on 08-Nov-2022 (Tue)

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.

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.

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].

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

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?

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.

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.

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.

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 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.

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].

Reflex posturing can occur in deep metabolic coma as well, eg, in hypoglycemia

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).

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'.)

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.

In severe sedative drug overdose or in hypothermia, the pupils are midposition and fixed; this syndrome can mimic brain death.

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).

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).

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.

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.

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].

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".)