183Coma CHAPTER 28

confusion through their sedative properties. Although many clinicians use benzodiazepines to treat acute confusion, their use

should be limited to cases in which delirium is caused by alcohol or

benzodiazepine withdrawal.

■ PREVENTION

In light of the high morbidity associated with delirium and the tremendously increased health care costs that accompany it, development

of an effective strategy to prevent delirium in hospitalized patients is

extremely important. Successful identification of high-risk patients

is the first step, followed by initiation of appropriate interventions.

Increasingly, hospitals are using nursing or physician-administered

tools to screen for high-risk individuals, triggering simple standardized

protocols used to manage risk factors for delirium, including sleepwake cycle reversal, immobility, visual impairment, hearing impairment, sleep deprivation, and dehydration. No specific medications

have been definitively shown to be effective for delirium prevention,

including trials of cholinesterase inhibitors and antipsychotic agents.

Melatonin and its agonist ramelteon have shown some promising

results in small preliminary trials. Recent studies in the ICU have

focused both on identifying sedatives, such as dexmedetomidine, that

are less likely to lead to delirium in critically ill patients and on developing protocols for daily awakenings in which infusions of sedative

medications are interrupted and the patient is reorientated by the staff.

All hospitals and health care systems should work toward decreasing

the incidence of delirium and promptly recognizing and treating the

disorder when it occurs.

■ FURTHER READING

Brown EG et al: Evaluation of a multicomponent pathway to address

inpatient delirium on a neurosciences ward. BMC Health Serv Res

18:106, 2018.

Constantin JM et al: Efficacy and safety of sedation with dexmedetomidine in critical care patients: A meta-analysis of randomized

controlled trials. Anaesth Crit Care Pain Med 35:7, 2016.

Girard TD et al: Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med 379:2506, 2018.

Goldberg TE et al: Association of delirium with long-term cognitive

decline: A meta-analysis. JAMA Neurol 77:1, 2020.

Hatta K et al: Preventive effects of ramelteon on delirium: A randomized placebo-controlled trial. JAMA Psychiatry 71:397, 2014.

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

lower threshold for arousability, in which the patient can be transiently

awakened by vigorous stimuli, accompanied by motor behavior that

leads to avoidance or withdrawal from noxious stimuli. Drowsiness

simulates light sleep and is characterized by easy arousal that may persist for brief periods. Stupor and drowsiness are usually accompanied

by some degree of confusion when the patient is alerted (Chap. 27).

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

28 Coma

S. Andrew Josephson, Allan H. Ropper,

Stephen L. Hauser

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, usually encountered 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 typically 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 sometimes 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. 307).

The prognosis for regaining meaningful mental faculties once the

vegetative state has supervened for several months is 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

problems and anguish for families and physicians. The question of

whether some of these patients have the capability for cognition has

been investigated by functional MRI and electroencephalogram (EEG)

studies that have demonstrated cerebral activation that is temporally

consistent 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.

Several syndromes that affect alertness are prone to be misinterpreted as stupor or coma, and 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 remains virtually

immobile and mute but can form impressions and think, as demonstrated by later recounting of events. This 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. 30).

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 nevertheless signs that the patient is responsive, although it takes

a careful examination to demonstrate these features. 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. The limbs may retain postures in which they have

been placed by the examiner (“waxy flexibility,” or catalepsy). With

recovery from catatonia, patients often have some memory of events

that occurred during their stupor. Catatonia is superficially similar

to akinetic mutism, but clinical evidence of cerebral damage such as

hyperreflexia and hypertonicity of the limbs is lacking in the former.

The special problem of coma in brain death is discussed below.

184 PART 2 Cardinal Manifestations and Presentation of Diseases

The locked-in state describes a type of pseudocoma in which an

awake but paralyzed 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 communicate. The pupils

are normally reactive. The usual cause is an infarction (e.g., basilar

artery thrombosis) or hemorrhage of the bilateral 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. 447), critical illness

neuropathy (Chap. 307), or pharmacologic neuromuscular blockade.

■ THE ANATOMY AND PHYSIOLOGY OF COMA

Almost all instances of coma can be traced to either (1) widespread

abnormalities of the cerebral hemispheres or (2) reduced activity of the

thalamocortical alerting system, the reticular activating system (RAS),

which is an assemblage of neurons located diffusely in the upper

brainstem and thalamus. 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 to either or both of these systems, suppression of reticulocerebral function commonly occurs by drugs, toxins, or metabolic derangements such as hypoglycemia, anoxia, uremia, and hepatic failure, or by

seizures; these types of metabolic causes of coma are far more common

than structural injuries.

Coma Due to Cerebral Mass Lesions and Herniation

Syndromes The skull prevents outward expansion of the brain, and

infoldings of the dura create compartments that restrict displacement

of brain tissue within the cranium. 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 intracerebral or overlying mass into a contiguous compartment that it normally

does not occupy. Coma from mass lesions, and many of its associated

signs, are attributable to these tissue shifts, and certain clinical features

are characteristic of specific configurations of herniation (Fig. 28-1).

In the most common form of herniation, brain tissue is displaced

from the supratentorial to the infratentorial compartment through the

tentorial opening, referred to as transtentorial herniation. The cause

is often a mass hemispheral lesion, with accompanying contralateral

hemiparesis. Uncal transtentorial herniation refers to impaction of the

anterior medial temporal gyrus (the uncus) into the tentorial opening

just anterior to and adjacent to the midbrain (Fig. 28-1A). The uncus

can compress 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

A

B

D

C

FIGURE 28-1 Types of cerebral herniation: (A) uncal; (B) central; (C) transfalcial;

and (D) foraminal.

A B

FIGURE 28-2 Axial (A) and coronal (B) T2-weighted magnetic resonance images

from a stuporous patient with a left third nerve palsy from a large left-sided

meningioma. A. The upper midbrain is compressed and displaced horizontally away

from the mass, and there is transtentorial herniation of the medial temporal lobe

structures, including the uncus. B. The lateral ventricle opposite to the mass has

become enlarged as a result of compression of the third ventricle.

peripherally in the nerve). The coma that typically follows is due to

lateral displacement of the midbrain (and therefore the RAS) against

the opposite tentorial edge by the displaced parahippocampal gyrus

(Fig. 28-2), compressing the opposite cerebral peduncle and producing

a Babinski sign and ipsilateral hemiparesis (the Kernohan-Woltman

sign). Herniation may also compress the anterior and posterior cerebral arteries as they pass over the tentorial reflections, with resultant

brain infarction. These distortions may also entrap portions of the

ventricular system, causing hydrocephalus.

Central transtentorial herniation denotes a symmetric downward

movement of the thalamic structures through the tentorial opening

with compression of the upper midbrain (Fig. 28-1B). 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. 28-1C) and

foraminal herniation (downward forcing of the cerebellar tonsils into

the foramen magnum, Fig. 28-1D), which causes early compression of

the medulla, respiratory arrest, and death.

Coma Due to Metabolic, Drug, and Toxic Disorders Many

systemic metabolic abnormalities cause coma by interrupting the delivery of energy substrates (e.g., oxygen, glucose) or by altering neuronal

excitability (drugs and alcohol, anesthesia, and epilepsy). These are

the most common causes of coma in large case series. The metabolic

abnormalities that produce coma may, in milder forms, induce a confusional state (metabolic encephalopathy) in which clouded consciousness and coma are in a continuum.

Cerebral neurons are dependent on cerebral blood flow (CBF) and

the delivery of oxygen and glucose. 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 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 first causes a metabolic encephalopathy due to reduced energy substrate but ultimately causes neuronal

destruction, most metabolic disorders such as hypoglycemia, hyponatremia, hyperosmolarity, hypercapnia, hypercalcemia, and hepatic and

renal failure cause no or only minor neuropathologic changes in the

185Coma CHAPTER 28

brain. The reversible effects of these conditions 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 and osmotic

swelling of the cells, mitochondrial energy failure, production of reactive nitrogen and oxygen species, increases in the inhibitory neurotransmitter GABA, and synthesis of putative “false” neurotransmitters.

Over time, development of a diffuse astrocytosis is typical of chronic

HE. Which, if any, of these is responsible for coma is not known.

The mechanism of the encephalopathy of renal failure is also uncertain and likely to be multifactorial; unlike ammonia, urea does not produce central nervous system (CNS) depression. 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, especially

if achieved quickly, induce confusion, and levels <119 mmol/L are

typically associated with coma and convulsions. In hyperosmolar

coma, the serum osmolarity is generally >350 mosmol/L. Hypercapnia

depresses the level of consciousness in proportion to the rise in carbon

dioxide (CO2

) in the blood. In all of these metabolic encephalopathies,

the degree of neurologic change depends 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.

Comas due to drugs and toxins are typically reversible and leave

no residual damage provided there has not been hypoxia or severe

hypotension. 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 occasionally 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, typified by barbiturates, can mimic all of the signs of brain death; thus, toxic etiologies

should 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, EEG monitoring is often used in the evaluation

of unexplained 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 Structural Damage to the Cerebral

Hemispheres This category, comprising several unrelated disorders, results from extensive bilateral structural cerebral damage. The

clinical appearance simulates a metabolic encephalopathy. Hypoxiaischemia is perhaps the best characterized form of this type of injury,

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 thrombotic thrombocytopenic purpura,

hyperviscosity, and cerebral malaria. Diffuse white matter damage

from cranial trauma or inflammatory demyelinating diseases can cause

a similar coma syndrome.

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. 443.

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 emergency

medical technicians on the scene, in person or by telephone, is an

important part of the evaluation when possible.

GENERAL PHYSICAL EXAMINATION

Signs of head trauma raise the possibility of coexisting spinal cord

injury, and in such cases, immobilization of the cervical spine is

essential to prevent further injury. 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 temperatureregulating 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; less dramatically low body temperatures can also cause coma in some instances.

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. Spontaneously moving about the bed, reaching up toward

the face, crossing legs, yawning, swallowing, coughing, and 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

186 PART 2 Cardinal Manifestations and Presentation of Diseases

facial muscle may be the only sign of seizures. Multifocal myoclonus

usually indicates a metabolic disorder, particularly uremia, anoxia,

drug intoxication, or rarely a prion disease (Chap. 438). 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) classically

suggest 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. However,

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 bony prominences and pinprick stimulation, when necessary,

are humane forms of noxious stimuli; pinching the skin causes

ecchymoses and is generally not performed 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

Assessment of brainstem function is essential to localization of

the lesion in coma (Fig. 28-3). 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 a lesion in the brainstem or a herniation syndrome from a cerebral mass lesion impacting the brainstem

secondarily. The most important brainstem reflexes 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 from herniation. A response to light may

be difficult to appreciate in pupils <2 mm in diameter, and bright

room lighting may mute pupillary reactivity. One enlarged (>6 mm)

and poorly reactive pupil signifies compression 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 other causes of 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 opioid

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

Pupillary light reflex

Reflex conjugate

eye movements

Medulla

Pons

M

L

F

III

V

Vll Vl

Vlll

III

Respiratory

neurons

Corneal-blink

reflex

FIGURE 28-3 Examination of brainstem reflexes in coma. Midbrain and third nerve

function are tested by pupillary reaction to light, pontine function by spontaneous

and reflex eye movements and corneal responses, and medullary function by

respiratory and pharyngeal responses. Reflex conjugate, horizontal eye movements

are dependent on the medial longitudinal fasciculus (MLF) interconnecting the

sixth and contralateral third nerve nuclei. Head rotation (oculocephalic reflex) or

caloric stimulation of the labyrinths (oculovestibular reflex) elicits contraversive eye

movements (for details, see text).

187Coma CHAPTER 28

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. 28-3). The

movements, called somewhat inaccurately “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 maneuvers should not be attempted in patients with 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.

The corneal reflex, elicited by touching the cornea with a wisp of

cotton and observing bilateral lid closure, depends on the integrity

of pontine pathways between the fifth (afferent) and both seventh

(efferent) cranial nerves; 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-induced depression of the medullary

respiratory centers. 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. Other cyclic breathing patterns have been described but

are of lesser significance.

■ LABORATORY STUDIES AND IMAGING

The studies that are most useful in the diagnosis of coma are chemicaltoxicologic analysis of blood and urine, cranial CT or MRI, EEG, and

cerebrospinal fluid (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 cases of

acute coma, when 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 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 cranial CT and MRI has focused attention on

causes of coma that are detectable by imaging (e.g., hemorrhage, tumor,

or hydrocephalus). Resorting primarily to this approach, although

at times expedient, is imprudent because most cases of coma (and

confusion) are metabolic or toxic in origin. Furthermore, a normal

CT scan does not exclude an anatomic lesion as the cause of coma;

for example, 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. Additional imaging

with CT angiography or MRI can be obtained if acute posterior circulation stroke is considered.

The EEG (Chap. 425) provides clues in metabolic or drug-induced

states but is rarely diagnostic in these disorders. However, it is the

essential test to reveal coma due to nonconvulsive seizures and shows

fairly characteristic patterns in herpesvirus encephalitis and prion 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 overdose with 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. A unique EEG

pattern in adults of “extreme delta brush” is characteristic of a specific

(anti–N-methyl-d-aspartate [NMDA] receptor) form of autoimmune

encephalitis. Normal α activity on the EEG, which is suppressed by

stimulating the patient, also alerts the clinician to the locked-in syndrome, 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. 138).

■ DIFFERENTIAL DIAGNOSIS OF COMA

(Table 28-1) The causes of coma can be divided into three broad categories: those without focal neurologic signs (e.g., metabolic and toxic

encephalopathies); those 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. 426). The most common diseases in this category 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 transient ischemic attack

warning spells, diplopia, dysarthria, vomiting, eye movement and

corneal response abnormalities, and asymmetric limb paresis); and

188 PART 2 Cardinal Manifestations and Presentation of Diseases

TABLE 28-1 Differential Diagnosis of Coma

1. Diseases that cause no focal brainstem or lateralizing neurologic signs

(CT scan is often normal)

a. Intoxications: alcohol, sedative drugs, opiates, etc.

b. Metabolic disturbances: anoxia, hyponatremia, hypernatremia,

hypercalcemia, diabetic acidosis, nonketotic hyperosmolar hyperglycemia,

hypoglycemia, uremia, hepatic coma, hypercarbia, Addisonian crisis,

hypo- and hyperthyroid states, profound nutritional deficiency

c. Severe systemic infections: pneumonia, septicemia, typhoid fever, malaria,

Waterhouse-Friderichsen syndrome

d. Shock from any cause

e. Status epilepticus, nonconvulsive status epilepticus, postictal states

f. Hyperperfusion syndromes including hypertensive encephalopathy,

eclampsia, posterior reversible encephalopathy syndrome (PRES)

g. Severe hyperthermia, hypothermia

h. Concussion

i. Acute hydrocephalus

2. Diseases that cause focal brainstem or lateralizing cerebral signs (CT scan is

typically abnormal)

a. Hemispheral hemorrhage (basal ganglionic, thalamic) or infarction (large

middle cerebral artery territory) with secondary brainstem compression

b. Brainstem infarction due to basilar artery thrombosis or embolism

c. Brain abscess, subdural empyema

d. Epidural and subdural hemorrhage, brain contusion

e. Brain tumor with surrounding edema

f. Cerebellar and pontine hemorrhage and infarction

g. Widespread traumatic brain injury

h. Metabolic coma (see above) in the setting of preexisting focal damage

3. Diseases that cause meningeal irritation with or without fever, and with an

excess of white blood cells or red blood cells in the CSF

a. Subarachnoid hemorrhage from ruptured aneurysm, arteriovenous

malformation, trauma

b. Infectious meningitis and meningoencephalitis

c. Paraneoplastic and autoimmune encephalitis

d. Carcinomatous and lymphomatous meningitis

(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.

■ BRAIN DEATH

Brain death 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. It 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 the

diagnosis, clinicians must be thorough and precise in determining

brain death. 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. Some centers advocate a brief period of observation between

two examiners’ tests during which the clinical signs of brain death are

sustained.

Established criteria 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; and (2) global

brainstem damage as 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 often 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 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 cardiovascular instability and alternative

means of testing can be employed.

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 be used to demonstrate the absence of blood flow when a confirmatory study is desired.

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.

TREATMENT

Coma

The immediate goal in a comatose patient is prevention of further

nervous system damage. Hypotension, hypoglycemia, hypercalcemia, hypoxia, hypercapnia, and hyperthermia should be corrected

rapidly. Hyponatremia should be corrected slowly to avoid injury

from osmotic demyelination (Chap. 307). An oropharyngeal airway is adequate to keep the pharynx open in a drowsy patient who

is breathing normally. Tracheal intubation is indicated if there is

apnea, upper airway obstruction, hypoventilation, or emesis, or

if the patient is at risk for aspiration. Mechanical ventilation is

required if there is hypoventilation or a need to induce hypocapnia

in order to lower ICP. The management of raised ICP is discussed in Chap. 307. IV access is established and naloxone and

dextrose are administered if opioid overdose or hypoglycemia are

possibilities; thiamine is given along with glucose to avoid provoking Wernicke’s encephalopathy in malnourished patients. In cases

of suspected ischemic stroke including basilar thrombosis with

brainstem ischemia, IV tissue plasminogen activator or mechanical

embolectomy is often used after cerebral hemorrhage has been

excluded and when the patient presents within established time

windows for these interventions (Chap. 427). Physostigmine may

awaken patients with anticholinergic-type drug overdose but should

be used only with careful monitoring; many physicians believe that

it should only be used to treat anticholinergic overdose–associated

cardiac arrhythmias. The use of benzodiazepine antagonists offers

some prospect of improvement after overdose; however, these drugs

are not commonly used empirically in part due to their tendency to

provoke seizures. Certain other toxic and drug-induced comas have

specific treatments such as fomepizole for ethylene glycol ingestion.

Administration of hypotonic IV solutions should be monitored

carefully in any serious acute brain illness because of the potential for

exacerbating brain swelling. Cervical spine injuries must not be overlooked, particularly before attempting intubation or evaluation of

oculocephalic responses. Fever and meningismus indicate an urgent

need for examination of the CSF to diagnose meningitis. Whenever acute bacterial meningitis is suspected, antibiotics including at

least vancomycin and a third-generation cephalosporin are typically

administered rapidly along with dexamethasone (see Chap. 138).

189 Dementia CHAPTER 29

■ PROGNOSIS

Some patients, especially children and young adults, may have ominous early clinical findings such as abnormal brainstem reflexes and

yet recover; early prognostication outside of brain death therefore is

unwise. Metabolic comas have a far better prognosis than traumatic

ones. 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; it has

predictive value in cases of brain trauma (see Chap. 443). For anoxic

coma, clinical signs such as the pupillary and motor responses after 1

day, 3 days, and 1 week have predictive value; however, some prediction rules are less reliable in the setting of therapeutic hypothermia,

and therefore, serial examinations and multimodal prognostication

approaches are advised in this setting. For example, the absence of the

cortical responses of the somatosensory evoked potentials has been

shown to be a strong indicator of poor outcome following hypoxic

injury.

The poor outcome of persistent vegetative and minimally conscious

states has already been mentioned, but reports of a small number of

patients displaying 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. Another series demonstrated that up to 15% of patients with

various forms of acute brain injury and absence of behavioral responses

to motor commands showed EEG activation in response to these commands. 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.

■ FURTHER READING

Claasen J et al: Detection of brain activation in unresponsive patients

with acute brain injury. N Engl J Med 380:2497, 2019.

Edlow JA et al: Diagnosis of reversible causes of coma. Lancet

384:2064, 2014.

Greer DM et al: Determination of brain death/death by neurologic

criteria: The World Brain Death Project. JAMA 324:1078, 2020.

Monti MM et al: Willful modulation of brain activity in disorders of

consciousness. N Engl J Med 362:579, 2010.

Posner JB et al: Plum and Posner’s Diagnosis of Stupor and Coma, 5th

ed. New York, Oxford University Press, 2019.

Wijdicks EFM: Predicting the outcome of a comatose patient at the

bedside. Pract Neurol 20:26, 2020.

Dementia, a syndrome with many causes, affects nearly 6 million people in the United States and results in a total annual health care cost

in excess of $300 billion. Dementia is defined as an acquired deterioration in cognitive abilities that impairs the successful performance of

activities of daily living. Episodic memory, the ability to recall events

specific in time and place, is the cognitive function most commonly

lost; 10% of persons age >70 years and 20–40% of individuals age >85

years have clinically identifiable memory loss. In addition to memory,

dementia may erode other mental faculties, including language, visuospatial, praxis, calculation, judgment, and problem-solving abilities.

29 Dementia

William W. Seeley, Gil D. Rabinovici,

Bruce L. Miller

Neuropsychiatric and social deficits also arise in many dementia

syndromes, manifesting as depression, apathy, anxiety, hallucinations,

delusions, agitation, insomnia, sleep disturbances, compulsions, or

disinhibition. The clinical course may be slowly progressive, as in

Alzheimer’s disease (AD); static, as in anoxic encephalopathy; or may

fluctuate from day to day or minute to minute, as in dementia with

Lewy bodies (DLB). Most patients with AD, the most prevalent form

of dementia, begin with episodic memory impairment, but in other

dementias, such as frontotemporal dementia (FTD), memory loss is

not typically a presenting feature. Focal cerebral disorders are discussed in Chap. 30 and illustrated in a video library in Chap. V2;

detailed discussions of AD can be found in Chap. 431; FTD and

related disorders in Chap. 432; vascular dementia in Chap. 433; DLB

in Chap. 434; Huntington’s disease (HD) in Chap. 436; and prion

diseases in Chap. 438.

FUNCTIONAL ANATOMY OF THE

DEMENTIAS

Dementia syndromes result from the disruption of specific large-scale

neuronal networks; the location and severity of synaptic and neuronal

loss combine to produce the clinical features (Chap. 30). Behavior,

mood, and attention are modulated by ascending noradrenergic, serotonergic, and dopaminergic pathways, whereas cholinergic signaling

is critical for attention and memory functions. The dementias differ

in the relative neurotransmitter deficit profiles; accordingly, accurate

diagnosis guides effective pharmacologic therapy.

AD typically begins in the entorhinal region of the medial temporal

lobe, spreads to the hippocampus and other limbic structures, and

moves through the basal temporal areas and then into the lateral and

posterior temporal and parietal neocortex, eventually causing a more

widespread degeneration. Vascular dementia is associated with focal

damage in a variable patchwork of cortical and subcortical regions

or white matter tracts that disconnects nodes within distributed networks. In keeping with its anatomy, AD typically presents with episodic

memory loss accompanied later by aphasia, executive dysfunction, or

navigational problems. In contrast, dementias that begin in frontal or

subcortical regions, such as FTD or HD, are less likely to begin with

memory problems and more likely to present with difficulties with

judgment, mood, executive control, movement, and behavior.

Lesions of frontal-striatal1

 pathways produce specific and predictable

effects on behavior. The dorsolateral prefrontal cortex has connections

with a central band of the caudate nucleus. Lesions of either the caudate

or dorsolateral prefrontal cortex, or their connecting white matter pathways, may result in executive dysfunction, manifesting as poor organization and planning, decreased cognitive flexibility, and impaired working

memory. The lateral orbital frontal cortex connects with the ventromedial caudate, and lesions of this system cause impulsiveness, distractibility, and disinhibition. The anterior cingulate cortex and adjacent medial

prefrontal cortex project to the nucleus accumbens, and interruption

of this system produces apathy, poverty of speech, emotional blunting, or even akinetic mutism. All corticostriatal systems also include

topographically organized projections through the globus pallidus and

thalamus, and damage to these nodes can likewise reproduce the clinical

syndrome associated with the corresponding cortical or striatal injuries.

Involvement of brainstem nuclei and cerebellar structures can further

contribute to cognitive, behavioral, and motor manifestations.

■ THE CAUSES OF DEMENTIA

The single strongest risk factor for dementia is increasing age. The

prevalence of disabling memory loss increases with each decade over

age 50 and is usually associated with the microscopic changes of AD

at autopsy. Yet some centenarians have intact memory function and

no evidence of clinically significant dementia. Whether dementia is an

inevitable consequence of normal human aging remains controversial

although the prevalence increases with every decade of life.

1

The striatum comprises the caudate/putamen/nucleus accumbens.