The differential diagnosis for the comatose patient is includes structural abnormality, seizure, encephalitis, metabolic derangements, and toxicologic etiologies. Identifying and treating the underlying pathology in a timely manner is critical for the patient’s outcome. We provide a structured approach to taking a history and performing a physical examination for this patient population. We discuss diagnostic testing and treatment methodologies for each of the common causes of coma. Our current understanding of the mechanisms of coma is insufficient to accurately predict the patient’s clinical trajectory and more work needs to be done to investigate potential treatments for this often fatal disorder.
Key points
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The differential diagnosis for the comatose patient is broad and includes structural abnormality, seizure, encephalitis, metabolic derangements, and toxicologic etiologies.
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Obtaining a good collateral history and physical examination are imperative for identifying the correct diagnosis.
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We discuss the diagnostic testing and treatment considerations for each cause of coma.
Introduction
Coma may be defined as a state of prolonged unresponsive unconsciousness. As such, it is not a disease process, but rather a symptom that may be caused by a variety of disease processes. Causes include structural, metabolic, toxicologic, and infectious etiologies; prognosis varies substantially with the underlying cause. The common pathway resulting in coma is thought to include disruption of neuronal function or pathways from the ascending reticular activating system through the thalami to the cortex. It is important to note that only lesions affecting the ascending reticular activating system or bilateral hemispheres result in coma and coma should never be attributed to unilateral cortical lesions.
Coma is by definition a medical emergency, because it impairs the patient’s ability to protect the airway; many underlying causes of coma are also independently emergent. In a study of International Classification of Diseases, 9th edition, codes, coma was responsible for 29 emergency department visits per 100,000 population, a decreasing number that likely represents under-reporting as emergency department workup to identify an underlying cause is improving.
Treatment of coma is targeted toward immediate stabilization, identification in particular of reversible underlying etiologies, and correcting alterations in normal physiologic processes. This article contains a differential diagnosis for coma etiologies, prioritized by acuity and reversibility, along with suggested diagnostic and stabilization strategies. In all cases, information obtainable from the patient will be limited, and consequently the initial differential must be formed on the basis of historical information from surrogates and physical examination.
History and physical examination pearls
History
The patient’s history should provide the majority of information needed to narrow the diagnosis. In addition to knowing the right questions to ask, knowing the order in which to ask them will help to triage the patient and to formulate a plan at the same time. In some cases collateral information will be unavailable resulting in reliance solely on physical examination and ancillary testing.
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Acuity and onset
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Was the change sudden?
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Was the patient showing earlier signs such as excessive sleepiness, confusion, or memory problems before coma onset?
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Was the patient experiencing other symptoms such as fevers, unusual movements, weakness, numbness or tingling, headaches, light sensitivity, or neck or back pain?
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What was the patient doing when this occurred?
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When was the last time seen in their usual state of health?
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History of brain surgery?
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Vascular risk factors
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Hypertension, hyperlipidemia, diabetes mellitus, coronary artery disease, smoking history, obstructive sleep apnea, atrial fibrillation, history of stroke or intracerebral hemorrhage, family history of aneurysms, or history of thrombosis or thromboembolism?
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Seizure risk factors
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Personal or family history of seizures or status epilepticus?
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Febrile seizures as a child?
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History of head trauma with loss of consciousness?
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History of central nervous system infection?
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History of psychiatric disease?
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History of depression or suicidal ideations?
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Prescribed psychiatric medications?
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Compliant with medications?
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When was the last refill and how much is left?
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History of substance abuse?
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Which substances?
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How much?
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Use of injectable drugs?
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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 adrenergic 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 hypotension. Additionally, particularly when seen in conjunction with hypertension and decreased or irregular breathing, known as Cushing’s triad, it may signify elevated intracranial pressure.
Hypertension, similarly, may directly cause encephalopathy and thus leads to a diagnosis of hypertensive emergency. However, hypertensive encephalopathy is usually relatively mild and the diagnosis should be reached only after excluding other acute processes. In acute brain injury blood pressure is augmented by the brain’s intrinsic autoregulatory mechanism to maintain cerebral blood flow. Hypertension can also be seen in patients with seizures or those with ingestion of adrenergic or anticholinergic substances.
Hypotension may result in cerebral hypoperfusion and coma. It is otherwise a nonspecific finding with a broad differential diagnosis, including various forms of end-organ dysfunction such as shock, end-stage kidney disease, or end-stage liver disease. It may also be seen in the setting of opiate, barbiturate or benzodiazepine intoxication, overdose of antihypertensive medication, or loss of sympathetic tone from a spinal cord injury.
Tachypnea may be a central phenomenon known as central neurogenic hyperventilation, occurring in response to a lesion in the midbrain or diencephalon. However, tachypnea is more frequently a result of a primary pulmonary process, a pain response, or as compensation for a metabolic acidosis as seen in sepsis and drug intoxication (Kussmaul’s breathing).
Apnea or irregular breathing patterns, when central in origin, have multiple variants including:
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Cheyne–Stokes respirations: Periods of “crescendo–decrescendo” tachypnea with periods of apnea, which can be seen in metabolic encephalopathy, supratentorial lesions, and lesions of the midbrain or diencephalon.
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Apneustic: Prolonged inspiration and expiration separated by periods of apnea, which can be seen in pontine lesions.
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Ataxic (Biot’s): Periods of tachypnea and apnea lacking the crescendo–decrescendo quality of Cheyne–Stokes respirations and is associated with lesions in the medulla. This breathing pattern usually carries a poor prognosis.
Additional examination findings
Hiccups may be seen with medullary lesions. Additionally, outside of gastrointestinal disease, vomiting may be indicative of hydrocephalus with increased pressure to the area postrema located on the floor of the fourth ventricle.
Head, Eyes, Ears, Nose, and Throat
Fundoscopic examination may show papilledema suggestive of elevated intracranial pressure. Presence of retinal hemorrhage or detachment is suggestive of head trauma. Periorbital ecchymosis (“raccoon eyes”), mastoid ecchymoses (“Battle’s sign”), and hemotympanum are concerning for basal skull fracture. Dry mucosal membranes may be a result of dehydration or intoxication with antidepressants, anticholinergics, neuroleptics, antihistamines, muscle relaxants, seizure medications, or antihypertensives. Conversely, excessive salivation, lacrimation, and diaphoresis can point to cholinergic intoxication. Finally, scleral icterus may be a sign of end-stage liver disease or hepatic encephalopathy with or without cerebral edema.
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 herniation with compression of cranial nerve III, or a midbrain lesion affecting the third nerve nucleus. Abnormal pupillary constriction or dilation can be caused by medications with adrenergic or cholinergic effects. When accompanying coma, miotic (“pinpoint”) pupils most commonly indicate intoxication with opiates or benzodiazepines, cholinergic substances such as organophosphates, or a structural lesion in the pons. Bilateral dilated pupils with decreased or absent pupillary constriction may be indicative of a severe diffuse cerebral process; however, this finding can also be found in profound intoxication, sedation, or hypothermia ( Table 1 ).
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 bidirectional, 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.
Other cranial nerve findings
Absence of the corneal, cough, or gag reflexes is another sign of severe diffuse cerebral dysfunction, but the etiology is nonspecific. Central facial asymmetry, in which eyebrow raise is preserved, is seen with cortical or subcortical injury. Head version may be indicative of a focal seizure originating from the contralateral hemisphere.
Motor and sensory findings
In comatose patients, the sensory portion of the neurologic examination is limited to their response to stimulation, which is performed during the motor examination. Increased tone or rigidity can indicate serotonin syndrome, neuroleptic malignant syndrome, malignant hyperthermia, subacute or chronic brain injury, seizure, or chronic spinal cord injury. Spontaneous and purposeful movement is often times a reassuring finding. Response to noxious stimulation in the upper extremities can be categorized as either localization, withdrawal, decorticate, or decerebrate posturing. Response to noxious stimulation in the lower extremities can be categorized as either spontaneous, withdrawal, or triple flexion. Triple flexion is a nonsustained, stereotyped flexion at the hip, knee, and ankle and is a brain stem–mediated response reflecting a loss of cortical involvement. Absence of motor responses is nonspecific and could indicate organic disease or other severe metabolic disease or intoxication.
Reflex testing
Hyperreflexia or clonus may be seen as part of serotonin syndrome, neuroleptic malignant 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 lesions, space-occupying lesions, and lesions causing diffusely elevated intracranial pressure through cerebrospinal fluid outflow obstruction. Some lesions may span multiple categories, such as a space-occupying intracranial hemorrhage owing to a ruptured arteriovenous malformation.
All patients presenting with coma should undergo an emergent head computed tomography (CT) scan to exclude space-occupying structural lesions and hydrocephalus; this is especially true for those with focal neurologic deficits, such as cranial nerve findings. The decision to perform neuroimaging must be made on clinical grounds and not delayed for results of laboratory testing, because many identifiable structural causes require time-critical treatment.
Comatose patients will have a decreased intrinsic ability to maintain their airway, and most will require intubation to ensure safety for neuroimaging. Any with overt evidence of elevated intracranial pressure such as a herniation syndrome warrant empiric osmotic therapy before neuroimaging, especially since this imaging requires prolonged supine positioning.
The identification of a discrete space-occupying lesion will usually require specialist consultation, because classification into operative versus nonoperative lesions is beyond the scope of most emergency medicine practitioners. Any lesion causing substantial mass effect, herniation, or suspicion for globally elevated intracranial pressure should be treated with osmotic therapy such as mannitol or hypertonic saline while awaiting neurosurgical consultation. If this situation requires central line placement, the subclavian site is preferred to limit potential obstructions of cerebral venous outflow. Steroid administration should be reserved for vasogenic edema owing to underlying tumor and is not recommended for edema surrounding hemorrhages. , Hydrocephalus severe enough to result in coma, particularly if caused by intraventricular hemorrhage or cerebrospinal fluid outflow obstruction, will likely require emergent endoventricular drain placement by neurosurgery. It should be mentioned that procedural management of infratentorial lesions is controversial and may include either endoventricular drain or suboccipital decompression at the discretion of the neurosurgical team.
If an intracranial hemorrhage is diagnosed, reversal of anticoagulation is recommended. Reversal of antiplatelet agents for intraparenchymal hemorrhages has been shown to double the risk of death or dependency and has therefore been removed as a routine practice recommendation. This development does not mean to imply that specific individual patients (such as those with active arterial bleeding or undergoing neurosurgical procedures) may not derive some benefit. A cornerstone of management of intracranial hemorrhage is careful management of blood pressure. A goal of systolic blood pressure is controversial, although targeting to less than 160 has been shown to decrease hematoma expansion without significant repercussions to renal function. , There is no evidence for the use of prophylactic antiepileptic drugs. Last, in patients with intracranial hemorrhage identified on noncontrast CT scan, CT angiography may identify a responsible neurovascular lesion warranting intervention.
Neurovascular etiologies of coma warrant specific discussion owing to their time-sensitive and treatable nature. Basilar system thrombosis carries an extremely poor untreated prognosis, and in the neurointerventional era has time-critical and potentially effective treatments. The sensitivity of a noncontrast head CT scan for basilar thrombosis has been reported to be as high as 50% to 70% , with high clinical pretest probability and when reviewed by expert neuroradiologists. In many clinical scenarios even this moderate sensitivity will not be achievable, and consequently CT angiography is increasingly becoming a standard diagnostic evaluation for comatose patients and especially those with cranial nerve findings. Identifying acute basilar clot has significant impact on outcomes, with 45% to 46% , of those treated via endovascular therapy having good outcomes (modified Rankin Scale of 0–2, functional independence) 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 oculomotor 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 bilateral, 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 undifferentiated coma vs neurologic intensive care unit for infarct vs trauma or neurotrauma intensive care unit for diffuse axonal injury or traumatic brain injury) ( Table 2 ).
Related posts:
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Diagnosis and Initial Emergency Department Management of Subarachnoid Hemorrhage
Sedation for Rapid Sequence Induction and Intubation of Neurologically Injured Patients
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