Stupor and Coma in Adults

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Stupor and coma in adults

Author: G Bryan Young, MD, FRCPC
Section Editors: Michael J Aminoff, MD, DSc, Robert S Hockberger, MD, FACEP
Deputy Editor: Janet L Wilterdink, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2021. | This topic last updated: Aug 13, 2020.
INTRODUCTION
Stupor and coma are clinical states in which patients have impaired responsiveness (or are
unresponsive) to external stimulation and are either difficult to arouse or are unarousable.
Coma is defined as "unarousable unresponsiveness" [1]. An alert patient has a normal state of
arousal. The terms "stupor," "lethargy," and "obtundation" refer to states between alertness and
coma. These imprecise descriptors should generally not be used in clinical situations without
further qualification.
An alteration in arousal represents an acute, life-threatening emergency, requiring prompt

intervention for preservation of life and brain function [2,3]. Although discussed separately
here, the assessment and management are performed jointly in practice ( table 1).
ETIOLOGIES AND PATHOPHYSIOLOGY
The ascending reticular activating system (ARAS) is a network of neurons originating in the
tegmentum of the upper pons and midbrain, believed to be integral to inducing and
maintaining alertness. These neurons project to structures in the diencephalon, including the
thalamus and hypothalamus, and from there to the cerebral cortex. Alterations in alertness can
be produced by focal lesions within the upper brainstem by directly damaging the ARAS.
Damage to the cerebral hemispheres can also produce coma, but in this case, the involvement
is necessarily bilateral and diffuse, or if unilateral, large enough to exert remote effects on the
contralateral hemisphere or brainstem. Magnetic resonance imaging (MRI) studies have
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indicated that coma in supratentorial mass lesions occurs both with lateral forces on the
contralateral hemisphere and with downward brainstem compression [4,5]. (See 'Coma
syndromes' below.)
The mechanism of coma in toxic, metabolic, and infectious etiologies and hypothermia is less
well understood and to some extent is cause specific. A simplified explanation is that these
conditions impair oxygen or substrate delivery, which in turn alters cerebral metabolism or
interferes with neuronal excitability and/or synaptic function.
Conditions causing stupor and coma cross a broad spectrum of medical and neurologic disease;
the list of potential differential diagnoses is long ( table 2). Most cases of stupor and coma
presenting to an emergency department are due to trauma, cerebrovascular disease,
intoxications, infections, seizures (including nonconvulsive status epilepticus [NCSE]) and
metabolic derangements; the precise case mix varies according to the setting and referral base
[1]. Also, case series often do not include those patients presenting in coma that complicates
resuscitation from cardiac arrest, or the postictal state after a witnessed epileptic seizure, but
these are common causes of coma as well.
HISTORY
The patient with impaired consciousness probably cannot contribute a history, but others often
can provide valuable information:
● It is often useful to obtain a history from witnesses, friends or family members, and
emergency medical technicians who might provide information that suggests the likely
etiology.
● The patient's personal effects: a medical alert bracelet or necklace and/or a card in the
wallet may contain a list of illnesses and medications.
● An old hospital chart may also contain information not otherwise available.
Potentially helpful questions for relatives, friends, and witnesses include:
● What was the time course of the loss of consciousness? Was it abrupt (eg, subarachnoid
hemorrhage, seizure), gradual (eg, brain tumor), or fluctuating (eg, recurring seizures,
subdural hematoma, metabolic encephalopathy)?
● Did focal signs or symptoms precede the loss of consciousness? As an example, an initial
hemiparesis suggests a structural lesion, likely with mass effect. Transient visual
symptoms (eg, diplopia or vertigo) suggest ischemia in the posterior circulation. Headache
and vomiting just prior to loss of consciousness could indicate an intracranial
hemorrhage.
● Did the patient have previous neurologic episodes that suggest transient ischemic attacks
or seizures?
● What recent illness has the patient had? Has there been altered behavior or function
recently? A fever suggests infection; an increasing headache suggests an expanding
intracranial lesion, infection, or venous sinus thrombosis; recent falls raise the possibility
of a subdural hematoma; recent confusion or delirium might indicate a metabolic or toxic
cause.
● What prescription or nonprescription drugs are used? Are there medical or psychiatric
conditions? Is there history of alcohol or drug abuse?
GENERAL EXAMINATION
A general physical examination should not be neglected in the patient with coma, as valuable
clues to the underlying etiology are often found ( table 3 and table 4).
● Vital signs – Extreme hypertension may suggest reversible posterior leukoencephalopathy

syndrome, hypertensive encephalopathy, or hypertensive
intracerebral/cerebellar/brainstem hemorrhage. Hypotension may reflect circulatory
failure from sepsis, hypovolemia, or cardiac failure, as well as certain drugs or Addison
disease.
Hyperthermia usually signifies an infection; heat stroke or anticholinergic intoxication are

other possibilities. Hypothermia could be accidental (cold exposure), primary (due to
hypothalamic dysfunction as in Wernicke encephalopathy or tumor), or secondary (eg,
adrenal failure, hypothyroidism, sepsis, drug or alcohol intoxication).
● Ventilatory pattern – An observation of hypo- or hyperventilation can be helpful in the

diagnosis of a patient with coma, especially when combined with blood gas results (
table 3).
Specific breathing patterns, while classically associated with regions of brainstem injury
during transtentorial herniation ( figure 1), are not that useful clinically. Cheyne-Stokes
respirations (a pattern of periodic waxing then waning hyperpnea, followed by brief
apnea) may occur with either impaired cardiac output or bicerebral dysfunction, and also
in older adult patients during sleep. The shorter-cycle Cheyne-Stokes respiration linked to
brainstem tegmental dysfunction may evolve into irregular respirations with progression
of downward herniation (see 'Coma syndromes' below). Apneustic breathing (in which
there is a prolonged inspiratory phase or end-inspiratory pause) is rare and usually
attributed to pontine tegmental lesions.
● Cutaneous and mucosal abnormalities – A rapid survey of the skin can have a high yield in
the evaluation of a patient with coma ( table 4).
Bruises can indicate head trauma, especially "raccoon eye" (periorbital ecchymosis). Battle
sign (bruising over the mastoid) and hemotympanum (blood behind the tympanic
membrane) are signs of basal skull fracture. Petechiae and ecchymoses can be seen in
bleeding diatheses (eg, thrombocytopenia, disseminated intravascular coagulation [DIC]),
some infections (eg, meningococcal septicemia, Rocky Mountain spotted fever), and
certain vasculitides. Subungual (splinter) and conjunctival hemorrhages are sometimes
seen in endocarditis. Petechiae confined to the head and neck may be found after
convulsive seizures due to acutely raised venous pressure. "Cherry red lips" can be seen in
carbon monoxide poisoning.
Perspiration is common in fevers, hypoglycemia, and pheochromocytoma. Bullous lesions

are characteristic of barbiturate intoxication (coma blisters).
Jaundice could indicate liver disease. A cherry red color, especially of the lips and mucous
membranes, suggests carbon monoxide intoxication. Pallor, especially with a sallow
appearance, may suggest uremia, myxedema, or severe anemia as in profound pernicious
anemia.
Needle tracks suggest intravenous (IV) drug abuse. A tongue bitten on the lateral aspect
suggests a recent convulsive seizure.
● Other – Most orthopedic injuries indicate trauma. Some, in particular posterior fracture
dislocation at the shoulder, manubriosternal dislocation, and vertebral compression
fractures (less commonly fractures of the femoral neck or acetabulum), also occur with
convulsive seizures.
Cerebrospinal fluid (CSF) rhinorrhea can occur with skull fracture and is important to
recognize, as recurrent pyogenic meningitis can occur as a later complication.
Resistance to passive neck flexion suggests meningismus, a sign of meningeal irritation

that occurs in meningitis and subarachnoid hemorrhage. However, these meningeal signs
are often absent in deep coma despite the presence of meningitis.
Examination of the lungs, heart, and abdomen may also provide clues to other organ
system disease.
NEUROLOGIC EXAMINATION
The neurologic examination in a comatose patient is necessarily brief and is directed at

determining whether the pathology is structural or due to metabolic dysfunction (including
drug effects and infection). The examiner assesses:
● Level of consciousness
● Motor responses
● Brainstem reflexes: pupillary light, extraocular, and corneal reflexes
Important findings are abnormal reflexes that indicate dysfunction in specific regions of the
brainstem, or a consistent asymmetry between right- and left-sided responses.
Level of consciousness — It is more useful to describe the patient's spontaneous behavior and
responses to stimuli than to use terms such as "stupor" or "obtunded." Even coma has a
spectrum of possible responses.
Arousability is assessed by noise (eg, shouting in the ear) and somatosensory stimulation.
Pressing on the supraorbital nerve (medial aspect of the supraorbital ridge) or the angle of the
jaw, or squeezing the trapezius, may have a higher yield than the more commonly used sternal
rub and nail pressure. Important responses include vocalization, eye opening, and limb
movement.
The Glasgow Coma Scale (GCS) demonstrates a hierarchy of responses in each of these areas,
which reflect the severity of the coma ( table 5). The GCS is useful as an index of the depth of
impaired consciousness and for prognosis, but does not aid in the diagnosis of coma (see
'Glasgow Coma Scale' below). The more recent Full Outline of UnResponsiveness (FOUR) scoring
system has some advantages for intubated patients [6].
Motor examination — It is important to assess muscle tone, as well as spontaneous and

elicited movements and reflexes. Asymmetries of these often indicate a hemiplegia of the
nonmoving side, implying a lesion affecting the opposite cerebral hemisphere or upper
brainstem.
Purposeful movements include crossing the midline, approaching the stimulus, pushing the
examiner's hand away, or actively withdrawing from the stimulus. In addition to decreased
spontaneous or purposeful movement, acute structural disease usually produces decreased
muscle tone or flaccidity. Flexion and extension movements usually represent reflex responses
arising from subcortical structures:
● Decorticate posturing consists of upper-extremity adduction and flexion at the elbows,

wrists, and fingers, together with lower-extremity extension, which includes extension and
adduction at the hip, extension at the knee, and plantar flexion and inversion at the ankle (
figure 2). This occurs with dysfunction at the cerebral cortical level or below and may
reflect a "release" of other spinal pathways.
● Decerebrate posturing consists of upper-extremity extension, adduction, and pronation

together with lower-extremity extension ( figure 2) and traditionally implies dysfunction
below the red nucleus, allowing the vestibulospinal tract to predominate.
The traditional neuroanatomic correlates of decorticate and decerebrate postures do not hold
as true for humans as for animals. As an example, often, decerebrate posturing is assumed in
patients with bilateral cerebral lesions well above the red nucleus. In general, patients with
decorticate posturing in response to pain have a better prognosis than those with decerebrate
posturing.
Reflex posturing can occur in deep metabolic coma as well, eg, in hypoglycemia. Muscle tone is
generally not affected by most metabolic conditions. Bilateral rigidity occurs in neuroleptic
malignant syndrome and malignant hyperthermia, and has also been described in hepatic
coma [7].
Multifocal myoclonus, which involves brief, random, asynchronous muscle jerks in limbs, trunk,
or face, strongly suggests a metabolic or toxic etiology. Tremor and asterixis also suggest a
metabolic encephalopathy. These occur with the limbs held in a posture against gravity. The
tremor is usually fairly rapid and is often present when the limb is actively moved (postural-
action tremor). Asterixis is a transient loss of postural tone, causing the upper limbs, head and
neck, or entire body to suddenly and briefly fall forward. More subtle myoclonic twitches of the
facial muscles or fingers, more synchronous or rhythmic movements, or spontaneous
nystagmus raise the possibility of nonconvulsive status epilepticus (NCSE).
Cranial nerves — The fundi should be carefully inspected, as they may yield important
diagnostic clues. A subhyaloid hemorrhage is virtually pathognomonic for aneurysmal
subarachnoid hemorrhage in a comatose patient. Papilledema suggests raised intracranial
pressure (ICP) or malignant hypertension. Roth spots (white-centered hemorrhages) are most
commonly associated with bacterial endocarditis, but they are also seen in leukemia,
vasculitides, and diabetic retinopathy.
The most important cranial nerve reflexes with respect to coma are pupillary, corneal, and the
vestibuloocular reflex (VOR). When assessing for possible brain death, a detailed review of
cranial nerve function is required. (See "Diagnosis of brain death", section on 'Neurologic
examination'.)
Pupils — The pupillary light reflex is tested in each eye individually to evaluate direct and
consensual responses (see "The detailed neurologic examination in adults", section on
'Pupillary light reflex (CN II and III)'). Disruption of the pupillary light reflex in comatose patients
usually occurs because of either:
● Downward herniation of mesial temporal structures from an expanding supratentorial

mass and/or a lateral shift in the supratentorial compartment with stretching of the
oculomotor nerve against the clivus; or
● Primary brainstem lesions
In either of these, the third cranial nerves or their nuclei in the midbrain are injured, producing
a unilateral or bilateral oculomotor palsy. When unilateral, the ipsilateral pupil is dilated and
unreactive directly and consensually, but the contralateral pupil reacts to light shone in either
eye. In some cases, the pupil is dilated on the "wrong side," a phenomenon that is inadequately
understood [8-10]. When bilateral, there is neither a direct nor a consensual response, the
pupils are symmetrically enlarged, and the eyes are deviated outward.
In transtentorial herniation, after initial dilation and loss of light reactivity, pupils become
somewhat reduced in size (4 to 5 mm) and remain unreactive; they are called midposition and
fixed. (See 'Coma syndromes' below.)
Pupil size and symmetry should be noted as well. Pupils are normally between 3 to 7 mm in
diameter and equal, although approximately 20 percent of normal individuals have up to 1 mm
difference in pupillary size. Typically, the pupils are spared in metabolic and toxic conditions,
except in certain toxic syndromes, which are associated with either miosis or mydriasis (
table 6). In severe sedative drug overdose or in hypothermia, the pupils are midposition and
fixed; this syndrome can mimic brain death.
Lesions in the pontine tegmentum, which selectively disrupt sympathetic outflow, can produce
very small (<1 to 2 mm) pupils in which a light response is barely perceptible, so-called pontine
pupils. Opiate overdose can also produce this sign.
Eye movements — Central structures involved in extraocular movements (oculomotor,

trochlear, and abducens nuclei and the medial longitudinal fasciculus) lie in the brainstem
tegmentum; these are controlled by the frontal eye fields.
Eye position should be noted. Large cerebral lesions produce a persistent conjugate deviation
of the eyes toward the side of the lesion (contralateral to limb paralysis if present). Persistent
eye deviation, especially if accompanied by nystagmus, may also suggest seizures; in this case,
the eye deviation is away from the side of the lesion. Lateral and downward eye deviation
(usually with pupillary involvement) suggests oculomotor involvement of the nerve or midbrain
nuclei, while medial deviation suggests sixth nerve palsy.
In the comatose patient, bilateral conjugate roving eye movements that appear full indicate an
intact brainstem, and further reflex testing is not required. This is also a relatively favorable
prognostic sign when seen early after hypoxic-ischemic insult. In the absence of this finding,
horizontal eye movements can be tested with two VORs:
● Oculocephalic maneuver (or doll's eyes) – In the oculocephalic maneuver, the head is
abruptly rotated from one side to the other in the horizontal plane ( figure 3). When the
oculocephalic reflex is present (positive doll's eyes), the eyes do not turn with the head,
but in the opposite direction, as if the patient is maintaining visual fixation on a single
point in space. The cervical spine must be cleared of fracture in any patient with
suspected head trauma before this is performed. This reflex is usually suppressed (and
therefore not tested) in conscious patients.
● Caloric testing – Caloric testing of the oculovestibular reflex provides a stronger stimulus
for reflex eye movements. In this test, the head or upper torso is inclined 30 degrees up
from the horizontal. After inspecting the ears for obstruction from wax or a perforated
drum, at least 50 mL of ice water is injected into the ear canal using a syringe with a small
catheter attached. This stimulus has the same effect on the horizontal semicircular canal
as sustained turning of the head in the opposite direction, and results in sustained
deviation of both eyes toward the ear being stimulated ( figure 3). Five minutes should
elapse before testing the other side.
A cold caloric response is also present in conscious people, producing not only deviation of the
eyes toward the stimulated ear, but also nystagmus (with the fast phase away from the
irrigated side), severe vertigo, nausea, and vomiting. If nystagmus occurs, the patient is awake
and not truly in coma; this can be a useful confirmatory test for psychogenic unresponsiveness.
However, the presence of nystagmus with caloric stimulation can also be seen in patients with
akinetic mutism as well as in patients with less profound coma (eg, moderate metabolic
encephalopathy).
Vertical eye movements can be tested either by moving the head and neck in the vertical plane
or by injecting ice water (causes the eyes to deviate downward in the unconscious patient) or
warm water (seven degrees above body temperature; causes the eyes to deviate upwards) into
both ear canals simultaneously.
With brainstem lesions, both VORs are often absent or abnormal. If pupillary sizes and reflexes
are normal and one eye abducts and the other fails to adduct, this indicates disruption of the
medial longitudinal fasciculus in the pons. Upper midbrain lesions, affecting the third cranial
nerve nuclei, may also lead to abduction without adduction (but usually with pupillary
involvement). Pontine involvement of the sixth nerve nuclei may selectively affect abduction. An
abducens palsy can also occur when the sixth nerve is stretched by expanding mass lesions or
trauma (a "false localizing" sign).
Profound toxic or metabolic pathology can also disrupt the VORs, usually the oculocephalic
reflex primarily. Abnormalities are generally symmetric and equally affect abduction and
adduction. Absent caloric responses with normal pupillary reflexes raises the possibility of
Wernicke encephalopathy, which selectively involves the VOR, sparing other brainstem reflexes
(see "Wernicke encephalopathy", section on 'Classic signs'). However, we have also seen this in
some cases of drug intoxication, especially with benzodiazepines.
Corneal reflex — The corneal reflex's afferent limb arises from small unmyelinated pain fibers
in the cornea and is mediated by the fifth or trigeminal nerve and nucleus; interneurons then
activate the dorsal parts of both ipsi- and contra-lateral facial nuclei in the pons. Hence, both
orbicularis oculi muscles contract when either cornea is touched. There are also connections
with the oculomotor nucleus, so that the eyeballs move upward in concert with lid closure.
The corneal reflex is tested by gently touching the edge of the cornea with a rolled tissue or
cotton swab and observing the responsive blink. As an alternative, squirts of water or saline are
less likely to scratch the cornea in repeated assessments. (See "The detailed neurologic
examination in adults", section on 'Facial sensation (CN V)'.)
The reflex can be suppressed initially contralateral to a large, acute cerebral lesion, as well as
with intrinsic brainstem lesions. Loss of the corneal reflex is also an index of the depth of
metabolic or toxic coma; bilaterally brisk corneal reflexes suggest the patient is only mildly
narcotized. Absent corneal reflexes 24 hours after cardiac arrest is usually, but not invariably, an
indication of poor prognosis (assuming the patient has not been sedated). Corneal reflexes may
also be reduced or absent at baseline in older or diabetic patients [11,12].
Coma syndromes — While there are numerous etiologies of coma with diverse presentations
as discussed above, a few specific syndromes are recognizable.
Herniation syndromes — Transtentorial herniation can occur with expanding mass lesions

(eg, intracerebral, subdural, or epidural hemorrhage, large ischemic stroke, abscess, tumor,
obstructive hydrocephalus). The initial impairment of consciousness with supratentorial mass
lesions usually relates to lateral rather than downward displacement. Horizontal shifts of
midline structures, especially the pineal body of greater than 8 mm, are associated with some
impairment of consciousness; patients with shifts of >11 mm are usually comatose [13]. Other
signs of increased ICP, papilledema, and Cushing triad (hypertension, bradycardia, irregular
respiration) may be observed in this setting.
Further shifts in brain structures can lead to downward, transtentorial herniation ( figure 1). It
is important to recognize the clinical signs of this process, as this can be rapidly fatal. While the
sequence is relatively predictable, the timing is not; deterioration can be precipitous.
Two variants are recognized: a central herniation and an uncal herniation syndrome. In the
latter, more laterally directed compressive forces lead to asymmetric herniation of the temporal
uncus. An ipsilateral third cranial nerve palsy (pupillary dilation, downward and outward eye
deviation) can occur prior to diencephalic signs as the nerve is displaced and stretched over the
clivus [14]. Loss of reactivity of the contralateral pupil usually reflects midbrain damage [15].
Hemiplegia due to compression of the cortical spinal tract in the midbrain often follows
immediately. The syndrome then follows the sequence of central herniation, outlined in the
figure ( figure 1).
Brainstem lesions — Coma from a primary brainstem process usually occurs in the setting of
infarction or hemorrhage of the upper pons and/or midbrain [16]. Osmotic demyelination
syndrome (formerly called central pontine myelinolysis) and brainstem encephalitis are other
causes. Bilateral long tract involvement is usual and may manifest with flaccid quadriparesis or
decerebrate posturing. Eye movements may be notably asymmetric or absent and pupils are
classically small. It is critical to ensure that these patients are not locked in (see 'Conditions
mistaken for coma' below). In a case series of nine patients with brainstem stroke, four
developed hyperthermia just prior to their death in the absence of identified infection [16].
Metabolic coma — A cardinal feature of metabolic coma is the symmetrical nature of the
neurologic deficits. Exceptions occur; in particular, hypo- and hyperglycemia are frequently
associated with lateralized motor findings. Fluctuations in the examination are common.
Tremor, asterixis, and multifocal myoclonus strongly suggest metabolic coma. Muscle tone is
usually decreased; decerebrate posturing is less common in metabolic coma, but may occur.
Pupils may appear abnormal but almost always are symmetric and constrict with light.
Suppression of VORs and corneal reflex occur with very deep metabolic coma.
Toxic syndromes — Drug overdoses or poisonings often appear similar to metabolic coma,

but may be associated with distinctive clinical features ( table 6). (See "General approach to
drug poisoning in adults".)
CONDITIONS MISTAKEN FOR COMA
Some conditions that appear to be coma but are not include the locked-in syndrome, akinetic
mutism, and psychogenic unresponsiveness:
Locked-in syndrome — The locked-in syndrome is a consequence of a focal injury to the base

of the pons, usually by embolic occlusion of the basilar artery [17,18]. Consciousness is
preserved; however, the patient cannot move muscles in the limbs, trunk, or face, except
voluntary blinking and vertical eye movements remain intact. Patients with this syndrome have
been mistakenly believed to be unconscious [19,20]. The locked-in syndrome may sometimes
be mimicked by a severe upper spinal cord lesion, a motor neuropathy, myopathy,
neuromuscular junction disease, or extreme muscular rigidity (as in severe parkinsonism or the
neuroleptic malignant syndrome). A careful neurologic examination can usually distinguish
between these entities and true coma. (See "Locked-in syndrome".)
Akinetic mutism — A lack of motor response in an awake individual might arise from injury to
the prefrontal or premotor (including supplementary motor) areas responsible for initiating
movements [21,22]. This executive problem is called akinetic mutism. The patient follows with
the eyes but does not initiate other movements or obey commands. The patient's tone, reflexes
(including response to cold caloric stimulation), and postural reflexes usually remain intact.
Psychogenic unresponsiveness — Psychogenic unresponsiveness refers to a prolonged,

motionless, dissociative attack in which the patient has absent or reduced response to external
stimuli [23]. The lack of responsiveness can vary from functional coma to a condition
resembling stupor or catatonia. Such patients often resist passive eye opening, roll over when
tickled to avoid the stimulus, or turn the eyes towards the floor regardless of which side they
are lying on. The presence of nystagmus with caloric stimulation in an apparently comatose
patient supports a diagnosis of psychogenic unresponsiveness but is not perfectly specific for
this diagnosis. (See 'Eye movements' above.)
The clinical features of catatonia are heterogenous. In some patients, catatonia is distinguished
from coma by the patient's preserved ability to maintain posture, even to sit or stand. In others,
the person appears awake but will not respond or initiate activity. Some patients with catatonia
may improve with low doses of benzodiazepines [24]. (See "Catatonia in adults: Epidemiology,
clinical features, assessment, and diagnosis".)
In pseudostupor, the patient may lapse into a sleep-like state when not stimulated; the
electroencephalogram (EEG), however, should show a wakefulness pattern.
EVALUATION
The goal of diagnostic testing in a patient in coma is to identify treatable conditions (infection,
metabolic abnormalities, seizures, intoxications/overdose, surgical lesions). Because neurologic
recovery is often reliant on early treatment, testing must proceed rapidly in concert with the
clinical evaluation ( table 1). Investigations almost always include laboratory testing and
neuroimaging. Some patients require lumbar puncture and electroencephalography (EEG).
Emergencies — Testing should be prioritized according to the clinical presentation. Caveats

include:
● The presence of papilledema or focal neurologic deficits suggesting a structural etiology

mandate an urgent head computed tomography (CT) scan, particularly if the clinical
presentation suggests an acute stroke, expanding mass lesion, and/or herniation
syndrome.
● Fever suggesting bacterial meningitis or viral encephalitis mandates an urgent lumbar

puncture. Neuroimaging prior to lumbar puncture in a comatose patient is recommended
[25]. (See "Clinical features and diagnosis of acute bacterial meningitis in adults", section
on 'Cerebrospinal fluid examination'.)
Laboratory tests — Screening laboratory tests for patients presenting in coma of uncertain

cause include:
● Complete blood count
● Serum electrolytes, calcium, magnesium, phosphate, glucose, urea, creatinine, liver

function tests, lactate, and osmolarity
● Arterial blood gas
● Prothrombin and partial thromboplastin time
● Drug screen (usually done on urine and serum), including ethyl alcohol, acetaminophen,
opiates, benzodiazepines, barbiturates, salicylates, cocaine, amphetamines, ethylene
glycol, and methanol
In selected patients, when other conditions are suspected or if the cause of coma remains
obscure, further laboratory testing is required:
● Adrenal and thyroid function tests
● Blood cultures
● Blood smear: screen for thrombotic thrombocytopenic purpura (fragmented erythrocytes,

elevated serum lactate dehydrogenase) or disseminated intravascular coagulation (DIC; D-
dimer and fibrinogen determination); consider antiphospholipid determination if a
coagulation problem is suspected
● Carboxyhemoglobin if carbon monoxide poisoning is suggested (patient found in a

burning building or in a stationary automobile)
● Serum drug concentrations for specific drugs
Neuroimaging — CT, allowing for quick assessment of intracranial structural changes, is

usually the test of choice for the initial evaluation of a coma patient. Except for focal brainstem
lesions, it is very sensitive for structural causes of coma, including subarachnoid hemorrhage
(95 percent in early presentation), other intracranial hemorrhage (essentially 100 percent),
acute hydrocephalus, tumors, marked cerebral edema, and large ischemic strokes. CT
angiography (where available) can be a helpful addition that allows assessment of the intra- and
extracranial arterial and venous circulation, particularly when brainstem stroke is suspected.
CT is inferior to magnetic resonance imaging (MRI) for detecting abnormalities in patients with
herpes simplex encephalitis, early ischemic strokes (especially involving the brainstem),
multiple small hemorrhages or white matter tract disruption associated with traumatic diffuse
axonal injury, anoxic-ischemic damage from cardiac arrest, and most disorders affecting the
white matter [26]. However, MRI takes longer to perform than CT, requires the patient to be
farther from monitoring personnel, and may be problematic for the unstable patient.
In general, CT is the test of choice for initial evaluation. Follow-up MRI is recommended when
CT and other testing do not explain, or incompletely explain, the clinical picture [26].
Lumbar puncture — Evaluation of cerebrospinal fluid (CSF) is a necessary part of the urgent

evaluation of a patient with suspected infection of the central nervous system. In a patient with
altered level of consciousness, neuroimaging to exclude an intracranial mass lesion is required

prior to lumbar puncture in order to avoid precipitating transtentorial herniation. Coagulation
test results should also be obtained beforehand. (See "Lumbar puncture: Technique,
indications, contraindications, and complications in adults".)
Because there might be some delay in obtaining CSF, empiric antimicrobial treatment is
recommended when the diagnosis of bacterial meningitis or herpes encephalitis is strongly
suspected, as early treatment improves prognosis of these conditions (see 'Management'
below). Treatment may impair the diagnostic sensitivity of CSF cultures but should not affect
other tests (white blood cell [WBC], Gram stain, polymerase chain reaction [PCR]). Blood
cultures should be obtained prior to antibiotic intervention, as they have a 50 to 75 percent
yield in bacterial meningitis [27-29].
CSF is also useful to exclude subarachnoid hemorrhage when CT is normal and the diagnosis
remains suspect, and may be helpful in the diagnosis of less common infections, as well as
demyelinating, inflammatory, and neoplastic conditions (eg, meningeal lymphomatosis or
carcinomatosis).
Electroencephalography — In the comatose patient, EEG is used primarily to detect seizures

[30]. If the patient has clinical findings suggestive of nonconvulsive seizures (see 'Motor
examination' above), or if the cause of coma remains obscure after other testing, then an EEG is
indicated.
In one series, 236 patients without overt seizure activity received an EEG as part of a coma
evaluation; 8 percent had nonconvulsive status epilepticus (NCSE) [31]. These patients had
alternative explanations for coma, including stroke, trauma, and anoxic brain injury. NCSE also
occurs in the setting of organ failure, drug toxicity, alcohol and benzodiazepine withdrawal, and
other metabolic disturbances [32-34]. Prolonged or continuous EEG monitoring increases the
yield for detecting nonconvulsive seizures; however, it is not clear that this influences outcome
[35-39].
In the setting of severe medical illness, NCSE presents a difficult diagnostic and treatment
challenge. While subtle signs may suggest the diagnosis (see 'Motor examination' above), NCSE
can often only be detected and verified by EEG. A high index of suspicion for the diagnosis is
required, as the underlying illness may often be deemed a sufficient explanation for altered
sensorium. NCSE is discussed in more detail separately. (See "Nonconvulsive status epilepticus:
Classification, clinical features, and diagnosis".)
Other nonepileptiform EEG findings can be helpful in the diagnosis of coma [30,40]. Diffusely
disorganized, slowed background rhythms confirm an impression of toxic metabolic
encephalopathy, while strongly lateralized findings suggest structural disease. More rhythmic,
slow EEG patterns, such as the classic triphasic waves of hepatic encephalopathy, sometimes
present a challenge in differentiating from seizures. The triphasic wave pattern is not specific
for hepatic encephalopathy, and can occur in other metabolic encephalopathies as well, eg,
uremia or sepsis.
Periodic lateralized epileptiform discharges (PLEDs) are classically associated with herpes
encephalitis, but may also occur in acute structural lesions, as well as in other central nervous
system infections, hypoxic-ischemic encephalopathy, and other metabolic diseases [41,42]. The
periodic complexes are more commonly generalized and bilaterally synchronous in metabolic,
including hypoxic-ischemic, encephalopathy, however.
In some patients with coma, 8 to 12 Hz activity is seen; this resembles normal alpha rhythm, but
extends beyond the posterior cerebral regions and does not react to stimuli [40]. This so-called
"alpha coma" is associated with pontine lesions, and has also been described with hypoxic-
ischemic encephalopathy following cardiac arrest, traumatic brain injury, and drug overdose.
This should not be confused with a normal EEG pattern, which suggests a psychogenic origin
for the patient's unresponsiveness.
EEG can also be helpful in determining the prognosis of victims of cardiac arrest; however,
somatosensory evoked potential testing is more prognostically definitive [42] (see "Hypoxic-
ischemic brain injury in adults: Evaluation and prognosis"). Continuous EEG may also be helpful
in showing the effects of treatment, eg, for seizures or vasospasm and in monitoring the depth
of anesthesia in the ICU [43].
MANAGEMENT
In the emergency department, basic care should be done in concert with the clinical and
laboratory investigations mentioned above ( table 1). Initial empiric therapy includes all of the
following:
● The primacy of ABCs (airway, breathing, and circulation) applies to cases of coma. Vital
signs should be taken, an initial Glasgow Coma Scale (GCS) score established ( table 5),
and a set of arterial blood gases, along with the other blood and urine tests (see
'Laboratory tests' above), sent to the laboratory.
● Patients with a GCS score of 8 or less usually require endotracheal intubation to protect
the airway. This can sometimes be avoided, eg, in patients with large hemispheric strokes
or alcohol withdrawal seizures. Intubation is also advised in the presence of hypoxemia
(oxygen saturation of <90 percent), recent vomiting, or poor cough or gag reflex. Oxygen
supplementation is often needed, whether or not assisted ventilation is required.
● It is best to treat hypotension (mean arterial blood pressure [BP] of <70 mmHg) with
volume expanders or vasopressors or both. With severe hypertension (mean arterial BP of
>130 mmHg) repeated doses of intravenous (IV) labetalol (5 to 20 mg boluses as needed)
are often adequate for initial stabilization. A 12-lead electrocardiogram should be done.
● It is recommended to give 25 g of dextrose (as 50 mL of a 50 percent dextrose solution)

while waiting for the blood tests if the cause of coma is unknown.
Thiamine, 100 mg, should be given with or preceding the glucose in any patient who may
be malnourished (to treat or to prevent precipitating acute Wernicke encephalopathy).
● Naloxone (0.4 to 2 mg IV) and flumazenil treatment should be reserved for patients with
known or strongly suspected drug overdose. While the use of a coma cocktail consisting of
glucose, thiamine, naloxone, and flumazenil has been promoted, a systemic review of
trials considering outcome and adverse effects suggested that it was reasonable to use
glucose and thiamine in unselected patients, but that naloxone and flumazenil should be
administered only selectively [44]. Gastric lavage and activated charcoal are also often
recommended for suspected toxic or drug ingestions. This topic is discussed in more
detail separately. (See "General approach to drug poisoning in adults".)
● If a herniation syndrome is evident clinically or appears imminent based on computed

tomography (CT) findings, urgent treatment is recommended. This includes administration
of mannitol (1 g/kg IV) and hyperventilation. (See "Evaluation and management of
elevated intracranial pressure in adults".)
● Hyperthermia (T >38.5°C) can contribute to brain damage in cases of ischemia; efforts to

lower fever with antipyretics and/or cooling blankets should be administered immediately.
Empiric antibiotic and antiviral therapy are recommended if bacterial meningitis (

table 7A-B and table 8) or viral encephalitis (acyclovir 10 mg/kg IV every eight hours)
are among the suspected entities. These should be continued until these conditions have
been excluded. (See "Initial therapy and prognosis of bacterial meningitis in adults",
section on 'Empiric regimens' and "Herpes simplex virus type 1 encephalitis", section on
'Treatment'.)
● Since hypothermia has neuroprotective effects in patients with cardiac arrest, only
extreme hypothermia (<33°C) should be treated. Efforts to search for and correct its cause
are more helpful than vigorously raising the body temperature to the normal range.
● If the patient has had a seizure, treatment with phenytoin or fosphenytoin (15 to 20 mg/kg
phenytoin equivalent IV) is recommended. If nonconvulsive seizures are suspected and an
electroencephalogram (EEG) is not available, a therapeutic trial of phenytoin or lorazepam
(1 to 2 mg IV) is reasonable.
Definitive therapy depends on establishing the precise diagnosis (sometimes more than one).
Monitoring the course of the patient by looking for improvement, worsening, and
complications follows, along with establishing a prognosis and communicating this to families.
PROGNOSIS
Coma is a transitional state that rarely lasts more than several weeks, except in cases of
ongoing sedative therapies or protracted sepsis. Patients either recover or evolve into brain
death or a persistent vegetative or minimally conscious state. (See "Hypoxic-ischemic brain
injury in adults: Evaluation and prognosis", section on 'Persistent vegetative state'.)
The prognosis depends on the underlying etiology, as well as the severity of the insult and
other premorbid factors, including age [45]. (See "Hypoxic-ischemic brain injury in adults:
Evaluation and prognosis" and "Acute toxic-metabolic encephalopathy in adults", section on
'Prognosis'.)
Scales to measure coma severity and aid in assessing prognosis include the Glasgow Coma
Scale (GCS) and the Full Outline of UnResponsiveness (FOUR) score.
Glasgow Coma Scale — The GCS grades coma severity according to three categories of
responsiveness: eye opening, motor, and verbal responses ( table 5). With good interobserver
reliability and ease of use, the admission GCS has been linked to prognosis prediction for a
number of conditions, including traumatic brain injury, subarachnoid hemorrhage, and
bacterial meningitis [29,46-48]. Intubation and use of sedating drugs interfere with its utility; for
this reason, it is useful to obtain a GCS on admission prior to these interventions. The GCS is not
useful for the diagnosis of coma.
FOUR score — An alternative scale, the FOUR score, has been developed and validated and may
have greater utility than the GCS in coma diagnosis, primarily by including a brainstem
examination ( table 9) [6]. In one study, the FOUR score had similar sensitivity and specificity
in predicting coma outcome; very low FOUR scores were highly predictive of in-hospital
mortality [49]. In another multicenter study, the FOUR score was found to have excellent inter-
rater agreement [50]. However, the FOUR score lacks the long track record of the GCS in
predicting prognosis and is more complicated to perform, which may be a barrier for non-
neurologists.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Brain death and
vegetative states".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Coma (The Basics)")
SUMMARY AND RECOMMENDATIONS
Stupor and coma are alterations in arousal; these are neurologic emergencies.
● Causes of coma are diverse and include structural brain disease and systemic disease.
Cerebrovascular disease, trauma, metabolic derangements, and intoxications are the most
common etiologies. (See 'Etiologies and pathophysiology' above.)
● A complete history and physical examination can provide valuable clues as to the
underlying etiology. (See 'History' above and 'General examination' above.)
● The neurologic examination in coma patients includes assessment of arousal, motor

examination, and cranial nerve reflexes. Important findings are abnormal reflexes that
indicate dysfunction in specific regions of the brainstem, or a consistent asymmetry
between right- and left-sided responses, which indicates structural brain pathology as a
cause. (See 'Neurologic examination' above.)
● Evaluation and early therapeutic interventions should proceed promptly, even

simultaneously. A rapid overview of the recommended steps for urgent evaluation and
management is presented in the table ( table 1).
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 5104 Version 20.0
GRAPHICS
Emergent evaluation and management of stupor and coma in adults
Evaluation
Vital signs and general examination
Neurologic examination and GCS
Screening laboratories (CBC, glucose, electrolytes, BUN, creatinine, PT, PTT, ABG, LFTs, drug screen)
ECG
Head CT scan: prioritize emergent if focal neurologic signs, papilledema, fever
Lumbar puncture: prioritize emergent after CT scan if fever, elevated WBC, meningismus; otherwise do
according to level of suspicion for diagnosis or if cause remains obscure
EEG: for possible nonconvulsive seizure, or if diagnosis remains obscure
Other laboratory tests: blood cultures, adrenal and thyroid tests, coagulation tests, carboxyhemoglobin,
specific drug concentrations – do according to level of suspicion for diagnosis or if cause remains obscure
Brain MRI with DWI, if cause remains obscure
Management
ABCs:
Intubate if GCS ≤8
Stabilize cervical spine
Supplement O2
IV access
Blood pressure support as needed
Glucose 50 percent IV 50 mL (after blood drawn, before results back)
Thiamine 100 mg IV
Treat definite seizures with phenytoin or equivalent
Consider empiric treatments:
For possible infection:
Ceftriaxone and vancomycin
Acyclovir
For possible ingestion:
Naloxone
Flumazenil
Gastric lavage/activated charcoal
For possible increased ICP:
Mannitol
For possible nonconvulsive status:
Lorazepam
Phenytoin or equivalent
GCS: Glasgow Coma Scale; CBC: complete blood count; BUN: blood urea nitrogen; PT: prothrombin time;
PTT: partial thromboplastin time; ABG: arterial blood gas; LFT: liver function tests; ECG:
electrocardiogram; CT: computed tomography; WBC: white blood cells; EEG: electroencephalography;
MRI: magnetic resonance imaging; DWI: diffusion weighted imaging; IV: intravenous; ICP: intracranial
pressure.
Graphic 51676 Version 6.0
Causes of coma
I. Symmetrical, nonstructural II. Symmetrical, structural
Toxins Supratentorial
Lead Bilateral internal carotid occlusion
Thallium Bilateral anterior cerebral artery occlusion
Mushrooms Sagittal sinus thrombosis
Cyanide Subarachnoid hemorrhage
Methanol Thalamic hemorrhage*
Ethylene glycol Trauma-contusion, concussion*
Carbon monoxide Hydrocephalus
Drugs Infratentorial
Sedatives Basilar occlusion*
Barbiturates* Midline brainstem tumor
Other hypnotics Pontine hemorrhage*
Tranquilizers Central pontine myelinolysis
Bromides III. Asymmetrical, structural

Alcohol
Supratentorial
Opiates
Thrombotic thrombocytopenic purpura¶
Paraldehyde
Disseminated intravascular coagulation
Salicylate
Nonbacterial thrombotic endocarditis (marantic
Psychotropics endocarditis)
Anticholinergics Subacute bacterial endocarditis

Amphetamines Fat emboli
Lithium Unilateral hemispheric mass (tumor, abscess,
Phencyclidine bleed) with herniation
Monoamine oxidase inhibitors Subdural hemorrhage bilateral
Intracerebral bleed
Metabolic
Pituitary apoplexy¶
Hypoxia
Massive or bilateral supratentorial infarction
Hypercapnia
Multifocal leukoencephalopathy
Hypernatremia*
Creutzfeldt-Jakob disease
Hypoglycemia*
Hyperglycemic nonketotic coma Adrenal leukodystrophy
Diabetic ketoacidosis Cerebral vasculitis
Lactic acidosis Cerebral abscess
Hypercalcemia Subdural empyema
Hypocalcemia Thrombophlebitis¶
Hypermagnesemia Multiple sclerosis
Hyperthermia Leukoencephalopathy associated with

chemotherapy
Hypothermia
Acute disseminated encephalomyelitis
Reye syndrome
Aminoacidemia
Infratentorial
Wernicke encephalopathy Brainstem infarction
Porphyria Brainstem hemorrhage
Hepatic encephalopathy* Brainstem thrombencephalitis
Uremia
Dialysis encephalopathy
Addisonian crisis
Hypothyroidism
Infections
Bacterial meningitis
Viral encephalitis
Postinfectious encephalomyelitis
Syphilis
Sepsis
Typhoid fever
Malaria
Waterhouse-Friderichsen syndrome
Psychiatric
Catatonia
Other
Postictal seizure*
Diffuse ischemia (myocardial infarction, heart

failure, arrhythmia)
Hypotension
Fat embolism*
Hypertensive encephalopathy
Hypothyroidism
Nonconvulsive status epilepticus
Heat stroke
* Relatively common asymmetrical presentation.
¶ Relatively symmetrical presentation.
Reproduced with permission from: Berger JR. Clinical Approach to Stupor and Coma. In: Neurology in Clinical Practice: Principles
of Diagnosis and Management, 4th ed, Bradley WG, Daroff RB, Fenichel GM, Jankovic J (Eds), Butterworth Heinemann,
Philadelphia, PA 2004. p.46. Copyright © 2004 Elsevier.
Ventilatory and arterial blood gas patterns in coma
Breathing Metabolic pH, PaCO2,

Specific conditions
pattern pattern HCO3
Hyperventilation Metabolic pH <7.3, PaCO2 Uremia, diabetic ketoacidosis, lactic acidosis,
acidosis <30 mmHg, salicylates, methanol, ethylene glycol.
HCO3 <17
mmol/L
Hyperventilation Respiratory pH >7.45, PaCO2 Hepatic failure, acute sepsis, acute salicylate
alkalosis <30 mmHg, intoxication, cardiopulmonary states with
HCO3 >17 hypoxemia, psychogenic causes.
mmol/L
Hypoventilation Respiratory pH <7.35 (if Respiratory failure from central (eg, brain or spinal
acidosis acute), PaCO2 cord) or peripheral nervous system disease, chest
>90 mmHg, conditions or deformities. Coma only with severe
HCO3 >17 hypercarbia.
mmol/L
Hypoventilation Metabolic pH >7.45, PaCO2 Vomiting, alkali ingestion. Usually no impairment of

alkalosis >45 mmHg, consciousness; if so, suspect psychogenic
HCO3 >30 unresponsiveness or additional cause.
mmol/L
Skin lesions and rashes in coma
Lesion or
Possible cause
rash
Ecchymosis Trauma, corticosteroid use, abnormal coagulation from liver disease or anticoagulants
Petechial- Meningococcemia, other bacterial sepsis (rarely), gonococcemia, staphylococcemia,

purpuric rash pseudomonas, subacute bacterial endocarditis, allergic vasculitis, purpura fulminans,
Rocky Mountain spotted fever, typhus, fat emboli
Petechiae Disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, drugs
Icterus Hepatic dysfunction or hemolytic anemia
Cherry-red skin Carbon monoxide poisoning
Generalized Hypoxemia or carbon dioxide poisoning

cyanosis
Grayish-blue Methemoglobin (aniline or nitrobenzene) intoxication

cyanosis
Localized Arterial emboli or vasculitis

cyanosis
Antecubital Opiate drug abuse

needle marks
Pale skin Anemia or hemorrhage
Sallow, puffy Hypopituitarism

appearance
Hypermelanosis Porphyria, Addison's disease, chronic nutritional deficiency, disseminated malignant

(increased melanoma, chemotherapy
pigment)
Telangiectasia Chronic alcoholism, occasionally vascular malformations of the brain
Vesicular rash Herpes simplex, varicella, Behcet disease, or drugs
Macular- Typhus, candida, cryptococcus, toxoplasmosis, subacute bacterial endocarditis,

papular rash staphylococcal toxic shock, typhoid, leptospirosis, Pseudomonas sepsis, immunologic
disorders (systemic lupus erythematosus, dermatomyositis, serum sickness)
Ecthyma Necrotic eschar often seen in the anogenital or axillary area in Pseudomonas sepsis
gangrenosum
Splinter Linear hemorrhages under the nail, seen in subacute bacterial endocarditis, anemia,
hemorrhages leukemia, and sepsis
Osler nodes Purplish or erythematous painful, tender nodules on palms and soles, seen in subacute
bacterial endocarditis
Gangrene of Emboli to larger peripheral arteries

digits'
extremities
Pigmented Tuberous sclerosis, neurofibromatosis

macules
Reproduced with permission from: Berger JR. Clinical Approach to Stupor and Coma. In: Neurology in Clinical Practice: Principles
of Diagnosis and Management, 4th ed, Bradley WG, Daroff RB, Fenichel GM, Jankovic J (Eds), Butterworth Heinmann, Philadelphia,
PA 2004. p.51. Copyright © 2004 Elsevier.
Transtentorial herniation
Data from: Plum F, Posner JB. The Diagnosis of Stupor and Coma III. FA Davis, Philadelphia 1995. p. 103.
Glasgow Coma Scale (GCS)
Score
Eye opening
Spontaneous 4
Response to verbal command 3
Response to pain 2
No eye opening 1
Best verbal response
Oriented 5
Confused 4
Inappropriate words 3
Incomprehensible sounds 2
No verbal response 1
Best motor response
Obeys commands 6
Localizing response to pain 5
Withdrawal response to pain 4
Flexion to pain 3
Extension to pain 2
No motor response 1
Total
The GCS is scored between 3 and 15, 3 being the worst and 15 the best. It is composed of three
parameters: best eye response (E), best verbal response (V), and best motor response (M). The
components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS score of 9.
A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate
injury, and a score of 8 or less represents severe brain injury.
Decorticate/decerebrate postures
Common poisoning syndromes (toxidromes)
Other Examples
Toxidrome Mental status Pupils Vital signs
manifestations age
Sympathomimetic Hyperalert, Mydriasis Hyperthermia, Diaphoresis, Cocaine,
agitation, tachycardia, tremors, amphetami
hallucinations, hypertension, hyperreflexia, cathinones,
paranoia widened pulse seizures ephedrine,
pressure, pseudoeph
tachypnea, phenylprop
hyperpnea theophyllin
Anticholinergic Hypervigilance, Mydriasis* Hyperthermia, Dry flushed skin, dry Antihistami

agitation, tachycardia, mucous tricyclic
hallucinations, hypertension, membranes, antidepress
delirium with tachypnea decreased bowel cyclobenzap
mumbling speech, sounds, urinary orphenadri
coma retention, antiparkins
myoclonus, antispasmo
choreoathetosis, phenothiaz
picking behavior, atropine,
seizures (rare) scopolamin
belladonna
(eg, Jimson
Hallucinogenic Hallucinations, Mydriasis Hyperthermia, Nystagmus Phencyclidi

perceptual (usually) tachycardia, mescaline,
distortions, hypertension, designer
depersonalization, tachypnea amphetami
synesthesia, MDMA ["Ecs
agitation MDEA)
Opioid CNS depression, Miosis Bradypnea, Hyporeflexia, Opioids (eg

coma apnea pulmonary edema, morphine,
characteristic; needle marks methadone
may develop: oxycodone,
hypothermia, hydromorp
bradycardia, diphenoxyla
hypotension
Sedative-hypnotic CNS depression, Variable Often normal, Hyporeflexia Benzodiaze

confusion, stupor, but may barbiturate
coma develop: carisoprodo
hypothermia, meprobama
bradycardia, glutethimid
hypotension, alcohols, zo
apnea,
bradypnea
Cholinergic Confusion, coma Miosis Bradycardia, Salivation, urinary Organopho

hypertension and fecal and carbam
or incontinence, insecticides
hypotension, diarrhea, emesis, agents, nico
tachypnea or diaphoresis, pilocarpine,
bradypnea lacrimation, GI physostigm
cramps, edrophoniu
bronchoconstriction, bethanecho
muscle urecholine
fasciculations and
weakness, seizures
Serotonin Confusion, Mydriasis Hyperthermia, Tremor, myoclonus, MAOIs alon

syndrome agitation, coma tachycardia, hyperreflexia, SSRIs, mepe
hypertension, clonus, diaphoresis, dextrometh
tachypnea flushing, trismus, TCAs, L-tryp
rigidity, diarrhea
* Tricyclic antidepressants can cause mydriasis or miosis.
LSD: lysergic acid diethylamide; MDMA: 3,4-methylenedioxymethamphetamine; MDEA:

methylenedioxymethamphetamine; CNS: central nervous system; GI: gastrointestinal; MAOI: monoamine
oxidase inhibitor; SSRI: selective serotonin reuptake inhibitor; TCA: tricyclic antidepressant.
Oculocephalic and caloric response
Oculocephalic (doll's eyes) response: This test should not be

performed if a cervical spine injury is suspected. Observe the motion of
the eyes while passively moving the head. In a comatose patient,
conjugate movement of the eyes in the direction opposite to the head
movement is expected. An absent or asymmetric response in an
unconscious patient implies brainstem dysfunction.
Caloric response: After visually checking that the tympanic membrane
is intact, ice cold water is used to irrigate the ear canal and should
produce a slow conjugate deviation toward the irrigated side. An absent
or asymmetric response indicates brainstem dysfunction. Intact eye
deviation with nystagmus suggests that the patient may not be in coma.
Adapted from: Bateman DE. Neurologic assessment of coma. J Neurol Neurosurg Psychiatry
2001; 71 Suppl 1:13.
Recommendations for empiric antimicrobial therapy for purulent meningitis

based on patient age and specific predisposing condition*
Predisposing
Common bacterial pathogens Antimicrobial therapy
factor
Age
<1 month Streptococcus agalactiae, Escherichia Ampicillin plus cefotaxime; OR

coli, Listeria monocytogenes ampicillin plus an aminoglycoside
1 to 23 months Streptococcus pneumoniae, Neisseria Vancomycin plus a third-generation

meningitidis, S. agalactiae, cephalosporin¶Δ◊
Haemophilus influenzae, E. coli
2 to 50 years N. meningitidis, S. pneumoniae Vancomycin plus a third-generation

cephalosporin¶Δ◊
>50 years S. pneumoniae, N. meningitidis, L. Vancomycin plus ampicillin plus a

monocytogenes, aerobic gram- third-generation cephalosporin¶Δ
negative bacilli
Head trauma
Basilar skull fracture S. pneumoniae, H. influenzae, group A Vancomycin plus a third-generation

beta-hemolytic streptococci cephalosporin¶Δ
Penetrating trauma Staphylococcus aureus, coagulase- Vancomycin plus cefepime; OR

negative staphylococci (especially vancomycin plus ceftazidime; OR
Staphylococcus epidermidis), aerobic vancomycin plus meropenem
gram-negative bacilli (including
Pseudomonas aeruginosa)
Postneurosurgery Aerobic gram-negative bacilli Vancomycin plus cefepime; OR

(including P. aeruginosa), S. aureus, vancomycin plus ceftazidime; OR
coagulase-negative staphylococci vancomycin plus meropenem
(especially S. epidermidis)
Immunocompromised S. pneumoniae, N. meningitidis, L. Vancomycin plus ampicillin plus

state monocytogenes, aerobic gram- cefepime; OR vancomycin plus
negative bacilli (including P. meropenem§
aeruginosa)
* For recommended doses, refer to the UpToDate content on treatment of bacterial meningitis in
children and adults.
¶ Ceftriaxone or cefotaxime.
Δ Some experts would add rifampin if dexamethasone is also given.
◊ Add ampicillin if meningitis caused by Listeria monocytogenes is suspected.
§ Meropenem provides sufficient coverage for Listeria when used as part of an initial regimen. However, if
Listeria is identified, the patient should generally be switched to a regimen that includes ampicillin. Refer
to the UpToDate topic that discusses treatment of Listeria for a discussion of regimen selection.
Modified with permission from: Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial
meningitis. Clin Infect Dis 2004; 39:1267. Copyright © 2004 University of Chicago Press.
Recommended intravenous dosages of antimicrobial therapy for adults with

bacterial meningitis who have normal renal and hepatic function
Antimicrobial agent Dose (adult)

Amikacin 5 mg/kg every 8 hours*
Ampicillin 2 g every 4 hours
Aztreonam 2 g every 6 to 8 hours
Cefepime 2 g every 8 hours
Cefotaxime 2 g every 4 to 6 hours
Ceftazidime 2 g every 8 hours
Ceftriaxone 2 g every 12 hours
Chloramphenicol 1 to 1.5 g every 6 hours¶
Ciprofloxacin 400 mg every 8 to 12 hours
Gentamicin 1.7 mg/kg every 8 hours*
Meropenem 2 g every 8 hours
Moxifloxacin 400 mg every 24 hoursΔ
Nafcillin 2 g IV every 4 hours
Oxacillin 2 g IV every 4 hours
Penicillin G potassium 4 million units every 4 hours
Rifampin 600 mg every 24 hours◊
Tobramycin 1.7 mg/kg every 8 hours*
Trimethoprim-sulfamethoxazole (cotrimoxazole) 5 mg/kg every 8 hours§¥
Vancomycin 15 to 20 mg/kg every 8 to 12 hours‡†
IV: intravenously; MRSA: methicillin-resistant Staphylococcus aureus; IDSA: Infectious Diseases Society of
America.
* Dose based on ideal body weight or dosing weight except in underweight patients. A calculator for
ideal body weight and dosing weight is available in UpToDate. Dosage and interval must be
individualized to produce a peak serum concentration of 7 to 9 mg/L and trough <1 to 2 mg/L for
gentamicin or tobramycin and a peak of 25 to 40 mg/L and trough <4 to 8 mg/L for amikacin. For
additional information, refer to the UpToDate topic on aminoglycosides.
¶ The higher dose is recommended for patients with pneumococcal meningitis.
Δ No data on optimal dosage needed in patients with bacterial meningitis.
◊ For the treatment of MRSA meningitis, the IDSA suggests a rifampin dose of 600 mg orally once daily
or 300 to 450 mg twice daily.[1]
§ Dosage is based on the trimethoprim component.
¥ We administer trimethoprim-sulfamethoxazole at a dose of 5 mg/kg (based on the trimethoprim

component) IV every 8 hours in patients with normal renal function. However, there are limited data on
the preferred dosing interval, and in case reports, the dose of trimethoprim-sulfamethoxazole has been
administered anywhere from every 6 to every 12 hours. For the treatment of MRSA meningitis, the IDSA
suggests a trimethoprim-sulfamethoxazole dose of 5 mg/kg (based on the trimethoprim component)
intravenously twice or three times daily.[1]
‡ For treatment of meningitis due to pathogens other than S. aureus, the vancomycin dose should not
exceed 2 g per dose or a total daily dose of 60 mg/kg. Adjust dose to achieve vancomycin serum trough
concentrations of 15 to 20 mcg/mL.[1]
† For treatment of meningitis due S. aureus, a vancomycin loading dose (20 to 35 mg/kg) is appropriate;
[2] within this range, we use a higher dose for critically ill patients. The loading dose is based on actual
body weight, rounded to the nearest 250 mg increment and not exceeding 3000 mg. The initial
maintenance dose and interval are determined by nomogram (typically 15 to 20 mg/kg every 8 to 12
hours for most patients with normal renal function). Subsequent dose and interval adjustments are
based on AUC-guided or trough-guided serum concentration monitoring. Refer to the UpToDate topic on
vancomycin dosing for a sample nomogram and discussion of vancomycin monitoring.
Reference:
1. Liu C, Bayer A, Cosgrove SE, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the
Treatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children: Executive Summary. Clin Infect
Dis 2011; 52:285.
2. Rybak MJ, Le J, Lodise TP, et al. Therapeutic Monitoring of Vancomycin for Serious Methicillin-Resistant Staphylococcus
Aureus Infections: A Revised Consensus Guideline and Review by the American Society of Health-System Pharmacists, the
Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases
Pharmacists. Am J Health Syst Pharm 2020; 77:835.
Modified with permission from: Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial
meningitis. Clin Infect Dis 2004; 39:1267. Copyright © 2004 University of Chicago Press.
Choice of empiric antibiotics in adults with possible community-acquired

bacterial meningitis with reported past hypersensitivity reactions to beta-
lactam antibiotics
Past beta-lactam reaction Initial regimen Comments
Mild cutaneous reactions to a Ceftriaxone or cefotaxime If Listeria coverage is required

penicillin (eg, mild drug plus (eg, patients >50 years of age
eruptions, with or without Vancomycin and/or immunocompromised
pruritus, immediate or hosts), trimethoprim-
delayed), including isolated sulfamethoxazole should be
mild hives to a penicillin initiated.
without other signs of
Immunocompromised patients
anaphylaxis, especially if the
generally require expanded
reaction occurred in childhood
gram-negative coverage (eg,
and/or >10 years ago.
cefepime or meropenem instead
of ceftriaxone or cefotaxime).* If
meropenem is used, it provides
sufficient coverage for Listeria
when used as part of an initial
empiric regimen.
Isolated mild hives to a Meropenem Meropenem provides sufficient

cephalosporin without other plus coverage for Listeria and
signs of anaphylaxis Vancomycin Pseudomonas aeruginosa when
(especially if the reaction used as part of an initial empiric
occurred in childhood and/or regimen.*
>10 years ago)
Or
Mild delayed type reactions to

cephalosporins.
Severe immediate allergy (eg, Moxifloxacin¶ If Listeria coverage is required

anaphylaxis) to a penicillin plus (eg, patients >50 years of age
and/or cephalosporin and/or immunocompromised
Vancomycin
hosts), trimethoprim-
Or
sulfamethoxazole should be
SJS/TEN, DRESS, or AGEP with initiated.
any beta-lactam other than
aztreonam.
gram-negative coverage.* If
expanded gram-negative
coverage is required, aztreonam
should be added as long as there
is no history of serious allergy

(eg, anaphylaxis, SJS/TEN, DRESS,
AGEP) to aztreonam itself or an
immediate or IgE-mediated
allergy to ceftazidime.
Other uncommon forms of Initial regimen Comments

hypersensitivity
Interstitial nephritisΔ , or Ceftriaxone or cefotaxime If Listeria coverage is required

plus (eg, patients >50 years of age
drug-induced liver diseaseΔ◊ ,
Vancomycin and/or immunocompromised
or
hosts), trimethoprim-
drug-induced cytopeniaΔ , or sulfamethoxazole should be
serum sicknessΔ initiated.

gram-negative coverage (eg,

cefepime or meropenem instead
of ceftriaxone or cefotaxime).* If
meropenem is used, it provides
sufficient coverage for Listeria
when used as part of an initial
empiric regimen.
This table discusses empiric antibiotic selection for the initial regimen in patients with a beta-lactam
allergy. Once the organism is identified, therapy should then be tailored to the best available agent. If the
most appropriate treatment was not initiated due to a beta-lactam allergy, the patient should be
managed in conjunction with a drug allergy specialist to see if the type of past allergy is amenable to
rechallenge or desensitization.
IV: intravenous; SJS/TEN: Stevens-Johnson syndrome/toxic epidermal necrolysis; DRESS: drug reaction
with eosinophilia and systemic symptoms; AGEP: acute generalized exanthematous pustulosis.
* Refer to the topic that discusses initial selection of antibiotics for treatment of bacterial meningitis for a
more detailed discussion of which patients require expanded gram-negative coverage and regimen
selection in this setting.
¶ Patients with a severe immediate allergy (eg, anaphylaxis) to a penicillin or cephalosporin can usually
tolerate meropenem, because cross-reactivity rates between penicillins or cephalosporins and
carbapenems for patients with proven immediate allergy are <1%. However, in such patients,
meropenem should be administered using a test dose procedure. Thus, to avoid delays in initiating
treatment, it is reasonable to administer moxifloxacin for the initial dose in an emergency room setting,
and then transition to meropenem while awaiting the final culture results. Test dose protocols are
reviewed in the topic that discusses the use of antibiotics in penicillin-allergic hospitalized patients.
Δ Interstitial nephritis, drug-induced liver disease, drug-induced cytopenias, and serum sickness (as well
as serum sickness-like reactions) tend to be drug specific. This type of reaction to a penicillin in the past
would not necessitate avoidance of cephalosporins.
◊ Commonly implicated drugs are amoxicillin-clavulanate in North America and flucloxacillin in Europe.
FOUR score
Eye response
4 = eyelids open or opened, tracking, or blinking to command
3 = eyelids open but not tracking
2 = eyelids closed but open to loud voice
1 = eyelids closed but open to pain
0 = eyelids remain closed with pain
Motor response
4 = thumbs-up, fist, or peace sign
3 = localizing to pain
2 = flexion response to pain
1 = extension response to pain
0 = no response to pain or generalized myoclonus status
Brainstem reflexes
4 = pupil and corneal reflexes present
3 = one pupil wide and fixed
2 = pupil or corneal reflexes absent
1 = pupil and corneal reflexes absent
0 = absent pupil, corneal, and cough reflex
Respiration
4 = not intubated, regular breathing pattern
3 = not intubated, Cheyne-Stokes breathing pattern
2 = not intubated, irregular breathing
1 = breathes above ventilator rate
0 = breathes at ventilator rate or apnea
FOUR score: Full Outline of UnResponsiveness.
Reproduced from: Fischer M, Ruegg S, Czaplinski A, et al. Inter-rater reliability of the Full Outline of UnResponsiveness score and
the Glasgow Coma Scale in critically ill patients: a prospective observational study. Crit Care 2010; 14:R64. Copyright © 2010
BioMed Central Ltd.
Contributor Disclosures
G Bryan Young, MD, FRCPC No relevant financial relationship(s) with ineligible companies to
disclose. Michael J Aminoff, MD, DSc Consultant/Advisory Boards: Brain Neurotherapy Bio [Parkinson
disease]. All of the relevant financial relationships listed have been mitigated. Robert S Hockberger, MD,
FACEP No relevant financial relationship(s) with ineligible companies to disclose. Janet L Wilterdink,
MD No relevant financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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24/12/21 12:55 Stupor and coma in adults - UpToDate

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An alteration in arousal represents an acute, life-threatening emergency, requiring prompt

ETIOLOGIES AND PATHOPHYSIOLOGY

Potentially helpful questions for relatives, friends, and witnesses include:

● Vital signs – Extreme hypertension may suggest reversible posterior leukoencephalopathy

Hyperthermia usually signifies an infection; heat stroke or anticholinergic intoxication are

● Ventilatory pattern – An observation of hypo- or hyperventilation can be helpful in the

Perspiration is common in fevers, hypoglycemia, and pheochromocytoma. Bullous lesions

Resistance to passive neck flexion suggests meningismus, a sign of meningeal irritation

are often absent in deep coma despite the presence of meningitis.

The neurologic examination in a comatose patient is necessarily brief and is directed at

Motor examination — It is important to assess muscle tone, as well as spontaneous and

● Decorticate posturing consists of upper-extremity adduction and flexion at the elbows,

● Decerebrate posturing consists of upper-extremity extension, adduction, and pronation

● Downward herniation of mesial temporal structures from an expanding supratentorial

● Primary brainstem lesions

Eye movements — Central structures involved in extraocular movements (oculomotor,

Herniation syndromes — Transtentorial herniation can occur with expanding mass lesions

Toxic syndromes — Drug overdoses or poisonings often appear similar to metabolic coma,

CONDITIONS MISTAKEN FOR COMA

Locked-in syndrome — The locked-in syndrome is a consequence of a focal injury to the base

Psychogenic unresponsiveness — Psychogenic unresponsiveness refers to a prolonged,

Emergencies — Testing should be prioritized according to the clinical presentation. Caveats

● The presence of papilledema or focal neurologic deficits suggesting a structural etiology

● Fever suggesting bacterial meningitis or viral encephalitis mandates an urgent lumbar

Laboratory tests — Screening laboratory tests for patients presenting in coma of uncertain

● Complete blood count

● Serum electrolytes, calcium, magnesium, phosphate, glucose, urea, creatinine, liver

● Arterial blood gas

● Prothrombin and partial thromboplastin time

● Adrenal and thyroid function tests

● Blood smear: screen for thrombotic thrombocytopenic purpura (fragmented erythrocytes,

● Carboxyhemoglobin if carbon monoxide poisoning is suggested (patient found in a

● Serum drug concentrations for specific drugs

Neuroimaging — CT, allowing for quick assessment of intracranial structural changes, is

Lumbar puncture — Evaluation of cerebrospinal fluid (CSF) is a necessary part of the urgent

altered level of consciousness, neuroimaging to exclude an intracranial mass lesion is required

Electroencephalography — In the comatose patient, EEG is used primarily to detect seizures

● It is recommended to give 25 g of dextrose (as 50 mL of a 50 percent dextrose solution)

● If a herniation syndrome is evident clinically or appears imminent based on computed

● Hyperthermia (T >38.5°C) can contribute to brain damage in cases of ischemia; efforts to

Empiric antibiotic and antiviral therapy are recommended if bacterial meningitis (

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Basics topics (see "Patient education: Coma (The Basics)")

SUMMARY AND RECOMMENDATIONS

● The neurologic examination in coma patients includes assessment of arousal, motor

● Evaluation and early therapeutic interventions should proceed promptly, even

Use of UpToDate is subject to the Subscription and License Agreement.

Neurosurgery 2001; 49:1251.

39. Brenner RP. Is it status? Epilepsia 2002; 43 Suppl 3:103.

Emergent evaluation and management of stupor and coma in adults

Neurologic examination and GCS

Head CT scan: prioritize emergent if focal neurologic signs, papilledema, fever

EEG: for possible nonconvulsive seizure, or if diagnosis remains obscure

Brain MRI with DWI, if cause remains obscure

Stabilize cervical spine

Blood pressure support as needed

Glucose 50 percent IV 50 mL (after blood drawn, before results back)

Treat definite seizures with phenytoin or equivalent

Consider empiric treatments: