnea. In some countries the combined clinical finding of coma, apnea, and loss of all tested brainstem reflexes ("brainstem death") is sufficient for diagnosing BD irrespective of the primary location of brain lesion. The present article aims to substantiate the need for ancillary testing in patients with primary infratentorial brain lesions. Anatomically, the "brainstem-death" syndrome can theoretically occur without relevant lesion of the mesopontine tegmental reticular formation (MPT-RF). Thus, a brainstem lesion may cause an apneic total locked-in syndrome, a rare syndrome with preserved capability for consciousness, mimicking "brainstem death". Findings in animals and humans have shown that alpha- or alpha/theta- EEG patterns in case of isolated brainstem lesion indicate intactness of relevant parts of the MPT-RF. In such patients the presence of irreversible coma has to be doubted, and the potential capacity for some degree of consciousness cannot be excluded as long as the EEG activity persists. Consequently the demonstration of either ancillary finding, electro-cortical inactivity or, preferably, cerebral circulatory arrest, is mandatory for diagnosing BD in patients with a primary infratentorial brain lesion.
This article clarifies some issues raised by Dr. Ariane Lewis in her recent “Current Opinion/Arguments” article on the case of Jahi McMath. Review of case materials. Jahi’s case most likely represents an instance of global ischemic penumbra (GIP) mimicking brain death (BD), with intracranial blood flow too low to support neuronal function or to be detected by radionuclide scan but sufficient to prevent widespread necrosis. Her MRI scan 9 months after the ischemic insult showed gross preservation of cortical and internal structures, incompatible with there ever having been a period of completely absent blood flow. Regarding Jahi’s alleged intermittent responsiveness, the set of videos, unsystematic as they are, constitutes convincing evidence that her movements in seeming response to command are not of spinal cord origin and are indeed voluntary responses, placing her in the category of minimally conscious state (MCS). In the absence of serial examinations by experts in MCS, the benefit of the doubt should be given. Unfortunately, her death on June 22, 2018, 4½ years after the diagnosis of BD, precludes such examinations. During those 4½ years, Jahi underwent menarche, with three documented menstrual periods, and ongoing pubertal development. Her case is an important example of false-positive diagnosis of BD, demonstrating the inability of current diagnostic standards to distinguish true BD from potentially reversible brain nonfunction due to GIP. The incidence of such mimicry is impossible to determine, because in most cases a BD diagnosis becomes a self-fulfilling prophecy.
Written by an eminent authority from the American Academy of Neurology's Committee on Ethics, Law, and Humanities, this book is an excellent text for all clinicians interested in ethical decision-making. The book features outstanding presentations on dying and palliative care, physician-assisted suicide and voluntary active euthanasia, medical futility, and the relationship between ethics and the law. New chapters in this edition discuss how clinicians resolve ethical dilemmas in practice and explore ethical issues in neuroscience research. Other highlights include updated material on palliative sedation, advance directives, ICU withdrawal of life-sustaining therapy, gene therapy, the very-low-birth-weight premature infant, the developmentally disabled patient, informed consent, organizational ethics, brain death controversies, and fMRI and PET studies relating to persistent vegetative state. © 2008 by Lippincott Williams & Wilkins, a Wolters Kluwer business © 1994 by Butterworth-Heinemann
• In a prospective study of 32 cases of brain death, gross and microscopic pathological appearances of the CNS were statistically analyzed and correlated with EEG and clinical findings. The diagnosis of a "respirator brain" is best made grossly after fixation, using commonly known gross pathological criteria. The microscopic changes are more unpredictable and variable than the gross findings. Respirator brain changes that can be relied on to confirm the clinical-EEG diagnosis of brain death generally take about 12 hours to become manifest after electrocerebral silence (ECS) and/or cerebral circulatory arrest, and are unaffected by the time interval between termination of respiratory support and refrigeration of the body or by delays in performance of the autopsy. Loss of brain-stem reflexes, evidence of herniation, and deterioration of the EEG to ECS correlate significantly with the development of a respirator brain in the respirator-dependent, comatose patient.
Non-perinatal hypoxic-ischaemic encephalopathy (HIE) has varying anatomical patterns dependent on the type of insult, the degree and duration of cerebral hypoxia, or presence and degree of hypoperfusion. Profound insults can affect the entire cerebral cortex or just the perirolandic cortex, the cerebellum and the deep grey matter structures. Less severe insults may affect only the watershed regions. The objective of this article is to review the anatomical patterns of non-perinatal HIEs by MRI.
To review and revise the 1987 pediatric brain death guidelines.
Relevant literature was reviewed. Recommendations were developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.
1) Determination of brain death in term newborns, infants, and children is a clinical diagnosis based on the absence of neurologic function with a known irreversible cause of coma. Because of insufficient data in the literature, recommendations for preterm infants <37 wks gestational age are not included in this guideline. 2) Hypotension, hypothermia, and metabolic disturbances should be treated and corrected and medications that can interfere with the neurologic examination and apnea testing should be discontinued allowing for adequate clearance before proceeding with these evaluations. 3) Two examinations, including apnea testing with each examination separated by an observation period, are required. Examinations should be performed by different attending physicians. Apnea testing may be performed by the same physician. An observation period of 24 hrs for term newborns (37 wks gestational age) to 30 days of age and 12 hrs for infants and children (>30 days to 18 yrs) is recommended. The first examination determines the child has met the accepted neurologic examination criteria for brain death. The second examination confirms brain death based on an unchanged and irreversible condition. Assessment of neurologic function after cardiopulmonary resuscitation or other severe acute brain injuries should be deferred for ≥24 hrs if there are concerns or inconsistencies in the examination. 4) Apnea testing to support the diagnosis of brain death must be performed safely and requires documentation of an arterial Paco2 20 mm Hg above the baseline and ≥60 mm Hg with no respiratory effort during the testing period. If the apnea test cannot be safely completed, an ancillary study should be performed. 5) Ancillary studies (electroencephalogram and radionuclide cerebral blood flow) are not required to establish brain death and are not a substitute for the neurologic examination. Ancillary studies may be used to assist the clinician in making the diagnosis of brain death a) when components of the examination or apnea testing cannot be completed safely as a result of the underlying medical condition of the patient; b) if there is uncertainty about the results of the neurologic examination; c) if a medication effect may be present; or d) to reduce the interexamination observation period. When ancillary studies are used, a second clinical examination and apnea test should be performed and components that can be completed must remain consistent with brain death. In this instance, the observation interval may be shortened and the second neurologic examination and apnea test (or all components that are able to be completed safely) can be performed at any time thereafter. 6) Death is declared when these criteria are fulfilled.
To provide an update of the 1995 American Academy of Neurology guideline with regard to the following questions: Are there patients who fulfill the clinical criteria of brain death who recover neurologic function? What is an adequate observation period to ensure that cessation of neurologic function is permanent? Are complex motor movements that falsely suggest retained brain function sometimes observed in brain death? What is the comparative safety of techniques for determining apnea? Are there new ancillary tests that accurately identify patients with brain death?
A systematic literature search was conducted and included a review of MEDLINE and EMBASE from January 1996 to May 2009. Studies were limited to adults.
In adults, there are no published reports of recovery of neurologic function after a diagnosis of brain death using the criteria reviewed in the 1995 American Academy of Neurology practice parameter. Complex-spontaneous motor movements and false-positive triggering of the ventilator may occur in patients who are brain dead. There is insufficient evidence to determine the minimally acceptable observation period to ensure that neurologic functions have ceased irreversibly. Apneic oxygenation diffusion to determine apnea is safe, but there is insufficient evidence to determine the comparative safety of techniques used for apnea testing. There is insufficient evidence to determine if newer ancillary tests accurately confirm the cessation of function of the entire brain.
An innocuous intravenous portable radioisotopic test using technetium 99m pertechnetate was employed to demonstrate the deficit of cerebral blood flow associated with brain death. The results are compared to those of bilateral carotid and vertebral angiography in 20 patients. Absence of a bolus tracing from the head in the presence of a control tracing of a bolus from the femoral artery in two successive studies one hour apart reliably correlated with the clinical and electroencephalographic findings signifying cerebral death in comatose, apneic patients. Angiography indicated absence of intracranial circulation in 10 patients. Stasis filling or retrograde emptying of arterial vessels (or both) occurred in 7 patients. There was no evidence of venous filling in any of these 17 patients; all of them had either an absent head bolus or an "intermediate tracing." Results indicate that either form of tracing represents a critical decrease of cerebral blood flow. Two other patients had evidence of severely impaired abnormal posterior fossa circulation without angiographic evidence of cerebral circulation; both of these patients had an absent head bolus. An additional patient had an unusually small head bolus, and angiography revealed extravasation of radiopaque material but no evidence of intracranial circulation. We conclude that the bolus technique is a helpful adjunct in diagnosing brain death.
Because of renewed public and scientific interest in the concept of brain death and its diagnostic criteria, an opinion survey was undertaken, polling the membership of the American Association of Neuropathologists, regarding the definition, gross and microscopical features, and pathogenesis of the syndrome popularly designated the "respirator brain." Of the 191 respondents who completed the questionnaire, 174 (91%) indicated that the term respirator brain is properly used to describe a specific pathological entity, and 160 (84%) considered the characteristics of respirator brain to be distinct from those of late fixation. Of the 174 respondents who accepted the designation, 148 (85%) regarded a history of respiratory dependency as essential, and a vast majority (95%) agreed that extensive tissue necrosis occurs with little inflammatory cell reaction; other criteria were more controversial. Microscopical changes that suggest a pathogenetic mechanism attracted a number of informative, limiting, or qualifying remarks. Nonetheless, 54% thought that impaired cerebral blood flow contributed to pathogenesis.
Because of the controversy over applying adult clinical and laboratory criteria to children suspected of brain death, xenon computed tomographic cerebral blood flow (XeCTCBF) and near simultaneous scintigraphy were studied in 10 children. Six met the clinical criteria, one of whom had three indeterminate scintigrams with only central flow on XeCTCBF. Another had considerable flow with scintigraphy and XeCTCBF. One with clinical and autopsy brainstem death but preserved cortical function also had flow on both. This preliminary study establishes that brain scintigraphy is occasionally hypersensitive to insufficient cerebral flow and promises more accurate early assessment with XeCTCBF. The expectation is that XeCTCBF can refine the criteria for the earlier establishment of brain death.
Causal factors in the development of “brain death” in respirator patients were analyzed in the present study. The syndrome, as manifested in the cases studied, is characterized by irreversible deterioration of nervous system function, with deepening coma and loss of electroencephalographic activity and, pathologically, by severe brain edema and softening, often with diffuse liquefaction necrosis. Results indicated that duration of treatment was not a factor in the respirator brain death syndrome. Of direct effect was the occurrence of systemic circulatory failure. Cardiac decompensation was a consistent component present in patients developing nervous system complications. In the respirator, with unrelieved congestive heart failure, stagnation of circulation occurs peripherally, in the extremities and intracranially, with consequent venous stasis-thrombosis, with ultimate total-organ venous infarction of the brain.
The development of effective therapies for acute ischemic stroke presumes the existence of potentially salvageable ischemic tissue when therapy is initiated because it is widely assumed that the effectiveness of most acute stroke therapies under development is related to reducing ultimate infarct size to promote functional improvement. Such salvageable ischemic tissue was previously labeled the ischemic penumbra and must be distinguished from irreversible injury.
Pathological identification of irreversibility (infarction) appears to lag behind the actual development of this condition, and reversible injury after focal ischemia should be differentiated from infarction. Imaging and biochemical markers apparently can provide clues for distinguishing potentially salvageable from irreversibly injured ischemic tissue in experimental and clinical stroke. Recent positron emission tomography and MRI studies suggest that these clinically available imaging technologies will be useful for determining the presence of ischemic penumbra in individual stroke patients. The progression from potentially reversible to irreversible injury after focal brain ischemia has many potential mechanisms that may be synergistic and vary among individuals.
Delineating and prioritizing these mechanisms provides the opportunity to develop multiple potential acute stroke therapies that ultimately will be used in combination, perhaps directed by imaging technology.
The concept of whole-brain death is under attack again. Scholars are arguing that the concept of brain death per se--regardless of the focus on "higher," "stem" or "whole"--is fundamentally flawed. These scholars have identified what they believe are serious discrepancies between the definition and criterion of brain death, and have pointed out that medical professionals and lay persons remain confused about its meaning. Yet whole-brain death remains the standard for determining death in much of the Western world and its defenders believe this concept best maps onto our everyday conception of death.
One rationale for equating "brain death" (BD) with death is that it reduces the body to a mere collection of organs, as evidenced by purported imminence of asystole despite maximal therapy. To test this hypothesis, cases of prolonged survival were collected and examined for factors influencing survival capacity.
Formal diagnosis of BD with survival of 1 week or longer. More than 12,200 sources yielded approximately 175 cases meeting selection criteria; 56 had sufficient information for meta-analysis. Diagnosis was judged reliable if standard criteria were described or physicians made formal declarations. Data were analyzed by means of Kaplan-Meier curves, with treatment withdrawals as "censored" data, compared by log-rank test.
Survival probability over time decreased exponentially in two phases, with initial half-life of 2 to 3 months, followed at 1 year by slow decline to more than 14 years. Survival capacity correlated inversely with age. Independently, primary brain pathology was associated with longer survival than were multisystem etiologies. Initial hemodynamic instability tended to resolve gradually; some patients were successfully discharged on ventilators to nursing facilities or even to their homes.
The tendency to asystole in BD can be transient and is attributable more to systemic factors than to absence of brain function per se. If BD is to be equated with death, it must be on some basis more plausible than loss of somatic integrative unity.
White matter lesions representing ischemic demyelination have evolved in terms of our understanding of their pathogenesis and potential clinical significance. Low density lesions on CT brain scan, most commonly seen in the periventricular region, also frequently seen in the centrum semiovale, have been termed 'leukoaraiosis'. In the past years, it was not uncommon at all to hear the term 'Binswanger's disease' used in an attempt to define the neurological sequelae of such lesions. Further refinement came with the advent of magnetic resonance imaging (MRI) brain scan which is particularly sensitive to such white matter areas of increased signal intensity, which tend to be seen particularly well on T2-weighted and fluid attenuation inversion recovery (FLAIR) scans. The major challenge has been to correlate the clinical attributes with such relatively frequent findings in the elderly population. Recent studies have looked at lesion load in a fashion analogous to that seen with multiple sclerosis. A particularly relevant clinical model for white matter disease is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) which combines the potential components of small vessel disease, resulting in progressive neurological deficit, with a common association with migraine which can also be associated with white matter lesions. However, the most common pathogenic factor associated with the microangiopathy, which appears to be at the heart of ischemic demyelination, continues to be hypertension. How well we are able to tie in the various pathological mechanisms associated with this end organ damage of the brain will determine how well we can arrive at effective interventions for a common contributor to neurological deficits in the elderly.
This report describes the brain autopsy of a boy who at age 4(1/2) years experienced an episode of fulminant Haemophilus influenzae type b bacterial meningitis, resulting in massive brain destruction and the clinical signs of brain death. However, medical intervention maintained him for an additional two decades. Subsequent autopsy revealed a calcified intracranial spherical structure weighing 750 g and consisting of a calcified shell containing grumous material and cystic spaces with no recognizable neural elements grossly or microscopically. This case represents an example of long survival of brain death with a living body.
Global hypoxic-ischemic injury (HII) to the brain is a significant cause of mortality and severe neurologic disability. Imaging plays an important role in the diagnosis and treatment of HII, helping guide case management in the acute setting and providing valuable information about long-term prognosis. Appropriate radiologic diagnosis of HII requires familiarity with the many imaging manifestations of this injury. Factors such as brain maturity, duration and severity of insult, and type and timing of imaging studies all influence findings in HII. Severe hypoxia-ischemia in both preterm and term neonates preferentially damages the deep gray matter, with perirolandic involvement more frequently observed in the latter age group. Less profound insults result in intraventricular hemorrhages and periventricular white matter injury in preterm neonates and parasagittal watershed territory infarcts in term neonates. In the postnatal period, severe insults result in diffuse gray matter injury, with relative sparing of the perirolandic cortex and the structures supplied by the posterior circulation. Profound hypoxia-ischemia in older children and adults affects the deep gray matter nuclei, cortices, hippocampi, and cerebellum. Because findings at conventional imaging may be subtle or even absent in the acute setting, particularly in neonates, magnetic resonance spectroscopy can help establish the diagnosis of HII. Promising new neuroprotective strategies designed to limit the extent of brain injury caused by hypoxia-ischemia are currently under investigation.
Neuropathology of brain death
- J E Leestma
Jahi McMath: a new state of disorder of consciousness
- C Machado
- Jahi