Coma is among the most common and striking problems in general medicine. It accounts for a substantial portion of admissions to emergency wards and occurs on all hospital services. It demands immediate attention and requires an organized approach.

There is a continuum of states of reduced alertness, the most severe form being coma, defined as a deep sleeplike state from which the patient cannot be aroused. Stupor refers to a higher degree of arousability in which the patient can be transiently awakened by vigorous stimuli, accompanied by motor behavior that leads to avoidance of uncomfortable or aggravating stimuli. Drowsiness, which is familiar to all persons, simulates light sleep and is characterized by easy arousal and the persistence of alertness for brief periods. Drowsiness and stupor are usually accompanied by some degree of confusion (Chap. 18). A precise narrative description of the level of arousal and of the type of responses evoked by various stimuli as observed at the bedside is preferable to ambiguous terms such as lethargy, semicoma, or obtundation.

Several conditions that render patients unresponsive and simulate coma are considered separately because of their special significance. The vegetative state signifies an awake-appearing but nonresponsive state in a patient who has emerged from coma. In the vegetative state, the eyelids may open, giving the appearance of wakefulness. Respiratory and autonomic functions are retained. Yawning, coughing, swallowing, and limb and head movements persist, and the patient may follow visually presented objects, but there are few, if any, meaningful responses to the external and internal environment—in essence, an “awake coma.” The term vegetative is unfortunate because it is subject to misinterpretation. There are always accompanying signs that indicate extensive damage in both cerebral hemispheres, e.g., decerebrate or decorticate limb posturing and absent responses to visual stimuli (see below). In the closely related but less severe minimally conscious state, the patient displays rudimentary vocal or motor behaviors, often spontaneous, but some in response to touch, visual stimuli, or command. Cardiac arrest with cerebral hypoperfusion and head injuries are the most common causes of the vegetative and minimally conscious states (Chap. 33). The prognosis for regaining mental faculties once the vegetative state has supervened for several months is very poor, and after a year, almost nil; hence the term persistent vegetative state. Most reports of dramatic recovery, when investigated carefully, are found to yield to the usual rules for prognosis, but there have been rare instances in which recovery has occurred to a severely disabled condition and, in rare childhood cases, to an even better state. The possibility of incorrectly attributing meaningful behavior to patients in the vegetative and minimally conscious states creates inordinate problems and anguish. On the other hand, the question of whether these patients lack any capability for cognition has been reopened by functional imaging studies that have demonstrated, in a small proportion of posttraumatic cases, meaningful cerebral activation in response to verbal and other stimuli.

Apart from the above conditions, several syndromes that affect alertness are prone to be misinterpreted as stupor or coma. Akinetic mutism refers to a partially or fully awake state in which the patient is able to form impressions and think, as demonstrated by later recounting of events, but remains virtually immobile and mute. The condition results from damage in the regions of the medial thalamic nuclei or the frontal lobes (particularly lesions situated deeply or on the orbitofrontal surfaces) or from extreme hydrocephalus. The term abulia describes a milder form of akinetic mutism characterized by mental and physical slowness and diminished ability to initiate activity. It is also usually the result of damage to the frontal lobes and its connections (Chap. 22).

Catatonia is a curious hypomobile and mute syndrome that occurs as part of a major psychosis, usually schizophrenia or major depression. Catatonic patients make few voluntary or responsive movements, although they blink, swallow, and may not appear distressed. There are nonetheless signs that the patient is responsive, although it may take ingenuity on the part of the examiner to demonstrate them. For example, eyelid elevation is actively resisted, blinking occurs in response to a visual threat, and the eyes move concomitantly with head rotation, all of which are inconsistent with the presence of a brain lesion causing unresponsiveness. It is characteristic but not invariable in catatonia for the limbs to retain the postures in which they have been placed by the examiner (“waxy flexibility,” or catalepsy). With recovery, patients often have some memory of events that occurred during their catatonic stupor. Catatonia is superficially similar to akinetic mutism, but clinical evidence of cerebral damage such as Babinski signs and hypertonicity of the limbs is lacking. The special problem of coma in brain death is discussed below.

The locked-in state describes yet another type of pseudocoma in which an awake patient has no means of producing speech or volitional movement but retains voluntary vertical eye movements and lid elevation, thus allowing the patient to signal with a clear mind. The pupils are normally reactive. Such individuals have written entire treatises using Morse code. The usual cause is an infarction or hemorrhage of the ventral pons that transects all descending motor (corticospinal and corticobulbar) pathways. A similar awake but de-efferented state occurs as a result of total paralysis of the musculature in severe cases of Guillain-Barré syndrome (Chap. 54), critical illness neuropathy (Chap. 33), and pharmacologic neuromuscular blockade.

Almost all instances of diminished alertness can be traced to widespread abnormalities of the cerebral hemispheres or to reduced activity of a special thalamocortical alerting system termed the reticular activating system (RAS). The proper functioning of this system, its ascending projections to the cortex, and the cortex itself are required to maintain alertness and coherence of thought. It follows that the principal causes of coma are (1) lesions that damage the RAS in the upper midbrain or its projections; (2) destruction of large portions of both cerebral hemispheres; or (3) suppression of reticulocerebral function by drugs, toxins, or metabolic derangements such as hypoglycemia, anoxia, uremia, and hepatic failure.

The proximity of the RAS to midbrain structures that control pupillary function and eye movements permits clinical localization of the cause of coma in many cases. Pupillary enlargement with loss of light reaction and loss of vertical and adduction movements of the eyes suggests that the lesion is in the upper brainstem where the nuclei subserving these functions reside. Conversely, preservation of pupillary light reactivity and of eye movements absolves the upper brainstem and indicates that widespread structural lesions or metabolic suppression of the cerebral hemispheres is responsible for coma.

Coma due to cerebral mass lesions and herniations

In addition to the fixed restriction of the skull, the cranial cavity is separated into compartments by infoldings of the dura. The two cerebral hemispheres are separated by the falx, and the anterior and posterior fossae by the tentorium. Herniation refers to displacement of brain tissue by an overlying or adjacent mass into a contiguous compartment that it normally does not occupy. Coma and many of its associated signs can be attributed to these tissue shifts, and certain clinical features are characteristic of specific configurations of herniation (Fig. 19-1). They are in essence “false localizing” signs because they derive from compression of brain structures at a distance from the mass.

In the most common form of herniation, brain tissue is displaced from the supratentorial to the infratentorial compartment through the tentorial opening; this is referred to as transtentorial herniation. Uncal transtentorial herniation refers to impaction of the anterior medial temporal gyrus (the uncus) into the tentorial opening just anterior to and adjacent to the midbrain (Fig. 19-1A). The uncus compresses the third nerve as the nerve traverses the subarachnoid space, causing enlargement of the ipsilateral pupil (the fibers subserving parasympathetic pupillary function are located peripherally in the nerve). The coma that follows is due to compression of the midbrain against the opposite tentorial edge by the displaced parahippocampal gyrus (Fig. 19-2). Lateral displacement of the midbrain may compress the opposite cerebral peduncle against the tentorial edge, producing a Babinski sign and hemiparesis contralateral to the hemiparesis that resulted from the mass (the Kernohan-Woltman sign). Herniation may also compress the anterior and posterior cerebral arteries as they pass over the tentorial reflections, with resultant brain infarction. The distortions may also entrap portions of the ventricular system, resulting in hydrocephalus.

Central transtentorial herniation denotes a symmetric downward movement of the thalamic structures through the tentorial opening with compression of the upper midbrain (Fig. 19-1B). Miotic pupils and drowsiness are the heralding signs, in contrast to a unilaterally enlarged pupil of the uncal syndrome. Both uncal and central transtentorial herniations cause progressive compression of the brainstem, with initial damage to the midbrain, then the pons, and finally the medulla. The result is an approximate sequence of neurologic signs that corresponds to each affected level. Other forms of herniation are transfalcial herniation (displacement of the cingulate gyrus under the falx and across the midline, Fig. 19-1C) and foraminal herniation (downward forcing of the cerebellar tonsils into the foramen magnum, Fig. 19-1D), which causes compression of the medulla, respiratory arrest, and death.

A direct relationship between the various configurations of transtentorial herniation and coma is not always found. Drowsiness and stupor can occur with moderate horizontal displacement of the diencephalon (thalamus), before transtentorial herniation is evident. This lateral shift may be quantified on axial images of computed tomography (CT) and magnetic resonance imaging (MRI) scans (Fig. 19-2). In cases of acutely enlarging masses, horizontal displacement of the pineal calcification of 3–5 mm is generally associated with drowsiness, 6–8 mm with stupor, and >9 mm with coma. Intrusion of the medial temporal lobe into the tentorial opening is also apparent on MRI and CT scans as obliteration of the cisterna that surrounds the upper brainstem.

Coma due to metabolic disorders

Many systemic metabolic abnormalities cause coma by interrupting the delivery of energy substrates (e.g., oxygen, glucose) or by altering neuronal excitability (drugs and alcohol, anesthesia, and epilepsy). The metabolic abnormalities that produce coma may, in milder forms, induce an acute confusional state. Thus, in metabolic encephalopathies, clouded consciousness and coma are in a continuum.

Cerebral neurons are fully dependent on cerebral blood flow (CBF) and the delivery of oxygen and glucose. CBF is ~75 mL per 100 g/min in gray matter and 30 mL per 100 g/min in white matter (mean ~55 mL per 100 g/min); oxygen consumption is 3.5 mL per 100 g/min, and glucose utilization is 5 mg per 100 g/min. Brain stores of glucose are able to provide energy for ~2 min after blood flow is interrupted, and oxygen stores last 8–10 s after the cessation of blood flow. Simultaneous hypoxia and ischemia exhaust glucose more rapidly. The electroencephalogram (EEG) rhythm in these circumstances becomes diffusely slowed, typical of metabolic encephalopathies, and as substrate delivery worsens, eventually brain electrical activity ceases.

Unlike hypoxia-ischemia, which causes neuronal destruction, most metabolic disorders such as hypoglycemia, hyponatremia, hyperosmolarity, hypercapnia, hypercalcemia, and hepatic and renal failure cause only minor neuropathologic changes. The reversible effects of these conditions on the brain are not understood but may result from impaired energy supplies, changes in ion fluxes across neuronal membranes, and neurotransmitter abnormalities. For example, the high ammonia concentration of hepatic coma interferes with cerebral energy metabolism and with the Na⁺, K⁺-ATPase pump, increases the number and size of astrocytes, and causes increased concentrations of potentially toxic products of ammonia metabolism; it may also affect neurotransmitters, including the production of putative “false” neurotransmitters that are active at receptor sites. Apart from hyperammonemia, which of these mechanisms is of critical importance is not clear. The mechanism of the encephalopathy of renal failure is also not known. Unlike ammonia, urea does not produce central nervous system (CNS) toxicity, and a multifactorial causation has been proposed for the encephalopathy, including increased permeability of the blood-brain barrier to toxic substances such as organic acids and an increase in brain calcium and cerebrospinal fluid (CSF) phosphate content.

Coma and seizures are common accompaniments of large shifts in sodium and water balance in the brain. These changes in osmolarity arise from systemic medical disorders, including diabetic ketoacidosis, the nonketotic hyperosmolar state, and hyponatremia from any cause (e.g., water intoxication, excessive secretion of antidiuretic hormone, or atrial natriuretic peptides). Sodium levels <125 mmol/L induce confusion, and levels <115 mmol/L are typically associated with coma and convulsions. In hyperosmolar coma, the serum osmolarity is generally >350 mosmol/L. Hypercapnia depresses the level of consciousness in proportion to the rise in carbon dioxide (CO₂) tension in the blood. In all of these metabolic encephalopathies, the degree of neurologic change depends to a large extent on the rapidity with which the serum changes occur. The pathophysiology of other metabolic encephalopathies such as those due to hypercalcemia, hypothyroidism, vitamin B₁₂ deficiency, and hypothermia are incompletely understood but must reflect derangements of CNS biochemistry, membrane function, or neurotransmitters.