In assessing confusion, stupor, or coma in an already hospitalized patient, it is most instructive to review the patient's medications carefully. A large number of compounds may reduce alertness to the point of profound somnolence or stupor, particularly if there are underlying medical problems (e.g., a liver failure). Prominent in lists of iatrogenic drug intoxications are anesthetics, sedatives, antiepileptic drugs, opiates, certain antibiotics, antidepressants, and antipsychosis compounds. Chronic administration of nitroprusside for hypertension can induce stupor from cyanide toxicity. From an initial survey, many of the common causes of coma, such as severe head injury, alcoholism or other forms of drug intoxication, and hypertensive brain hemorrhage, are readily recognized.
Alterations in vital signs (temperature, heart rate, respiratory rate, and blood pressure) are important aids in diagnosis. Fever is most often the result of a systemic infection such as pneumonia or bacterial meningitis or viral encephalitis. An excessively high body temperature (42°C [107.6°F] or 43°C [109.4°F]) associated with dry skin should arouse suspicion of heat stroke or intoxication by a drug with anticholinergic activity. Fever should not be too easily ascribed to a brain lesion that has disturbed the temperature-regulating center, so-called central fever, which is a rare occurrence. Hypothermia is observed in patients with alcohol or barbiturate intoxication, drowning, exposure to cold, peripheral circulatory failure, advanced tuberculous meningitis, and myxedema.
Slow breathing points to opiate or barbiturate intoxication and occasionally to hypothyroidism, whereas deep, rapid breathing (Kussmaul respiration) should suggest the presence of pneumonia, diabetic or uremic acidosis, pulmonary edema, or the less-common occurrence of an intracranial disease that causes central neurogenic hyper-ventilation. Diseases that elevate intracranial pressure or damage the brain often cause slow, irregular, or cyclic Cheyne-Stokes respiration. The various disordered patterns of breathing and their clinical significance are described further on. Vomiting at the outset of sudden coma, particularly if combined with pronounced hypertension, is characteristic of cerebral hemorrhage within the hemispheres, brainstem, cerebellum, or subarachnoid spaces. Marked hypertension is observed in patients with cerebral hemorrhage and in hypertensive encephalopathy and in children with markedly elevated intracranial pressure. Hypotension is the usual finding in states of depressed consciousness because of diabetes, alcohol or barbiturate intoxication, internal hemorrhage, myocardial infarction, dissecting aortic aneurysm, septicemia, Addison disease, or massive brain trauma. The heart rate, if exceptionally slow, suggests heart block from medications such as tricyclic antidepressants or anticonvulsants, or if combined with periodic breathing and hypertension, an increase in intracranial pressure.
Inspection of the skin may yield valuable information. Cyanosis of the lips and nail beds signifies inadequate oxygenation. Cherry-red coloration is typical of carbon monoxide poisoning. Multiple bruises (particularly a bruise or boggy area in the scalp), bleeding, CSF leakage from an ear or the nose, or periorbital hemorrhage greatly raises the likelihood of cranial fracture and intracranial trauma or of a severe coagulopathy causing intracranial bleeding. Telangiectases and hyperemia of the face and conjunctivae are the common stigmata of alcoholism; myxedema imparts a characteristic puffiness of the face, and hypopituitarism an equally characteristic sallow complexion. Marked pallor suggests internal hemorrhage. A macular-hemorrhagic rash indicates the possibility of meningococcal infection, staphylococcal endocarditis, typhus, or Rocky Mountain spotted fever. Excessive sweating suggests hypoglycemia or shock, and excessively dry skin, diabetic acidosis, or uremia. Large blisters, sometimes bloody, may form over pressure points such as the buttocks if the patient has been motionless for a time; this sign is particularly characteristic of the deeply unresponsive and prolonged motionless state of acute sedation, alcohol and opiate intoxication. Thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation, and fat embolism may cause diffuse petechiae or purpura; the last of these are often aggregated in the anterior axillary folds.
The odor of the breath may provide a clue to the etiology of coma. Alcohol is easily recognized. The spoiled-fruit odor of diabetic ketoacidotic coma, the uriniferous odor of uremia, the musky and slightly fecal fetor of hepatic coma, and the burnt almond odor of cyanide poisoning are distinctive enough to be identified by physicians who possess a keen sense of smell. The distinctive odor of melena is a sign of rapid gastrointestinal bleeding.
Neurologic Examination of the Stuporous or Comatose Patient
Although limited in some ways in comparison to the examination of the alert patient, the neurologic examination of the comatose patient is relatively simple. Watching the patient for a few moments often yields considerable information. The predominant postures of the limbs and body; the presence or absence of spontaneous movements on one side; the position of the head and eyes; and the rate, depth, and rhythm of respiration each give substantial information. The state of responsiveness is then estimated by noting the patient's reaction to calling his name, to simple commands, or to noxious stimuli such as tickling the nares, supraorbital or sternal pressure, pinching the side of the neck or inner parts of the arms or thighs, or applying pressure to the knuckles. By gradually increasing the strength of these stimuli, one can roughly estimate both the degree of unresponsiveness and changes from hour to hour. Vocalization may persist in stupor and is the first response to be lost as coma appears. Grimacing and deft avoidance movements of stimulated parts of the body are preserved in stupor; their presence substantiates the integrity of corticobulbar and corticospinal tracts. Yawning and spontaneous shifting of body positions indicate a minimal degree of unresponsiveness. These signs have been elegantly summarized by Fisher based on his own observations. The widely adopted Glasgow Coma Scale, constructed originally as a quick and simple means of quantitating the responsiveness of patients with cerebral trauma, can be used in the grading of other acute coma-producing diseases as mentioned earlier in this chapter (see also Chap. 35). Several other scales such as the "FOUR Score" (Wijdicks et al 2005) have been devised and are used in various units.
It is usually possible to determine whether coma is associated with meningeal irritation. In all but the deepest stages of coma, meningeal irritation from either bacterial meningitis or subarachnoid hemorrhage will cause resistance to the initial excursion of passive flexion of the neck but not to extension, turning, or tilting of the head. Meningismus is a fairly specific but somewhat insensitive sign of meningeal irritation as commented in Chap. 1. Resistance to movement of the neck in all directions may be part of generalized muscular rigidity or dystonia (as in phenothiazine intoxication) or indicate disease of the cervical spine. In the infant, bulging of the anterior fontanel is at times a more reliable sign of meningitis than is a stiff neck. A temporal lobe or cerebellar herniation or decerebrate rigidity may also create resistance to passive flexion of the neck and be confused with meningeal irritation.
A coma-causing lesion in a cerebral hemisphere can be detected by careful observation of spontaneous movements, responses to stimulation, prevailing postures, and by examination of the cranial nerves. Hemiplegia is revealed by a lack of restless movements of the limbs on one side and by inadequate protective movements in response to painful stimuli. The weakened limbs are usually slack and, if lifted from the bed, they "fall flail." The hemiplegic leg lies in a position of external rotation (this may also be caused by a fractured femur), and the affected thigh appears wider and flatter than the nonhemiplegic one. In expiration, the cheek and lips puff out on the paralyzed side of the face. A lesion in one cerebral hemisphere causes the eyes to be turned away from the paralyzed side (toward the lesion, as described below); the opposite occurs with brainstem lesions. In most cases, a hemiplegia and an accompanying Babinski sign are indicative of a contralateral hemispheral lesion; but with lateral mass effect and compression of the opposite cerebral peduncle against the tentorium, extensor posturing, a Babinski sign, and weakness of arm and leg may appear ipsilateral to the lesion (the earlier-mentioned Kernohan-Woltman sign). A moan or grimace may be provoked by painful stimuli applied to one side but not to the other, reflecting hemianesthesia. During grimacing in response to stimuli, facial weakness may be noted.
Of the various indicators of brainstem function, the most useful are pupillary size and reactivity, ocular movements, oculovestibular reflexes and, to a lesser extent, the pattern of breathing. These functions, like consciousness itself, are dependent on the integrity of structures in the midbrain and rostral pons.
These are of great diagnostic importance in the comatose patient. A unilaterally enlarged pupil is an early indicator of stretching or compression of the third nerve and reflects the presence of an overlying ipsilateral hemispheral mass as described earlier in the section on herniations. A loss of light reaction usually precedes enlargement of the pupil. As a transitional phenomenon, the pupil may become oval or pear-shaped or appear to be off center (corectopia) because of a differential loss of innervation of a portion of the pupillary sphincter. The light-unreactive pupil continues to enlarge to a size of 6 to 9 mm diameter and is soon joined by a slight outward deviation of the eye. In unusual instances, the pupil contralateral to the mass may enlarge first; this has reportedly been the case in 10 percent of subdural hematomas but has been far less frequent in our experience. As midbrain displacement continues, both pupils dilate and become unreactive to light, probably as a result of compression of the oculomotor nuclei in the rostral midbrain (Ropper, 1990). The last step in the evolution of brainstem compression tends to be a slight reduction in pupillary size on both sides, to 5 mm or smaller. Normal pupillary size, shape, and light reflexes indicate integrity of midbrain structures and direct attention to a cause of coma other than a mass.
Pontine tegmental lesions cause extremely miotic pupils (<1 mm in diameter) with barely perceptible reaction to strong light; this is characteristic of the early phase of pontine hemorrhage. The ipsilateral pupillary dilatation from pinching the side of the neck (the ciliospinal reflex) is usually lost in brainstem lesions. The Horner syndrome (miosis, ptosis, and reduced facial sweating) may be observed ipsilateral to a lesion of the brainstem or hypothalamus or as a sign of dissection of the internal carotid artery.
With coma caused by drug intoxications and intrinsic metabolic disorders, pupillary reactions are usually spared, but there are notable exceptions. Serum concentrations of opiates that are high enough to cause coma have as a consistent sign pinpoint pupils, with constriction to light that may be so slight that it is detectable only with a magnifying glass. High-dose barbiturates may act similarly, but the pupillary diameter tends to be 1 mm or more. Systemic poisoning with atropine or with drugs that have atropinic qualities, especially the tricyclic antidepressants, is characterized by wide dilatation and fixity of the pupils. Hippus, or fluctuating pupillary size, is occasionally characteristic of metabolic encephalopathy.
Movements of Eyes and Eyelids and Corneal Responses
These are altered in a variety of ways in coma. In light coma of metabolic origin, the eyes rove conjugately from side to side in seemingly random fashion, sometimes resting briefly in an eccentric position. These movements disappear as coma deepens, and the eyes then remain motionless and slightly exotropic.
A lateral and slight downward deviation of one eye suggests the presence of a third-nerve palsy, and a medial deviation, a sixth-nerve palsy. There is persistent conjugate deviation of the eyes to one side—away from the side of the paralysis with a large cerebral lesion (looking toward the lesion) and toward the side of the paralysis with a unilateral pontine lesion (looking away from the lesion). "Wrong-way eyes" a paradoxical conjugate deviation to the side opposite the lesion may sometimes occur with thalamic and upper brainstem lesions. During a focal seizure the eyes turn or jerk toward the convulsing side (opposite to the irritative focus). The globes turn down and inward (looking at the nose) with hematomas or ischemic lesions of the thalamus and upper midbrain (a variant of Parinaud syndrome). Retraction and convergence nystagmus and "ocular bobbing," described in Chap. 14, occur with lesions in the tegmentum of the mid-brain and pons, respectively. "Ocular dipping," in which the eyes move down slowly and return rapidly to the meridian, is observed with coma caused by anoxia and drug intoxications; horizontal eye movements are preserved with ocular dipping but obliterated in cases of ocular bobbing as a result of destruction of pontine gaze centers. Coma-producing structural lesions of the brainstem abolish most if not all conjugate ocular movements, whereas metabolic disorders generally do not (except for instances of deep hepatic coma and antiepileptic drug overdose).
Oculocephalic reflexes (doll's-eye movements) are elicited by turning or tilting the head. The response in coma of metabolic origin or that caused by bihemispheric structural lesions consists of conjugate movement of the eyes in the opposite direction. Elicitation of these ocular reflexes in a comatose patient provides two pieces of information: (1) evidence of unimpeded function of the midbrain and pontine tegmental structures that integrate ocular movements and of the oculomotor nerves, and (2) loss of the cortical inhibition that normally holds these movements in check. In other words, the presence of unimpaired reflex eye movements implies that coma is not caused by compression or destruction of the upper midbrain. There must instead be widespread cerebral dysfunction, such as occurs after anoxia or with metabolic–toxic suppression of cortical neuronal activity. It must be conceded, however, that sedative or anticonvulsant intoxication profound enough to cause coma may obliterate the brainstem mechanisms for oculocephalic reactions and, in extreme cases, even the vestibular-ocular (caloric) responses as noted below.
Asymmetry of the elicited eye movements remains a dependable sign of focal brainstem disease. In instances of coma caused by a large mass in one cerebral hemisphere that secondarily compresses the upper brainstem, the oculocephalic reflexes are usually present, but the movement of the eye on the side of the mass may be impeded in adduction as a result of a compressive third-nerve paresis.
Irrigation of one ear with 10 mL of cold water (or room-temperature water if the patient is arousable) causes slow conjugate deviation of the eyes toward the irrigated ear, followed in a few seconds by compensatory nystagmus (fast component away from the stimulated side). This is the oculovestibular, or caloric test. The ears are irrigated separately several minutes apart. In comatose patients, the fast "corrective" phase of nystagmus is lost and the eyes are tonically deflected to the side irrigated with cold water or away from the side irrigated with warm water; this position may be held for 2 to 3 min. Brainstem lesions disrupt these vestibuloocular reflexes; if one eye abducts and the other fails to adduct, one can conclude that the medial longitudinal fasciculus has been interrupted (an internuclear ophthalmoplegia on the side of adductor paralysis). Abducens palsy is indicated by an esotropic resting position and a lack of outward deviation of one eye with the reflex maneuvers. The complete absence of ocular movement in response to oculovestibular testing indicates a severe disruption of brainstem tegmental systems in the pons or midbrain or, as already mentioned, a profound overdose of sedative, anesthetic, or anticonvulsant drugs.
A reduction in the frequency and eventual loss of spontaneous blinking, then a loss of response to touching the eyelashes, and, finally, a lack of response to corneal touch (the corneal reflex afferent limb travels in the trigeminal nerve and efferent limb, facial nerve) are among the most dependable signs of deepening coma. A marked asymmetry in corneal responses indicates either an acute lesion of the opposite hemisphere or, less often, an ipsilateral lesion in the brainstem.
Spontaneous Limb Movements
Restless movements of both arms and both legs and grasping and picking movements signify that the corticospinal tracts are more or less intact. Oppositional resistance to passive movement (paratonic rigidity), complex avoidance movements, and discrete protective movements have the same meaning; especially if they are bilateral and they suggest the coma is not deep. Abduction movements (away from the midline) to escape a noxious stimulus have the same significance and differentiate a motor response from posturing, described below. Focal motor epilepsy indicates that the corticospinal pathway to the convulsing side is intact. With massive destruction of a cerebral hemisphere, as occurs in hypertensive hemorrhage or internal carotid–middle cerebral artery occlusion, seizure activity may be manifest solely in the ipsilateral limbs, the contralateral limbs being prevented from participating by the hemiplegia. Elaborate forms of semivoluntary movement may be manifest on the nonhemiparetic side in patients with extensive disease in one hemisphere; they probably represent some type of disinhibition of cortical and subcortical movement patterns. Choreic, athetotic, or hemiballistic movements indicate a disorder of the basal ganglionic and subthalamic structures, just as they do in the alert patient, but are not helpful in localizing the cause of coma.
Posturing in the Comatose Patient
An abnormal posture of some consequence is decerebrate rigidity, which in its fully developed form consists of opisthotonos, clenching of the jaws, and stiff extension of the limbs, with internal rotation of the arms and plantar flexion of the feet (see Chap. 3). It is most often manifest as brief tonic extension of the limbs. This postural pattern was first described by Sherrington, who produced it in cats and monkeys by transecting the brainstem at the intercollicular level. Decerebrate posture was noted in animals to be ipsilateral to a one-sided lesion, hence not a result of involvement of the corticospinal tracts; the opposite is true in humans. A precise anatomic correlation between posturing and the level of the lesion is rarely possible in patients who develop stereotyped extensor posturing as it arises in a variety of settings—with midbrain compression caused by a hemispheral mass; with cerebellar or other posterior fossa lesions; in certain metabolic disorders such as anoxia and hypoglycemia; and, rarely, with hepatic coma and profound drug or alcohol intoxication. Patients with an acute lesion of one cerebral hemisphere may show a similar type of extensor posturing of the contralateral and sometimes ipsilateral limbs, and this may coexist with the ability to make purposeful movements of the same limb. Extensor postures, unilateral or bilateral, occur spontaneously, but more often they are in response to manipulation of the limbs or a tactile or noxious stimulus. Another related pattern consists of extensor posturing of an arm and leg on one side, and flexion and abduction of the opposite arm.
In some patients with the extensor postural changes the lesion is clearly in the cerebral white matter or basal ganglia, which is difficult to reconcile with the classic physiologic explanation for decerebrate posturing. Decerebrate posturing, either in experimental preparations or in humans, is usually not a persistent state. Hence the term decerebrate state, as suggested by Feldman, is preferable to decerebrate rigidity, which implies a fixed, tonic extensor attitude.
Decorticate posturing, usually, with arm or arms in flexion and adduction and leg(s) extended, signifies lesions at a more rostral level of the nervous system—in the cerebral white matter or internal capsule and thalamus. Bilateral decorticate rigidity is essentially a bilateral spastic hemiplegia. Diagonal postures, e.g., flexion of one arm and extension of the opposite arm and leg, usually indicate a supratentorial lesion. Forceful extensor postures of the arms and weak flexor responses of the legs are usually seen with lesions at about the level of the vestibular nuclei. Lesions below this level lead to flaccidity and abolition of all postures and movements. If preceded by decorticate or decerebrate postures, the coma is profound and usually progresses to brain death.
Only in the most advanced forms of intoxication and metabolic coma, as might occur with anoxic necrosis of neurons throughout the entire brain, are coughing, swallowing, hiccoughing, and spontaneous respiration all abolished. Further, the tendon and plantar reflexes may give little indication of what is happening. Tendon reflexes are preserved until the late stages of coma that is due to metabolic disturbances and intoxications. In coma caused by a large cerebral infarct or hemorrhage, the tendon reflexes may be normal or only reduced on the hemiplegic side and the plantar reflexes may initially be absent before becoming extensor. Plantar flexor responses, succeeding extensor responses, signify either a return to normalcy or, in the context of deepening coma, a transition to brain death.
Massive supratentorial lesions, bilateral deep-seated cerebral lesions, and mild metabolic disturbances give rise to altered patterns of breathing, particularly periods of waxing and waning hyperpnea alternating with a shorter period of apnea (Cheyne-Stokes respiration). This phenomenon has been attributed, on uncertain grounds, to isolation of the brainstem respiratory centers from the cerebrum, rendering them more sensitive than usual to carbon dioxide (hyperventilation drive). It is postulated that as a result of overbreathing, the blood carbon dioxide drops below the concentration required to stimulate the centers, and breathing gradually stops. Carbon dioxide then reaccumulates until it exceeds the respiratory threshold, and the cycle then repeats itself. Alternatively, the periodicity has been attributed to the stimulating effect of a low arterial PO2 on a depressed respiratory center. In either case, the presence of Cheyne-Stokes breathing signifies bilateral dysfunction of cerebral structures, usually deep in the hemispheres or diencephalon, usually from intoxication or a metabolic derangement or occasionally, from bilateral structural lesions such as subdural hematomas. In itself, Cheyne-Stokes breathing is not a grave sign. It may occur during sleep in elderly individuals and can be a manifestation of a variety of cardio-pulmonary disorders in awake patients. Only when it gives way to more irregular respiratory patterns that reflect structural damage of the brainstem is the patient in imminent danger, as discussed below.
A number of other aberrant breathing rhythms occur from brainstem lesions (these are reviewed in Chap. 26), but few are specifically localizing. The more conspicuous respiratory arrhythmias are associated with lesions below the level of the reticular-activating system and are therefore found in the late stages of brainstem compression or with destructive brainstem lesions such as infarction, hemorrhage, or infiltrating tumor.
Lesions of the lower midbrain-upper pontine tegmentum, either primary or secondary to transtentorial herniation, may give rise to central neurogenic hyperventilation (CNH). This disorder is characterized by an increase in the rate and depth of respiration to an extent that produces advanced respiratory alkalosis. The pattern must be distinguished from compensatory overbreathing caused by systemic acidosis, particularly diabetic ketoacidosis (Kussmaul breathing). In addition, mild degrees of hyperventilation are common after a number of acute neurologic events, notably head injury. The neurologic basis of central neurogenic hyperventilation is uncertain. It is theorized to represent a release of the reflex mechanisms for respiratory control in the lower brainstem. It has been observed with tumors of the medulla, lower pons, and midbrain. However, North and Jennett, in a study of respiratory abnormalities in neurosurgical patients, found no consistent correlation between tachypnea and the site of the lesion. As noteworthy, primary brain lymphoma without brainstem involvement has emerged as a curious cause of central hyperventilation, of which we have seen several examples (Pauzner et al).
Low pontine lesions, usually caused by basilar artery occlusion, sometimes cause apneustic breathing (a pause of 2 to 3 s in full inspiration) or so-called short-cycle Cheyne-Stokes respiration, in which a few rapid deep breaths alternate with apneic cycles. With lesions of the dorsomedial part of the medulla, the rhythm of breathing is chaotic, being irregularly interrupted and each breath varying in rate and depth (Biot breathing; also called "ataxia of breathing"). This pattern progresses to one of intermittent prolonged inspiratory gasps that are recognized by all physicians as agonal in nature, and finally to apnea. In fact, respiratory arrest is the mode of death of most patients with serious central nervous system (CNS) disease.
Probably all of these erratic patterns of breathing are interrelated in some manner. Webber and Speck have shown that apnea, Biot breathing, and gasping could be produced in the same animal with lesions in the dorsolateral pontine tegmentum by altering the depth of anesthesia. As pointed out by Fisher and by Plum and Posner, when certain supratentorial lesions progress to the point of temporal lobe and cerebellar herniation, one may observe a succession of respiratory patterns (Cheyne-Stokes, then hyperventilation, then Biot breathing), indicating an extension of the functional disorder from upper to lower brainstem; but again, such a sequence is not always observed. Rapidly evolving lesions of the posterior fossa, mainly masses in the cerebellum, more often cause sudden respiratory arrest without any of the aforementioned abnormalities of breathing as intermediaries; presumably apnea results from fulminant medullary compression by the cerebellar tonsils.
Clinical Signs of Increased Intracranial Pressure
A history of headache before the onset of coma, vomiting, severe hypertension beyond the patient's static level, unexplained bradycardia, and subhyaloid retinal hemorrhages (Terson syndrome) are immediate clues to the presence of increased intracranial pressure, usually from one of the types of intracranial hemorrhage. Papilledema develops within 12 to 24 h in cases of brain trauma and hemorrhage, and if it is apparent when coma supervenes, it usually signifies brain tumor or abscess, i.e., a lesion of longer duration. Increased intracranial pressure produces coma by impeding global cerebral blood flow; but this occurs only at extremely high levels of pressure. Increased pressure within one compartment displaces central structures and produces a series of "false localizing" signs because of lateral distortion of deep brain tissue and herniations, as noted in the earlier discussion of this type. However, the absence of papilledema does not exclude the presence of increased intracranial pressure, particularly in the elderly.
The syndrome of acute hydrocephalus, most often from subarachnoid hemorrhage or from obstruction of the ventricular system by a tumor in the posterior fossa, induces a state of abulia (slowed responsivity), followed by stupor, and then coma with bilateral Babinski signs. The pupils are small and the tone in the legs is increased or there may be extensor posturing. The signs of hydrocephalus may be accompanied by headache and systemic hypertension, mediated through raised intracranial pressure. Chapter 30 discusses this subject further.
Laboratory Procedures for the Diagnosis of Coma
Unless the cause of coma is established at once by history and physical examination, it becomes necessary to carry out a number of laboratory procedures. In patients with signs of raised intracranial pressure or indications of brain displacements, CT scan or MRI should be obtained as the primary procedure. As discussed in Chap. 2, lumbar puncture, although carrying a small risk of promoting further herniation, is nevertheless necessary in some instances to exclude bacterial meningitis or encephalitis. If poisoning or drug overdosage is suspected, aspiration and analysis of the gastric contents are sometimes helpful, but greater reliance should be placed on chromatographic analysis of the blood and urine ("toxic screen"). Accurate means are available for measuring the blood concentrations of most antiepileptic drugs, opiates, diazepines, barbiturates, alcohol, and a wide range of other toxic substances. These screening procedures vary widely between hospitals and certain toxins must be specifically sought. A specimen of urine is obtained by catheter for determination of specific gravity and for glucose, acetone, and protein content. Proteinuria may also be found for 2 or 3 days after a subarachnoid hemorrhage or with high fever. Urine of high specific gravity, glycosuria, and acetonuria occurs almost invariably in diabetic coma; but transient glycosuria and hyperglycemia may be precipitated solely by a massive cerebral lesion. Blood counts should be obtained and in malarial districts, a blood smear should be examined for parasites. Neutrophilic leukocytosis occurs in bacterial infections and mild elevations of the white blood cell counts also with brain hemorrhage and infarction, although rarely exceeding 12,000/mm3. Venous blood should be examined for the concentrations of glucose, urea, carbon dioxide, bicarbonate, ammonia, sodium, potassium, chloride, calcium, and AST (aspartate serum transaminase); analysis of blood gases and carboxyhemoglobin should be obtained in appropriate cases of anoxia or exposure to carbon monoxide by smoke inhalation or faulty heating systems.
It should be kept in mind that disorders of water and sodium balance, reflected in hyper- or hyponatremia, may be the result of cerebral disease (excess antidiuretic hormone [ADH] secretion, diabetes insipidus, atrial natriuretic factor release), as well as being the proximate cause of coma.
An EEG may be highly informative if no adequate explanation for coma is forthcoming from the initial examinations. At times, this is the only way to reveal nonconvulsive status epilepticus as the cause of stupor.
Classification of Coma and Differential Diagnosis (See Also Table 17-3)
Table 17-3 Important Points in the Differential Diagnosis of the Common Causes of Coma ||Download (.pdf)
Table 17-3 Important Points in the Differential Diagnosis of the Common Causes of Coma
IMPORTANT CLINICAL FINDINGS
IMPORTANT LABORATORY FINDINGS
Coma with focal or lateralizing signs
Hemiplegia, hypertension, cyclic breathing, specific ocular signs (See Chaps. 14 and 33)
Hyperdense blood on CT
Sudden onset, often with headache, vomiting; history of chronic hypertension; late pupillary enlargement
Basilar artery occlusion (thrombotic or embolic)
Extensor posturing and bilateral Babinski signs; early loss of oculocephalic responses; ocular bobbing
Hyperdense basilar artery (acute thrombosis) on CT; reduced diffusivity and T2 hyperintensity (on MRI) in brainstem and PCA territory; normal cerebrospinal fluid (CSF)
Onset subacute (thrombosis), or sudden (rostral basilar embolism)
Territorial infarction in internal carotid territory
Hemiplegia, unilateral unresponsive, or enlarged pupil
Extensive edema, loss of gray-white matter differentiation, sulcal and ventricular effacement, subfalcine and uncal herniation
Coma preceded by drowsiness for several days after stroke
Slow or cyclic respiration, rising blood pressure, hemiparesis, unilateral enlarged pupil
Hyperdense blood on CT; CSF xanthochromic with relatively low protein
Signs or history of trauma, headache, confusion, progressive drowsiness
Signs of cranial and facial injury
CT and MRI show contusions, hemorrhages, and other injuries; CSF may be bloody
Unstable blood pressure, associated systemic injuries
Neurologic signs depending on location
Rim-enhancing mass with surrounding edema
Systemic infection or neurosurgical procedure, fever
Hypertensive encephalopathy; eclampsia
Blood pressure >210/110 mm Hg (lower in eclampsia and in children), headache, seizures, hypertensive retinal changes
Posterior predominant hypodensity on CT and T2 hyperintensity on MRI affecting gray matter and subcortical white matter; CSF pressure elevated
Acute or subacute evolution, use of aminophylline or catecholamine medications
Thrombotic thrombocytopenic purpura (TTP)
Petechiae, seizures shifting focal signs
Multiple small cortical infarctions and/or microhemorrhages; thrombocytopenia
Similar to fat embolism; multifocal microvasculopathy
Coma without focal or lateralizing signs, with signs of meningeal irritation
Meningitis and encephalitis
Stiff neck, Kernig sign, fever, headache
Possible cerebral edema; meningeal enhancement; pleocytosis, increased protein, low glucose in CSF
Subacute or acute onset
Stertorous breathing, hypertension, stiff neck, Kernig sign
Cisternal and sulcal blood; bloody or xanthochromic CSF under increased pressure
Sudden onset with severe headache
Coma without focal neurologic signs or meningeal irritation; CT scan and CSF normal
Hypothermia, hypotension, flushed skin, alcohol breath
Elevated blood alcohol
May be combined with head injury, infection, or hepatic failure
Drug in urine and blood; electroencephalogram (EEG) often shows fast activity
History of intake of drug; suicide attempt
Slow respiration, cyanosis, constricted pupils
Administration of naloxone causes awakening and withdrawal signs
Carbon monoxide intoxication
Reduced diffusivity in globus pallidi; Carboxyhemoglobin
Rigidity, decerebrate postures, fever, seizures, myoclonus
Reduced diffusivity and edema in cerebral and cerebellar cortex and deep nuclei; CSF normal; EEG may be isoelectric or show high-voltage delta
Abrupt onset following cardiopulmonary arrest; damage permanent if anoxia exceeds 3–5 min
Same as in anoxia
Low blood and CSF glucose
Characteristic slow evolution through stages of nervousness, hunger, sweating, flushed face; then pallor, shallow respirations, and seizures
Signs of extracellular fluid deficit, hyperventilation with Kussmaul respiration, "fruity" breath
Glycosuria, hyperglycemia, acidosis; reduced serum bicarbonate; ketonemia and ketonuria, or hyperosmolarity
History of polyuria, polydipsia, weight loss, or diabetes
Hypertension; sallow, dry skin, uriniferous breath, twitch-convulsive syndrome
Protein and casts in urine; elevated blood urea nitrogen and serum creatinine; anemia, acidosis, hypocalcemia
Progressive apathy, confusion, and asterixis precede coma
Jaundice, ascites, and other signs of portal hypertension; asterixis
T1 hyperintensity from manganese deposition in globus pallidi and other structures; Elevated blood NH3 levels; CSF yellow (bilirubin) with normal or slightly elevated protein
Onset over a few days or after paracentesis or hemorrhage from varices; confusion, stupor, asterixis, and characteristic EEG changes precede coma
Papilledema, diffuse myoclonus, asterixis
Increased CSF pressure; PCO2 may exceed 75 mm Hg; EEG theta and delta activity
Advanced pulmonary disease; profound coma and brain damage uncommon
Severe infections (septic shock); heat stroke
Extreme hyperthermia, rapid respiration
Vary according to cause
Evidence of a specific infection or exposure to extreme heat
Episodic disturbance of behavior or convulsive movements
In status epilepticus, reduced diffusivity on MRI in the involved cortex; characteristic EEG changes
History of previous attacks
The demonstration of focal brain disease by hemiparesis, and meningeal irritation with abnormalities of the CSF serve to divide the diseases that cause coma into three classes, as follows:
I. Diseases that cause no focal or lateralizing neurologic signs, usually with normal brainstem functions. CT scan and cellular content of the CSF are normal.
Exogenous intoxications: alcohols, barbiturates and other sedative drugs, opiates (Chaps. 42 and 43)
Endogenous metabolic disturbances: anoxia, diabetic acidosis, uremia, hepatic failure, nonketotic hyperosmolar hyperglycemia, hypo- and hypernatremia, hypoglycemia, addisonian crisis, profound nutritional deficiency, carbon monoxide poisoning, thyroid states, hypercalcemia (Chaps. 40 and 41)
Severe systemic infections: pneumonia, peritonitis, typhoid fever, malaria, septicemia, Waterhouse-Friderichsen syndrome
Circulatory collapse (shock) from any cause
Postseizure states and convulsive and nonconvulsive status epilepticus (Chap. 16)
Hypertensive encephalopathy and eclampsia (Chap. 34)
Hyperthermia and hypothermia (Chap. 40)
Concussion (Chap. 35)
Acute hydrocephalus (Chap. 30)
Late stages of certain degenerative diseases and Creutzfeldt-Jakob disease
II. Diseases that cause meningeal irritation and an excess of white blood cells (WBCs) or red blood cells (RBCs) in the CSF, usually without focal or lateralizing cerebral or brainstem signs. CT scanning or MRI (which preferably should precede lumbar puncture) may be normal or abnormal.
Subarachnoid hemorrhage from ruptured aneurysm, arteriovenous malformation, and cerebral trauma (Chaps. 34 and 35)
Acute bacterial meningitis (Chap. 32)
Viral meningoencephalitis (Chap. 33)
Neoplastic meningeal infiltration (Chap. 31)
Parasitic meningitis (Chap. 32)
Pituitary apoplexy (Chap. 31)
III. Diseases that cause focal brainstem or lateralizing cerebral signs, with or without changes in the CSF. CT scan and MRI are abnormal.
Hemispheral hemorrhage or massive cerebral infarction (Chap. 34)
Brainstem infarction caused by basilar artery thrombosis or embolism (Chap. 34)
Brain abscess, subdural empyema, herpes encephalitis (Chap. 32)
Epidural and subdural hemorrhage and brain contusion (Chap. 35)
Brain tumor (Chap. 31)
Cerebellar and pontine hemorrhage (Chap. 34)
Miscellaneous: cortical vein thrombosis, focal embolic infarction caused by bacterial endocarditis, acute disseminated (postinfectious) encephalomyelitis, intravascular lymphoma, TTP, diffuse fat embolism, and others
Problems in Differential Diagnosis of Coma (Table 17-3)
Using the clinical criteria outlined above, one can usually ascertain whether a given case of coma falls into one of these three categories. Concerning the group without focal or lateralizing or meningeal signs (which includes most of the metabolic encephalopathies, intoxications, concussion, and postseizure states), it must be kept in mind that residua from previous neurologic disease may confuse the clinical picture. Thus, an earlier hemiparesis from vascular disease or trauma may reassert itself in the course of uremic or hepatic coma with hypotension, hypoglycemia, diabetic acidosis, or following a seizure. In hypertensive encephalopathy, focal signs may also be present. Occasionally, for no understandable reason, one leg may seem to move less, one plantar reflex may be extensor, or seizures may be predominantly or entirely unilateral in a metabolic coma, particularly in the hyperglycemic–hyperosmolar states. Babinski signs and extensor rigidity, conventionally considered to be indicators of structural disease, do sometimes occur in profound intoxications with a number of agents or with hepatic encephalopathy.
The diagnosis of concussion or of postictal coma depends on observation of the precipitating event or indirect evidence, as discussed in Chap. 35. Usually, a convulsive seizure is marked by a bitten tongue, urinary incontinence, and an elevated creatine kinase–skeletal muscle fraction; it may be followed by another seizure or burst of seizures. The presence of small clonic or myoclonic convulsive movements of a hand or foot or fluttering of the eyelids or eyes requires that an EEG be performed to determine whether status epilepticus is the cause of coma. This state, nonconvulsive status epilepticus, described in Chap. 16, must be considered in the diagnosis of unexplained coma, especially in known epileptics (Table 17-3).
With respect to the second group in the above classification with signs primarily of meningeal irritation (head retraction, stiffness of neck on forward bending, Kernig and Brudzinski signs), bacterial meningitis and subarachnoid hemorrhage are the usual causes. However, if the coma is profound, stiff neck may be absent in both infants and adults. In such cases the spinal fluid must be examined in order to establish the diagnosis. In most cases of bacterial meningitis, the CSF pressure is elevated but is not exceptionally high (usually < 400 mm H2O). However, in cases associated with brain swelling, the CSF pressure is greatly elevated; the pupils become fixed and dilated, and there may be signs of compression of the brainstem with arrest of respiration. Patients in coma from ruptured aneurysms also have high CSF pressure; the CSF is overtly bloody and the blood is invariably visible in the CT scan throughout the basal cisterns and ventricles if the bleeding has been severe enough to cause coma.
In the third group of patients, it is the focality of sensorimotor signs and the abnormal pupillary and ocular reflexes, postural states, and breathing patterns that provide the clues to serious structural lesions in the cerebral hemispheres and their pressure effects upon segmental brainstem functions. As the brainstem features become more prominent, they may obscure earlier signs of cerebral disease.
It is worth emphasizing once more that profound hepatic, hypoglycemic, hyperglycemic, and hypoxic states may resemble the coma due to a brainstem lesion in that asymmetrical motor signs, focal seizures, and decerebrate postures arise and deep coma from drug intoxication may obliterate reflex eye movements. Conversely, certain structural lesions of the cerebral hemispheres are so diffuse as to produce a picture that simulates a metabolic disturbance; TTP, fat embolism, vasculitis, intravascular lymphoma, acute disseminated encephalomyelitis, and the late effects of global ischemia–anoxia are examples of such states. At other times, they cause a diffuse encephalopathy with superimposed focal signs.
Unilateral cerebral infarction because of anterior, middle, or posterior cerebral artery occlusion produces no more than drowsiness, as a rule; however, with massive unilateral infarction as a result of carotid artery occlusion, coma can occur if extensive brain edema and secondary tissue shift develop. There are exceptional cases wherein stupor results from massive infarction of the dominant (left) hemisphere. Edema of a degree serious enough to compress the brainstem and cause coma seldom develops before 12 or 24 h. Rapidly evolving hydrocephalus causes smallness of the pupils, rapid respiration, extensor rigidity of the legs, Babinski signs, and sometimes a loss of eye movements.
Of course, diagnosis has as its prime purpose the direction of therapy. The treatable causes of coma are drug and alcohol intoxications, shock from infection, cardiac failure, or systemic bleeding, uremia, epidural and subdural hematomas, brain abscess, bacterial and fungal meningitis, diabetic acidosis or hyperosmolar state, hypoglycemia, hypo- or hypernatremia, hepatic coma, hypercalcemia, uremia, status epilepticus, Wernicke disease, Hashimoto encephalopathy, and hypertensive encephalopathy. Also treatable to a varying degree are cerebellar hemorrhages, which can be removed successfully; edema from massive stroke, which may be ameliorated by hemicraniectomy; and hydrocephalus from any cause, which may respond to ventricular drainage.
Management of the Acutely Comatose Patient
Seriously impaired states of consciousness, regardless of their cause, are often fatal not only because they represent an advanced stage of many diseases but also because they add their own particular burdens to the primary disease. The physician's main objective, of course, is to find the cause of the coma and to treat it appropriately. It often happens, however, that the disease process is one for which there is no specific therapy; or, as in hypoxia or hypoglycemia, the acute, irreversible effects have already occurred before the patient comes to the attention of the physician. Again, the problem may be highly complex, for the disturbance may be attributable not to a single cause but to several factors acting in unison, no one of which could account for the total clinical picture. In certain circumstances two processes contribute to depressing consciousness, particularly head injury combined with drug or alcohol intoxication. In lieu of specific therapy, supportive measures must be used; indeed, the patient's chances of surviving the original disease often depend on the effectiveness of these general medical measures.
The successful management of the insensate patient requires the services of a well-coordinated team of nurses and a physician. Necessary treatments must be instituted rapidly, even before all the diagnostic steps have been completed; diagnosis and treatment may have to proceed concurrently. The following is a brief outline of the principles involved in the treatment of such patients. The details of management of shock, fluid and electrolyte imbalance, and other complications that threaten the comatose patient (pneumonia, urinary tract infections, deep venous thrombosis, etc.) can be found in Harrison's Principles of Internal Medicine.
Shallow and irregular respirations, stertorous breathing (indicating obstruction to inspiration), and cyanosis require the establishment of a clear airway and delivery of oxygen. The patient should initially be placed in a lateral position so that secretions and vomitus do not enter the tracheobronchial tree. Secretions and vomitus should be removed by suctioning as soon as they accumulate; otherwise they will lead to atelectasis and bronchopneumonia. Arterial blood gases should be measured and further observed by monitoring of oxygen saturation. A patient's inability to protect against aspiration and the presence of either hypoxia or hypoventilation dictate the use of endotracheal intubation and a positive-pressure respirator.
The management of shock, if present, takes precedence over all other diagnostic and therapeutic measures.
Concurrently, an intravenous line is established and blood samples are drawn for determination of glucose, intoxicating drugs, and electrolytes and for tests of liver and kidney function. Naloxone, 0.5 mg, should be given intravenously if a narcotic overdose is a possibility. Hypoglycemia that has produced stupor or coma requires the infusion of glucose, usually 25 to 50 mL of a 50 percent solution followed by a 5 percent infusion; this must be supplemented with thiamine. A urine sample is obtained for drug and glucose testing. If the diagnosis is uncertain, both naloxone and the glucose-thiamine combination should be administered.
With the development of elevated intracranial pressure from a mass lesion, mannitol, 25 to 50 g in a 20 percent solution, should be given intravenously over 10 to 20 min and hyperventilation instituted if deterioration occurs, as judged by pupillary enlargement or deepening coma. Repeated CT scanning allows the physician to follow the size of the lesion and degree of localized edema and to detect displacements of cerebral tissue. With massive cerebral lesions, it may be appropriate to place a pressure-measuring device in the cranium of selected patients (see Chap. 35 for details of intracranial pressure monitoring and treatment).
A lumbar puncture should be performed if meningitis or subarachnoid hemorrhage is suspected on the basis of headache and meningismus (and fever in the case of infectious meningitis), keeping in mind the risks of this procedure and the means of dealing with them. A CT scan may have disclosed a primary subarachnoid hemorrhage, in which case lumbar puncture is not necessary. In the case of meningitis, broad-spectrum antibiotics that penetrate the meninges should be instituted immediately, independent of the timing of the lumbar puncture. The choice of drug is then determined by the principles set forth in Chap. 32. If CSF pressure is greatly elevated when measured from a lumbar puncture that has been performed to diagnose bacterial meningitis, it has been recommended that the stylette should be left in the lumen of the needle, as little CSF should be withdrawn as is necessary for diagnostic purposes, and mannitol or hypertonic saline should be administered to lower the pressure.
Convulsions should be controlled by measures outlined in Chap. 16, usually by intravenous diazepines.
As indicated earlier, gastric aspiration and lavage with normal saline may be diagnostically and therapeutically useful in some instances of coma due to drug ingestion. Salicylates, opiates, and anticholinergic drugs (tricyclic antidepressants, phenothiazines, scopolamine), all of which induce gastric atony, may be recovered many hours after ingestion. Caustic materials should not be lavaged because of the danger of gastrointestinal perforation. The administration of activated charcoal is indicated in certain drug poisonings. Measures to prevent gastric hemorrhage and excessive gastric acid secretion are usually advisable.
The temperature-regulating mechanisms may be disturbed and extreme hypothermia or hyperthermia should be corrected. In severe hyperthermia, evaporative-cooling measures are indicated in addition to antipyretics.
The bladder should not be permitted to become distended; if the patient does not void, decompression should be carried out with an indwelling catheter. Needless to say, the patient should not be permitted to lie in a wet or soiled bed.
Diseases of the CNS may disrupt the control of water, glucose, and sodium. The unconscious patient can no longer adjust the intake of food and fluids by hunger and thirst. Both salt-losing and salt-retaining syndromes have been described with brain disease (see Chap. 27). Water intoxication and severe hyponatremia may of themselves prove damaging. If coma is prolonged, the insertion of a nasogastric tube will ease the problems of feeding the patient and maintaining fluid and electrolyte balance. It is quite acceptable to leave the tube in place for long periods. Otherwise, approximately 35 mL/kg of isotonic fluid should be administered per 24 h (5 percent dextrose in 0.45 percent saline with potassium supplementation unless there is brain edema, in which case the use of hypertonic normal saline is indicated).
Aspiration pneumonia is avoided by prevention of vomiting (gastric tube and endotracheal intubation), proper positioning of the patient, and restriction of oral fluids. Should aspiration pneumonia occur, it requires treatment with appropriate antibiotics and aggressive pulmonary physical therapy. Oral decontamination with chlorhexidine is advised to reduce the incidence of ventilator-associated pneumonia.
Leg vein thrombosis, a common occurrence in comatose and hemiplegic patients, often does not manifest itself by obvious clinical signs. An attempt may be made to prevent it by the subcutaneous administration of heparin, 5,000 U q12h, or of low-molecular-weight heparin, and by the use of intermittent pneumatic compression boots. There are few absolute contraindications to the prophylactic use of low-dose anticoagulants such as heparin and enoxaparin.
If the patient is capable of moving, suitable restraints should be used to prevent him from falling out of bed and to avert self-injury from convulsions.
Regular conjunctival lubrication and oral cleansing should be instituted.
Prognosis of Coma (See Also "Prognosis of Hypoxic-Ischemic Brain Injury" in Chap. 40.)
As a general rule, recovery from coma of metabolic and toxic causes is far better than from anoxic coma, with head injury occupying an intermediate prognostic position. Most patients who are initially comatose as a result of a stroke will die; subarachnoid hemorrhage in which coma is a result of hydrocephalus is an exception and those cases in which brain shift is relieved by craniectomy are also exceptions. In regard to all forms of coma, but particularly after cardiac arrest, if there are no pupillary, corneal, or oculovestibular responses within 1 day of the onset of coma, the chances of regaining independent function are practically nil (Levy et al). Other signs that predict a poor outcome are absence of corneal reflexes, eye-opening responses, atonia of the limbs at 1 and 3 days after the onset of coma, and absence of the cortical component of the somatosensory-evoked responses on both sides (see Booth et al for an analysis of prior studies and consult Chap. 40 for further details). It is the unfortunate survivor from this latter group who may remain in a vegetative state for months or years, breathing without aid and with preserved hypothalamopituitary functions. The frequency of vegetative state after head injury and the negligible chances of improvement if the condition persists for several months have already been discussed, and a discussion of the outcome of anoxic–ischemic coma can be found in Chap. 40. The novel perspectives that have been introduced by demonstrating residual and willful cognitive activity in survivors of traumatic brain injury have been discussed in an earlier section.
In all other cases, the nature of the underlying disease determines outcome; the reader should refer to the appropriate sections of this book for details.