Chapter 300: Coma

Coma is among the most common neurologic emergencies encountered general medicine and requires an organized approach. It accounts for a substantial portion of admissions to emergency wards and occurs on all hospital services.

There exists a continuum of states of reduced alertness, the most severe form being coma, defined as a deep sleeplike state with eyes closed from which the patient cannot be aroused. Stupor refers to a higher degree of arousability in which the patient can be transiently awakened by vigorous stimuli, accompanied by motor behavior that leads to avoidance or withdrawal from uncomfortable or aggravating stimuli. Drowsiness simulates light sleep and is characterized by easy arousal and the persistence of alertness for brief periods. Stupor and drowsiness are usually accompanied by some degree of confusion (Chap. 24). 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 use of ambiguous terms such as lethargy, semicoma, or obtundation.

Several conditions that render patients unresponsive and simulate coma are considered separately because of their special significance. The vegetative state signifies an awake-appearing but nonresponsive state often in a patient who has emerged from coma. In the vegetative state, the eyelids may open periodically, giving the appearance of wakefulness. Respiratory and autonomic functions are retained. Yawning, coughing, swallowing, and limb and head movements persist, but there are few, if any, meaningful responses to the external and internal environment. There are always accompanying signs that indicate extensive damage in both cerebral hemispheres, e.g., decerebrate or decorticate limb posturing and absent responses to visual stimuli (see below). In the closely related but less severe minimally conscious state, the patient displays rudimentary vocal or motor behaviors, often spontaneous, but some in response to touch, visual stimuli, or command. Cardiac arrest with cerebral hypoperfusion and head trauma are the most common causes of the vegetative and minimally conscious states (Chap. 301).

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. Patients in the minimally conscious state carry a better prognosis for some recovery compared to those in a persistent vegetative state, but even in these patients, dramatic recovery after 12 months is unusual.

The possibility of incorrectly attributing meaningful behavior to patients in the vegetative and minimally conscious states creates inordinate problems and anguish for families and physicians. On the other hand, the question of whether these patients lack any capability for cognition has been reopened by functional MRI and EEG studies that have demonstrated, in a small proportion of usually posttraumatic cases, meaningful cerebral activation in response to verbal and other stimuli as discussed in more detail below. This finding suggests at a minimum that some of these patients could in the future be able to communicate their needs using technological advances and that further research could shed light on treatment approaches targeting areas of the brain and their connections that seem to be preserved in individual patients.

Apart from the above conditions, several syndromes that affect alertness are prone to be misinterpreted as stupor or coma. Clinicians should be aware of these pitfalls when diagnosing coma at the bedside. 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 medial frontal lobes and their connections (Chap. 26).

Catatonia is a hypomobile and mute syndrome that occurs usually as part of a major psychosis, typically 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 a careful examination 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 hyperreflexia and hypertonicity of the limbs is lacking. The special problem of coma in brain death is discussed below.

The locked-in state describes an important type of pseudocoma in which an awake patient has no means of producing speech or volitional limb 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. The usual cause is an infarction (e.g., basilar artery thrombosis) or hemorrhage of the ventral pons that transects all descending motor (corticospinal and corticobulbar) pathways. Another awake but de-efferented state occurs as a result of total paralysis of the musculature in severe cases of neuromuscular weakness such as in Guillain-Barré syndrome (Chap. 439), critical illness neuropathy (Chap. 301), and pharmacologic neuromuscular blockade.

Almost all instances of coma can be traced to either (1) widespread abnormalities of the cerebral hemispheres or to (2) reduced activity of a special thalamocortical alerting system termed the reticular activating system (RAS) which is diffusely located in the brainstem. 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. In addition to structural damage of these two systems, suppression of reticulocerebral function can occur by drugs, toxins, or metabolic derangements such as hypoglycemia, anoxia, uremia, and hepatic failure; these types of metabolic causes of coma are far more common than structural injuries.

Coma Due to Cerebral Mass Lesions and Herniation Syndromes

In addition to the fixed restriction of the skull, the cranial cavity is separated into compartments by infoldings of the dura. The two cerebral hemispheres are separated by the falx, and the anterior and posterior fossae by the tentorium. Herniation refers to displacement of brain tissue by an overlying or adjacent mass into a contiguous compartment that it normally does not occupy. Coma and many of its associated signs can be attributed to these tissue shifts, and certain clinical features are characteristic of specific configurations of herniation (Fig. 300-1). They are in essence “false localizing” signs because they derive from compression of brain structures at a distance from the mass lesion that is the direct cause of coma.

In the most common form of herniation, brain tissue is displaced from the supratentorial to the infratentorial compartment through the tentorial opening; this is referred to as transtentorial herniation. Uncal transtentorial herniation refers specifically to impaction of the anterior medial temporal gyrus (the uncus) into the tentorial opening just anterior to and adjacent to the midbrain (Fig. 300-1A). The uncus compresses the third nerve as the nerve traverses the subarachnoid space, causing enlargement of the ipsilateral pupil as the first sign (the fibers subserving parasympathetic pupillary function are located peripherally in the nerve). The coma that follows is due to compression of the midbrain (and therefore the RAS) against the opposite tentorial edge by the displaced parahippocampal gyrus (Fig. 300-2). Lateral displacement of the midbrain may compress the opposite cerebral peduncle against the tentorial edge, producing a Babinski sign and hemiparesis contralateral to the hemiparesis that resulted from the mass (the Kernohan-Woltman sign). Herniation may also compress the anterior and posterior cerebral arteries as they pass over the tentorial reflections, with resultant brain infarction. These distortions may also entrap portions of the ventricular system, resulting in hydrocephalus.

Central transtentorial herniation denotes a symmetric downward movement of the thalamic structures through the tentorial opening with compression of the upper midbrain (Fig. 300-1B). Miotic pupils and drowsiness are the heralding signs, in contrast to a unilaterally enlarged pupil of the uncal syndrome. Both uncal and central transtentorial herniations cause progressive compression of the brainstem and RAS, with initial damage to the midbrain, then the pons, and finally the medulla. The result is an approximate sequence of neurologic signs that corresponds to each affected level, with respiratory centers in the brainstem often spared until late in the herniation syndrome. Other forms of herniation include transfalcial herniation (displacement of the cingulate gyrus under the falx and across the midline, Fig. 300-1C) and foraminal herniation (downward forcing of the cerebellar tonsils into the foramen magnum, Fig. 300-1D), which causes early compression of the medulla, respiratory arrest, and death.

A direct relationship between the various configurations of transtentorial herniation and coma is not always found. Drowsiness and stupor can occur with moderate horizontal displacement of the diencephalon (thalamus), before transtentorial herniation is evident. This lateral shift may be quantified on axial images of computed tomography (CT) and magnetic resonance imaging (MRI) scans (Fig. 300-2). In cases of acutely enlarging masses, horizontal displacement of the pineal gland (often calcified in adults) of 3–5 mm is generally associated with drowsiness, 6–8 mm with stupor, and >9 mm with coma. Intrusion of the medial temporal lobe into the tentorial opening is also apparent on MRI and CT scans as obliteration of the cisterna that surrounds the upper brainstem.

Coma Due to Metabolic Disorders and Toxins (including Drug-induced)

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

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

Unlike hypoxia-ischemia, which causes neuronal destruction, most metabolic disorders such as hypoglycemia, hyponatremia, hyperosmolarity, hypercapnia, hypercalcemia, and hepatic and renal failure cause only minor neuropathologic changes. The reversible effects of these conditions on the brain are not 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.

Coma due to drugs and toxins are typically in large measure reversible and leave 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 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. Some drug intoxications, such as with barbiturates, can mimic all of the signs of brain death, thus toxic etiologies must always be excluded prior to making a diagnosis of brain death.

Epileptic Coma

Generalized electrical seizures are associated with coma, even in the absence of motor convulsions (nonconvulsive status epilepticus). As a result, consideration of EEG monitoring is essential in the workup of coma to exclude this treatable etiology. 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 continuous, generalized slowing of the background EEG activity similar to that of metabolic encephalopathies. It typically lasts for a few minutes, but in some cases can be prolonged for hours or even rarely for days.

Coma Due to Widespread Damage to the Cerebral Hemispheres

This category, comprising a number of unrelated disorders, results from extensive bilateral structural cerebral damage that simulates a metabolic disorder. Hypoxia-ischemia is perhaps the best characterized and one in which it is not possible initially to distinguish the acute reversible effects of oxygen deprivation of the brain from the subsequent effects of anoxic neuronal damage. Similar cerebral damage may be produced by disorders that occlude widespread 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 can cause a similar coma syndrome.

APPROACH TO THE PATIENT

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 are usually revealed by measurement of electrolytes, glucose, calcium, magnesium, osmolarity, and renal (blood urea nitrogen) and hepatic (NH₃) function. Toxicologic analysis may be 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 some chronic alcoholics 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. A normal CT scan does not exclude an anatomic lesion as the cause of coma; early bilateral hemisphere infarction, acute brainstem infarction, encephalitis, meningitis, mechanical shearing of axons as a result of closed head trauma, sagittal sinus thrombosis, hypoxic injury and subdural hematoma isodense to adjacent brain are some of the disorders that may not be detected. 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.

The EEG (Chap. 418) provides clues in metabolic or drug-induced states but is rarely diagnostic. However, it is the essential test to reveal coma due to nonconvulsive seizures, and shows fairly characteristic patterns in herpesvirus encephalitis and prion (Creutzfeldt-Jakob) disease. The EEG may be further helpful in disclosing generalized slowing of the background activity, 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., benzodiazepines). 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.

Lumbar puncture should be performed if no cause is readily apparent, as examination of the CSF remains indispensable in the diagnosis of various forms of meningitis and encephalitis. An imaging study should be performed prior to lumbar puncture to exclude a large intracranial mass lesion which could lead to herniation with lumbar puncture. Blood cultures and administration of antibiotics should precede the imaging study if infectious meningitis is suspected (Chap. 133).

(Table 300-1) The causes of coma can be divided into three broad categories: cases without focal neurologic signs (e.g., metabolic and toxic encephalopathies); cases with prominent focal signs (e.g., stroke, cerebral hemorrhage); and meningitis syndromes, characterized by fever or stiff neck and an excess of cells in the spinal fluid (e.g., bacterial meningitis, subarachnoid hemorrhage, encephalitis). Causes of sudden coma include drug ingestion, cerebral hemorrhage, trauma, cardiac arrest, epilepsy, and basilar artery occlusion. Coma that appears subacutely is usually related to a preexisting medical or neurologic problem or, less often, to secondary brain swelling surrounding a mass such as tumor or cerebral infarction.

The diagnosis of coma due to cerebrovascular disease can be difficult (Chap. 419). 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, and hyperventilation); (3) cerebellar hemorrhage (occipital headache, vomiting, gaze paresis, and inability to stand and walk); (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 sudden severe headache and vomiting). The most common stroke, infarction in the territory of the middle cerebral artery, does not cause coma, but edema surrounding large infarctions may expand over several days and cause coma from mass effect.

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. At times, the coma may be featureless without lateralizing signs, although papilledema is often present.

This is a state of irreversible cessation of all cerebral and brainstem function with preservation of cardiac activity and maintenance of respiratory and somatic function by artificial means. Brain death is the only type of brain damage recognized as morally, ethically, and legally equivalent to death. Criteria have been advanced for the diagnosis of brain death, and it is essential to adhere to consensus standards as multiple studies have shown variability in local practice. Given the implications of such a diagnosis, clinicians must be thorough and precise in determining brain death. Established criteria are simple, can be assessed at the bedside, and allow no chance of diagnostic error. They contain two essential elements, after assuring that no confounding factors (e.g., hypothermia, drug intoxication) are present: (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, absent corneal reflexes, loss of oculovestibular reflexes, and destruction of the medulla, manifested by complete and irreversible apnea. Diabetes insipidus is usually present, but may only develop hours or days after the other clinical signs of brain death appear. The pupils are usually midsized but may be enlarged. Loss of deep tendon reflexes is not required because the spinal cord remains functional. Occasionally other reflexes that originate from the spine may be present and should not preclude a diagnosis of brain death.

Demonstration that apnea is due to 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 preoxygenation with 100% oxygen prior to and following removal of the ventilator. CO₂ tension increases ~0.3–0.4 kPa/min (2–3 mmHg/min) during apnea. Apnea is confirmed if no respiratory effort has been observed in the presence of a sufficiently elevated PCO₂. The apnea test is usually stopped if there is serious cardiovascular instability.

An isoelectric EEG may be used as an optional confirmatory test for total cerebral damage. Radionuclide brain scanning, cerebral angiography, or transcranial Doppler measurements may also be included to demonstrate the absence of blood flow when a confirmatory study is desired.

Some period of observation, usually 6–24 h, is recommended, 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.

It is largely accepted in Western society that the ventilator can be disconnected from a brain-dead patient and that organ donation is subsequently possible. Good communication between the physician and the family is important with appropriate preparation of the family for brain death testing and diagnosis.

Some patients, especially children and young adults, may have ominous early clinical findings such as abnormal brainstem reflexes and yet recover; ultra-early prognostication outside of brain death therefore is unwise. 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 (see Chap. 435). For anoxic 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; however, some of these prediction rules are less reliable in the setting of therapeutic hypothermia and therefore serial examinations are advised in this setting. The absence of the cortical responses of the somatosensory evoked potentials has also been shown to be a strong indicator of poor outcome following hypoxic injury.

The uniformly poor outcome of persistent vegetative state has already been mentioned, but recent reports of a number of such patients displaying consistent cortical activation on functional MRI in response to salient stimuli have begun to alter the perception of such individuals. In one series, about 10% of vegetative patients (mainly following traumatic brain injury) could activate their frontal or temporal lobes in response to requests by an examiner to imagine certain visuospatial tasks. In one case, a rudimentary form of communication could be established. There are also reports in exceptional patients of improvement in cognitive function with the implantation of thalamic-stimulating electrodes or the use of novel activating agents including zolpidem. It is prudent to avoid generalizations from these findings, but the need for future studies of novel techniques to help communication and possibly recovery is needed.

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