but PCR for JC virus is positive; the EEG is usu-
ally diffusely or multifocally abnormal. The MRI
is characterized by multiple discrete areas of
white matter with hyperintensity on the FLAIR
image, but there is often no enhancement with
gadolinium, indicating a minimal inflammatory
response; those who do mount an inflammatory
response have a better prognosis.
468
The pathology is one of diffuse multifocal
demyelination of white matter, with oligoden-
droglial nuclei containing eosinophilic inclu-
sions, viral particles, and bizarre giant astro-
cytes, suggesting neoplastic transformation.
Multifocal, Diffuse, and Metabolic Brain Diseases Causing Delirium, Stupor, or Coma
279
Epilepsy
Seizures are characterized by intense, repeti-
tive neuronal discharge followed by postictal
metabolic cerebral depression of varying de-
grees and duration. In general, this requires re-
entrant neuronal circuits that mainly occur in
the forebrain when lesions involve the struc-
tures of the cortical mantle. In the experi-
mental animal, one can demonstrate that major
seizures produce a 200% to 300% increase in
cerebral metabolic demand, a substantial de-
gree of systemic hypertension, and an enor-
mously increased CBF.
469
Repetitive convul-
sions result in a progressive, abnormal increase
in the permeability of the blood-brain bar-
rier.
470
If substrate depletion or a relative de-
cline in blood flow occurs during seizures, the
brain maintains its metabolism by the con-
sumption of endogenous substrates. With sus-
tained status epilepticus in such animals, pro-
gressive hypoxic-ischemic structural neuronal
damage results soon after. Similar but neces-
sarily less comprehensive analyses indicate that
seizures cause comparable changes in the hu-
man brain.
Postictal coma in humans ranges in intensity
from complete unresponsiveness to stupor;
protracted deep unresponsiveness lasting more
than 15 to 30 minutes suggests continued non-
convulsive seizures or extension of an under-
lying structural lesion that caused the seizure.
Although rare, postictal coma may persist for
up to 24 hours without the presence of struc-
tural brain injury. In such instances, one should
suspect nonconvulsive status epilepticus.
471
Postictal patients in coma usually are hyper-
pneic until the individual clears the lactic aci-
demia produced by the repetitive firing of ner-
ves and muscles of the convulsion during a
period of impaired breathing; pupillary light
reflexes are intact and oculovestibular re-
sponses active. The motor system usually is
unremarkable except for extensor plantar re-
sponses in about half the patients. When a
patient is first discovered during the period of
postictal unresponsiveness, it is often difficult
to determine the cause. However, the diagnosis
is clarified quickly because the patient usually
rapidly awakens to give his or her history. The
problem the physician most frequently faces is
retrospective: Was a past, unobserved episode
of unconsciousness caused by epilepsy or syn-
Figure 5–12. Progressive multifocal leukoencephalopa-
thy. This 45-year-old man with AIDS became confused
and disoriented. Examination revealed a mild right hemi-
paresis. Spinal fluid was positive for JC virus. The magnetic
resonance image revealed multiple areas hyperintense on
the FLAIR image (A) and hypointense on T1 (B). He
gradually became more stuporous, went into a coma, and
died. Autopsy revealed progressive multifocal leukoence-
phalopathy.
280
Plum and Posner’s Diagnosis of Stupor and Coma
cope? In three conditions, coma associated
with seizures can be sufficiently prolonged to
present diagnostic problems.
The first instance is status epilepticus,
472
a
series of generalized convulsions occurring at
intervals so closely spaced (i.e., every few min-
utes) that consciousness is not regained be-
tween them. This state strikes about 10% of
patients with untreated or inadequately treated
epilepsy and often follows the abrupt with-
drawal of anticonvulsants. Status epilepticus is
a serious medical emergency since the cumu-
lative systemic and cerebral anoxia induced by
repeated generalized seizures can produce ir-
reversible brain damage or death; its diagnosis is
readily made when repeated convulsions punc-
tuate a state of otherwise nonspecific coma.
A second example of prolonged coma, stu-
por, or delirium following seizures can occur in
elderly patients with an epileptogenic scar or
lesion (e.g., from past cerebral infarction) who
also suffer from cerebral vascular insufficiency
or mild to moderate senile cerebral degenera-
tion with dementia. In these patients, the
enormous cerebral metabolic demand imposed
by the seizures, plus systemic hypoxemia dur-
ing the attack, often is sufficient to compromise
an already borderline cerebral function and
produce several hours of postictal coma fol-
lowed by several days of delirium. Most such
patients ultimately recover their preseizure
cerebral function, but each attack risks dam-
aging more and more brain, making effective
prevention and prompt treatment important.
A third condition in which sustained coma
may be associated with seizures occurs when
the loss of consciousness is not simply postictal,
but is the result of a cerebral disease that also
caused the seizures. Many underlying destruc-
tive and metabolic cerebral disorders produce
both seizures and coma and must be differen-
tiated by other signs, symptoms, and laboratory
studies. If one takes previously healthy patients
in our own series, a single or brief series of
convulsions was followed by sustained uncon-
sciousness only when caused by acute enceph-
alitis, encephalomyelitis, or acute hyponatremia.
However, one may not always have the history
available, and many other structural lesions of
brain can cause repetitive convulsions followed
by a prolonged postictal stupor. It is an axiom of
treatment that convulsions should be stopped
as promptly as possible, as both the seizures
themselves and the accompanying systemic hy-
poxemia are sources of potentially serious brain
damage.
Not all patients with epilepsy have convul-
sions. Nonconvulsive status epilepticus is char-
acterized by delirium, stupor, or coma result-
ing from generalized seizure activity without or
with only minor motor activity. In one series of
236 comatose patients with no overt clinical
seizure activity, EEG demonstrated that 8% of
patients met criteria of nonconvulsive status
epilepticus. In this series, the definition inclu-
ded ‘‘continuous or nearly continuous electro-
graphic seizure activity lasting at least 30 min-
utes.’’
473
The diagnosis can be suspected if the
patient has a history of risk factors such as
noncompliance with anticonvulsant drugs
474
or
a careful neurologic examination reveals par-
ticular abnormalities such as subtle motor ac-
tivity (particularly twitching of the face and
distal extremities
474
) or intermittent bouts of
nystagmoid eye movements. If the EEG iden-
tifies unequivocal continuous epileptic activi-
ty,
475
the diagnosis is established. Unfortuna-
tely, an electrographic diagnosis is often
difficult. Patients may have electrographic ac-
tivity that suggests seizures but may simply
represent diffuse brain damage, or the sei-
zure activity may occur in a part of the brain,
such as the medial temporal or orbitofrontal
cortex, from which it may be difficult to record
electrographic seizure activity. When the diag-
nosis is strongly suspected, a trial of an intra-
venous anticonvulsant (usually a benzodiaze-
pine) may be warranted. Improvement in both
the EEG and the patient’s clinical state con-
firms the diagnosis. The disorder carries a poor
prognosis, probably related more to the un-
derlying cause of the nonconvulsive status ra-
ther than the seizure activity itself.
476
Mixed Metabolic Encephalopathy
All too often, clinical signs and symptoms
suggest that a stuporous or comatose patient is
suffering from a diffuse metabolic disorder of
brain, but laboratory evaluation either reveals a
variety of modest abnormalities, none of which
appears severe enough to be responsible for
the patient’s abnormal state of consciousness,
or there is no metabolic or toxic abnormality
detected. In the first instance, the additive ef-
fect of multiple mild metabolic abnormalities
may lead to a severe encephalopathy, which
Multifocal, Diffuse, and Metabolic Brain Diseases Causing Delirium, Stupor, or Coma
281
can sometimes be remedied by correcting any
one of the modest abnormalities.
321
Patient 5–28
A 74-year-old man with disseminated carcinoma
of the prostate was admitted to hospital confused
and disoriented. The findings on general physi-
cal examination included normal vital signs, ca-
chexia, and an enlarged liver. He was stuporous
but arousable by noxious stimuli. When aroused,
he was confused and disoriented. His respirations
were 16 per minute, his pupils were 2 mm and
reactive, and there was a full range of ocular
movement to doll’s head maneuver. He withdrew
all four extremities appropriately, deep tendon
reflexes were hyperactive, and plantar responses
were flexor. When he was roused to hold his
hands outstretched, there was bilateral asterixis.
The remainder of the segmental neurologic ex-
amination was within normal limits. Laboratory
abnormalities included a hemoglobin of 8 g/dL, a
calcium of 11.5 mg/dL, a grossly elevated alkaline
phosphatase, and modestly elevated liver en-
zymes. The CT scan showed modest cerebral at-
rophy. Arterial blood gases revealed an oxygen
tension of 55 mm Hg, a pH of 7.49, and a PCO
2
of
30 mm Hg. A small infiltrate was present in the
right middle lobe of the lung on chest x-ray. A
diagnosis of mixed metabolic encephalopathy was
made with anemia, hypoxia, liver metastases, and
hypercalcemia all playing a role.
Oxygen given by nasal prongs raised the arterial
blood PO
2
but failed to change his clinical state.
Two units of blood raised his hemoglobin to 10 g/
dL; when this was combined with the oxygen, he
awoke and, although disoriented at the time, was
otherwise alert and behaved appropriately. At the
time he awakened, no change had developed in
his serum calcium or abnormal liver function tests.
A more difficult problem arises when no
metabolic or toxic abnormalities are detected.
In that circumstance, the first step in diagnosis
should be to check all medications the patient
has received in the past 48 hours. Barring sed-
ative or narcotic drugs, one should check the
platelet count and coagulation profile. Some of
these patients have subsequently proved to have
disseminatedintravascularcoagulationwithneu-
rologic symptoms appearing before coagula-
tion profiles became abnormal. In others, a bio-
chemical defect present prior to the patient’s
being examined may have left residual brain
damage even though the underlying biochemi-
cal abnormality has been corrected. Carbon mo-
noxide poisoning and hypoglycemia are exam-
ples of this. In still other patients, drug ingestion
with chemical substances not detected by usual
laboratory tests may be the cause. In some pa-
tients, the diagnosis is never established, and
one must presume that some unidentified toxin
or not understood metabolic abnormality was
present. When faced with such a problem, the
physician should apply supportive therapy as
outlined in Chapter 7 while continuing to search
diligently to identify metabolic abnormalities as
the illness pursues its course.
ACUTE DELIRIOUS STATES
Delirium and confusional states usually pre-
cede metabolic stupor or coma and can be the
presenting problem in many of the diseases
described in this chapter or listed in Table 5–1.
An additional group of disorders cause a severe
and acute delirium that is usually self-limited,
but may, occasionally, be fatal if not appro-
priately treated. Because these states usually
do not cause stupor or coma, they have not
been discussed elsewhere in this text, but they
are responsible for acute changes in the state
of consciousness that often challenge and per-
plex the physician. Two such entities, both drug
withdrawal syndromes, particularly alcohol, and
postoperative delirium, are discussed here.
The clinical picture of these two states can be
similar. A patient who was previously alert and
oriented (although frequently with some un-
derlying mild dementia) suddenly becomes
restless. His or her affect changes such that
while previously calm, he or she becomes agi-
tated, fearful, or depressed, and emotionally
labile. The patient is less able than previously to
give attention to his or her environment; minor
defects in cognitive functions can be detected
on careful testing if the patient will cooperate.
Most of the patients become insomniac, and
many are paranoid and misinterpret sensory
stimuli, both auditory and visual. They often
hallucinate. Autonomic dysfunction including
tachycardia, hypertension, diaphoresis, dilated
pupils, and at times fever is common. (Fever
282
Plum and Posner’s Diagnosis of Stupor and Coma
should never be dismissed simply as a result of
delirium until a careful search has ruled out
infection, which may contribute to the genesis
of the delirium.) In its florid form, the patient is
tremulous, extremely restless, and often fear-
ful; asterixis and multifocal myoclonus may be
present. Many patients are totally disoriented
but may elaborately describe an incorrect en-
vironment. When the delirium is severe, such
patients are so restless that they cannot lie still,
and their thrashing and rolling about in bed
may damage a recently operated site and put
additional strain on an impaired cardiovascular
system. They are so distractible that cognitive
testing is impossible. They may engage equally
the examiner and imaginary figures in conver-
sation. The speech is so dysarthric that even
when the delirious patient does reply correctly
to questions, he or she often cannot be under-
stood. If untreated, the agitation of delirium
may lead to exhaustion and even death. How-
ever, even the most severe of the delirious
states, delirium tremens, has only a modest
mortality if treated with appropriate sedative
therapy. As indicated in Chapter 1, a stroke in
the nondominant temporal or parietal lobe can
sometimes cause an acute delirious state.
Drug Withdrawal Delirium
(Delirium Tremens)
The most common of the acute and florid de-
lirious states is delirium tremens. Although it is
caused by withdrawal of alcohol and generally
follows complete cessation of drinking, usually
by 3 to 4 days, it may occur in a patient still
drinking a diminished amount of ethanol.
Similar clinical findings may follow benzodi-
azepine, barbiturate, or other sedative drug
withdrawal.
477,478
In each of these withdrawal
states generalized convulsions may, indepen-
dent of the delirium, also occur. Particularly
perplexing to the physician are those patients
not known to be alcoholics or chronic sedative
drug users who enter the hospital for elective
surgery and, during the course of workup or
shortly following the operation, become acutely
delirious. The disease generally runs its course
in less than a week. If treated with sedative
drugs and good supportive therapy, most pa-
tients recover fully, although a mortality rang-
ing from 2% to 15% has been reported from
various sources. Much of this mortality is prob-
ably due to other complications of alcoholism,
such as liver failure, or to sympathetic activation
that commonly accompanies the disorder. The
pathogenesis of drug withdrawal syndromes may
depend on their effect on receptors, particularly
NMDA and GABA
A
receptors. NMDA recep-
tors are up-regulated during chronic alcohol
exposure and because it is a GABA
A
potentia-
tor, GABA
A
receptors may be down-regulated.
Hence, abrupt cessation increases brain excit-
ability leading to clinically evident anxiety, irri-
tability, agitation, and tremor.
479
Postoperative Delirium
Postoperative delirium is one of the most florid
and frightening postoperative complications to
confront the surgeon. Its incidence is un-
known, but may affect 20% to 60% of elderly
patients after operation for hip fracture or
cardiac surgery.
480
The clinical picture may
vary from mild cognitive impairment to an
acute confusional state resembling delirium
tremens (see above). Factors include older age,
previous cognitive impairment, anemia, elec-
trolyte abnormalities, a history of alcoholism,
narcotic or benzodiazepine use, and a history of
cerebral vascular disease.
480
In a group of 818
patients in a surgical intensive care unit, de-
lirium developed in 11%.
481
Cardiac surgery
was not a risk factor, but respiratory dysfunc-
tion, infections, anemia, hypocalcemia, hypo-
natremia, azotemia, liver function abnormali-
ties, and metabolic acidosis were.
The pathogenesis is unknown. It is probably
multifactorial including cerebral emboli after
hip or cardiac surgery,
482
anesthesia, use of opi-
oids or other sedative drugs, sleep deprivation,
circadian disorientation in an intensive care
unit, and pain. In most instances the outcome
is benign, but some patients succumb probably
due to their original medical illness while still
encephalopathic.
Intensive Care Unit Delirium
Acute delirium frequently occurs in patients
hospitalized in intensive care units. Many such
patients are postoperative, and all the factors
listed under postoperative complications un-
doubtedly play some causal role. Wilson, how-
ever, found that the incidence of postoperative
Multifocal, Diffuse, and Metabolic Brain Diseases Causing Delirium, Stupor, or Coma
283
delirium in an intensive care unit without
windows was more than double that in patients
housed in a unit with windows.
483
He con-
cluded that sensory deprivation, which results
in dissociation from normal circadian cues, was
a factor in postoperative delirium. The findings
stress the importance of environmental stimu-
lation to help potentially confused patients
orient themselves.
Drug-Induced Delirium
Myriad drugs, both licit and illicit, can cause
acute delirium. Some of these are listed in
Tables 5–12 and 5–13, but these are only par-
tial listings. Any patient, particularly an elderly
one who develops an unexplained acute delir-
ium, should be considered as having a drug
intoxication until proved otherwise. In addition
to the supportive care given for delirium, all
drugs not essential for maintenance of life
should be withdrawn until it can be determined
that they are not contributing to the patient’s
confusion.
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