Clinical manifestations

Presentation and course

With regards to the different levels of arousal, coma represents a deep unresponsive state from which, regardless of the strength of the stimuli, no reaction can be elicited. To understand it, some differentiation between the different states of arousal is warranted (15).

Differentiating coma from brain death relies on the vital functions of the brainstem and whether these can be elicited, with a coexisting lack of cortical response suggestive of volition (04). On the other hand, sleep, although instinctively different, shares common features on EEG patterns. Non-REM sleep can be easily identified if no history or exam is available. Depending on the cause, coma can manifest on EEG with high-amplitude slow-wave activity (delta), which suggests suppression of direct and indirect activating pathways projecting from the thalami to the bilateral cerebral cortex. However, aside from being a physiological state that can be easily interrupted, sleep is also dynamic and cyclic, fluctuating between “slow-wave” stages to faster brainwaves in REM. The comatose state is characterized by lack of reactivity and absence of cycling.

The vegetative state consists of an unresponsive-wakefulness pattern that is longer in this spectrum of impaired arousal. Some patients will progress to this state after being in a coma. EEG findings characteristic of the sleep-awake cycle are evident. Some responses to stimuli may be present but unpurposeful and are thought to be reflective of remaining brainstem functionality.

In the minimally conscious state, there is awareness of self or surroundings, evidenced by limited though frank responsiveness, such as visual tracking. There is, however, no reliable exchange between the examiner and the patient (15; 04).

Prognosis and complications

Prediction of recovery from a comatose state always represents a challenge to the clinician. The etiology and circumstances surrounding the event (total downtime in cardiac arrest, reversibility of cause of coma, etc.) are often useful in estimating the chances or the length of the recovery process. This can vary widely, from complete and expedited recovery to lengthy partial recovery, full dependence, persistent vegetative state, or death.

Biological basis

Neuroanatomy and physiology. Levels of consciousness involve different processes within three spheres: alertness, attention, and awareness (04). Alertness strongly correlates with normal function of the brainstem and diencephalon. Attention requires the added processes from associative cortices bilaterally and plays an important role in higher function assessment. Awareness leads to internal perception of circumstances and surroundings yet remains poorly understood.

Different neurotransmitters play a role in different anatomical structures for the maintenance of the arousal system. It is now understood that the role of these chemicals depends on the pathways involved. Brainstem tracts associated with wakefulness form the reticular activating system.

These connections reach hypothalamic and thalamic structures and project to higher cortical regions to achieve the full state of consciousness.

Neurotransmitter role and pathways. Pontomesencephalic glutamate-containing neurons project to the interlaminar nucleus of the thalamus, hypothalamus, and basal forebrain, all of which maintain alertness. Glutamate neurons are also seen arising from the supramammillary nucleus with the same final projections.

Acetylcholine neurons adjacent to the reticular formation also project to the intralaminar nucleus. It is thought that these connections indirectly facilitate excitatory signals to the cortex arising from the thalamus.

Dopamine in the mesocortical pathway projects from the ventral tegmentum towards the prefrontal cortex.

Norepinephrine has a general excitatory effect on the thalamus. It is known that neurons in the locus coeruleus change their firing rate according to the consciousness state.

Serotonin neurons in the raphe nucleus also have different effects, with variability in the sleep-wake cycle. The rostral aspect projects to the forebrain, mesencephalon, and basal ganglia. The caudal portion of the raphe nucleus, located in the lower pons and medulla, projects to cerebellum and spinal cord.

Lastly, histamine neurons projecting from the tuberomammillary region are also thought to play a role in alertness. Other contributors, such as adenosine, orexin, and GABA, have variable or indirect effects on alertness and attention, as evidenced by the decreased firing rate of these neurons in the sleep state (04; 11).

Etiology and pathogenesis

Etiology and assessment. Etiology varies according to the implicated pathways. From a localizing standpoint, coma can be attributed to lesions in the bilateral hemispheres or diencephalon (simultaneous and widespread), or the reticular activating systems within the upper brainstem. Regardless of the localization of the triggering event, once in a coma, both the cortical and subcortical functions become depressed, decreasing its metabolism by half (04).

Understanding that consciousness comprises an orchestra of intact pathways forming a network rather than a specific working region in the brain is essential to differentiate pathological mechanisms leading to coma. When assessing a patient in a comatose state, the clinician should suspect injury to the reticular activating system or to the bilateral diencephalic or cerebral hemispheres to establish a list of possible causes (11). Structural lesions have become more easily diagnosed with the advantages of imaging studies.

Prioritizing history taking provides information about circumstances surrounding the event, which can guide the differential. Secondly, physical examination of the comatose patient aids in localization. Given that the reticular activating system extends through almost the entirety of the brainstem, subtle findings on examination can hint towards different regions. In the event of intact surrogate brainstem function, higher lesions are suspected, changing the scope of the differential to diencephalic, and cortical lesions would require simultaneous bilateral insult to produce coma.

Many cases of coma are due to toxic or metabolic-induced dysfunction; other causes grossly include vascular or space-occupying and pressure-related lesions. This article focuses on lesions within the brainstem as well as diencephalic structures (hypothalamus and thalamus). To guide a proper differential diagnosis, the clinician should be aware of some key features of the neurologic assessment on initial encounter.

First assessment

Hypotension. Mean arterial pressure (MAP) ranges for brain autoregulation vary according to individual physiology and comorbidities. MAP of 60 mmHg is used uniformly as a reference, but individual considerations are a must. Caution should be taken regarding cerebral perfusion pressure and whether brain compensatory mechanisms are overcome by hemodynamic shock.

Hypertension. Hypertension can provoke both ischemia and hemorrhages that may subsequently lead to a comatose state due to direct brain parenchyma damage or to mass effect and impending herniation. On the other hand, hypertension can also be a manifestation of increased intracranial pressure, and it is recognized as part of the Cushing triad (hypertension, bradycardia, and respiratory abnormalities).

Respiratory patterns. Respiratory patterns are often irregular and can be seen with brainstem lesions, though they can also be a manifestation of intoxication (Table 1).

Hyperthermia. Hyperthermia can be seen in a metabolic or infectious context. Neurogenic causes of hyperthermia are typically associated with hemorrhage within the subarachnoid space or hypothalamic lesions. Neurogenic hyperthermia typically develops over time rather than as an initial manifestation of a comatose state.

Glasglow Coma Scale. The Glasglow Coma Scale assesses three different domains to grade the severity of disease according to the level of consciousness. The Glasglow Coma Scale utilizes eye opening and verbal and motor responses to a maximum score of 15 in patients who are spontaneously awake and interactive and to a minimum score of 3 in cases of complete unresponsiveness and no movements appreciated.

Full Outline of UnResponsiveness (FOUR) score. The FOUR score has similar components as the Glasglow Coma Scale, with eye and motor responses in addition to brainstem reflexes and breathing. The score ranges between 16 in fully awake and interactive patients and 0. The breathing section is scored from regularity of respiratory pattern to apnea and ventilator-controlled breathing (Table 1) (20; 10).

Neurologic examination in the comatose patient

Ocular system. Gaze position, pupillary size, reactivity, and symmetry are valuable pieces of information. Pupillary size and reactivity can inform about autonomic balance. Midsized, fixed pupils indicate loss of autonomic tone. Pinpoint pupils may suggest disruption of sympathetic ascending tracts, localizing to the pontine region, as well as toxic causes, such as opioid intoxication. On the contrary, dilated pupils suggest parasympathetic tone loss when bilateral, whereas unilateral lesions are more indicative of compressed fibers surrounding the ipsilateral cranial nerve III.

Resting gaze position

Conjugate lateral deviation. Conjugate lateral deviation can be due to pontine lesions if paramedian pontine reticular formation is involved; deviation is ipsilateral to hemiparesis if the corticospinal tract is involved.

In pontine lesions affecting gaze, head turn maneuver (to elicit oculocephalic reflex) does not correct deviation.

Injury to the frontal eye fields can also produce gaze deviation. These patients have deviation contralateral to hemiparesis if the corticospinal tract is involved. This gaze can be transiently overcome with head turn maneuver.

Dysconjugate lateral deviation. Dysconjugate lateral deviation can be seen in either cranial nerves III or VI or represent internuclear ophthalmoplegia depending on the details of the deficit. Lesions attributable to cranial nerve III localize to the midbrain and adjacent structures. Those attributed to cranial nerve VI localize to the pons, and internuclear ophthalmoplegia localizes to anywhere in the paramedian pontine reticular formation / medial longitudinal fasciculus complex tracts within the midbrain and pons.

Downward deviation. Downward deviation is suggestive of increased pressure over the tectum, though it is also seen in metabolic encephalopathies.

Skew deviation. Skew deviation is a sustained asymmetric misalignment in the vertical plane that suggests brainstem or cerebellar lesions.

Spontaneous ocular movements

Roving movements are horizontal and slow, and conjugate movements are indicative of proper oculomotor nuclei function. The presence of these movements suggests an intact brainstem function due to the complexity of coordinated signals that are necessary to achieve them.

Ocular bobbing is a vertical conjugate jerking movement with a rapid downward phase, followed by a slow midline return. This finding indicates a pontine lesion. Ocular dipping (inverse ocular bobbing) has a slow downward phase, with rapid correction to the horizontal meridian; it indicates diffuse cerebral injury.

Head turn maneuver and caloric testing

Oculocephalic reflex should be attempted via sudden head turn or caloric testing (in cases of suspected neck instability). Only unconscious patients with intact cranial nerve function III and VI will have oculocephalic reflex present.

A positive reflex (conjugate deviation contralateral to head turn) indicates intact cranial nerve function in the context of suppressed higher cortical signals. Of note, dysconjugate responses during this test suggest cranial nerve palsy.

Caloric testing elicits the same signal pathways, though interpretation changes depending on the stimulus used.

Tympanic membranes should be checked in all patients with traumatic brain injury and in cases of suspected disruption. In such cases, the test should be postponed.

Instillation of cold water to the external ear canal, with intact cranial nerve function, causes Opposite Same side (to stimulus) gaze deviation. Instillation of warm water causes Same Opposite side gaze deviation. The mnemonic COWS (Cold Opposite, Warm Same) is used to refer to the fast phase of the intact reflexive response, which is indicative of proper cranial nerve function nystagmus that occurs in awake patients.

Motor system. Observation is key to the initial assessment. The first step in the motor examination is noting any spontaneous movements at rest and deciding whether these movements are purposeful.

On stimulation, some movements may be elicited and should be subsequently characterized as reflexive versus localizing. Localizing responses involve any movement directed towards the side of stimulation. If noxious stimulation is inflicted over the right side, any movement on the left reaching to the right qualifies as localizing, as well as withdrawal of the stimulated limb. Reflexive movements include all posturing phenomena, whether spontaneous or stimulated. Reflexes also include any stereotypical and nonprotective movements in the stimulated limb.

Decorticate posturing manifests as elbow and wrist flexion, with extension of the lower extremities. This finding localizes injury above the red nucleus in the midbrain. This posture is a consequence of the unopposed rubrospinal tract signals.

Decerebrate posturing consists of the pronation of the upper extremities, with extension of the four limbs. This posture localizes the lesion between the red nuclei (midbrain) and the vestibular nuclei (pons/medulla). In this case, cortical influences (mainly inhibitory signals) are disconnected, and along with rubrospinal tract disruption (suppressed flexor signals to upper extremities), extension of both upper and lower extremities results from the predominant and unopposed vestibulospinal tract (01; 08; 10).

Respiratory system. Breathing assessment through observation can be challenging in a comatose patient who has likely required mechanical ventilation support. However, some distinguishing patterns are used to understand and help estimate the extent of the neurologic injury.

Table 1. Respiratory Patterns, Description, and Localization of Injury

Differential diagnosis

Confusing conditions

Structurally speaking, thalamic lesions are frequently seen in the context of vascular syndromes (basilar tip occlusion) due to their irrigation from posterior cerebral arteries, which become compromised with parent vessel occlusion. Hypothalamic injury tends to be more frequently associated with occupying lesions in the vicinity (pituitary mass/enlargement) and metabolic changes and are less likely of a vascular nature. Hypothalamic blood flow comes from the anterior system of the circle of Willis, mainly by medial cerebral artery–penetrating branches.

The midbrain and pons can be subject to different mechanisms of injury. These include neurovascular (ischemic or hemorrhagic), space-occupying (increased intracranial pressure causing compression), or toxic-metabolic (osmotic changes).

Vascular causes. In patients with sudden-onset decreased level of consciousness and coma, vascular lesions within the vertebrobasilar system (responsible for brainstem irrigation) should be ruled out.

The penetrating vessels branching off the basilar artery include the anterior inferior cerebellar artery (AICA) and superior cerebellar artery (SCA), which irrigate the tegmentum of the pons, as well as the terminal posterior cerebral artery branches that supply the midbrain and most of the thalamus (01; 05). Pontine lesions can be caused by basilar artery occlusion or smaller penetrating branches. They may present with bilateral deficits and intact awareness with only preserved vertical eye movements (locked-in syndrome). This is a challenging diagnosis given the broad neurologic findings in a conscious patient.

It is important to understand that beyond the anatomical boundaries of a brainstem lesion, cortical injury causing coma localizes to the bilateral frontoparietal regions, which tends to be less frequently seen and of significantly higher morbidity and mortality when present (01).

Metabolic, toxic, and drug-induced causes. Altered levels of consciousness due to metabolic causes, though potentially profound, tend to be progressive rather than sudden, even in the acute phase. During this progression, exams often fluctuate prior to advancing into a comatose state.

After initial assessment, every patient should undergo basic blood work to address potential “easily” reversible causes, such as hypoxemia, hypo/hyperglycemia, and electrolyte derangements. Further testing should include liver function test, ammonia, and toxicology panel in the appropriate setting.

Structural occupying lesions. These lesions are typically present with a preceding event that is often the initial chief complaint or reason for consultation. Occupying lesions, regardless of possible rapid growth, have an insidious onset of symptoms that often localize to specific brain structures rather than presenting as sudden-onset coma.

Nonconvulsive status epilepticus or prolonged postictal state represent other plausible causes when assessing a comatose patient.

Diagnostic workup

Combined history taking, observation, and neurologic exam help guide further steps to achieve diagnosis. Initial laboratory tests include basic metabolic panel, blood gases, liver function test, toxicology, and alcohol levels.

Imaging studies

A non-contrast CT scan can help rule out large vascular pathology, whether hemorrhagic or ischemic, when this is suspected.

MRI of the brain provides further information regarding occupying lesions and edema and helps identify metabolic and hypoxic ischemic encephalopathy in the appropriate context.

PET scans are typically reserved as ancillary testing when brain death protocol is carried out.

Functional neurodiagnostic studies

Electroencephalography (EEG). EEG is relevant when suspecting subclinical status epilepticus and provides guidance in prognostication after a known brain injury. Sleep-wake pattern changes in a persistently unconscious/unresponsive patient may indicate transition from a comatose to a persistent vegetative state.

The EEG background gives information about baseline cortical function, which is typically abnormal but varies in the comatose state. The presence of a posterior dominant rhythm is indicative of normal brain function in a wakefulness state with eyes closed. This is particularly useful in catatonic or psychogenic unresponsiveness. Lack thereof indicates unspecified brain injury.

Assessing the symmetry of brainwaves can help in localizing the side of cortical injury. Reactivity becomes a critical surrogate of clinical responsiveness when the exam is inconclusive. Changes in the background on external stimuli should be expected with normal brain function.

It is important to note that scalp EEG graphs reflect the summation of the circuit between the reticular activating system, thalamus, basal forebrain, and cortex. In the comatose state, unlike the sleep state (with typical stage changes), electrographic findings are consistent with large sinusoidal waves in the delta frequency range resembling NREM sleep. Some exceptions include alpha-coma, burst suppression patterns, or electrical silence.

Once again, the use of these tools and their interpretation must be in combination with an accurate history and thorough neurologic exam.

Somatosensory evoked potential (SSEP). SSEP has been used over the decades to assess cortical relayed signals after conduction stimulation in a peripheral nerve. There are many studies evaluating the reliability of this test in comatose patients and its prognostic value.

SSEP consists of stimulation of the peripheral nerve, mainly the median nerve, with simultaneous recording through EEG electrodes. The N20 peak stands for the negative deflection wave seen at 20 milliseconds in normal subjects during this test. It represents the earliest response to peripheral nerve stimulation and originates from the somatosensory cortex recorded in the scalp surface over the contralateral parietal area (08).

Most of these studies aim to predict progression to persistent vegetative state versus brain death rather than the possibility of positive outcome. This is due to more reliable results when responses are absent, indicating progression to persistent vegetative state or brain death and leaving those with preserved and abnormal responses with uncertain outcomes. Notably, research in the area has mainly focused on hypoxic ischemic and traumatic brain injury groups (16).

Brainstem auditory evoked potential (BAEP). BAEP has been studied to assess brainstem auditory pathways and cranial nerve VIII. Along with middle-latency auditory potentials, which are recorded in the cortical surface, BAEP predicts poor prognosis with abnormal results (07).

Cognitive event-related potentials. The aim of cognitive event-related potentials is to evaluate sensory and cognitive function in comatose patients. This tool consists of evaluating quantitative EEG patterns at rest (unstimulated) and averaging this activity in association with that of stimulation time. The result is a net recording of signals activated by sensory or cognitive pathways, ranging from the perceptive stage (SSEP) to higher processing, in attempts to estimate residual cognitive function. These more recent studies are limited due to the heterogeneity of the tasks and methodology (18).

Intracranial monitoring. Intracranial monitoring is a diagnostic tool reserved for cases in which increased intracranial pressure is suspected. It is also currently being used in clinical trials to guide management based on cerebral perfusion, oxygenation, and pressure parameters in traumatic brain injury (02).

When combined with extraventricular catheter drainage, it becomes a diagnostic and therapeutic tool in cases of suspected or high-risk obstructive hydrocephalus.

Management

Easily reversible causes (eg, hypoglycemia) should always be quickly sought and addressed considering possible rapid improvement in neurologic function.

Initial management

The ABC mnemonic (Airway, Breathing, Circulation) prevails when caring for unconscious patients (Table 2). Once addressed, empiric use of thiamine along with dextrose fluids in hypoglycemic patients prevents further decompensation in cases of unknown underlying thiamine deficiency (Wernicke encephalopathy). The use of naloxone in the emergency department has become common practice when the rapid initial assessment is inconclusive. After the first examination, however broad, a differential diagnosis should be established. A detailed neurologic examination can help distinguish primary versus systemic causes of a comatose state.

Table 2. Initial Management and Rapid Assessment of Comatose Patient

Vascular causes. Basilar artery occlusion must always be ruled out first in a comatose patient when no other information is available and ABC as well as possible reversible causes have been addressed. Chemical thrombolysis is offered for patients who meet eligibility criteria (time of onset of symptoms less than 6 hours; no obvious contraindications). Mechanical thrombectomy is an option in eligible centers. These measures are potentially lifesaving.

Other large vessel occlusions may present in a comatose state; however, there are typically localizing features that provide clues for the examiner. Regardless, management remains similar.

Cerebral edema, space-occupying lesion, and increased intracranial pressure. If elevated intracranial pressure is suspected, the following measures should be taken as this represents an immediate life-threatening condition.

Metabolic, toxic, and drug-induced causes. These may be reversible over time if not associated with prolonged hypoxia or hemodynamic compromise. Supportive management is indicated, along with reversible measures as deemed appropriate (bicarbonate drip in severe acidemia, renal replacement therapy in uremia, lactulose in hyperammonemia, etc).

Nonconvulsive status epilepticus (NCSE). Once identified, regardless of being the primary cause or secondary manifestation of a comatose state, the NCSE warrants aggressive management as postulated by the American Epilepsy Society guidelines for convulsive status. The goal of NCSE control targets electrographic cessation of seizures. There is no evidence available to guide depth or length of electrographic suppression to correlate with outcomes. Current practice aims for at least 24 hours of therapeutic coma. Observational studies indicate that a high steady dose of anesthetic use is associated with better outcomes. On the other hand, extending therapeutic coma beyond 35 hours was associated with seizure recurrence during the weaning period (14).

The following is a summary of the current approach to management of status epilepticus once ABC and stabilizing measures are in place.

Post cardiac arrest syndrome. Patients evaluated after cardiac arrest represent a different entity altogether. The management of these patients aims to prevent and treat brain injury due to hypoxic-ischemic circumstances. Key parameters to focus on include cerebral perfusion pressure (calculated with MAP and ICP), intracranial pressure, and optimization of oxygen supply (ventilation). Primary prevention of brain injury in this context lies almost purely in CPR quality.

Once spontaneous circulation is achieved, the goal is to prevent recurrence of cardiac arrest, decrease the brain metabolic rate, and guarantee proper irrigation and oxygenation (17). Targeted temperature management has been used and debated, following center-specific protocols in eligible patients, depending on presentation and cardiac rhythm at the time of arrest. The goal is to lower the brain metabolic rate through hypothermia, ultimately avoiding fever.

There are many trials that aim to establish a temperature range that can provide benefits with potentially fewer complications and side effects (03). Further details of this evidence and protocols are beyond the scope of this article.

Outcomes

In cases in which prognosis is guarded or possibilities are too broad to foresee, fluent communication with family members and decision makers takes priority. Helping families understand the disease process and evolution can guide future courses of action in the best interest of the patient.

Future considerations

Research is currently focused on finding tools to guide care and prognosis, which, in turn, will aid in identifying therapeutic targets for comatose patients. Many of these efforts are dedicated to post cardiac arrest and severe traumatic brain injury populations. This is likely due to the broad range of pathologies that can cause or contribute to the comatose state, making it difficult to standardize management or predict outcomes in this heterogeneous population.

Functional MRI, SSEP, and quantitative EEG monitoring are now postulated as potential surrogates of neurologic examination in a comatose patient, and their use is under investigation. The current use of multimodality monitoring may also provide meaningful information for prognostication in the future.

The end goal remains combining assertive efforts to support patients and families in this conundrum, with the hope of lowering mortality and dependence in the long term.