determine if the reduced consciousness has a
structural cause (and therefore may require im-
mediate imaging and perhaps surgical treat-
ment) or a metabolic cause (in which case the
diagnostic approach can be more lengthy and
extensive). Chapters 3 and 4 discuss patho-
physiology and specific causes of structural in-
jury to the brain that result in defects of con-
sciousness. Chapter 5 examines the broad range
of metabolic causes of unconsciousness, and
the specific treatments they require. Chapter 6
explores psychiatric causes of unresponsive-
ness, which must be differentiated from or-
ganic causes of stupor and coma. Chapter 7
provides a systematic discussion of the treat-
ment of both structural and metabolic coma.
Chapter 8 explores the outcomes of coma of
different causes, including the prognosis for
useful recovery and the states of long-term im-
pairment of consciousness. Chapter 9 reviews
some ethical problems encountered in treating
unconscious individuals.
DEFINITIONS
Consciousness
Consciousness is the state of full awareness of
the self and one’s relationship to the environ-
ment. Clinically, the level of consciousness of a
patient is defined operationally at the bedside
by the responses of the patient to the examiner.
It is clear from this definition that it is possi-
ble for a patient to be conscious yet not respon-
sive to the examiner, for example, if the patient
lacks sensory inputs, is paralyzed (see locked-
in syndrome, page 7), or for psychologic reasons
decides not to respond. Thus, the determina-
tion of the state of consciousness can be a
technically challenging exercise. In the defini-
tions that follow, we assume that the patient is
not unresponsive due to sensory or motor im-
pairment or psychiatric disease.
Consciousness has two major components:
content and arousal. The content of conscious-
ness represents the sum of all functions medi-
ated at a cerebral cortical level, including both
cognitive and affective responses. These func-
tions are subserved by unique networks of cor-
tical neurons, and it is possible for a lesion that
is strategically placed to disrupt one of the net-
works, causing a fractional loss of conscious-
ness.
1
Such patients may have preserved aware-
ness of most stimuli, but having suffered the
loss of a critical population of neurons (e.g., for
recognizing language symbol content, differ-
ences between colors or faces, or the presence
of the left side of space), the patient literally
becomes unconscious of that class of stimuli.
Patients with these deficits are often charac-
terized as ‘‘confused’’ by inexperienced exam-
iners, because they do not respond as expected
to behavioral stimuli. More experienced clini-
cians recognize the focal cognitive deficits and
that the alteration of consciousness is confined
to one class of stimuli. Occasionally, patients with
right parietotemporal lesions may be sufficiently
inattentive as to appear to be globally confused,
but they are not sleepy and are, in fact, usually
agitated.
2
Thus, unless the damage to cortical net-
works is diffuse or very widespread, the level of
consciousness is not reduced. For example, pa-
tients with advanced Alzheimer’s disease may
lose memory and other cognitive functions, but
remain awake and alert until the damage is so
extensive and severe that response to stimuli is
reduced as well (see vegetative state, page 8).
Hence, a reduced level of consciousness is not
due to focal impairments of cognitive function,
but rather to a global reduction in the level of
behavioral responsiveness. In addition to being
caused by widespread cortical impairment, a
reduced level of consciousness can result from
injury to a specific set of brainstem and di-
encephalic pathways that regulate the overall
level of cortical function, and hence conscious-
ness (Figure 1–1). The normal activity of this
arousal system is linked behaviorally to the
appearance of wakefulness. It should be appar-
ent that cognition is not possible without a rea-
sonable degree of arousal.
Sleep is a recurrent, physiologic, but not path-
ologic, form of reduced consciousness in which
the responsiveness of brain systems responsible
for cognitive function is globally reduced, so that
the brain does not respond readily to environ-
mental stimuli. Pathologic alteration of the re-
lationships between the brain systems that are
responsible for wakefulness and sleep can im-
pair consciousness. The systems subserving nor-
mal sleep and wakefulness are reviewed later
in this chapter. A key difference between sleep
and coma is that sleep is intrinsically reversible:
sufficient stimulation will return the individual
to a normal waking state. In contrast, if patients
Pathophysiology of Signs and Symptoms of Coma
5
with pathologic alterations of consciousness can
be awakened at all, they rapidly fall back into a
sleep-like state when stimulation ceases.
Patients who have a sleep-like appearance
and remain behaviorally unresponsive to all
external stimuli are unconscious by any defini-
tion. However, continuous sleep-like coma as a
result of brain injury rarely lasts more than 2 to
4 weeks.
Acutely Altered States
of Consciousness
Clouding of consciousness is a term applied to
minimally reduced wakefulness or awareness,
which may include hyperexcitability and irrit-
ability alternating with drowsiness. A key dis-
tinction must be made in such patients between
those who are confused (i.e., do not respond ap-
propriately to their environment) because of a
focal deficit of cognitive function versus those
who have more global impairment. The beclou-
ded patient is usually incompletely oriented to
time and sometimes to place. Such patients are
inattentive and perform poorly on repeating
numbers backward (the normal range is at least
four or five) and remembering details or even
the meaning of stories. Drowsiness is often pro-
minent during the day, but agitation may pre-
dominate at night.
The pathophysiology of brain function in such
patients has rarely been studied, but Posner and
Plum
3
found that cerebral oxygen consumption
had declined by 20% below normal levels in
patients with hepatic encephalopathy with leth-
argy and global confusion, and Shimojyo and
colleagues noted similar reductions in patients
with lethargy and global confusion due to Wer-
nicke’s encephalopathy.
4
More recently, Trze-
pacz and colleagues have identified decreased
regional cerebral blood flow (CBF) bilaterally in
the frontotemporal cortex and right basal gan-
glia of patients with subclinical hepatic ence-
phalopathy.
5
Increases in CBF during treatment
of cobalamin deficiency correlate with clinical
improvement.
6
Other studies have implicated
reduced cholinergic function; excess release of
dopamine, norepinephrine, and glutamate; and
both decreased and increased serotonergic and
gamma-aminobutyric acid (GABA) activity.
7
The pathogenesis of clouding of consciousness
and delirium is discussed in more detail in
Chapter 5.
Delirium, from the Latin ‘‘to go out of the
furrow,’’ is a more floridly abnormal mental
state characterized by misperception of sensory
stimuli and, often, vivid hallucinations. Deli-
rium is defined by the Diagnostic and Statisti-
cal Manual of Mental Disorders, 4th edition
(DSM-IV),
8
as follows: ‘‘A. Disturbance of con-
sciousness (i.e., reduced clarity of awareness of
the environment) with reduced ability to focus,
sustain or shift attention. B. A change in cog-
nition (such as memory deficit, disorientation,
language disturbance) or the development of a
perceptual disturbance that is not better ac-
counted for by a pre-existing, established or
evolving dementia. C. The disturbance devel-
ops over a short period of time (usually hours
to days) and tends to fluctuate during the course
of the day.’’
Delirious patients are disoriented, first to
time, next to place, and then to persons in their
environment. Rarely are patients unaware of
who they are, although sometimes married
women will revert to their maiden name. Pa-
tients are often fearful or irritable and may
overreact or misinterpret normal activities of
physicians and nurses. Delusions or hallucina-
tions may place the patient completely out of
contact with the environment and the exam-
iner. Full-blown delirious states tend to come
on rapidly and rarely last more than 4 to 7 days.
However, fragments of misperceptions may
persist for several weeks, especially among al-
coholics and patients with cerebral involvement
from collagen vascular diseases.
Delirium with agitation occasionally may be
seen as a consequence of focal lesions of the
right parieto-occipitotemporal cortex,
2,9
but
generally is indicative of bilateral impairment
of cortical function in toxic-metabolic states,
such as atropine poisoning, alcohol or seda-
tive drug (e.g., benzodiazepine) withdrawal,
acute porphyria, or hepatic or renal failure. It
also occurs with systemic infectious processes
or as a component of encephalitis, during
which immune mediators such as cytokines
and eicosanoid derivatives may cloud mental
function.
Obtundation, from the Latin ‘‘to beat against
or blunt,’’ literally means mental blunting or
torpidity. In a medical setting, such patients have
a mild to moderate reduction in alertness, ac-
companied by a lesser interest in the environ-
ment. Such patients have slower psychologic
responses to stimulation. They may have an
6
Plum and Posner’s Diagnosis of Stupor and Coma