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

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.

Literature review current through: Jul 2019. | This topic last updated: Jul 18, 2018.

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 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).
 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:

● In the oculocephalic maneuver (or doll's eyes), 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 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. (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 'Lumbar puncture'.)

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".)

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).

● 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 (0.4 to 2.0 mg
IV) and flumazenil treatment should be used only in the setting of known or
strongly suspected drug overdose [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 (eg, ceftriaxone 2 g IV every 12
hours and vancomycin 2 g/day IV in four divided doses) 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
"Clinical features and diagnosis of acute bacterial meningitis in adults",
section on 'If LP is delayed' 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 7) [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).

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