confusion about the source of the findings
should be short-lived.
DESTRUCTIVE LESIONS
AS A CAUSE OF COMA
Destructive lesions of the ascending arousal
system or its forebrain targets are paradoxically
less of an immediate diagnostic concern for the
examining neurologist. Unlike compressive le-
sions, which can often be reversed by removing
a mass, destructive lesions typically cannot be
reversed. Although it is important to recognize
the hallmarks of a destructive, as opposed to a
compressive, lesion, the real value comes in dis-
tinguishing patients who may benefit from im-
mediate therapeutic intervention from those
who need mainly supportive care.
DIFFUSE, BILATERAL
CORTICAL DESTRUCTION
Diffuse, bilateral destruction of the cerebral
cortex or its underlying white matter can occur
as a result of deprivation of metabolic substrate
(i.e., oxygen, glucose, or the blood that carries
them) or as a consequence of certain metabolic
or infectious diseases. This condition is often
the consequence of prolonged cardiac arrest in
a patient who is eventually resuscitated, but it
may also occur in patients who have diffuse hyp-
oxia due to pulmonary failure or occasionally in
patients with severe and prolonged hypoglyce-
mia. The lack of metabolic substrate causes neu-
rons in layers III and V of the cerebral cortex,
and in the CA1 and CA3 fields of the hippo-
campal formation, to be damaged,
71,72
presum-
ably as a result of excitatory amino acid toxicity
(see Figure 1–10). During periods of metabolic
deprivation, there is rundown of the ion gradi-
ents that support normal membrane polariza-
tion, resulting in depolarization of neurons and
release of their neurotransmitters. Excess ex-
citatory transmitter, particularly acting on
N-methyl-d-aspartate (NMDA) receptors that
allow the intracellular shift of calcium ions, re-
sults in activation of genetic neuronal death
programs and the elimination of neurons that
receive intense excitatory amino acid inputs.
73
Because excitatory amino acids are used ex-
tensively for corticocortical communication, the
neurons that are at greatest risk are those that
receive those connections, which in turn are the
ones that are most responsible for cortical out-
put as well. The remaining neurons are essen-
tially cut off from one another and from their
outputs, and thus are unable to provide mean-
ingful behavioral response.
Patients who have suffered from a period of
hypoxia of somewhat lesser degree may appear
to recover after brain oxygenation is restored.
However, over the following week or so there
may be a progressive degeneration of the sub-
cortical white matter, essentially isolating the
cortex from its major inputs and outputs.
74
This
condition is seen most commonly after carbon
monoxide poisoning (see page 30), but may
occur after other sublethal episodes of hypoxia.
The mechanism of white matter injury is not
known, although it may be related to similar
white matter injury that is seen in Leigh’s dis-
ease,
mitochondrial
encephalopathy
with
‘‘strokes,’’ and other disorders of cerebral in-
termediary metabolism that leave the brain with
inadequate but sublethal impairment of oxida-
tive energy metabolism.
75
Other metabolic leukoencephalopathies,
such as metachromatic leukodystrophy and
Canavan’s disease, rarely occur in adults but
are considerations when assessing infants or
very young children. Adrenoleukodystrophy
may cause mainly posterior hemispheric white
matter disease, but rarely affects the level of
consciousness until very late in the disease.
Infectious causes of dysfunction of the ce-
rebral cortex or subjacent white matter include
prion infections (Creutzfeldt-Jakob disease,
Gerstmann-Stra¨ussler syndrome, etc.) and pro-
gressive multifocal leukoencephalopathy. These
disorders progress over a period of weeks to
months, and so rarely present a diagnostic di-
lemma by the time global consciousness is im-
paired. Subacute sclerosing panencephalitis,
due to slow viral infection with the measles
virus, can also cause this picture, but it is rarely
seen in populations in which measles vacci-
nation is practiced.
DESTRUCTIVE DISEASE OF
THE DIENCEPHALON
Bilateral destructive lesions of the diencephalon
are a rare cause of coma, in part because the
diencephalon receives its blood supply directly
from feeding vessels that take off from the major
114
Plum and Posner’s Diagnosis of Stupor and Coma
arteries of the circle of Willis. Hence, although
vascular disease may affect the diencephalon
when any one major arterial source is compro-
mised, it is typically unilateral and does not im-
pair consciousness. An exception occurs when
there is occlusion of the tip of the basilar artery,
which supplies the posterior cerebral and com-
municating arteries bilaterally. The posterior
thalamic penetrating arteries take their origin
from these posterior components of the circle of
Willis, and as a consequence there may be bi-
lateral posterior thalamic infarction with a single
site of vascular occlusion.
76
However, nearly all
cases in which there is impairment of con-
sciousness also have some midbrain ischemia as
well (see vascular causes of coma in Chapter 4,
page 152).
Occasional inflammatory and infectious
disorders may have a predilection for the di-
encephalon. Fatal familial insomnia, a prion
disorder, is reported to affect the thalamus se-
lectively, and this has been proposed as a cause
of the sleep disorder (although this pro-
duces hyperwakefulness, not coma).
77
Behc¸et’s
disease may cause sterile abscess formation in
the diencephalon, which may depress the level
of consciousness.
78
Autoimmune disorders may also affect the
diencephalon. In patients with anti-Ma anti-
tumor antibodies, there are often diencephalic
lesions as well as excessive sleepiness and some-
times other symptoms of narcolepsy, such as
cataplexy.
79
It is now recognized that in most
patients with narcolepsy, there is a progressive
loss of neurons in the lateral hypothalamus
that express the neurotransmitter orexin, also
called hypocretin.
80,81
This selective loss of
orexin neurons is believed to be autoimmune
in origin, although this remains to be demon-
strated definitively.
82
Loss of orexin neurons
results in excessive sleepiness, but should not
cause impairment of consciousness while
awake.
Rarely, primary brain tumors may arise in
the diencephalon. These may be either astrocy-
tomas or primary central nervous system lym-
phomas, and they can cause impairment of
consciousness as an early sign. Suprasellar tu-
mors such as craniopharyngioma or suprasellar
germinoma, or suprasellar extension of a large
pituitary adenoma, can compress the dienceph-
alon, but does not usually cause destruction
unless attempts at surgical excision cause local
vasospasm.
83
DESTRUCTIVE LESIONS
OF THE BRAINSTEM
In destructive disorders of the brainstem, acute
loss of consciousness is typically accompanied
by a distinctive pattern of pupillary, oculomotor,
motor, and respiratory signs that indicate the
level of the brainstem that has been damaged.
Unlike rostrocaudal deterioration, however, in
which all functions of the brainstem above the
level are lost, tegmental lesions of the brainstem
often are accompanied by more limited findings
that pinpoint the level of the lesion.
Destructive lesions at the level of the mid-
brain tegmentum typically destroy the ocu-
lomotor nuclei bilaterally, resulting in fixed
midposition pupils and paresis of adduction,
elevation, and depression of the eyes. At the
same time, the abduction of the eyes with ocu-
locephalic maneuvers is preserved. If the ce-
rebral peduncles are also damaged, as with a
basilar artery occlusion, there is bilateral flac-
cid paralysis.
A destructive lesion of the rostral pontine
tegmentum spares the oculomotor nuclei, so
that the pupils remain reactive to light. If the
lateral pontine tegmentum is involved, the de-
scending sympathetic and ascending pupillodi-
lator pathways are both damaged, resulting in
tiny pupils whose reaction to light may be dis-
cernible only by using a magnifying glass. Dam-
age to the medial longitudinal fasciculus causes
loss of adduction, elevation, and depression in
response to vestibular stimulation, but abduc-
tion is preserved, as are behaviorally directed
vertical and vergence eye movements. If the
lesion extends somewhat caudally into the
midpons, there may be gaze paresis toward
the side of the lesion or slow vertical eye move-
ments, called ocular bobbing, or its variants
(Table 2–3). When the lesion involves the base
of the pons, there may be bilateral flaccid pa-
ralysis. However, this is not necessarily seen
if the lesion is confined to the pontine teg-
mentum. Facial or trigeminal lower motor neu-
ron paralysis can also be seen if the lesion ex-
tends into the more caudal pons. Involvement
of the pons may also produce apneustic or ataxic
breathing.
On the other hand, destructive lesions that
are confined to the lower pons or medulla do
not cause loss of consciousness.
84
Such patients
may, however, have sufficient damage to the
Structural Causes of Stupor and Coma
115