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" . 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 . 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
●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 .
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 .
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 . 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 . Loss of reactivity of the contralateral pupil usually reflects midbrain damage . 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 . 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 .
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 . 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 . (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 . (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 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 . 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 .
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 . 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) . 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 . 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  (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 .
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 . 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 . (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) . 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 . In another multicenter study, the FOUR score was found to have excellent inter-rater agreement . 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 disorders of consciousness".)
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).
2 : Gerace RV, McCauley WA, Wijdicks EF. Emergency management of the comatose patient. In: Coma and Impaired Consciousness: a Clinical Perspective, Young GB, Ropper AH, Bolton CF (Eds), McGraw Hill, New York 1998. p.563.
4 : A preliminary MRI study of the geometry of brain displacement and level of consciousness with acute intracranial masses.
5 : Magnetic resonance imaging measurements and clinical changes accompanying transtentorial and foramen magnum brain herniation.
7 : Altered striatal dopamine D2 receptor density and dopamine transport in a patient with hepatic encephalopathy.
9 : Initial enlargement of the opposite pupil as a false localising sign in intraparenchymal frontal haemorrhage.
10 : Unilateral fixed dilation of the pupil as a false-localizing sign with intracranial hemorrhage: case report and literature review.
12 : Diabetic polyneuropathy. Corneal sensitivity, vibratory perception and Achilles tendon reflex in diabetics.
13 : Lateral displacement of the brain and level of consciousness in patients with an acute hemispheral mass.
26 : Value of conventional, and diffusion- and perfusion weighted MRI in the management of patients with unclear cerebral pathology, admitted to the intensive care unit.
28 : Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing.
34 : Nonconvulsive status epilepticus associated with cephalosporins in patients with renal failure.
35 : Detection of electrographic seizures with continuous EEG monitoring in critically ill patients.
42 : Generalised periodic epileptiform discharges: clinical features, neuroradiological evaluation and prognosis in 37 adult patients.
44 : The poisoned patient with altered consciousness. Controversies in the use of a 'coma cocktail'.
46 : Importance of a reliable admission Glasgow Coma Scale score for determining the need for evacuation of posttraumatic subdural hematomas: a prospective study of 65 patients.
47 : Early identification of patients at risk for symptomatic vasospasm after aneurysmal subarachnoid hemorrhage.
48 : Is this patient dead, vegetative, or severely neurologically impaired? Assessing outcome for comatose survivors of cardiac arrest.
49 : FOUR score and Glasgow Coma Scale in predicting outcome of comatose patients: a pooled analysis.
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