Unlike hypoxia-ischemia, which causes neuronal destruction, most metabolic disorders such as hypoglycemia, hyponatremia, hyperosmolarity, hypercapnia, hypercalcemia, and hepatic and renal failure cause only minor neuropathologic changes. The reversible effects of these conditions on the brain are not fully understood but may result from impaired energy supplies, changes in ion fluxes across neuronal membranes, and neurotransmitter abnormalities. In hepatic encephalopathy (HE), high ammonia concentrations lead to increased synthesis of glutamine in astrocytes with osmotic swelling, mitochondrial energy failure, production of reactive nitrogen and oxygen species, increases in the inhibitory neurotransmitter GABA, and synthesis of putative “false” neurotransmitters. Other factors, including coexisting inflammation and metabolic abnormalities, also contribute to the coma in some patients. Over time, development of a diffuse astrocytosis is typical of chronic HE. The mechanism of the encephalopathy of renal failure is also multifactorial. Unlike ammonia, urea does not produce central nervous system (CNS) toxicity, and contributors to uremic encephalopathy may include accumulation of neurotoxic substances such as creatinine, guanidine, and related compounds, depletion of catecholamines, altered glutamate and GABA tone, increases in brain calcium, inflammation with disruption of the blood brain barrier, and frequent coexisting vascular disease.
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 <119 mmol/L are typically associated with coma and convulsions, especially when these levels are achieved quickly. 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) in the blood. In all of these metabolic encephalopathies, the degree of neurologic change depends to a large extent on the rapidity with which the serum changes occur. The pathophysiology of other metabolic encephalopathies such as those due to hypercalcemia, hypothyroidism, vitamin B12 deficiency, and hypothermia are incompletely understood but must reflect derangements of CNS biochemistry, membrane function, or neurotransmitters.
APPROACH TO THE PATIENT Coma
A video examination of the comatose patient is shown in Chap. V4. 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. 435.
HISTORY The cause of coma may be immediately evident as in cases of trauma, cardiac arrest, or observed drug ingestion. In the remainder, certain points are useful: (1) the circumstances and rapidity with which neurologic symptoms developed; (2) antecedent symptoms (confusion, weakness, headache, fever, seizures, dizziness, double vision, or vomiting); (3) the use of medications, 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 when possible.
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 fever attributable to a lesion that has disturbed hypothalamic temperature-regulating centers (“central fever”) and this diagnosis should only be considered after an exhaustive search for other causes fails to reveal an explanation for fever. A slight elevation in temperature may follow vigorous convulsions. Hypothermia is observed with alcohol, barbiturate, sedative, or phenothiazine intoxication; hypoglycemia; peripheral circulatory failure; or extreme hypothyroidism. Hypothermia itself causes coma when the temperature is <31°C (87.8°F) regardless of the underlying etiology. Tachypnea may indicate systemic acidosis or pneumonia. Aberrant respiratory patterns that reflect brainstem disorders are discussed below. Marked hypertension suggests hypertensive encephalopathy, cerebral hemorrhage, large cerebral infarction, or head injury. Hypotension is characteristic of coma from alcohol or barbiturate intoxication, internal hemorrhage or myocardial infarction causing poor delivery of blood to the brain, sepsis, profound hypothyroidism, or Addisonian crisis. The funduscopic examination can detect increased intracranial pressure (ICP) (papilledema), subarachnoid hemorrhage (subhyaloid hemorrhages), and hypertensive encephalopathy (exudates, hemorrhages, vessel-crossing changes, papilledema). Cutaneous petechiae suggest thrombotic thrombocytopenic purpura, meningococcemia, or a bleeding diathesis associated with an intracerebral hemorrhage. Cyanosis and reddish or anemic skin coloration are other indications of an underlying systemic disease or carbon monoxide as 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 hemiplegia. Subtle, 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, or rarely a prion disease (Chap. 430). In a drowsy and confused patient, bilateral asterixis is a 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 (decorticate posturing) suggests bilateral damage rostral to the midbrain, whereas extension of the elbows and wrists with pronation (decerebrate posturing) indicates damage to motor tracts caudal to the midbrain. These localizations 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.
LEVEL OF AROUSAL A sequence of increasingly intense stimuli is first 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 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 coexist with purposeful limb movements, reflecting incomplete damage to the motor system.
BRAINSTEM REFLEXES Given that the nuclei of the cranial nerves and the RAS are both located in the brainstem, assessment of brainstem function is essential to localization of the lesion in coma (Fig. 300-3). Patients with preserved brainstem reflexes typically have a bihemispheric localization to coma, including toxic or drug intoxication, whereas patients with abnormal brainstem reflexes either have an RAS localization to their coma or are suffering from a herniation syndrome impacting the brainstem remotely from a cerebral mass lesion. The most important brainstem reflexes that are examined are pupillary size and reaction to light, spontaneous and elicited eye movements, corneal responses, and the respiratory pattern.
Pupillary Signs Pupillary reactions are examined with a bright, diffuse light. Reactive and round pupils of midsize (2.5–5 mm) essentially exclude upper 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, nebulizer treatments, and direct ocular trauma are among the causes of misleading pupillary enlargement.
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 below) assist in distinguishing between these. 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 an occasional finding in patients with a large cerebral hemorrhage that affects the thalamus.
Ocular Movements The eyes are first observed by elevating the lids and observing the resting position and spontaneous movements of the globes. 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 extensive damage in the midbrain and pons and has the same significance as normal reflex eye movements (see below). Conjugate horizontal ocular deviation to one side indicates damage to the frontal lobe on the same side or less commonly the pons on the opposite side. This phenomenon is summarized by the following maxim: The eyes look toward a hemispheral lesion and away from a brainstem lesion. Seizures involving the frontal lobe drive the eyes to the opposite side, simulating a pontine destructive lesion. 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 usually 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. 300-3). The movements, called somewhat inappropriately “doll’s eyes,” are normally suppressed in the awake patient with intact frontal lobes. The ability to elicit them therefore reflects both reduced cortical influence on the brainstem and intact brainstem pathways. The opposite, an absence of reflex eye movements, usually signifies damage within the brainstem but can result from overdoses of certain drugs. In this circumstance, normal pupillary size and light reaction distinguishes most drug-induced comas from structural brainstem damage. Oculocephalic reflexes should never be elicited in patients with possible head or neck trauma, as vigorous head movements can precipitate or worsen a spinal cord injury.
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 cold 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 cold-water irrigation. In comatose patients, nystagmus in the opposite direction may not occur. The acronym “COWS” has been used to remind generations of medical students of the direction of nystagmus—cold water opposite, warm water same—but since nystagmus is often absent in the opposite direction due to frontal lobe dysfunction in coma, this mnemonic does not often hold true.
When 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 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 typical 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. 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.