Coma

Dr. Sham Kulkarni

(Under the guidance of Unit-2)

Source: Harrison’s 21st Edition

• Coma refers to the continuum of states of reduced alertness, the most severe form
being coma, defined as a deep sleep like state with eyes closed, from which the
patient cannot be aroused

• Stupor refers to a lower threshold for arousability, in which the patient can be
transiently awakened by vigorous stimuli, accompanied by motor behavior that
leads to avoidance or withdrawal from noxious stimuli.

• Stupor and drowsiness are usually accompanied by some degree of confusion

when the patient is alerted

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The vegetative state signifies an awake-appearing but nonresponsive state, usually
encountered in a patient who has emerged from coma. In the vegetative state, the eyelids
may open periodically, giving the appearance of wakefulness.

Respiratory and autonomic functions are retained. Yawning, coughing, swallowing, and
limb and head movements persist, but there are few, if any, meaningful responses to the
external and internal environment. There are typically accompanying signs that indicate
extensive damage in both cerebral hemispheres, e.g., decerebrate or decorticate limb
posturing and absent responses to visual stimuli.

In the closely related but less severe minimally conscious state, the patient displays
rudimentary vocal or motor behaviors, often spontaneous, but sometimes in response to
touch, visual stimuli, or command.
Cardiac arrest with cerebral hypoperfusion and head trauma are the most common causes of
the vegetative and minimally conscious states.

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Several syndromes that affect alertness are prone to be misinterpreted as stupor or coma, and
clinicians should be aware of these pitfalls when diagnosing coma at the bedside.

Akinetic mutism refers to a partially or fully awake state in which the patient remains virtually
immobile and mute but can form impressions and think, as demonstrated by later recounting of
events.

This condition results from damage in the regions of the medial thalamic nuclei or the frontal
lobes (particularly lesions situated deeply or on the orbitofrontal surfaces) or from extreme
hydrocephalus.

The term abulia describes a milder form of akinetic mutism characterized by mental and
physical slowness and diminished ability to initiate activity.

It is also usually the result of damage to the medial frontal lobes and their connections.
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 Catatonia
Catatonia is a hypomobile and mute syndrome that occurs usually as part of a major
psychosis, typically schizophrenia or major depression.

The locked-in state describes a type of pseudo coma in which an awake but paralyzed patient
has no means of producing speech or volitional limb movement but retains voluntary vertical
eye movements and lid elevation, thus allowing the patient to communicate.

The pupils are normally reactive. The usual cause is an infarction (e.g., basilar artery
thrombosis) or hemorrhage of the bilateral ventral pons that transects all descending motor
(corticospinal and corticobulbar) pathways.

Another awake but de-efferented state occurs as a result of total paralysis of the musculature
in severe cases of neuromuscular weakness such as in Guillain-Barré syndrome, critical
illness neuropathy ), or pharmacologic neuromuscular blockade.
THE ANATOMY AND PHYSIOLOGY OF
COMA
1. Widespread abnormalities of the cerebral hemispheres

2. Reduced activity of the thalamocortical alerting system, the reticular activating system
(RAS), which is an assemblage of neurons located diffusely in the upper brainstem and
thalamus.

The proper functioning of this system, its ascending projections to the cortex, and the cortex
itself are required to maintain alertness and coherence of thought.

In addition to structural damage to either or both of these systems, suppression of

reticulocerebral function commonly occurs by drugs, toxins, or metabolic derangements such
as hypoglycemia, anoxia, uremia, and hepatic failure, or by seizures; these types of metabolic
causes of coma are far more common than structural injuries

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 Coma Due to Cerebral Mass Lesions and
Herniation Syndromes
Herniation refers to displacement of brain tissue by an intracerebral or overlying mass into a
contiguous compartment that it normally does not occupy.

Most common form of herniation, brain tissue is displaced from the supratentorial to the
infratentorial compartment through the tentorial opening, referred to as transtentorial
herniation.

The cause is often a mass hemispheral lesion, with accompanying contralateral hemiparesis.
Uncal transtentorial herniation refers to impaction of the anterior medial temporal gyrus (the
uncus) into the tentorial opening just anterior to and adjacent to the midbrain.

The uncus can compress the third nerve as the nerve traverses the subarachnoid space,
causing enlargement of the ipsilateral pupil as the first sign.
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Types of Cerebral herniation: A-Uncal; B-Central; C-Transfalcial; D-Foraminal
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The coma that typically follows is due to lateral displacement of the midbrain (and
therefore the RAS) against the opposite tentorial edge by the displaced parahippocampal
gyrus, compressing the opposite cerebral peduncle and producing a Babinski sign and
ipsilateral hemiparesis (the Kernohan-Woltman sign).

Herniation may also compress the anterior and posterior cerebral arteries as they pass over
the tentorial reflections, with resultant brain infarction. These distortions may also entrap
portions of the ventricular system, causing hydrocephalus.

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 Coma Due to Metabolic, Drug, and Toxic
Disorder
systemic metabolic abnormalities cause coma by interrupting the delivery of energy
substrates (e.g., oxygen, glucose) or by altering neuronal excitability (drugs and alcohol,
anesthesia, and epilepsy).

These are the most common causes of coma in large case series.

Unlike hypoxia-ischemia, which first causes a metabolic encephalopathy due to reduced

energy substrate but ultimately causes neuronal destruction, most metabolic disorders such as
hypoglycemia, hyponatremia, hyperosmolarity, hypercapnia, hypercalcemia, and hepatic and
renal failure cause no or only minor neuropathologic change.

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In Hepatic Encephalopathy (HE), high ammonia concentrations lead to increased synthesis
of glutamine in astrocytes and osmotic swelling of the cells, mitochondrial energy failure,
production of reactive nitrogen and oxygen species, increases in the inhibitory
neurotransmitter GABA, and synthesis of putative “false” neurotransmitters.

Over time, development of a diffuse astrocytosis is typical of chronic HE. Which, if any, of
these is responsible for coma is not known

The mechanism of the encephalopathy of renal failure is also uncertain and likely to be
multifactorial; unlike ammonia, urea does not produce central nervous system (CNS)
depression. Contributors to uremic encephalopathy may include accumulation of neurotoxic
substances such as creatinine, guanidine, and related compounds; depletion of
catecholamines; altered glutamate and GABA tone; increases in brain calcium; inflammation
with disruption of the blood-brain barrier; and frequent coexisting vascular disease.

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Coma and Seizures are common accompaniments of large shifts in sodium and water
balance in the brain.

These changes in osmolarity arise from systemic medical disorders, including diabetic
ketoacidosis, the nonketotic hyperosmolar state, and hyponatremia from any cause (e.g.,
water intoxication, excessive secretion of antidiuretic hormone, or atrial natriuretic peptides).

Sodium levels <125 mmol/L, especially if achieved quickly, induce confusion, and levels
<119 mmol/L are typically associated with coma and convulsions.
In hyperosmolar coma, the serum osmolarity is generally >350 mosmol/L. Hypercapnia
depresses the level of consciousness in proportion to the rise in carbon dioxide (CO2 ) in the
blood.

In all of these metabolic encephalopathies, the degree of neurologic change depends on the
rapidity with which the serum changes occur.
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Comas due to drugs and toxins are typically reversible and leave no residual damage
provided there has not been hypoxia or severe hypotension.

Many drugs and toxins are capable of depressing nervous system function.

Some produce coma by affecting both the RAS and the cerebral cortex.

Overdose of medications that have atropinic actions produces signs such as dilated pupils,
tachycardia, and dry skin; opiate overdose produces pinpoint pupils <1 mm in diameter.

Some drug intoxications, typified by barbiturates, can mimic all of the signs of brain death;
thus, toxic etiologies should be excluded prior to making a diagnosis of brain death.

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 Epileptic Coma
Generalized electrical seizures are associated with coma, even in the absence of motor
convulsions (nonconvulsive status epilepticus).

As a result, EEG monitoring is often used in the evaluation of unexplained coma to exclude
this treatable etiology.

The self-limited coma that follows a seizure, the postictal state, may be due to exhaustion of
energy reserves or effects of locally toxic molecules that are the by-product of seizures.

The postictal state produces continuous, generalized slowing of the background EEG activity
similar to that of metabolic encephalopathies.

It typically lasts for a few minutes but in some cases can be prolonged for hours or even
rarely for days
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 Coma Due to Widespread Structural Damage to the
Cerebral Hemispheres

This category, comprising several unrelated disorders, results from extensive bilateral
structural cerebral damage.

The clinical appearance simulates a metabolic encephalopathy.

Hypoxia- ischemia is perhaps the best characterized form of this type of injury, in which it is
not possible initially to distinguish the acute reversible effects of oxygen deprivation of the
brain from the subsequent effects of anoxic neuronal damage.

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Similar cerebral damage may be produced by disorders that occlude widespread small blood
vessels throughout the brain; examples include thrombotic thrombocytopenic purpura

Hyperviscosity, and cerebral malaria. Diffuse white matter damage from cranial trauma or
inflammatory demyelinating diseases can cause a similar coma syndrome.

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 APPROACH TO THE PATIENT
HISTORY

The cause of coma may be immediately evident as in cases of trauma, cardiac arrest, or
observed drug ingestion.

In the remainder, certain points as below are useful:

(1) the circumstances and rapidity with which neurologic symptoms developed;
(2) antecedent symptoms (confusion, weakness, headache, fever, seizures, dizziness, double
vision, or vomiting);
(3) the use of medications, drugs, or alcohol; and
(4) chronic liver, kidney, lung, heart, or other medical disease

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 GENERAL PHYSICAL EXAMINATION
Signs of head trauma raise the possibility of coexisting spinal cord injury, and in such cases,
immobilization of the cervical spine is essential to prevent further injury.

Fever suggests a systemic infection, bacterial meningitis, encephalitis, heat stroke,

neuroleptic malignant syndrome, malignant hyperthermia due to anesthetics, or
anticholinergic drug intoxication.

Hypothermia is observed with alcohol, barbiturate, sedative, or phenothiazine intoxication;

hypoglycemia; peripheral circulatory failure; or extreme hypothyroidism.

Hypothermia itself causes coma when the temperature is <31°C (87.8°F) regardless of the
underlying etiology; less dramatically low body temperatures can also cause coma in some
instances.
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Marked hypertension suggests hypertensive encephalopathy, cerebral hemorrhage, large
cerebral infarction, or head injury.

Hypotension is characteristic of coma from alcohol or barbiturate intoxication, internal

hemorrhage or myocardial infarction causing poor delivery of blood to the brain, sepsis,
profound hypothyroidism, or Addisonian crisis.

The funduscopic examination can detect increased intracranial pressure (ICP) (papilledema),
subarachnoid hemorrhage (subhyaloid hemorrhages), and hypertensive encephalopathy
(exudates, hemorrhages, vessel-crossing changes, papilledema).

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Cutaneous petechiae suggest thrombotic thrombocytopenic purpura, meningococcemia, or a
bleeding diathesis associated with an intracerebral hemorrhage.

Cyanosis and reddish or anemic skin coloration are other indications of an underlying systemic
disease or carbon monoxide as responsible for the coma.

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The patient should first be observed without intervention by the examiner. Spontaneously
moving about the bed, reaching up toward the face, crossing legs, yawning, swallowing,
coughing, and moaning reflect a drowsy state that is close to normal awakeness.

Lack of restless movements on one side or an outturned leg suggests hemiplegia.

Intermittent twitching movements of a foot, finger, or facial muscle may be the only sign of
seizure

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Multifocal myoclonus usually indicates a metabolic disorder, particularly uremia, anoxia,
drug intoxication, or rarely a prion disease

In a drowsy and confused patient, bilateral asterixis is a sign of metabolic encephalopathy

or drug intoxication.

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Decorticate rigidity and decerebrate rigidity, or “posturing,” describe stereotyped arm and
leg movements occurring spontaneously or elicited by sensory stimulation.

Flexion of the elbows and wrists and supination of the arm (decorticate posturing)
classically suggest bilateral damage rostral to the midbrain, extension of the elbows and
wrists with pronation (decerebrate posturing) indicates damage to motor tracts caudal to the
midbrain.

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 LEVEL OF AROUSAL
Increasingly intense stimuli is first used to determine the threshold for arousal and the
motor response of each side of the body.

Tickling the nostrils with a cotton wisp is a moderate stimulus to arousal—all but deeply
stuporous and comatose patients will move the head away and arouse to some degree.

An even greater degree of responsiveness is present if the patient uses his hand to remove
an offending stimulus.

Pressure on bony prominences and pinprick stimulation, when necessary, are humane
forms of noxious stimuli; pinching the skin causes ecchymoses and is generally not
performed but may be useful in eliciting abduction withdrawal movements of the limbs.

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 BRAINSTEM REFLEXES
The most important brainstem reflexes are

1. Pupillary size and reaction to light

2. Spontaneous and elicited eye movements

3. Corneal responses

4. Respiratory pattern.

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 Pupillary Signs
Reactive and round pupils of midsize (2.5–5 mm) essentially exclude upper midbrain
damage, either primary or secondary to compression from herniation. A response to light
may be difficult to appreciate in pupils <2 mm in diameter, and bright room lighting may
mute pupillary reactivity. One enlarged (>6 mm) and poorly reactive pupil signifies
compression of the third nerve from the effects of a cerebral mass above.

An oval and slightly eccentric pupil is a transitional sign that accompanies early midbrain–
third nerve compression. The most extreme pupillary sign, bilaterally dilated and
unreactive pupils, indicates severe midbrain damage, usually from compression by a
supratentorial mass. Ingestion of drugs with anticholinergic activity, the use of mydriatic
eye drops, nebulizer treatments, and direct ocular trauma are other causes of pupillary
enlargement.
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Reactive and bilaterally small (1–2.5 mm) but not pinpoint pupils are seen in metabolic
encephalopathies or in deep bilateral hemispheral lesions such as hydrocephalus or thalamic
hemorrhage.

Even smaller reactive pupils (<1 mm) characterize opioid overdoses but also occur with
extensive pontine hemorrhage.

Unilateral miosis in coma has been attributed to dysfunction of sympathetic efferents

originating in the posterior hypothalamus and descending in the tegmentum of the
brainstem to the cervical cord.

It is an occasional finding in patients with a large cerebral hemorrhage that affects the
thalamus.

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 Ocular Movements
Spontaneous eye movements in coma often take the form of conjugate horizontal roving.

This finding alone exonerates extensive damage in the midbrain and pons and has the same
significance as normal reflex eye movements

Conjugate horizontal ocular deviation to one side indicates damage to the frontal lobe on
the same side or less commonly the pons on the opposite side.

This phenomenon is summarized by the below:

The eyes look toward a hemispheral lesion and away from a brainstem lesion

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Seizures involving the frontal lobe drive the eyes to the opposite side, simulating a pontine
destructive lesion.

The eyes may occasionally turn paradoxically away from the side of a deep hemispheral
lesion (“wrong-way eyes”).

The eyes turn down and inward with thalamic and upper midbrain lesions, typically
thalamic hemorrhage. “Ocular bobbing” describes brisk downward and slow upward
movements of the eyes associated with loss of horizontal eye movements and is diagnostic
of bilateral pontine damage, usually from thrombosis of the basilar artery.

Ocular dipping” is a slower, arrhythmic downward movement followed by a faster upward

movement in patients with normal reflex horizontal gaze; it usually indicates diffuse
cortical anoxic damage.

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The oculocephalic reflexes, elicited by moving the head from side to side or vertically and
observing eye movements in the direction opposite to the head movement, depend on the
integrity of the ocular motor nuclei and their interconnecting tracts that extend from the
midbrain to the pons and medulla.

The movements, called somewhat inaccurately “doll’s eyes,” are normally suppressed in the
awake patient with intact frontal lobes.

The ability to elicit them therefore reflects both reduced cortical influence on the brainstem
and intact brainstem pathways.

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The opposite, an absence of reflex eye movements, usually signifies damage within the
brainstem but can result from overdoses of certain drugs.

In this circumstance, normal pupillary size and light reaction distinguishes most drug-induced
comas from structural brainstem damage.

Oculocephalic maneuvers should not be attempted in patients with neck trauma, as vigorous
head movements can precipitate or worsen a spinal cord injury

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Thermal, or “caloric,” stimulation of the vestibular apparatus (oculovestibular response)
provides a more intense stimulus for the oculocephalic reflex but provides essentially the
same information.

The test is performed by irrigating the external auditory canal with cold water in order to
induce convection currents in the labyrinths.

After a brief latency, the result is tonic deviation of both eyes to the side of cold-water
irrigation. In comatose patients, nystagmus in the opposite direction may not occur.

The acronym “COWS” has been used to remind generations of medical students of the
direction of nystagmus—cold water opposite, warm water same—but since nystagmus is
often absent in the opposite direction due to frontal lobe dysfunction in coma, this mnemonic
does not often hold true.

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The corneal reflex, elicited by touching the cornea with a wisp of cotton and observing
bilateral lid closure, depends on the integrity of pontine pathways between the fifth
(afferent) and both seventh (efferent) cranial nerves; it is a useful test of pontine function.

CNS-depressant drugs diminish or eliminate the corneal responses soon after reflex eye
movements are paralyzed but before the pupils become unreactive to light.

The corneal response may be lost for a time on the side of an acute hemiplegia.

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Respiratory Patterns : These are of less localizing value in comparison to other brainstem
signs.

Shallow, slow, but regular breathing suggests metabolic or drug-induced depression of the
medullary respiratory centers.

Cheyne-Stokes respiration in its typical cyclic form, ending with a brief apneic period,
signifies bihemispheral damage or metabolic suppression and commonly accompanies light
coma.

Rapid, deep (Kussmaul) breathing usually implies metabolic acidosis but may also occur
with pontomesencephalic lesions.

Agonal gasps are the result of lower brainstem (medullary) damage and are recognized as
the terminal respiratory pattern of severe brain damage.

Other cyclic breathing patterns have been described but are of lesser significance.
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35
 LABORATORY STUDIES AND IMAGING
Most useful in the diagnosis of coma are chemicaltoxicologic analysis of blood and urine,
cranial CT or MRI, EEG, and cerebrospinal fluid (CSF) examination.

Arterial blood gas analysis is helpful in patients with lung disease and acid-base disorders.

Presence of exogenous drugs or toxins, especially alcohol, does not exclude the possibility
that other factors, particularly head trauma, are contributing to the clinical state.

An ethanol level of 43 mmol/L (0.2 g/dL) in nonhabituated patients generally causes

impaired mental activity; a level of >65 mmol/L (0.3 g/dL) is associated with stupor.

The development of tolerance may allow some chronic alcoholics to remain awake at levels
>87 mmol/L (0.4 g/dL).
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Availability of cranial CT and MRI has focused attention on causes of coma that are
detectable by imaging (e.g., hemorrhage, tumor, or hydrocephalus).

Resorting primarily to this approach, although at times expedient, is imprudent because

most cases of coma (and confusion) are metabolic or toxic in origin.

Furthermore, a normal CT scan does not exclude an anatomic lesion as the cause of coma;
for example, early bilateral hemisphere infarction, acute brainstem infarction, encephalitis,
meningitis, mechanical shearing of axons as a result of closed head trauma, sagittal sinus
thrombosis, hypoxic injury, and subdural hematoma isodense to adjacent brain are some of
the disorders that may not be detected.

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The EEG provides clues in metabolic or drug-induced states but is rarely diagnostic in these
disorders.

However, it is the essential test to reveal coma due to nonconvulsive seizures and shows fairly
characteristic patterns in herpesvirus encephalitis and prion disease.

The EEG may be further helpful in disclosing generalized slowing of the background activity,
a reflection of the severity of an encephalopathy.

Predominant high-voltage slowing (δ or triphasic waves) in the frontal regions is typical of

metabolic coma, as from hepatic failure, and widespread fast (β) activity implicates overdose
with sedative drugs (e.g., benzodiazepines).

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A special pattern of “alpha coma,” defined by widespread, variable 8- to 12-Hz activity,
superficially resembles the normal α rhythm of waking but, unlike normal α activity, is not
altered by environmental stimuli.

Alpha coma results from pontine or diffuse cortical damage and is associated with a poor
prognosis.

A unique EEG pattern in adults of “extreme delta brush” is characteristic of a specific (anti–N-
methyl-d-aspartate [NMDA] receptor) form of autoimmune encephalitis.

Normal α activity on the EEG, which is suppressed by stimulating the patient, also alerts the
clinician to the locked-in syndrome, hysteria, or catatonia.

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Lumbar puncture should be performed if no cause is readily apparent, as examination of
the CSF remains indispensable in the diagnosis of various forms of meningitis and
encephalitis.

An imaging study should be performed prior to lumbar puncture to exclude a large

intracranial mass lesion, which could lead to herniation with lumbar puncture.

Blood cultures and administration of antibiotics should precede the imaging study if
infectious meningitis is suspected

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 Treatment
The immediate goal in a comatose patient is prevention of further nervous system damage.

Hypotension, hypoglycemia, hypercalcemia, hypoxia, hypercapnia, and hyperthermia should

be corrected rapidly.

Hyponatremia should be corrected slowly to avoid injury from osmotic demyelination.

An oropharyngeal airway is adequate to keep the pharynx open in a drowsy patient who is
breathing normally.

Tracheal intubation is indicated if there is apnea, upper airway obstruction, hypoventilation, or

emesis, or if the patient is at risk for aspiration.

Mechanical ventilation is required if there is hypoventilation or a need to induce hypocapnia

in order to lower ICP.
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IV access is established and naloxone and dextrose are administered if opioid overdose or
hypoglycemia are possibilities; thiamine is given along with glucose to avoid provoking
Wernicke’s encephalopathy in malnourished patients.

In cases of suspected ischemic stroke including basilar thrombosis with brainstem ischemia,
IV tissue plasminogen activator or mechanical embolectomy is often used after cerebral
hemorrhage has been excluded and when the patient presents within established time windows
for these intervention

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Physostigmine may awaken patients with anticholinergic-type drug overdose but should be
used only with careful monitoring; many physicians believe that it should only be used to treat
anticholinergic overdose–associated cardiac arrhythmias.

The use of benzodiazepine antagonists offers some prospect of improvement after overdose;
however, these drugs are not commonly used empirically in part due to their tendency to
provoke seizures.

Certain other toxic and drug-induced comas have specific treatments such as fomepizole for
ethylene glycol ingestion.

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Administration of hypotonic IV solutions should be monitored carefully in any serious acute
brain illness because of the potential for exacerbating brain swelling.

Cervical spine injuries must not be overlooked, particularly before attempting intubation or
evaluation of oculocephalic responses.

Fever and meningismus indicate an urgent need for examination of the CSF to diagnose
meningitis.

Whenever acute bacterial meningitis is suspected, antibiotics including at least vancomycin

and a third-generation cephalosporin are typically administered rapidly along with
dexamethasone

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 Prognosis

Metabolic comas have a far better prognosis than traumatic ones.

Systems for estimating prognosis in adults should be taken as approximations, and medical
judgments must be tempered by factors such as age, underlying systemic disease, and general
medical condition.

In an attempt to collect prognostic information from large numbers of patients with head
injury, the Glasgow Coma Scale was devised; it has predictive value in cases of brain trauma

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Glasgow coma scale

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The use of multiple severity indicators is intended to improve sensitivity in the detection of
mTBI (GCS 13–15), while also taking into consideration traditional acute injury
characteristics that have been presumed to predict outcome following mild and moderate
brain injury.

Loss of consciousness (LOC) and posttraumatic amnesia (PTA) remain the most common
injury characteristics referenced in these classification systems.

In the case of moderate (GCS 9–12) and severe (GCS 3–8) TBI, GCS score and the duration
of LOC and PTA can be robust predictors of long-term outcome and morbidity.

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For anoxic coma, clinical signs such as the pupillary and motor responses after 1 day, 3 days,
and 1 week have predictive value; however, some prediction rules are less reliable in the
setting of therapeutic hypothermia, and therefore, serial examinations and multimodal
prognostication approaches are advised in this setting.

For example, the absence of the cortical responses of the somatosensory evoked potentials
has been shown to be a strong indicator of poor outcome following hypoxic injury.

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About 10% of vegetative patients (mainly following traumatic brain injury) could activate
their frontal or temporal lobes in response to requests by an examiner to imagine certain
visuospatial tasks.

Another series demonstrated that up to 15% of patients with various forms of acute brain
injury and absence of behavioral responses to motor commands showed EEG activation in
response to these commands. It is prudent to avoid generalizations

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