Comma
Comma
KEYWORDS
Coma Neurocritical care Disorders of consciousness
KEY POINTS
The differential diagnosis for the comatose patient is broad and includes structural abnor-
mality, seizure, encephalitis, metabolic derangements, and toxicologic etiologies.
Obtaining a good collateral history and physical examination are imperative for identifying
the correct diagnosis.
We discuss the diagnostic testing and treatment considerations for each cause of coma.
INTRODUCTION
Dartmouth Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH 03756, USA
* Corresponding author.
E-mail address: Anna.Karpenko@hitchcock.org
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156 Karpenko & Keegan
and consequently the initial differential must be formed on the basis of historical infor-
mation from surrogates and physical examination.
Physical Examination
Vital signs
Tachycardia is nonspecific and may reflect hemodynamic compromise. The patient
may have an elevated heart rate owing to pain, seizure, or intoxication with an adren-
ergic or anticholinergic substance. Rapid atrial fibrillation may be reactive but should
raise concern for ischemic stroke as the cause of altered sensorium.
Bradycardia may result in cerebral hypoperfusion when associated with relative hy-
potension. Additionally, particularly when seen in conjunction with hypertension and
decreased or irregular breathing, known as Cushing’s triad, it may signify elevated
intracranial pressure.
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Coma 157
Neurologic Examination
Pupils
Anisocoria is present in the general population and may be a benign finding, especially
if reactivity is intact. A unilateral dilated and nonreactive pupil may suggest uncal her-
niation with compression of cranial nerve III, or a midbrain lesion affecting the third
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158 Karpenko & Keegan
Extraocular motion
Vestibulo-ocular reflex Loss of this reflex suggests an abnormality in the brain stem or
higher cortical function, but is nonspecific in etiology. This condition can be assessed
with oculocephalic maneuver or cold caloric testing. Forced gaze deviation or gaze
preference involves functional disruption for the frontal eye fields. The patient will
gaze toward the side of stroke or away from the seizure focus. Dysconjugate gaze
is generally nonspecific for diagnostic purposes, although skew deviation is a vertical
misalignment of the eyes and is a sign of a brain stem or cerebellar lesion. Although
unilateral nystagmus may be seen in peripheral vestibular disease, when it is bidirec-
tional, vertical or rotatory, and nonfatiguing, it is indicative of a cerebellar or brain stem
lesion or substance intoxication such as phencyclidine. A downward fixed gaze, also
known as “setting sun sign,” is caused by a midbrain lesion (Parinaud syndrome).
Ocular bobbing is associated with pontine lesions.
Reflex testing
Hyperreflexia or clonus may be seen as part of serotonin syndrome, neuroleptic ma-
lignant syndrome, malignant hyperthermia or tetanus. Hyporeflexia may be seen in
acute brain or spinal cord injury or a neuromuscular process such as botulism.
DIFFERENTIAL DIAGNOSIS
Structural Causes
It is critical in patients with undifferentiated coma to exclude structural causes,
because they form some of the most acute and in many cases very treatable causes
of coma. Broadly speaking, structural causes of coma can be grouped into vascular
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Table 1
Abnormal eye findings and causes
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Coma 161
patients and especially those with cranial nerve findings. Identifying acute basilar clot
has significant impact on outcomes, with 45% to 46%10,11 of those treated via endo-
vascular therapy having good outcomes (modified Rankin Scale of 0–2, functional in-
dependence) versus an untreated historical norm of approximately 10%.
In some cases, pontine injury may cause locked-in syndrome, which can be difficult
to differentiate from coma. In this syndrome, motor function is impaired but sensory
function and consciousness are preserved; patients may be able to use their eyes
to communicate and have variably preserved cranial nerve function depending on
the exact level of the lesion. Careful attention to cranial nerve and particularly the oc-
ulomotor components of the examination will ensure that locked-in syndrome is not
mistaken for coma. Although most strokes causing acute coma are basilar in nature,
there are uncommon supratentorial causes as well. These by necessity must be bilat-
eral, and may include strokes affecting multiple territories. Possible etiologies include
cardioembolic strokes as well as strokes arising from the artery of Percheron, which is
an anatomic variant in which the arterial supply of the bilateral paramedian thalami
arises unilaterally.
Depending on local institutional practices and resources, MRI may be considered in
the evaluation of structural causes of coma. This modality may be particularly helpful
in identifying brain stem pathology, including early infarction in the absence of overt
large vessel occlusion, as well as diffuse axonal injury from traumatic brain injury. In
most cases, this determination will not result in an immediate treatment change and
so may be deferred in many institutions; however, early identification of brain stem
infarct may obviate a comprehensive search for other etiologies, inform code status
discussions, and change disposition (ie, medical intensive care unit for undifferenti-
ated coma vs neurologic intensive care unit for infarct vs trauma or neurotrauma inten-
sive care unit for diffuse axonal injury or traumatic brain injury) (Table 2).
Nonconvulsive Status Epilepticus Versus Postictal State
Status epilepticus is defined as at least 5 minutes of clinical or electrographic seizure
activity, or multiple seizures without a return to neurologic baseline. Status epilepticus
is further divided into convulsive or nonconvulsive. Generalized convulsive status epi-
lepticus is characterized by tonic or tonic–clonic movements accompanied by an
altered mental status. In contrast, nonconvulsive status epilepticus does not have
obvious signs suggesting prolonged seizures, but rather is defined electrographically.
Patients with nonconvulsive status epilepticus may have subtle signs of seizures such
as facial or extremity twitching, eye deviation or nystagmus, or it may manifest only as
an abnormal mental status. Alternatively, the patient may present with agitation, apha-
sia, staring, confusion or coma.
Uncontrolled generalized convulsive status epilepticus may transition into noncon-
vulsive status epilepticus; therefore, timely recognition and treatment are essential.
Table 2
Structural causes of Coma
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Patients who present with nonconvulsive status epilepticus usually have underlying
comorbidities and are acutely ill. The differential of the inciting disease is broad and
includes toxic or metabolic derangements, infection, or structural brain lesions. Non-
convulsive status epilepticus is also generally more refractory to treatment.12
Diagnostic testing
A noncontrast CT scan of the head is standard of care to rule out acute structural eti-
ologies. MRI of the brain with and without contrast can be considered once the patient
has been stabilized.
An electroencephalogram (EEG) is the only definitive method of making the diagnosis
of nonconvulsive status epilepticus, and to differentiate nonconvulsive status epilepti-
cus from postictal state. Continuous EEG monitoring is preferred over routine EEG.
The duration of EEG monitoring is uncertain; however, for patients who have risk factors
for developing status epilepticus, 24 hours of monitoring should be considered.13
Laboratory testing should include glucose, basic metabolic panel, complete blood
count, lactate, and creatine kinase levels, which may be elevated in prolonged seizure.
Serum prolactin level is nonspecific for the diagnosis of status epilepticus; however, it
may be useful in differentiating patients with epileptic seizures from those with psy-
chogenic nonepileptic seizures if drawn at most 20 minutes from the time of seizure.14
Antiepileptic drug levels should be obtained when appropriate.
A lumbar puncture may be of value to acutely exclude central nervous system infec-
tion. It may also allow for testing of infrequent causes, such as autoimmune enceph-
alitis or occult malignancy when the etiology is uncertain. If a lumbar puncture is
performed in the setting of suspected or confirmed status epilepticus additional cere-
brospinal fluid should be banked to facilitate possible specialized testing.
Treatment
After initial stabilization and airway attainment, targeted therapy includes the
following. Benzodiazepines are the first-line treatment for status epilepticus. Intrave-
nous (IV) or intramuscular lorazepam or midazolam are preferred for their favorable
pharmacodynamics. Lorazepam should be dosed at 0.1 mg/kg, divided into multiple
doses to attenuate subsequent hypotension and respiratory depression. Similarly,
midazolam should be dosed at 0.2 mg/kg.
Concurrently, the patient should receive an antiepileptic drug, including:
Levetiracetam 1000 to 3000 mg
Minimal side effects
Lacosamide 200 to 400 mg
Minimal side effects
Phenytoin 20 mg/kg load, may repeat 5 to 10 mg/kg dose in 10 minutes
Phenytoin load may result in arrhythmias or hypotension; for this reason fos-
phenytoin is preferred
Valproate 20 to 40 mg/kg
Side effects include hepatotoxicity, thrombocytopenia, and pancreatitis
Phenobarbital 15 to 20 mg/kg
Side effects include hypotension and respiratory depression
If the patient continues to seize despite appropriate benzodiazepine dosing and at
least one antiepileptic drug, they are defined as having refractory status epilepticus. A
continuous infusion should be initiated and titrated to seizure suppression on EEG.
Propofol: Load with a 1 to 2 mg/kg bolus followed by infusion starting at 20 mg/
kg/min.
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Human T-cell
lymphotropic
virus 1 and 2
Parvovirus
Hepatitis A and
B virus
Lymphocytic
choriomeningitis
Rabies virus
Measles
Mumps
Rubella
Coma
165
166 Karpenko & Keegan
Table 4
Toxicologic causes of Coma
Treatment
If there is suspicion for infectious cause, steroids and empiric antimicrobial medication
should be started without delay. For streptococcal meningitis, steroids have been
shown to reduce mortality if given before or with the initial dose of antibiotics.17
The recommended empiric regimen includes:
Dexamethasone 0.15 mg/kg every 6 hours for 2 to 4 days
Vancomycin: 15 to 20 mg/kg every 8 to 12 hours
Third generation cephalosporin:– for example, ceftriaxone 2 g every 12 hours
Acyclovir 10 mg/kg every 8 hours
If the patient is more than 50 years old or immunosuppressed, ampicillin should
be added for coverage of atypical organisms
If the patient has had a recent neurosurgical procedure, a fourth-generation
cephalosporin such as cefepime should replace the third-generation
cephalosporin
Fever should be treated to avoid secondary brain injury. Prophylaxis with antiseizure
medication is not recommended unless the patient has clinical or electrographic sei-
zures. Autoimmune encephalitides are treated acutely with high dose steroids (meth-
ylprednisolone 1 g/d for 5 days), intravenous immunoglobulin (2 g/kg divided over
5 days) or plasma exchange. Steroid-sparing agents may be considered if there is a
good clinical response to acute treatment.
Toxicologic Causes
Because coma may be caused by numerous toxins and laboratory identification of
them is time consuming and at times misleading (eg, having limited ability to differen-
tiate acute drug toxicity from recent ingestion), an initial differential diagnosis must be
formed and empiric therapy begun based solely on history and physical examination,
with urine toxicologic screens and other laboratory testing serving primarily purposes
of confirmation and assisting in longitudinal care. The more common, time-sensitive,
and treatable toxicologic causes of coma are discussed in detail elsewhere in this
article. A wide range of uncommon toxins exist and require supportive care while
seeking expert consultation (Table 5).
One of the most common and most immediately reversible etiologies is opiate
toxicity, in which case coma is usually accompanied by miosis and decreased respi-
ratory drive. Although most frequent in recreational drug users, iatrogenic opiate
toxicity, for example, among elderly patients with fluctuating renal function, should
also be considered. Clinicians should have a low threshold for administration of
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Coma 167
Table 5
Cerebrospinal fluid findings
White
Opening Blood
Pressure Cell
(cmH2O) Glucose (mg/dL) Protein (mg/dL) Count Differential
Normal 5–20 >50 or 2/3 serum <50 <5 No differential
glucose
Bacterial Elevated <50 elevated >500 Neutrophilic
predominance
Viral Normal Normal Normal or slightly <1000 Lymphocytic
elevated predominance
Fungal or Elevated Normal or low Elevated <1000 Lymphocytic
tuberculosis predominance
Autoimmune Normal Normal Elevated <500 Lymphocytic
predominance
naloxone, a competitive opiate antagonist, because it has a benign side effect profile
and may help to avoid intubation. It should be noted that meperidine and propoxy-
phene result in mydriasis; naloxone administration should not be withheld solely on
the basis of this physical examination finding. Last, naloxone has a short half-life, often
shorter than that of the opiate itself, and especially in the context of an unknown opiate
ingestion patients must be monitored for recurrence of toxicity as the naloxone is
metabolized.
Benzodiazepines are another medication class with substantial potential to cause
coma, particularly in intentional/suicidal ingestions. Benzodiazepines taken in isolation
are rarely fatal and there are no pathognomonic physical examination findings18; sus-
picion must be based on historical clues. The main physical examination finding
consistent with benzodiazepine toxicity is depressed mental status, which may be
as severe as complete electroencephalographic silence on EEG. Compromised respi-
rations are possible but much less common than with opiate or barbiturate ingestions.
Flumazenil is a competitive antagonist that can be used to reverse cases of known
acute-only benzodiazepine toxicity, but should be avoided in cases of unknown or
chronic benzodiazepine administration to avoid precipitating potentially life-
threatening withdrawal and intractable seizures. Care in such cases is primarily sup-
portive while awaiting toxin metabolism.
Barbiturate ingestion presents similarly to benzodiazepine toxicity but with more
pronounced respiratory and cardiovascular suppression; no specific reversal agent
is available and care is supportive including mechanical ventilation and vasopressor
support.
Acute alcohol intoxication may result in coma when blood levels exceed 0.3%;
approximately 1% of all alcohol intoxication visits require critical care,19 which is
generally supportive and may include management of accompanying bradycardia
and hypotension. Rapid testing of exhaled breath levels or blood levels is commonly
available and may assist with risk stratification and disposition decisions. Rapid
testing for toxic alcohols such as methanol, ethylene glycol, and isopropyl alcohol is
largely unavailable; elevated osmolar gap and anion gap metabolic acidosis (in the
cases of methanol and ethylene glycol) should raise clinical suspicion. When clinical
suspicion exists, empiric administration of fomepizole, an alcohol dehydrogenase
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Metabolic Causes
Hypoglycemia is one of the most common and most immediately reversible causes
of coma. Any patient presenting with coma should either have a fingerstick glucose
checked or empiric administration of dextrose (preceded by thiamine if the clinical
context suggests concurrent alcohol abuse). Patients who are chronically hypergly-
cemic may become symptomatic even with low-normal glucose levels. An underly-
ing explanation for hypoglycemia such as insulin overdose should always be
sought; in the case of accidental overdose of short-acting insulin, emergency
department observation and discharge may be all that is indicated, whereas pa-
tients with intentional overdoses, overdoses of long-acting insulin, and unexplained
hypoglycemia should be admitted for more prolonged monitoring and further
workup.
Hypercarbic respiratory insufficiency also frequently leads to depressed mental sta-
tus and coma. At times patients may present with clinically evidence hypoventilation
as a cause; pulmonary disease such as chronic obstructive pulmonary disease may
also play a less overt role. Given that venous carbon dioxide cannot be lower than
arterial carbon dioxide, a normal venous blood gas is sufficient to exclude clinically
significant hypercarbia. If the venous carbon dioxide is elevated an arterial blood
gas should generally be performed to confirm this finding. Although depressed mental
status is a contraindication to unsupervised biphasic positive airway pressure, cases
of hypercarbia attributed to neuromuscular disease or respiratory muscle fatigue may
benefit from a short-term (20–30 minutes) trial of biphasic positive airway pressure un-
der direct observation to determine if improved carbon dioxide clearance will result in
a mental status suitable for longer term biphasic positive airway pressure. Worsening
hypercarbia or failure of mental status changes to resolve should prompt intubation.
As opposed to neuromuscular causes, cases of central hypoventilation will generally
not respond to biphasic positive airway pressure and mechanical ventilation will be
required. Once hypercarbia has been resolved, patients should be reevaluated to
exclude additional contributors to coma (eg, opiate administration leading to
hypercarbia).
When severe, numerous electrolyte abnormalities may result in coma. Routine lab-
oratory evaluation should include serum electrolytes, including calcium and magne-
sium levels. Correction of identified abnormalities should be initiated in the
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Coma 169
emergency department before admission; most patients will likely require inpatient
management. Evaluation for underlying causes of electrolyte abnormalities can gener-
ally be deferred to the inpatient setting. Last, although usually obvious from historical
or environmental clues, hypothermia may also result in coma and it should be ensured
that all comatose patients have a core temperature documented as part of their initial
evaluation.
Hepatic Encephalopathy
Any patient with history or clinical examination stigmata (such as jaundice or spider tel-
angiectasias) of liver disease presenting with coma should have an ammonia level
checked to determine if hepatic encephalopathy may be responsible. The pathogenesis
of hepatic encephalopathy is incompletely understood and the degree of hyperammo-
nemia does not directly correlate with degree of encephalopathy. Consequently, for
those with any ammonia elevation, treatment with lactulose should be initiated and
continued until clinical resolution of symptoms; rifaximin may be a useful adjunct and
is thought to decrease intestinal bacterial ammonia production. Contributing conditions
such as upper gastrointestinal tract bleeding should be identified and corrected. Admin-
istration of flumazenil may be considered because it has been shown to improve symp-
toms of hepatic encephalopathy, even in the absence of benzodiazepine use; however,
this effect may often be transient and no statistically significant effect on mortality has
been demonstrated.23
Endocrine
Thyroid dysfunction in the form of severe decompensated hypothyroidism can result
in an entity termed “myxedema coma.” This syndrome includes hypoactive delirium or
coma, hypoventilation, bradycardia, hypotension, hypothermia, thick coarse skin, and
thinning hair. Seizures may occur as well, especially in the setting of severe metabolic
derangements. It is important to also investigate precipitating factors such as infec-
tion, cold exposure, and recent trauma. An association exists between decompen-
sated hypothyroidism and intoxication with opioids or other classes of sedating
medications, as well as with amiodarone use.
Diagnostic testing
The mainstay of diagnosis is confirmatory thyroid function tests: serum thyroid-
stimulating hormone (elevated in primary hypothyroidism but reduced in secondary hy-
pothyroidism), free thyroxine (reduced). Cortisol is often decreased as a result of either
primary or secondary adrenal insufficiency and in this case cosyntropin stimulation test
may be helpful. Hypoglycemia may result from decreased gluconeogenesis and adrenal
insufficiency. Hyponatremia is usually a result of coexisting syndrome of inappropriate
diuretic hormone. Elevated creatine kinase and a reduced glomerular filtration rate may
be present. Furthermore, hypoxemia and hypercapnia may be seen on blood gas. The
electrocardiogram may show sinus arrhythmias and QT prolongation. Therefore, contin-
uous monitoring is recommended. Additionally, EEG monitoring should be performed to
exclude nonconvulsive status epilepticus. Lumbar puncture, if performed incidentally,
may have an elevated protein but is otherwise diagnostically nonspecific. There are usu-
ally no specific abnormalities seen on neuroimaging.
Treatment
Because incidence of myxedema coma is relatively low, there is clinical equipoise as
to the exact treatment regimen. Though traditionally a large dose of levothyroxine was
the preferred approach, there exist alternative regimens combining tri-iodothyronine
and thyroxine replacement. One such regimen is listed here.24
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170 Karpenko & Keegan
The Curing Coma Campaign was launched in 2019 and consists of a multidisciplinary
scientific advisory committee dedicated to furthering our understanding and treatment
of coma. The campaign is organized into 3 pillars. The first pillar includes classifica-
tion, or endotyping, of different types of coma based on pathophysiology. The second
pillar focuses on continuing investigation of neuroprognostic biomarkers, the refine-
ment of which would inform the treating clinician of the expected clinical recovery
for each endotype of coma. Finally, the third pillar centers on the efforts to implement
proof-of-concept trials targeted at pharmacologic and electrophysiologic interven-
tions to improve outcomes for patients with disorders of consciousness.25 This
concerted international mission holds the potential to advance our current prognosti-
cation practice patterns and to improve the long-term outcomes of comatose
patients.
DISCLOSURE
REFERENCES
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