Allan H. Ropper
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. Coma 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 only 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. 16). 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 other conditions that render patients unresponsive and thereby simulate coma are considered separately because of their special significance. The vegetative state signifies an awake 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, as well as 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 as 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 later). In the closely related but less severe minimally conscious state, the patient has 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. 28). 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 has created inordinate problems and anguish for families. On the other hand, the question of whether these patients lack any capability for cognition has been reopened by functional imaging studies demonstrating, in a small proportion of posttraumatic cases, cerebral activation in response to external 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. 18). 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 later in this chapter.
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 deefferented state occurs as a result of total paralysis of the musculature in severe cases of Guillain-Barré syndrome (Chap. 46), critical illness neuropathy (Chap. 28), and pharmacologic neuromuscular blockade.
THE ANATOMY AND PHYSIOLOGY OF COMA
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; and (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. 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
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 into a 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 herniations (Fig. 17-1). They are in essence “false localizing” signs since they derive from compression of brain structures at a distance from the mass.
Types of cerebral herniation. (A) Uncal; (B) central; (C) transfalcial; (D) foraminal.
The most common herniations are those in which a part of the brain is displaced from the supratentorial to the infratentorial compartment through the tentorial opening; this is referred to as transtentorialherniation. 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. 17-1A). The uncus compresses the third nerve as it traverses the subarachnoid space, causing enlargement of the ipsilateral pupil (putatively because 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. 17-2). Lateral displacement of the midbrain may compress the opposite cerebral peduncle, producing a Babinski’s sign and hemiparesis contralateral to the original hemiparesis (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.
Coronal (A) and axial (B) magnetic resonance images from a stuporous patient with a left third nerve palsy as a result of a large left-sided subdural hematoma (seen as a gray-white rim). The upper midbrain and lower thalamic regions are compressed and displaced horizontally away from the mass, and there is transtentorial herniation of the medial temporal lobe structures, including the uncus anteriorly. The lateral ventricle opposite to the hematoma has become enlarged as a result of compression of the third ventricle.
Central transtentorial herniation denotes a symmetric downward movement of the thalamic medial structures through the tentorial opening with compression of the upper midbrain (Fig. 17-1B). Miotic pupils and drowsiness are the heralding signs. Both temporal and central transtentorial herniations have been considered causes of progressive compression of the brainstem, with initial damage to the midbrain, then the pons, and finally the medulla. The result is a 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. 17-1C), and foraminal herniation (downward forcing of the cerebellar tonsils into the foramen magnum, Fig. 17-1D), 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 CT and MRI scans (Fig. 17-2). In cases of acutely appearing 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 surround the upper brainstem.
Coma due to metabolic disorders
Many systemic metabolic abnormalities cause coma by interrupting the delivery of energy substrates (e.g., hypoxia, ischemia, hypoglycemia) or by altering neuronal excitability (drug and alcohol intoxication, anesthesia, and epilepsy). The same 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 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 conditions of substrate delivery worsen, 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 causes of 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 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 hypercalcemia, hypothyroidism, vitamin B12 deficiency, and hypothermia are incompletely understood but must also reflect derangements of CNS biochemistry, membrane function, and neurotransmitters.
Generalized electrical discharges of the cortex (seizures) are associated with coma, even in the absence of epileptic motor activity (convulsions). The self-limited coma that follows a seizure, the postictal state, may be due to exhaustion of energy reserves or effects of locally toxic molecules that are the by-product of seizures. The postictal state produces a pattern of continuous, generalized slowing of the background EEG activity similar to that of other metabolic encephalopathies.
Toxic (including drug–induced) coma
This common class of encephalopathy is in large measure reversible and leaves no residual damage provided there has not been cardiorespiratory failure. Many drugs and toxins are capable of depressing nervous system function. Some produce coma by affecting both the brainstem nuclei, including the RAS, and the cerebral cortex. The combination of cortical and brainstem signs, which occurs in certain drug overdoses, may lead to an incorrect diagnosis of structural brainstem disease. Overdose of medications that have atropinic actions produces signs such as dilated pupils, tachycardia, and dry skin; opiate overdose produces pinpoint pupils <1 mm in diameter.
Coma due to widespread damage to the cerebral hemispheres
This category, comprising a number of unrelated disorders, results from widespread structural cerebral damage, thereby simulating a metabolic disorder of the cortex. Hypoxia-ischemia is perhaps the best known and one in which it is not possible initially to distinguish the acute reversible effects of hypoperfusion and oxygen deprivation of the brain from the subsequent effects of neuronal damage. Similar bihemispheral damage is produced by disorders that occlude small blood vessels throughout the brain; examples include cerebral malaria, thrombotic thrombocytopenic purpura, and hyperviscosity. Diffuse white matter damage from cranial trauma or inflammatory demyelinating diseases causes a similar syndrome of coma.
APPROACH TO THE
Acute respiratory and cardiovascular problems should be attended to prior to neurologic assessment. In most instances, a complete medical evaluation, except for vital signs, funduscopy, and examination for nuchal rigidity, may be deferred until the neurologic evaluation has established the severity and nature of coma. The approach to the patient with coma from cranial trauma is discussed in Chap. 36.
HISTORY In many cases, the cause of coma is immediately evident (e.g., trauma, cardiac arrest, or reported drug ingestion). In the remainder, certain points are especially useful: (1) the circumstances and rapidity with which neurologic symptoms developed; (2) the antecedent symptoms (confusion, weakness, headache, fever, seizures, dizziness, double vision, or vomiting); (3) the use of medications, illicit drugs, or alcohol; and (4) chronic liver, kidney, lung, heart, or other medical disease. Direct interrogation of family, observers, and ambulance technicians on the scene, in person or by telephone, is an important part of the evaluation.
GENERAL PHYSICAL EXAMINATION Fever suggests a systemic infection, bacterial meningitis, encephalitis, heat stroke, neuroleptic malignant syndrome, malignant hyperthermia due to anesthetics or anticholinergic drug intoxication; only rarely is it attributable to a lesion that has disturbed hypothalamic temperature-regulating centers (“central fever”). A slight elevation in temperature may follow vigorous convulsions. Hypothermia is observed with exposure; alcoholic, barbiturate, sedative, or phenothiazine intoxication; hypoglycemia; peripheral circulatory failure; or extreme hypothyroidism. Hypothermia itself causes coma only when the temperature is <31°C (87.8°F). Tachypnea may indicate systemic acidosis or pneumonia or rarely infiltration of the brain with lymphoma. Aberrant respiratory patterns that reflect brainstem disorders are discussed later. Marked hypertension suggests hypertensive encephalopathy, but it may also be secondary to a rapid rise in intracranial pressure (ICP) (the Cushing response) most often after cerebral hemorrhage or head injury. Hypotension is characteristic of coma from alcohol or barbiturate intoxication, internal hemorrhage, myocardial infarction, sepsis, profound hypothyroidism, or Addisonian crisis.
The funduscopic examination can detect subarachnoid hemorrhage (subhyaloid hemorrhages), hypertensive encephalopathy (exudates, hemorrhages, vessel-crossing changes, papilledema), and increased ICP (papilledema). Cutaneous petechiae suggest thrombotic thrombocytopenic purpura, meningococcemia, or a bleeding diathesis associated with an intracerebral hemorrhage. Cyanosis, reddish or anemic skin coloration are other indications of an underlying systemic disease responsible for the coma.
NEUROLOGIC EXAMINATION The patient should first be observed without intervention by the examiner. Tossing about in the bed, reaching up toward the face, crossing legs, yawning, swallowing, coughing, or moaning reflect a drowsy state that is close to normal awakeness. Lack of restless movements on one side or an outturned leg suggests a hemiplegia. Intermittent twitching movements of a foot, finger, or facial muscle may be the only sign of seizures. Multifocal myoclonus almost always indicates a metabolic disorder, particularly uremia, anoxia, drug intoxication (especially with lithium or haloperidol), or a prion disease (Chap. 43). In a drowsy and confused patient, bilateral asterixis is a certain sign of metabolic encephalopathy or drug intoxication.
Decorticate rigidity and decerebrate rigidity, or “posturing,” describe stereotyped arm and leg movements occurring spontaneously or elicited by sensory stimulation. Flexion of the elbows and wrists and supination of the arm (decortication) suggests bilateral damage rostral to the midbrain, whereas extension of the elbows and wrists with pronation (decerebration) indicates damage to motor tracts in the midbrain or caudal diencephalon. The less frequent combination of arm extension with leg flexion or flaccid legs is associated with lesions in the pons. These concepts have been adapted from animal work and cannot be applied with precision to coma in humans. In fact, acute and widespread disorders of any type, regardless of location, frequently cause limb extension, and almost all extensor posturing becomes predominantly flexor as time passes.
LEVEL OF AROUSAL A sequence of increasingly intense stimuli is used to determine the threshold for arousal and the motor response of each side of the body. The results of testing may vary from minute to minute, and serial examinations are most useful. Tickling the nostrils with a cotton wisp is a moderate stimulus to arousal—all but deeply stuporous and comatose patients will move the head away and arouse to some degree. An even greater degree of responsiveness is present if the patient uses his hand to remove an offending stimulus. Pressure on the knuckles or bony prominences and pinprick stimulation are humane forms of noxious stimuli; pinching the skin causes unsightly ecchymoses and is generally not necessary but may be useful in eliciting abduction withdrawal movements of the limbs. Posturing in response to noxious stimuli indicates severe damage to the corticospinal system, whereas abduction-avoidance movement of a limb is usually purposeful and denotes an intact corticospinal system. Posturing may also be unilateral and coexists with purposeful limb movements, reflecting incomplete damage to the motor system.
BRAINSTEM REFLEXES Assessment of brainstem function is essential to localization of the lesion in coma (Fig. 17-3). The brainstem reflexes that are conveniently examined are pupillary size and reaction to light, spontaneous and elicited eye movements, corneal responses, and the respiratory pattern. As a rule, coma is due to bilateral hemispheral disease when these brainstem activities are preserved, particularly the pupillary reactions and eye movements. However, the presence of abnormal brainstem signs does not always indicate that the primary lesion is in the brainstem because hemispheral masses can cause secondary brainstem pathology by transtentorial herniation.
Examination of brainstem reflexes in coma. Midbrain and third nerve function are tested by pupillary reaction to light, pontine function by spontaneous and reflex eye movements and corneal responses, and medullary function by respiratory and pharyngeal responses. Reflex conjugate, horizontal eye movements are dependent on the medial longitudinal fasciculus (MLF) interconnecting the sixth and contralateral third nerve nuclei. Head rotation (oculocephalic reflex) or caloric stimulation of the labyrinths (oculovestibular reflex) elicits contraversive eye movements (for details, see text).
Pupillary Signs Pupillary reactions are examined with a bright, diffuse light (not an ophthalmoscope). Reactive and round pupils of midsize (2.5–5 mm) essentially exclude midbrain damage, either primary or secondary to compression. A response to light may be difficult to appreciate in pupils <2 mm in diameter, and bright room lighting mutes pupillary reactivity. One enlarged and poorly reactive pupil (>6 mm) signifies compression or stretching of the third nerve from the effects of a cerebral mass above. Enlargement of the pupil contralateral to a hemispheral mass may occur but is infrequent. An oval and slightly eccentric pupil is a transitional sign that accompanies early midbrain–third nerve compression. The most extreme pupillary sign, bilaterally dilated and unreactive pupils, indicates severe midbrain damage, usually from compression by a supratentorial mass. Ingestion of drugs with anticholinergic activity, the use of mydriatic eye drops, and direct ocular trauma are among the causes of misleading pupillary enlargement.
Unilateral miosis in coma has been attributed to dysfunction of sympathetic efferents originating in the posterior hypothalamus and descending in the tegmentum of the brainstem to the cervical cord. It is therefore of limited localizing value but is an occasional finding in patients with a large cerebral hemorrhage that affects the thalamus. Reactive and bilaterally small (1–2.5 mm) but not pinpoint pupils are seen in metabolic encephalopathies or in deep bilateral hemispheral lesions such as hydrocephalus or thalamic hemorrhage. Even smaller reactive pupils (<1 mm) characterize narcotic or barbiturate overdoses but also occur with extensive pontine hemorrhage. The response to naloxone and the presence of reflex eye movements (see next) assist in distinguishing these.
Ocular Movements The eyes are first observed by elevating the lids and noting the resting position and spontaneous movements of the globes. Lid tone, tested by lifting the eyelids and noting their resistance to opening and the speed of closure, is progressively reduced as unresponsiveness progresses. Horizontal divergence of the eyes at rest is normal in drowsiness. As coma deepens, the ocular axes may become parallel again.
Spontaneous eye movements in coma often take the form of conjugate horizontal roving. This finding alone exonerates damage in the midbrain and pons and has the same significance as normal reflex eye movements (see next). Conjugate horizontal ocular deviation to one side indicates damage to the pons on the opposite side or alternatively, to the frontal lobe on the same side. This phenomenon is summarized by the following maxim: The eyes look toward a hemispheral lesion and away from a brainstem lesion. Seizures also drive the eyes to one side but usually with superimposed clonic movements of the globes. The eyes may occasionally turn paradoxically away from the side of a deep hemispheral lesion (“wrong-way eyes”). The eyes turn down and inward with thalamic and upper midbrain lesions, typically thalamic hemorrhage. “Ocular bobbing” describes brisk downward and slow upward movements of the eyes associated with loss of horizontal eye movements and is diagnostic of bilateral pontine damage, usually from thrombosis of the basilar artery. “Ocular dipping” is a slower, arrhythmic downward movement followed by a faster upward movement in patients with normal reflex horizontal gaze; it indicates diffuse cortical anoxic damage.
The oculocephalic reflexes, elicited by moving the head from side to side or vertically and observing eye movements in the direction opposite to the head movement, depend on the integrity of the ocular motor nuclei and their interconnecting tracts that extend from the midbrain to the pons and medulla (Fig. 17-3). The movements, called somewhat inappropriately “doll’s eyes” (which refers more accurately to the reflex elevation of the eyelids with flexion of the neck), are normally suppressed in the awake patient. The ability to elicit them therefore indicates both reduced cortical influence on the brainstem and intact brainstem pathways, indicating that coma is caused by a lesion or dysfunction in the cerebral hemispheres. The opposite, an absence of reflex eye movements, usually signifies damage within the brainstem but can result infrequently from overdoses of certain drugs. Normal pupillary size and light reaction distinguishes most drug-induced comas from structural brainstem damage.
Thermal, or “caloric,” stimulation of the vestibular apparatus (oculovestibular response) provides a more intense stimulus for the oculocephalic reflex but provides essentially the same information. The test is performed by irrigating the external auditory canal with cool water in order to induce convection currents in the labyrinths. After a brief latency, the result is tonic deviation of both eyes to the side of cool-water irrigation and nystagmus in the opposite direction. (The acronym “COWS” has been used to remind generations of medical students of the direction of nystagmus—“cold water opposite, warm water same.”) The loss of induced conjugate ocular movements indicates brainstem damage. The presence of corrective nystagmus indicates that the frontal lobes are functioning and connected to the brainstem; thus functional or hysterical coma is likely.
By touching the cornea with a wisp of cotton, a response consisting of brief bilateral lid closure is normally observed. The corneal reflex depends on the integrity of pontine pathways between the fifth (afferent) and both seventh (efferent) cranial nerves; in conjunction with reflex eye movements, it is a useful test of pontine function. CNS-depressant drugs diminish or eliminate the corneal responses soon after reflex eye movements are paralyzed but before the pupils become unreactive to light. The corneal (and pharyngeal) response may be lost for a time on the side of an acute hemiplegia.
Respiratory Patterns These are of less localizing value in comparison to other brainstem signs. Shallow, slow, but regular breathing suggests metabolic or drug depression. Cheyne-Stokes respiration in its classic cyclic form, ending with a brief apneic period, signifies bihemispheral damage or metabolic suppression and commonly accompanies light coma. Rapid, deep (Kussmaul) breathing usually implies metabolic acidosis but may also occur with pontomesencephalic lesions. Tachypnea occurs with lymphoma of the CNS. Agonal gasps are the result of lower brainstem (medullary) damage and are recognized as the terminal respiratory pattern of severe brain damage. A number of other cyclic breathing variations have been described but are of lesser significance.
LABORATORY STUDIES AND IMAGING
The studies that are most useful in the diagnosis of coma are: chemical-toxicologic analysis of blood and urine, cranial CT or MRI, EEG, and CSF examination. Arterial blood gas analysis is helpful in patients with lung disease and acid-base disorders. The metabolic aberrations commonly encountered in clinical practice require measurement of electrolytes, glucose, calcium, osmolarity, and renal (blood urea nitrogen) and hepatic (NH3) function. Toxicologic analysis is necessary in any case of acute coma where the diagnosis is not immediately clear. However, the presence of exogenous drugs or toxins, especially alcohol, does not exclude the possibility that other factors, particularly head trauma, are also contributing to the clinical state. An ethanol level of 43 mmol/L (0.2 g/dL) in nonhabituated patients generally causes impaired mental activity; a level of >65 mmol/L (0.3 g/dL) is associated with stupor. The development of tolerance may allow the chronic alcoholic to remain awake at levels >87 mmol/L (0.4 g/dL).
The availability of CT and MRI has focused attention on causes of coma that are detectable by imaging (e.g., hemorrhage, tumor, or hydrocephalus). Resorting primarily to this approach, although at times expedient, is imprudent because most cases of coma (and confusion) are metabolic or toxic in origin. Furthermore, the notion that a normal CT scan excludes anatomic lesion as the cause of coma is erroneous. Bilateral hemisphere infarction, acute brainstem infarction, encephalitis, meningitis, mechanical shearing of axons as a result of closed head trauma, sagittal sinus thrombosis, and subdural hematoma isodense to adjacent brain are some of the disorders that may not be detected. Nevertheless, if the source of coma remains unknown, a scan should be obtained.
The EEG (Chap. 5) is useful in metabolic or drug-induced states but is rarely diagnostic, except when coma is due to clinically unrecognized seizure, to herpesvirus encephalitis, or to prion (Creutzfeldt-Jakob) disease. The amount of background slowing of the EEG is a reflection of the severity of an encephalopathy. Predominant high-voltage slowing (δ or triphasic waves) in the frontal regions is typical of metabolic coma, as from hepatic failure, and widespread fast (β) activity implicates sedative drugs (e.g., diazepines, barbiturates). A special pattern of “alpha coma,” defined by widespread, variable 8- to 12-Hz activity, superficially resembles the normal α rhythm of waking but, unlike normal α activity, is not altered by environmental stimuli. Alpha coma results from pontine or diffuse cortical damage and is associated with a poor prognosis. Normal α activity on the EEG, which is suppressed by stimulating the patient, also alerts the clinician to the locked-in syndrome or to hysteria or catatonia. The most important use of EEG recordings in coma is to reveal clinically inapparent epileptic discharges.
Lumbar puncture is performed less frequently than in the past for coma diagnosis because neuroimaging effectively excludes intracerebral and extensive subarachnoid hemorrhage. However, examination of the CSF remains indispensable in the diagnosis of meningitis and encephalitis. For patients with an altered level of consciousness, it is generally recommended that an imaging study be performed prior to lumbar puncture to exclude a large intracranial mass lesion. Blood culture and antibiotic administration usually precede the imaging study if meningitis is suspected (Chap. 6).
DIFFERENTIAL DIAGNOSIS OF COMA
(Table 17-1) The causes of coma can be divided into three broad categories: those without focal neurologic signs (e.g., metabolic and toxic encephalopathies); meningitis syndromes, characterized by fever or stiff neck and an excess of cells in the spinal fluid (e.g., bacterial meningitis, subarachnoid hemorrhage); and conditions associated with prominent focal signs (e.g., stroke, cerebral hemorrhage). In most instances, coma is part of an obvious medical problem, such as drug ingestion, hypoxia, stroke, trauma, or liver or kidney failure. Conditions that cause sudden coma include drug ingestion, cerebral hemorrhage, trauma, cardiac arrest, epilepsy, or basilar artery embolism. Coma that appears subacutely is usually related to a preexisting medical or neurologic problem or, less often, to secondary brain swelling of a mass such as tumor or cerebral infarction.
DIFFERENTIAL DIAGNOSIS OF COMA
When cerebrovascular disease is the cause of coma, diagnosis can be difficult (Chap. 27). The most common diseases are (1) basal ganglia and thalamic hemorrhage (acute but not instantaneous onset, vomiting, headache, hemiplegia, and characteristic eye signs); (2) pontine hemorrhage (sudden onset, pinpoint pupils, loss of reflex eye movements and corneal responses, ocular bobbing, posturing, hyperventilation, and excessive sweating); (3) cerebellar hemorrhage (occipital headache, vomiting, gaze paresis, and inability to stand); (4) basilar artery thrombosis (neurologic prodrome or warning spells, diplopia, dysarthria, vomiting, eye movement and corneal response abnormalities, and asymmetric limb paresis); and (5) subarachnoid hemorrhage (precipitous coma after headache and vomiting). The most common stroke, infarction in the territory of the middle cerebral artery, does not generally cause coma, but edema surrounding large infarctions may expand during the first few days and act as a mass.
The syndrome of acute hydrocephalus accompanies many intracranial diseases, particularly subarachnoid hemorrhage. It is characterized by headache and sometimes vomiting that may progress quickly to coma with extensor posturing of the limbs, bilateral Babinski signs, small unreactive pupils, and impaired oculocephalic movements in the vertical direction.
If the history and examination do not indicate the cause of coma, then information obtained from CT or MRI is needed. The majority of medical causes of coma can be established without a neuroimaging study. Sometimes imaging results can be misleading such as when small subdural hematomas or old strokes are found, but the patient’s coma is due to intoxication.
This is a state of cessation of cerebral function with preservation of cardiac activity and maintenance of somatic function by artificial means. It is the only type of brain damage recognized as equivalent to death. Several sets of criteria have been advanced for the diagnosis of brain death and it is essential to adhere to those standards endorsed by the local medical community. Ideal criteria are simple, can be assessed at the bedside, and allow no chance of diagnostic error. They contain three essential elements: (1) widespread cortical destruction that is reflected by deep coma and unresponsiveness to all forms of stimulation; (2) global brainstem damage demonstrated by absent pupillary light reaction and by the loss of oculovestibular and corneal reflexes; and (3) destruction of the medulla, manifested by complete apnea. The heart rate is invariant and unresponsive to atropine. Diabetes insipidus is often present but may only develop hours or days after the other clinical signs of brain death. The pupils are usually midsized but may be enlarged; they should not, however, be small. Loss of deep tendon reflexes is not required because the spinal cord remains functional. Babinski signs are generally absent and the toe response is often flexor.
Demonstration that apnea is due to irreversible medullary damage requires that the Pco2 be high enough to stimulate respiration during a test of spontaneous breathing. Apnea testing can be done safely by the use of diffusion oxygenation prior to removing the ventilator. This is accomplished by preoxygenation with 100% oxygen, which is then sustained during the test by oxygen administered through a tracheal cannula. co2 tension increases ~0.3–0.4 kPa/min (2–3 mmHg/min) during apnea. At the end of a period of observation, typically several minutes, arterial Pco2 should be at least >6.6–8.0 kPa (50–60 mmHg) for the test to be valid. Apnea is confirmed if no respiratory effort has been observed in the presence of a sufficiently elevated Pco2. Other techniques, including the administration of co2 to accelerate the test, are used in special circumstances. The test is usually stopped if there is serious cardiovascular instability.
An isoelectric EEG may be used as a confirmatory test for total cerebral damage. Radionuclide brain scanning, cerebral angiography, or transcranial Doppler measurements may also be included to demonstrate the absence of CBF but they have not been extensively correlated with pathologic changes.
The possibility of profound drug-induced or hypothermic depression of the nervous system should be excluded, and some period of observation, usually 6–24 h, is desirable, during which the clinical signs of brain death are sustained. It is advisable to delay clinical testing for at least 24 h if a cardiac arrest has caused brain death or if the inciting disease is not known.
Although it is largely accepted in Western society that the respirator can be disconnected from a brain-dead patient, problems frequently arise because of poor communication and inadequate preparation of the family by the physician. Reasonable medical practice, ideally with the agreement of the family, allows the removal of support or transfer out of an intensive care unit of patients who are not brain dead but whose neurologic conditions are nonetheless hopeless.
The immediate goal in a comatose patient is prevention of further nervous system damage. Hypotension, hypoglycemia, hypercalcemia, hypoxia, hypercapnia, and hyperthermia should be corrected rapidly. An oropharyngeal airway is adequate to keep the pharynx open in a drowsy patient who is breathing normally. Tracheal intubation is indicated if there is apnea, upper airway obstruction, hypoventilation, or emesis, or if the patient is liable to aspirate because of coma. Mechanical ventilation is required if there is hypoventilation or a need to induce hypocapnia in order to lower ICP. IV access is established, and naloxone and dextrose are administered if narcotic overdose or hypoglycemia are possibilities; thiamine is given along with glucose to avoid provoking Wernicke’s disease in malnourished patients. In cases of suspected basilar thrombosis with brainstem ischemia, IV heparin or a thrombolytic agent is often utilized, after cerebral hemorrhage has been excluded by a neuroimaging study. Physostigmine may awaken patients with anticholinergic-type drug overdose but should be used only with careful monitoring; many physicians believe that it should only be used to treat anticholinergic overdose–associated cardiac arrhythmias. The use of benzodiazepine antagonists offers some prospect of improvement after overdose of soporific drugs and has transient benefit in hepatic encephalopathy.
Administration of hypotonic solutions should be monitored carefully in any serious acute brain illness because of the potential for exacerbating brain swelling. Cervical spine injuries must not be overlooked, particularly before attempting intubation or evaluation of oculocephalic responses. Fever and meningismus indicate an urgent need for examination of the CSF to diagnose meningitis. If the lumbar puncture in a case of suspected meningitis is delayed, an antibiotic such as a third-generation cephalosporin may be administered, preferably after obtaining blood cultures. The management of raised ICP is discussed in Chap. 28.
One hopes to avoid the anguishing outcome of a patient who is left severely disabled or vegetative. The uniformly poor outcome of the persistent vegetative state has already been mentioned. Children and young adults may have ominous early clinical findings such as abnormal brainstem reflexes and yet recover; temporization in offering a prognosis in this group of patients is wise. Metabolic comas have a far better prognosis than traumatic ones. All systems for estimating prognosis in adults should be taken as approximations, and medical judgments must be tempered by factors such as age, underlying systemic disease, and general medical condition. In an attempt to collect prognostic information from large numbers of patients with head injury, the Glasgow Coma Scale was devised; empirically, it has predictive value in cases of brain trauma (Table 36-2). For anoxic and metabolic coma, clinical signs such as the pupillary and motor responses after 1 day, 3 days, and 1 week have been shown to have predictive value (Fig. 28-4). Other studies suggest that the absence of corneal responses may have the most discriminative value. The absence of the cortical waves of the somatosensory evoked potentials has also proved a strong indicator of poor outcome in coma from any cause.
There have been recent advances using functional imaging that demonstrate some preserved cognitive abilities of vegetative and minimally conscious patients. In one series, about 10% of such patients could be trained to activate the frontal or temporal lobes in response to requests by an examiner to imagine certain visuospatial tasks. In one case, a rudimentary form of one-way communication could be established. There are also reports in a limited number of patients of improvement in cognitive function with the implantation of thalamic-stimulating electrodes. It is prudent to avoid generalizations from these experiments.