Original Article
Neuropathological Findings in the Brain of Karen Ann Quinlan -- The Role of the Thalamus in the Persistent Vegetative State
N Engl J Med 1994; 330:1469-1475May 26, 1994
- Abstract
Background
Karen Ann Quinlan had a cardiopulmonary arrest in 1975 and died 10 years later, having never regained consciousness. Her story prompted a national debate about the appropriateness of life-sustaining treatment in patients who are in a persistent vegetative state and led to the development of medicolegal guidelines for the care of such patients. This report describes the neuropathologic features of Quinlan's brain.
Methods
The entire brain and spinal cord were systematically sampled for histologic examination. The brain stem and central cerebrum were embedded en bloc and serially sectioned. Three-dimensional computer reconstructions helped visualize the topographic features of the lesions.
Results
Contrary to expectation, the most severe damage was not in the cerebral cortex but in the thalamus, and the brain stem was relatively intact. The neuropathological findings included extensive bilateral thalamic scarring, bilateral cortical scars primarily in the occipital pole and parasagittal parieto-occipital region, and bilateral damage to cerebellar and focal-basal-ganglia regions. The brain stem and basal forebrain and the hypothalamic components of the ascending arousal systems and brain-stem regions critical to cardiac and respiratory control were undamaged. The lesions were consistent with hypoxia-ischemia after the cardiopulmonary arrest.
Conclusions
Although the neuropathological findings in the case of Karen Ann Quinlan were complex, the disproportionately severe damage in the thalamus as compared with the cerebral cortex supports the hypothesis that the thalamus is critical for cognition and awareness and may be less essential for arousal.
Media in This Article
Figure 1
The Brain at Autopsy.Figure 2
Light-Microscopical Section of the Whole Brain.Article Activity
- Article
In 1975 the case of Karen Ann Quinlan dramatized the moral and legal debate over life-sustaining treatment after the irreversible loss of all meaningful cognitive functions1-3. After a cardiopulmonary arrest and coma, Quinlan was in a persistent vegetative state. Her parents sought permission from the court to let her die naturally by the discontinuation of “extraordinary” treatment -- in particular, mechanical ventilation -- which they thought was sustaining her “hopeless” condition. The Quinlans eventually won their case, and the ventilator was removed in 1976. Quinlan nevertheless survived another nine years in a persistent vegetative state. Her case led to the development of medicolegal guidelines for the care of such patients2,3.
In the persistent vegetative state, there is wakefulness (arousal) but neither cognition nor awareness3-6. Patients in this state have survived up to 37 years6 with intact sleep-wake cycles and cardiopulmonary regulation but no manifestation of awareness, thought, or emotion3-5. A full description of the persistent vegetative state appears elsewhere in this issue6. This report describes the neuropathological findings in Karen Ann Quinlan, thereby completing the clinical data in this landmark case.
Case Report
The clinical history and findings are based on examination of the patient by one of us, interviews with the attending physicians, and a review of all relevant documents, including medical and nursing records. At 21 years of age, Karen Ann Quinlan had a cardiopulmonary arrest after accidentally ingesting a combination of prescription sedatives and alcohol. When she was found, she was unresponsive, apneic, pulseless, and cyanotic with dilated pupils. She received cardiopulmonary resuscitation. In the emergency room, a pulse was present, but she was otherwise unchanged and was placed on a ventilator. Within the first hour after cardiopulmonary arrest, spontaneous respirations and normal vital signs had returned, but the patient remained unresponsive to noxious stimuli and was areflexic. During the first 12 hours, there was sequential improvement, with the development of pinpoint pupils and sluggish reaction to light, upper-extremity flexion, toe inversion, responsivity to pain, gag and cough reflexes, spontaneous movement of all extremities, and finally, opening of the eyes in response to auditory stimuli. Aspiration pneumonia led to a tracheostomy on the second day. Hypoxia occurred transiently, with a low arterial partial pressure of oxygen of 45 mm Hg. During the first week after the arrest, stimulus-induced postural patterns were seen, including flexion and clenching of the hands, plantar flexion and inversion of the feet, turning of the head to the right, yawning, and grunting. With intense stimulation, there was flexion of the upper and lower extremities with marked spastic rigidity, opisthotonos, and upward rolling of the eyes. There was no response to threatening gestures. Oculocephalic and oculovestibular reflexes had returned to normal. All extremities withdrew in response to a pinprick.
During the first six months after the arrest, Quinlan had unequivocal sleep-wake cycles but never showed signs of awareness of her environment or cognitive function. During sleep she rarely triggered the ventilator. Severe contractures developed, and orofacial movements (e.g., grimacing) dominated the arousal responses in association with marked diaphoresis, tachycardia, and tachypnea. Quinlan's movements were never goal-directed but always stereotypical and reproducible with a given stimulus. Although she had the full range of eye movement, her eyes moved randomly with occasional disconjugate components, and she never responded to stimuli with meaningful extraocular movements. Quinlan had sufficient primary motor competence to respond in a meaningful fashion had any cognitive function been intact, which buttressed the clinical diagnosis of a persistent vegetative state, not a locked-in state (i.e., conscious but with severe paralysis, making vocal communication impossible). A brain scan and bilateral carotid and vertebral angiograms were unremarkable. Electroencephalograms showed cortical activity (predominantly low-voltage fast activity [beta]) when the patient was awake. When she appeared to be asleep, there was intermittent low-voltage activity of 3 to 7 Hz θ, infrequent activity in the alpha range, and occasional slower activity in the delta range. During the first six months after the arrest, the patient became severely cachectic, and her weight stabilized at 32 to 34 kg (down from 52 kg) with hypercaloric feeding. Multiple lung, bladder, and decubitus-ulcer infections were treated.
During the second six months after the arrest, Quinlan began to trigger the ventilator more frequently while asleep, and she was weaned from it over a period of a month, one year after the arrest. Seizures (episodic twitching of the extremities, mouth, and eyes for about 30 seconds) developed and were successfully treated with phenytoin. A computed tomographic scan five years after the arrest revealed cerebral and cerebellar atrophy with generalized dilatation of ventricular and cisternal systems. Fourteen months after the arrest, Quinlan was transferred to a nursing home where she remained in a persistent vegetative state until her death nine years later from overwhelming infection.
General Autopsy Findings
An autopsy was performed 13 hours after death. The immediate cause of death was a combination of bacterial bronchopneumonia, vegetative endocarditis, and meningitis. The findings included severe cachexia (body weight, 27 kg); hyperextension of the neck with deviation of the face to the right; severe flexion contractures and skeletal-muscle atrophy; chronic decubitus ulcers; septic emboli in the heart, kidney, spleen, and small intestine; a subacute renal infarct; and adrenal lipid depletion.
Neuropathological Findings
The brain and spinal cord were fixed in 20 percent formalin for three years. The central cerebrum from the frontal horn to the atria of the lateral ventricles was embedded en bloc in paraffin (Paraplast) and cut into serial sections that were 20 micrometers thick. This cerebral block contained the entire thalamus, hypothalamus, basal ganglia, hippocampus, amygdala, basal forebrain, temporal lobe, posterior frontal cortex, and parietal cortex to the level of the atria. Six other cerebral blocks, anterior and posterior to this large block and approximately 5 mm thick, were processed similarly. Sections every 2 mm were stained alternately with a combination of hematoxylin and eosin and Luxol fast blue and with cresyl violet. The brain stem was embedded in toto and sectioned serially; alternating sections every 260 micrometers were stained with hematoxylin and eosin and Luxol fast blue or with cresyl violet, and selected sections were immunostained for glial fibrillary acidic protein. Representative sections of the cerebellum and spinal cord were also examined. To help correlate the clinical and anatomical findings, three-dimensional computer reconstructions were generated from serial sections of the central cerebrum and the entire brain stem7. For the reconstruction of the cerebrum, every 100th section (a total of 22 sections) was analyzed, and for the reconstruction of the brain stem, every 60th section (a total of 40 sections) was analyzed. A three-dimensional atlas of the distribution of lesions was made by computerized digitization of the boundaries of individual nuclei, fiber tracts, and lesions7. Reference atlases of the human thalamus and brain stem were used8,9.
The unfixed brain was underweight (835 g; normal weight, 1300 g) owing to atrophic tissue, primarily in the cerebral cortex, cerebellum, and thalamus. Bacterial meningitis with microabscesses scattered throughout the brain parenchyma, representing the terminal process, did not compromise the assessment of the underlying, long-standing brain damage. Cortical scarring was severe in the parasagittal region bilaterally from the precentral gyrus of the posterior frontal lobe to the parieto-occipital fissure in the distribution of the arterial border zones of the middle, anterior, and posterior cerebral arteries (Figure 1Figure 1
The Brain at Autopsy., 2, and 3). Neuronal loss with gliosis was severe in this parasagittal lesion, and there was loss of myelin and gliosis in the underlying white matter, associated corpus callosum, and superior portions of the posterior limb of the internal capsule (Figure 2Figure 2Light-Microscopical Section of the Whole Brain. and Figure 3Figure 3
Three-Dimensional Reconstruction of the Distribution of Scarring (of All Degrees of Severity) in the Central Cerebrum.). The parietal cortical atrophy involved superior areas 5 and 7 but spared inferior areas 39 and 40. The occipital poles, including the primary visual cortex (area 17), were also severely atrophic bilaterally, with profound neuronal loss, gliosis, and myelin loss. Focal, microscopic scars (minimal-to-moderate neuronal loss and gliosis) were identified in the insula, cingulate gyrus, orbitofrontal cortex (the arterial border zone of the anterior and middle cerebral arteries), and parahippocampal gyrus bilaterally (Figure 3). Throughout the remaining cerebral cortex, there was no obvious neuronal loss (Figure 4Figure 4
Light-Microscopical View of the Frontal Cortex.). In several prefrontal regions there were subtle focal increases in astroglial nuclei, particularly in the upper laminae, but neuronal loss was not apparent. The central white matter was characterized by a mild pallor of the myelin in the prefrontal and temporal lobes bilaterally, but there was no reactive gliosis or obvious breakdown of myelin. There was moderate hydrocephalus ex vacuo (Figure 2). Wallerian degeneration was present in the corticospinal tracts bilaterally.The thalamus was bilaterally and symmetrically atrophic (Figure 2, 3, and 5). Damage was characterized by gliosis and neuronal loss ranging from minimal to complete within individual nuclei (Figure 5Figure 5
Three-Dimensional Reconstruction (Panel A) and Light-Microscopical Section (Panel B) of the Thalamus.). The extensive damage obliterated the cytoarchitectonic boundaries and resulted in overall contraction and anatomical distortion of the thalamus; nevertheless, efforts were made to assess the degree of involvement within a nucleus by correlating the lesion with the approximate boundaries of the nucleus in reference atlases8. The most severe damage was in a paramedian and lateral distribution, particularly in the central and posterior portions, and involved the anterior, ventral lateral, dorsomedial, and lateral posterior nuclei (Figure 5). The pulvinar was also severely affected but contained islands of residual neurons. The ventroposterior lateral and medial nuclei were moderately involved. Damage in the intralaminar nuclei ranged from mild (in the parafascicular nucleus) and moderate (in the centromedial nucleus) to severe (in all others). There was severe neuronal loss in the middle-to-posterior portions of the reticular nucleus. The medial and lateral geniculate nuclei were severely affected medially, and there was wallerian degeneration of the optic radiations. There was virtually no damage in the midline paraventricular nucleus, medioventral nucleus, lateral dorsal nucleus, and subthalamic nucleus bilaterally. The zonae incerta and pretectum were mildly gliotic.In the caudate nucleus and putamen, there was bilateral and symmetric neuronal loss and gliosis in the posterior and superior regions, and there was mild gliosis in the globus pallidus. The nucleus basalis of Meynert, septal nuclei, amygdala, and nucleus accumbens were histologically intact. In the hypothalamus, the nuclei appeared to be intact, except for the mamillary bodies, in which there was severe neuronal loss and gliosis; the fornix, alveus, and fimbria were pale. There was neuronal loss and gliosis in area CA4 of the hippocampus. The entire cerebellum was severely sclerotic (Figure 1), with loss of Purkinje and granule cells, Bergmann gliosis, and demyelination. Neuronal loss was severe in the dentate nuclei.
Brain-stem regions subserving arousal, sleep, autonomic and ventilatory control, and upper-airway regulation were histologically intact. These regions included the reticular formation (e.g., the nucleus pontis oralis, nucleus pontis caudalis, and nucleus paragigantocellularis lateralis), locus coeruleus, interpeduncular nucleus, raphe nuclei, parabrachial complex, vagal nuclei, and hypoglossal nucleus. The one exception was the rostral nucleus cuneiformis (midbrain reticular formation), which was slightly gliotic. In the inferior olive (cerebellar relay), there was severe neuronal loss and gliosis bilaterally; these changes were considered secondary to retrograde transsynaptic degeneration from the widespread loss of Purkinje cells. There was severe neuronal loss, gliosis, and axonal spheroids in the nuclei gracilis and cuneatus medialis, with bilateral degeneration of the posterior columns, which was most pronounced in the cervical fasciculus gracilis. Myelin staining was slightly pale in peripheral nerves.
Discussion
The pathologic features of Karen Ann Quinlan's brain included bilateral and symmetric damage in the thalamus; bilateral scars restricted primarily to the parasagittal parieto-occipital region and occipital pole in an otherwise relatively well-preserved cerebral cortex; bilateral damage to cerebellar and focal-basal-ganglia regions; and relative sparing of the brain stem, basal forebrain, and hypothalamus, with the exception of atrophic mamillary bodies. The lesions were consistent with hypoxic ischemic injury and cerebral edema due to the cardiopulmonary arrest that had occurred 10 years before death. An analysis of these lesions suggests at least three mechanisms of damage: a hypoxic insult to vulnerable neuronal populations (e.g., the cerebellar cortex), ischemic damage to arterial border zones (e.g., the parasagittal parieto-occipital region), and ischemic damage due to vascular compression from possible brain herniations that were partial or were reversed immediately after the cardiopulmonary arrest (e.g., the calcarine cortex in the posterior cerebral-artery distribution)10. The hypoxic ischemic damage to the thalamus may reflect a combination of compressive and intrinsic susceptibility factors, with the most severe damage in the paramedian and posterolateral regions supplied primarily by the thalamogeniculate branches of the posterior cerebral artery. The degeneration of the posterior column probably resulted from nutritional deficiencies and compression of the peripheral nerves, which are recognized complications of the persistent vegetative state11.
The persistent vegetative state raises fundamental questions about the neuroanatomical basis of human consciousness and the nature of brain damage that leads to a dissociation of cognition and awareness from arousal4. Previous clinical and anatomical studies of the persistent vegetative state have reported extensive bilateral damage to the cerebral cortex, sometimes approaching total decortication, with variable involvement of subcortical regions (including the thalamus) and sparing of the brain-stem regions that control ventilation, autonomic activity, and pupillary function12-17. Separation of the cerebral cortex from its subcortical connections by widespread, bilateral demyelination has likewise been observed18,19. Such reports reinforce the accepted role of the cerebral cortex in cognition and awareness and of the brain stem in the vegetative state. In Quinlan's case, however, the most extensive and bilateral damage was not in the cerebral cortex or white matter. In other patients in the persistent vegetative state, cerebral cortical damage has varied widely, and as in Quinlan, has sometimes seemed insufficient to cause the global defects4. One explanation emphasizes the extensive connections between cortical regions and suggests that focal cortical damage may alter function in undamaged regions4. Another explanation attributes the global defects to the cumulative effect of a combination of cortical or subcortical lesions20. The presence of bilateral lesions in the thalamus observed in Quinlan as well as in other patients,16,21,22 however, suggests that widespread damage to this structure may produce or contribute substantially to a clinical state similar to that resulting from widespread and bilateral damage in the cerebral cortex or white matter alone.
The hypothesis that the thalamus plays a key part in the persistent vegetative state is supported by the highly interdependent relation between the thalamus and the cerebral cortex and by increasing recognition of the role of the thalamus in cognitive processing. Several studies suggest that cognitive functions are mediated by parallel distributed networks in the association cortex23-27. The vertical column, considered the basic unit of the cerebral cortex, forms information-processing modules with adjacent columns that are connected with other specific cortical and subcortical regions, including thalamic nuclei23-27. Components of a particular cognitive function are distributed among the connected regions in a particular network, with each region involved in a different aspect of the function; consequently, lesions in one region of a network may impair that region's component of cognitive ability or all the components mediated by the network as a whole23-28. The idea that thalamic nuclei are critical components of distributed networks is supported by clinical observations that a lesion in a thalamic nucleus that is preferentially connected with a particular region of the cortical association (e.g., the dorsomedial nucleus with the prefrontal cortex) results in functional impairment similar to that associated with damage in the cortical region itself26,28-32. In Quinlan's case, some of the most severe damage was in thalamic nuclei closely connected with regions of the cortical association that are involved in multiple and diverse cognitive functions, including selective attention,23,26,28-32 suggesting that this damage was the chief cause of her global impairment. This idea is further supported by reports of dementia that is indistinguishable from that produced by diffuse cerebral cortical disease in patients with bilateral tumors, infarcts, or degeneration restricted to the thalamus28,33,34.
Quinlan had intact arousal in spite of extensive bilateral damage in the thalamus. Historically, arousal has been thought to be dependent on the activation of the cerebral cortex by a relay of inputs from the brain-stem reticular formation through diffuse and widespread projections from the intralaminar and midline nuclei of the thalamus (known as the reticular activating system)26,28,35-37. In addition, the thalamic reticular nucleus has been described as the pacemaker that globally modulates thalamic activity during various levels of arousal from brain-stem inputs36,37. Recently, however, the essential role of the thalamus in arousal has been challenged, in part by the recognition that the cerebral cortex can be directly activated by cholinergic, serotonergic, noradrenergic, and histaminergic arousal systems that originate in the brain stem, basal forebrain, or hypothalamus and do not project through the thalamus35-39. In Quinlan's case, the relative sparing of these components of the extrathalamic ascending arousal systems, in association with bilateral thalamic damage and only a focally damaged cerebral cortex, supports the hypothesis from studies of animals that thalamic and extrathalamic pathways mediate arousal in parallel and that the thalamus may not be essential for arousal when the extrathalamic pathways are intact. Residual neurons were present in intralaminar and reticular regions in Quinlan's case, and certain midline nuclei were spared. Thus, arousal may have resulted from a combination of extrathalamic and residual thalamic activation. Nevertheless, the findings in her case reinforce the idea that arousal is mediated by pathways that are separate from those involved in cognition and awareness and suggest that stimulation of the cerebral cortex by thalamic and extrathalamic ascending systems may be sufficient for arousal but not for cognition and awareness (which nevertheless depend on arousal)4.
The persistent vegetative state in Ms. Quinlan probably did not result from thalamic damage alone. It is likely, for example, that lesions in the parieto-occipital border zones contributed to the attention defect, because the involved parietal area is part of the distributed attention network and isolated bilateral parietal lesions can result in inattention to visual stimuli26,28. The multiple focal lesions in Quinlan's brain may support the hypothesis that the persistent vegetative state results from a complex interplay of discrete cortical and subcortical damage and represents the sum of primary and secondary pathogenic factors, which varies among patients, particularly since lesions in the persistent vegetative state are virtually never restricted to a single locus12-22. However, focal extrathalamic lesions such as those observed in Quinlan (parasagittal atrophy, occipital atrophy, and cerebellar sclerosis) are not themselves known to cause global deficits in cognition, awareness, and affect26,28,40,41. Extensive thalamic damage with little or only focal damage in the cerebral cortex has been noted in other patients in the persistent vegetative state16,21,22. Such thalamic damage, however, has been related primarily to the role of the thalamus in the reticular activating system16 and, more recently, to its role in cognition,22 as we have emphasized in Quinlan's case. Similarly, previous reports have considered thalamic neuronal loss in the persistent vegetative state to be secondary to transsynaptic degeneration from cortical lesions or to be too small to result in global deficits13. The severity, uniformity, bilaterality, and vascular topographic features of the thalamic damage in Quinlan's case suggest that it was primary damage after the cardiopulmonary arrest. The gliosis observed in focal cerebral cortical regions, on the other hand, may reflect subtle neuronal loss secondary to transsynaptic degeneration from thalamic damage and long-standing cortical deactivation and decreased use of oxygen and glucose in the persistent vegetative state42,43.
In conclusion, although the neuropathological findings in Quinlan's case were multifocal and complex, the disproportionately severe and bilateral damage in the thalamus as compared with the damage in the cerebral cortex supports the hypothesis that the thalamus is critical for cognition and awareness and may be less essential for arousal. Taken with emerging information about the part that the thalamus plays in cognition and reports of thalamic dementia, these findings point to the role of the thalamus in the pathogenesis of the persistent vegetative state.
Presented at the annual meeting of the American Association of Neuropathologists, St. Louis, June 18-21, 1992.
Supported in part by the Children's Hospital Mental Retardation Core Grant (P30-HD18655) and a grant from the Heckscher Foundation for Children, New York (to Dr. Korein).
We are indebted to Mr. and Mrs. Joseph Quinlan, the parents of Karen Ann Quinlan, for their permission to conduct this study and for their aid in advancing medical knowledge; to the parents' attorney, P.W. Armstrong, Esq.; to Dr. E.S. Cho, Department of Pathology (Neuropathology), University of Medicine and Dentistry of New Jersey, for referring this case for neuropathological examination; to Drs. Kristen M. Harris and John Davis, Image Graphics Laboratory, for technical assistance in the three-dimensional computerized reconstructions; to Mr. Dixon Yun for photographic assistance; to Dr. Patrick Barnes for postmortem neuroimaging; to Ms. Regena Bradeen for assistance in the preparation of the manuscript; and to Drs. Holcombe E. Grier, Dawna D. Armstrong, and Martin A. Samuels for helpful comments on the manuscript.
Source Information
From the Departments of Pathology (H.C.K.) and Neurology (H.C.K., A.P., P.D.), Children's Hospital and Harvard Medical School, Boston; the Department of Neurology, New York University Medical Center and Bellevue Hospital, New York (J.K.); and the New Jersey Medical Examiner's Office and Edwin H. Albano Institute of Forensic Science, Newark (R.G.).
Address reprint requests to Dr. Kinney at the Dept. of Pathology, Enders Bldg., Rm. 209, Children's Hospital, 300 Longwood Ave., Boston, MA 02115.
- References
References
1
In re Quinlan, 70 N.J. 10, 355 A2d 647, cert. denied sub nom. Garger v. New Jersey, 429 U.S. 922 (1976).
2
Armstrong PW ,Colen BD . From Quinlan to Jobes: the courts and the PVS patient. Hastings Cent Rep 1988;18:37-40
Web of Science | Medline3
Position of the American Academy of Neurology on certain aspects of the care and management of the persistent vegetative state patient: adopted by the Executive Board, American Academy of Neurology, April 21, 1988, Cincinnati, Ohio
Web of Science | Medline4
Plum F, Posner JB. The diagnosis of stupor and coma. Vol. 19 of Contemporary neurology. 3rd ed. Philadelphia: F.A. Davis, 1980:1-86.
5
Korein J . Brain death: interrelated medical and social issues: terminology, definitions, and usage. Ann N Y Acad Sci 1978;315:6-18
CrossRef | Medline6
The Multi-Society Task Force on PVS
Full Text | Web of Science | Medline7
Filiano JJ ,Kinney HC . Arcuate nucleus hypoplasia in the sudden infant death syndrome. J Neuropathol Exp Neurol 1992;51:394-403
CrossRef | Web of Science | Medline8
Hirai T ,Jones EG . A new parcellation of the human thalamus on the basis of histochemical staining. Brain Res Brain Res Rev 1989;14:1-34
CrossRef | Web of Science | Medline9
Olszewsky J, Baxter D. Cytoarchitecture of the human brain stem. 2nd ed. Basel, Switzerland: S. Karger, 1981.
10
Lindenberg R . Compression of brain arteries as pathogenetic factor for tissue necroses and their areas of predilection. J Neuropathol Exp Neurol 1955;14:223-243
CrossRef | Web of Science | Medline11
Mamoli B, Sluga E, Zacherl H, Gerstenbrand F. The apallic syndrome and secondary lesions of peripheral nerves. In: Ore GD, Gerstenbrand F, Lucking CH, Peters G, Peters UH, eds. The apallic syndrome. New York: Springer-Verlag, 1977:14-21.
12
Brierley JB ,Graham DI ,Adams JH ,Simpson JA . Neocortical death after cardiac arrest: a clinical, neurophysiological, and neuropathological report of two cases. Lancet 1971;2:560-565
Web of Science | Medline13
Dougherty JH Jr ,Rawlinson DG ,Levy DE ,Plum F . Hypoxic-ischemic brain injury and the vegetative state: clinical and neuropathologic correlation. Neurology 1981;31:991-997
Web of Science | Medline14
Ingvar DH ,Brun A ,Johansson L ,Samuelsson SM . Survival after severe cerebral anoxia with destruction of the cerebral cortex: the apallic syndrome. Ann N Y Acad Sci 1978;315:184-214
CrossRef | Medline15
French JD . Brain lesions associated with prolonged unconsciousness. Arch Neurol Psychiatr 1952;68:727-740
Web of Science16
Korein J ,Maccario M . On the diagnosis of cerebral death: a prospective study on 55 patients to define irreversible coma. Clin Electroencephalogr 1971;2:178-19917
Brierley JB ,Miller AA . Fatal brain damage after dental anaesthesia: its nature, etiology, and prevention. Lancet 1966;2:869-873
CrossRef | Web of Science | Medline18
Strich SJ . Diffuse degeneration of the cerebral white matter in severe dementia following head injury. J Neurol Neurosurg Psychiatry 1956;19:163-185
CrossRef | Web of Science | Medline19
Ginsberg MD ,Hedley-Whyte ET ,Richardson EP Jr . Hypoxic-ischemic leukoencephalopathy in man. Arch Neurol 1976;33:5-14
Web of Science | Medline20
Arensi C ,Nerenatiu F ,Carp N . Persistent vegetative state after multiple head trauma: a clinicopathologic study. Acta Neurochir (Wien) 1981;59:45-53
CrossRef | Web of Science | Medline21
Jellinger K. Pathology and pathogenesis of apallic syndromes following closed head injuries. In: Ore GD, Gerstenbrand F, Lucking CH, Peters G, Peters UH, eds. The apallic syndrome. New York: Springer-Verlag, 1977:14-21.
22
Relkin NR ,Petito CK ,Plum F . Coma and the vegetative state associated with thalamic injury after cardiac arrest. Ann Neurol 1990;28:221-221 abstract.
Web of Science23
Goldman-Rakic PS . Topography of cognition: parallel distributed networks in primate association cortex. Annu Rev Neurosci 1988;11:137-156
CrossRef | Web of Science | Medline24
Mountcastle VB ,Lynch JC ,Georgopoulos A ,Sakata H ,Acuna C . Posterior parietal association cortex of the monkey: command functions for operations within extrapersonal space. J Neurophysiol 1975;38:871-908
Web of Science | Medline25
Selemon LD ,Goldman-Rakic PS . Common cortical and subcortical targets of the dorsolateral prefrontal and posterior parietal cortices in the rhesus monkey: evidence for a distributed neural network subserving spatially guided behavior. J Neurosci 1988;8:4049-4068
Web of Science | Medline26
Mesulam M-M . A cortical network for directed attention and unilateral neglect. Ann Neurol 1981;10:309-325
CrossRef | Web of Science | Medline27
Mountcastle VB. An organizing principle for cerebral function: the unit module and the distributed system. In: Edelman GM, Mountcastle VB. The mindful brain: cortical organization and the group-selective theory of higher brain function. Cambridge, Mass.: MIT Press, 1978:7-50.
28
Mesulam M-M. Patterns in behavioral neuroanatomy: association areas, the limbic system, and hemispheric specialization. In: Mesulam M-M, ed. Principles of behavioral neurology. Philadelphia: F.A. Davis, 1985:1-70.
29
Cambier J ,Elghozi D ,Strube E . Lesions du thalamus droit avec syndrome de l'hemisphere mineur: discussion du concept de negligence thalamique. Rev Neurol (Paris) 1980;136:105-116
Web of Science30
Squire LR ,Moore RY . Dorsal thalamic lesion in a noted case of human memory dysfunction. Ann Neurol 1979;6:503-506
CrossRef | Web of Science | Medline31
Castaigne P ,Buge A ,Cambier J ,Escourolle R ,Brunet P ,Degos JD . Demence thalamique d'origine vasculaire par ramollissement bilateral, limite au territoire du pedicule retro-mamillaire: a propos de deux observations anatomo-cliniques. Rev Neurol (Paris) 1966;114:89-107
Web of Science | Medline32
Watson RT ,Valenstein E ,Heilman KM . Thalamic neglect: possible role of the medial thalamus and nucleus reticularis in behavior. Arch Neurol 1981;38:501-506
Web of Science | Medline33
Schulman S . Bilateral symmetrical degeneration of the thalamus: a clinico-pathological study. J Neuropathol Exp Neurol 1957;16:446-470
CrossRef | Web of Science | Medline34
Kinney H ,Burger PC ,Vogel FS . Subacute diencephalic angioencephalopathy -- report of an additional case. J Neurol Sci 1980;45:73-81
CrossRef | Web of Science | Medline35
Jones BE. Influence of the brainstem reticular formation, including intrinsic monoaminergic and cholinergic neurons, on forebrain mechanisms of sleep and waking. In: Mancia A, Marini G, eds. The diencephalon and sleep. New York: Raven Press, 1990:31-48.
36
McCormick DA . Neurotransmitter actions in the thalamus and cerebral cortex and their role in neuromodulation of thalamocortical activity. Prog Neurobiol 1992;39:337-388
CrossRef | Web of Science | Medline37
Steriade M ,McCormick DA ,Sejnowski TJ . Thalamocortical oscillations in the sleeping and aroused brain. Science 1993;262:679-685
CrossRef | Web of Science | Medline38
Foote SL ,Morrison JH . Extrathalamic modulation of cortical function. Annu Rev Neurosci 1987;10:67-95
CrossRef | Web of Science | Medline39
Vanderwolf CH . Cerebral activity and behavior: control by central cholinergic and serotonergic systems. Int Rev Neurobiol 1988;30:225-340
CrossRef | Web of Science | Medline40
Aldrich MS ,Alessi AG ,Beck RW ,Gilman S . Cortical blindness: etiology, diagnosis, and prognosis. Ann Neurol 1987;21:149-158
CrossRef | Web of Science | Medline41
Leiner HC ,Leiner AL ,Dow RS . The human cerebro-cerebeller system: its computing, cognitive, and language skills. Behav Brain Res 1991;44:113-128
CrossRef | Web of Science | Medline42
Ingvar DH ,Sourander P . Destruction of the reticular core of the brain stem: a patho-anatomical follow-up of a case of coma of three years' duration. Arch Neurol 1970;23:1-8
Web of Science | Medline43
Levy DE ,Sidtis JJ ,Rottenberg DA , et al. Differences in cerebral blood flow and glucose utilization in vegetative versus locked-in patients. Ann Neurol 1987;22:673-682
CrossRef | Web of Science | Medline
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Nuria Lull, Enrique Noé, Juan José Lull, Javier García-Panach, Javier Chirivella, Joan Ferri, Diego López-Aznar, Pablo Sopena, Montse Robles. (2010) Voxel-based statistical analysis of thalamic glucose metabolism in traumatic brain injury: Relationship with consciousness and cognition. Brain Injury 24:9, 1098-1107
CrossRef6
Jai Madhok, Anil Maybhate, Wei Xiong, Matthew A. Koenig, Romergryko G. Geocadin, Xiaofeng Jia, Nitish V. Thakor. (2010) Quantitative assessment of somatosensory-evoked potentials after cardiac arrest in rats: Prognostication of functional outcomes*. Critical Care Medicine 38:8, 1709-1717
CrossRef7
N. Lull, E. Noé, J.J. Lull, J. García-Panach, G. García-Martí, J. Chirivella, J. Ferri, R. Sopena, L. de La Cueva, M. Robles. (2010) Metabolismo talámico y situación neurológica tras un traumatismo craneoencefálico. Estudio mediante PET-FDG y morfometría basada en vóxel. Neurología 25:3, 174-180
CrossRef8
N. Lull, E. Noé, J.J. Lull, J. García-Panach, G. García-Martí, J. Chirivella, J. Ferri, R. Sopena, L. de La Cueva, M. Robles. (2010) Thalamic metabolism and neurological outcome after traumatic brain injury. A voxel-based morphometric FDG-PET study. Neurología (English Edition) 25:3, 174-180
CrossRef9
C. Machado,, J. Korein,. (2009) Persistent Vegetative and Minimally Conscious States. Reviews in the Neurosciences 20:3-4, 203-220
CrossRef10
POONAM LIGAM, ROBIN L. HAYNES, REBECCA D. FOLKERTH, LENA LIU, MAY YANG, JOSEPH J. VOLPE, HANNAH C. KINNEY. (2009) Thalamic Damage in Periventricular Leukomalacia: Novel Pathologic Observations Relevant to Cognitive Deficits in Survivors of Prematurity. Pediatric Research 65:5, 524-529
CrossRef11
Nicholas D. Schiff. (2009) Central Thalamic Deep-Brain Stimulation in the Severely Injured Brain. Annals of the New York Academy of Sciences 1157:1, 101-116
CrossRef12
John M. Luce, Douglas B. White. (2009) A History of Ethics and Law in the Intensive Care Unit. Critical Care Clinics 25:1, 221-237
CrossRef13
HEIDI LOUISE RICHARDSON, ADRIAN MARK WALKER, ROSEMARY SYLVIA CLAIRE HORNE. (2008) Sleep position alters arousal processes maximally at the high-risk age for sudden infant death syndrome. Journal of Sleep Research 17:4, 450-457
CrossRef14
Margaret L. Campbell. (2008) Treating Distress at the End of Life. AACN Advanced Critical Care 19:3, 340-344
CrossRef15
Klaus Wild, Franz Gerstenbrand, Giuliano Dolce, Heinrich Binder, Pieter E. Vos, Leopold Saltuari, Yuri Alekseenko, Rita Formisano, Annegret Ritz, Erika Ortega-Suhrkamp, Johannes R. Jörg, Alexander A. Potapov, José León-Carrión, Rimantas Vilcinis, George A. Zitnay. (2007) Guidelines for Quality Management of Apallic Syndrome / Vegetative State. European Journal of Trauma and Emergency Surgery 33:3, 268-292
CrossRef16
Joseph J. Fins. (2007) Border Zones of Consciousness: Another Immigration Debate?. The American Journal of Bioethics 7:1, 51-54
CrossRef17
Petra Stoerig. 2006. Neural Correlates of Consciousness as State and Trait. .
CrossRef18
PIM VAN LOMMEL. (2006) Near-Death Experience, Consciousness, and the Brain: A New Concept about the Continuity of Our Consciousness Based on Recent Scientific Research on Near-Death Experience in Survivors of Cardiac Arrest. World Futures: The Journal of General Evolution 62:1-2, 134-151
CrossRef19
Ashok Panigrahy, Patrick D. Barnes, Robert L. Robertson, Lynn A. Sleeper, James W. Sayre. (2005) Quantitative analysis of the corpus callosum in children with cerebral palsy and developmental delay: correlation with cerebral white matter volume. Pediatric Radiology 35:12, 1199-1207
CrossRef20
E. F. M. Wijdicks, R. E. Cranford. (2005) Clinical Diagnosis of Prolonged States of Impaired Consciousness in Adults. Mayo Clinic Proceedings 80:8, 1037-1046
CrossRef21
Anil K. Seth, Bernard J. Baars. (2005) Neural Darwinism and consciousness. Consciousness and Cognition 14:1, 140-168
CrossRef22
Hajnalka Bokor, Samuel G.A. Frère, Mark D. Eyre, Andrea Slézia, István Ulbert, Anita Lüthi, László Acsády. (2005) Selective GABAergic Control of Higher-Order Thalamic Relays. Neuron 45:6, 929-940
CrossRef23
Freimut D. Juengling, Jan Kassubek, Hans-Jürgen Huppertz, Thomas Krause, Thomas Els. (2005) Separating functional and structural damage in persistent vegetative state using combined voxel-based analysis of 3-D MRI and FDG-PET. Journal of the Neurological Sciences 228:2, 179-184
CrossRef24
Robert Wade Kenny. (2005) A Cycle of Terms Implicit in the Idea of Medicine: Karen Ann Quinlan as a Rhetorical Icon and the Transvaluation of the Ethics of Euthanasia. Health Communication 17:1, 17-39
CrossRef25
Ericka L. Fink, Henry Alexander, Christina D. Marco, C. Edward Dixon, Patrick M. Kochanek, Larry W. Jenkins, Yichen Lai, Holly A. Donovan, Robert W. Hickey, Robert S. Clark. (2004) Experimental model of pediatric asphyxial cardiopulmonary arrest in rats. Pediatric Critical Care Medicine 5:2, 139-144
CrossRef26
Laurence M. Katz, Amanda Young, Jonathan E. Frank, Yuanfan Wang, Kyunam Park. (2004) Neurotensin-induced hypothermia improves neurologic outcome after hypoxic-ischemia*. Critical Care Medicine 32:3, 806-810
CrossRef27
J.C Solacroup, J.H Tourrette. (2003) Apport de la neuroradiologie à l'évaluation et au pronostic de l'éveil des comas traumatiques. Annales de Réadaptation et de Médecine Physique 46:2, 104-115
CrossRef28
Ronald M Harper, Christopher A Richard, Luke A Henderson, Paul M Macey, Katherine E Macey. (2002) Structural mechanisms underlying autonomic reactions in pediatric arousal. Sleep Medicine 3, S53-S56
CrossRef29
Oded Szold, Irith I. Reider-Groswasser, Ron Ben Abraham, Galit Aviram, Yoram Segev, Philippe Biderman, Patrick Sorkine. (2002) Gray–white matter discrimination—a possible marker for brain damage in heat stroke?. European Journal of Radiology 43:1, 1-5
CrossRef30
Robert Wade Kenny. (2001) Toward a Better Death: Applying Burkean Principles of Symbolic Action to Interpret Family Adaptation to Karen Ann Quinlan's Coma. Health Communication 13:4, 363-385
CrossRef31
Patricia Tassi, Alain Muzet. (2001) Defining the states of consciousness. Neuroscience & Biobehavioral Reviews 25:2, 175-191
CrossRef32
Nicholas D Schiff, Fred Plum. (2000) The Role of Arousal and ???Gating??? Systems in the Neurology of Impaired Consciousness. Journal of Clinical Neurophysiology 17:5, 438-452
CrossRef33
Aldo Ragazzoni, Antonello Grippo, Fabrizio Tozzi, Gaetano Zaccara. (2000) Event-related potentials in patients with total locked-in state due to fulminant Guillain–Barré syndrome. International Journal of Psychophysiology 37:1, 99-109
CrossRef34
S. Laureys, S. Goldman, C. Phillips, P. Van Bogaert, J. Aerts, A. Luxen, G. Franck, P. Maquet. (1999) Impaired Effective Cortical Connectivity in Vegetative State: Preliminary Investigation Using PET. NeuroImage 9:4, 377-382
CrossRef35
Nicholas D. Schiff, Fred Plum. (1999) Cortical function in the persistent vegetative state. Trends in Cognitive Sciences 3:2, 43-44
CrossRef36
Derk W Krieger. (1998) Evoked potentials not just to confirm hopelessness in anoxic brain injury. The Lancet 352:9143, 1796-1797
CrossRef37
Andreas Kampfl, Gerhard Franz, Franz Aichner, Bettina Pfausler, Hans-Peter Haring, Stefan Felber, Gabriele Luz, Michael Schocke, Erich Schmutzhard. (1998) The persistent vegetative state after closed head injury: clinical and magnetic resonance imaging findings in 42 patients. Journal of Neurosurgery 88:5, 809-816
CrossRef38
M.Elizabeth Sandel, Kathleen R. Bell, Linda J. Michaud. (1998) 1. Traumatic brain injury: Prevention, pathophysiology, and outcome prediction. Archives of Physical Medicine and Rehabilitation 79:3, S3-S9
CrossRef39
D. Moskopp. (1998) On brain death criteria. European Journal of Anaesthesiology 15:Supplement 17, 101-102
CrossRef40
H. RICHARD BERESFORD. (1997) The Persitent Vegetative State: A View across the Legal Divide. Annals of the New York Academy of Sciences 835:1 Frontiers of, 386-394
CrossRef41
Clifton W. Callaway. (1997) Improving neurologic outcomes after out-of-hospital cardiac arrest. Prehospital Emergency Care 1:1, 45-57
CrossRef42
M. Klein. (1997) Perception of pain in the persistent vegetative state?. European Journal of Pain 1:2, 165-167
CrossRef43
Claudio Bassetti, Johannes Marhis, Matthias Gugger, Karl O. Lovblad, Christian W. Hess. (1996) Hypersomnia following paramedian thalamic stroke: A report of 12 patients. Annals of Neurology 39:4, 471-480
CrossRef44
Blair H. Turner, Margaret E. Knapp. (1995) Consciousness: A neurobiological approach. Integrative Physiological and Behavioral Science 30:2, 151-156
CrossRef45
Subimal Datta. (1995) Neuronal activity in the peribrachial area: Relationship to behavioral state control. Neuroscience & Biobehavioral Reviews 19:1, 67-84
CrossRef46
Julie O’Sullivan Maillet. (1995) Position of The American Dietetic Association. Journal of the American Dietetic Association 95:2, 231-234
CrossRef47
(1994) The Persistent Vegetative State. New England Journal of Medicine 331:20, 1380-1381
Full Text48
(1994) The Brain of Karen Ann Quinlan. New England Journal of Medicine 331:20, 1378-1380
Full Text49
F.A. Falco, A. Soricelli, L. Majello, A. Modafferi, D. Grossi. (1994) Bilateral thalamic damage, cortical hypometabolism and behavioural disturbances. European Journal of Neurology 1:2, 165-169
CrossRef50
Angell, Marcia, . (1994) After Quinlan: The Dilemma of the Persistent Vegetative State. New England Journal of Medicine 330:21, 1524-1525
Full Text51
The Multi-Society Task Force on PVS. (1994) Medical Aspects of the Persistent Vegetative State. New England Journal of Medicine 330:21, 1499-1508
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