Coma

Chapter 30 | Part 2: Cardinal Manifestations and Presentation of Diseases

KEY CLINICAL POINTS

• Coma results from either widespread bilateral cerebral hemisphere abnormalities OR reduced activity of the reticular activating system (RAS) in the upper brainstem and thalamus
• Metabolic/toxic causes of coma are far more common than structural injuries and typically preserve brainstem reflexes
• Pupillary examination is critical: reactive midsize pupils exclude midbrain damage; unilateral dilation suggests third nerve compression from herniation
• Brain death requires demonstration of irreversible cessation of all cerebral and brainstem function with absent pupillary, corneal, oculovestibular reflexes, and apnea despite adequate CO2 stimulation
• Immediate management priorities include correcting hypotension, hypoglycemia, hypoxia, hypercapnia, and hyperthermia while protecting the airway

1. DEFINITION & OVERVIEW

Coma is among the most common neurologic emergencies encountered in general medicine, accounting for a substantial portion of emergency department visits and occurring on all hospital services. There exists a continuum of states of reduced alertness, with coma being the most severe form.

Continuum of Altered Consciousness States

State	Arousal	Awareness	Key Features
Drowsiness	Easy arousal	Confused when aroused	Simulates light sleep, brief arousal periods
Stupor	Vigorous stimuli required	Transient, confused	Motor avoidance/withdrawal from noxious stimuli
Coma	Unarousable	Absent	Eyes closed, sleeplike state
Vegetative State	Appears awake (eyes open)	Absent	Autonomic functions retained, no meaningful responses
Minimally Conscious State	Variable	Rudimentary	Spontaneous or stimulus-evoked behaviors
Locked-In State	Fully awake	Intact	Paralysis with preserved vertical eye movements

1.1 Definitions of Altered Consciousness States

Coma: A deep sleeplike state with eyes closed from which the patient cannot be aroused. Stupor: A lower threshold for arousability in which the patient can be transiently awakened by vigorous stimuli, accompanied by motor behavior leading to avoidance or withdrawal from noxious stimuli. Drowsiness: Simulates light sleep, characterized by easy arousal that may persist for brief periods. Stupor and drowsiness are usually accompanied by some degree of confusion when the patient is alerted. Clinical Pearl: A precise narrative description of the level of arousal and type of responses evoked by various stimuli is preferable to ambiguous terms such as lethargy, semicoma, or obtundation.

1.2 Conditions That Simulate Coma

Vegetative State: An awake-appearing but nonresponsive state, usually encountered in a patient who has emerged from coma. Eyelids open periodically giving appearance of wakefulness. Respiratory and autonomic functions are retained. Yawning, coughing, swallowing, and limb movements persist, but few meaningful responses to environment. Signs of extensive bilateral hemispheral damage typically present (decerebrate/decorticate posturing, absent visual responses). Minimally Conscious State: Less severe than vegetative state; patient displays rudimentary vocal or motor behaviors, sometimes spontaneous, sometimes in response to touch, visual stimuli, or command. Better prognosis for recovery than persistent vegetative state. Persistent Vegetative State: Prognosis for regaining meaningful mental faculties after several months is poor; after 1 year, almost nil. Most dramatic recoveries yield severely disabled conditions. Patients in minimally conscious state have better prognosis, but dramatic recovery after 12 months is unusual. Cardiac arrest with cerebral hypoperfusion and head trauma are the most common causes of vegetative and minimally conscious states.

1.3 Pseudocoma Syndromes

Akinetic Mutism: Partially or fully awake state in which patient remains virtually immobile and mute but can form impressions and think (demonstrated by later recounting of events). Results from damage to medial thalamic nuclei, frontal lobes (particularly deep or orbitofrontal lesions), or extreme hydrocephalus. Abulia: Milder form of akinetic mutism characterized by mental and physical slowness and diminished ability to initiate activity. Usually results from damage to medial frontal lobes and their connections. Catatonia: Hypomobile and mute syndrome occurring as part of major psychiatric disorder (typically schizophrenia or major depression). Key distinguishing features: - Eyelid elevation is actively resisted - Blinking occurs in response to visual threat - Eyes move concomitantly with head rotation - Limbs may retain postures placed by examiner ("waxy flexibility" or catalepsy) - May show remarkable reversal with lorazepam administration - Lacks hyperreflexia and hypertonicity seen in structural brain lesions Locked-In State: Pseudocoma 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 (allowing communication). Pupils are normally reactive. Usual cause is infarction or hemorrhage of ventral pons bilaterally (e.g., basilar artery thrombosis) transecting all descending motor pathways and horizontal eye movement pathways. Also occurs with total paralysis from severe Guillain-Barré syndrome, critical illness neuropathy, or pharmacologic neuromuscular blockade.

2. ANATOMY AND PHYSIOLOGY OF COMA

Almost all instances of coma can be traced to either: (1) widespread abnormalities of both cerebral hemispheres, or (2) reduced activity of the thalamocortical alerting system—the reticular activating system (RAS). The RAS is an assemblage of neurons located diffusely in the upper brainstem and thalamus. Proper functioning of this system, its ascending projections to the cortex, and the cortex itself are required to maintain alertness and coherence of thought.

Herniation Syndromes: Clinical Features

Type	Mechanism	Key Clinical Signs	First Sign
Uncal Transtentorial	Medial temporal lobe impaction at tentorial opening	Ipsilateral pupil dilation, contralateral hemiparesis, then bilateral signs	Ipsilateral pupil enlargement
Central Transtentorial	Symmetric downward thalamic displacement	Miotic pupils, drowsiness, progressive brainstem dysfunction	Miotic pupils and drowsiness
Transfalcial	Cingulate gyrus displacement under falx	May cause anterior cerebral artery compression	Variable
Foraminal	Cerebellar tonsils into foramen magnum	Medullary compression, respiratory arrest	Respiratory dysfunction

2.1 Coma Due to Cerebral Mass Lesions and Herniation Syndromes

The skull prevents outward expansion of the brain, and dural infoldings create compartments that restrict displacement of brain tissue. The cerebral hemispheres are separated by the falx; anterior and posterior fossae are separated by the tentorium. Herniation refers to displacement of brain tissue by an intracerebral or overlying mass into a contiguous compartment it normally does not occupy. Coma from mass lesions and many associated signs are attributable to these tissue shifts.

2.2 Types of Herniation

Uncal Transtentorial Herniation: Most common form. Impaction of anterior medial temporal gyrus (uncus) into tentorial opening anterior to and adjacent to midbrain. - First sign: Ipsilateral pupil enlargement (third nerve compression; parasympathetic fibers are located peripherally in the nerve) - Coma results from vertical and lateral displacement of midbrain (and RAS) against opposite tentorial edge by displaced parahippocampal gyrus - May compress opposite cerebral peduncle causing ipsilateral Babinski sign and hemiparesis (Kernohan-Woltman sign) - May compress anterior and posterior cerebral arteries causing infarction - May entrap portions of ventricular system causing hydrocephalus - Oval, slightly eccentric pupil is transitional sign of early midbrain-third nerve compression Central Transtentorial Herniation: Symmetric downward movement of thalamic structures through tentorial opening with compression of upper midbrain. - Heralding signs: Miotic pupils and drowsiness (contrast with unilateral enlarged pupil in uncal syndrome) - Both uncal and central herniation cause progressive compression of brainstem and RAS - Damage sequence: Rostral (midbrain) → pons → medulla - Respiratory centers often spared until late - Orderly sequence not always respected; rapid deterioration can occur Transfalcial Herniation: Displacement of cingulate gyrus under the falx and across midline. Foraminal Herniation: Downward forcing of cerebellar tonsils into foramen magnum. - Causes early compression of medulla and respiratory arrest

2.3 Coma Due to Metabolic, Drug, and Toxic Disorders

These are the most common causes of coma in general practice. Many systemic metabolic abnormalities cause coma by interrupting delivery of energy substrates (oxygen, glucose) or by altering neuronal excitability. Cerebral Energy Requirements: - Brain glucose stores provide energy for ~2 minutes after blood flow interruption - Oxygen stores last 8-10 seconds after cessation of blood flow - Simultaneous hypoxia and ischemia exhaust glucose more rapidly EEG Findings: Background activity becomes diffusely slowed (typical of metabolic encephalopathies); as substrate delivery worsens, brain electrical activity eventually ceases. Reversible vs. Irreversible Injury: Unlike systemic hypoxia-ischemia (which ultimately causes neuronal destruction), most metabolic disorders cause no or only minor neuropathologic changes: - Hypoglycemia - Hyponatremia - Hyperosmolarity - Hypercapnia - Hypercalcemia - Hepatic failure - Renal failure Reversible effects may result from: impaired energy supplies, changes in ion fluxes across neuronal membranes, and neurotransmitter abnormalities.

2.4 Hepatic Encephalopathy Mechanisms

High ammonia concentrations have been proposed to lead to: - Increased synthesis of glutamine in astrocytes and osmotic swelling - Mitochondrial energy failure - Production of reactive nitrogen and oxygen species - Increases in inhibitory neurotransmitter GABA - Synthesis of putative "false" neurotransmitters Over time, diffuse astrocytosis develops (typical of chronic hepatic encephalopathy). No single mechanism provides a fully adequate explanation.

2.5 Uremic Encephalopathy Mechanisms

Mechanism is uncertain and likely multifactorial. Unlike ammonia, urea does not produce CNS depression when infused into normal persons. Contributors may include: - Accumulation of neurotoxic substances (creatinine, guanidine, related compounds) - Depletion of catecholamines - Altered glutamate and GABA tone - Increases in brain calcium - Inflammation with disruption of blood-brain barrier

2.6 Osmolar Disturbances

Coma and seizures commonly accompany large shifts in sodium and water balance: - Diabetic ketoacidosis - Nonketotic hyperosmolar state - Hyponatremia (from any cause: water intoxication, excessive ADH secretion, atrial natriuretic peptides) Sodium Thresholds: - <125 mmol/L (especially if achieved quickly): Induces confusion - <119 mmol/L (when arrived at acutely): Typically associated with coma and convulsions Hyperosmolar Coma: Serum osmolarity generally >350 mosmol/L Hypercapnia: Depresses consciousness in proportion to rise in blood CO I Key Point: The degree of neurologic change depends on the rapidity with which serum changes occur.

2.7 Drug and Toxin-Induced Coma

Typically reversible, leaving no residual damage provided there has not been hypoxia or severe hypotension. Many drugs and toxins depress nervous system function by affecting both RAS and cerebral cortex. Important Considerations: - Combination of cortical and brainstem signs may lead to incorrect diagnosis of structural brainstem disease - Atropinic drugs: Dilated pupils, tachycardia, dry skin - Opiate overdose: Pinpoint pupils (<1 mm) - Barbiturates: Can mimic all signs of brain death (must exclude before diagnosing brain death)

2.8 Epileptic Coma

Nonconvulsive Status Epilepticus: Generalized electrical seizures associated with coma even without motor convulsions. EEG monitoring is often used in unexplained coma to exclude this treatable etiology. Postictal State: Self-limited coma following seizure, may be due to exhaustion of energy reserves or toxic metabolic by-products. EEG shows continuous, generalized slowing similar to metabolic encephalopathies. Duration: typically minutes, but can be prolonged hours or rarely days.

2.9 Coma Due to Widespread Structural Damage

Extensive bilateral structural cerebral damage simulates metabolic encephalopathy. Examples: - Hypoxia-ischemia: Most common; initially cannot distinguish acute reversible effects from subsequent neuronal damage - Widespread small vessel occlusion: Thrombotic thrombocytopenic purpura, hyperviscosity, cerebral malaria - Diffuse white matter damage: Cranial trauma, delayed effects of some opioid intoxications, inflammatory demyelinating diseases

3. CLINICAL FEATURES

The clinical evaluation of coma requires systematic assessment of general physical findings, neurologic examination including level of arousal, brainstem reflexes, and motor responses.

General Physical Examination Findings in Coma

Finding	Possible Etiologies
Fever	Systemic infection, meningitis, encephalitis, heat stroke, NMS, malignant hyperthermia, anticholinergic toxicity

Finding	Possible Etiologies
Hypothermia (<31°C)	Cold exposure, drowning, alcohol, barbiturates, sedatives, phenothiazines, hypoglycemia, circulatory failure, myxedema
Marked hypertension	Hypertensive encephalopathy, cerebral hemorrhage, large infarction, head injury
Hypotension	Alcohol/barbiturate intoxication, internal hemorrhage, MI, sepsis, hypothyroidism, Addisonian crisis
Papilledema	Increased intracranial pressure
Subhyaloid hemorrhages	Subarachnoid hemorrhage
Petechiae	TTP, meningococcemia, bleeding diathesis with ICH
Cherry-red skin	Carbon monoxide poisoning

3.1 General Physical Examination Findings

Head Trauma Signs: Raise possibility of coexisting spinal cord injury—immobilization of cervical spine is essential. Fever suggests: - Systemic infection - Bacterial meningitis - Encephalitis - Heat stroke - Neuroleptic malignant syndrome - Malignant hyperthermia (from anesthetics) - Anticholinergic drug intoxication - "Central fever" from hypothalamic lesions is rare—diagnosis only after exhaustive search for other causes - Slight temperature elevation may follow vigorous convulsions Hypothermia is observed with: - Cold ambient temperature exposure - Drowning - Alcohol intoxication - Barbiturate, sedative, or phenothiazine intoxication - Hypoglycemia - Peripheral circulatory failure - Extreme hypothyroidism - Temperature <31°C (87.8°F) causes coma regardless of underlying etiology Tachypnea: May indicate systemic acidosis or pneumonia Marked Hypertension suggests: - Hypertensive encephalopathy - Cerebral hemorrhage - Large cerebral infarction - Head injury Hypotension is characteristic of: - Alcohol or barbiturate intoxication - Internal hemorrhage or MI causing poor cerebral blood delivery - Sepsis - Profound hypothyroidism - Addisonian crisis Funduscopic Examination can detect: - Papilledema (increased ICP) - Subhyaloid hemorrhages (subarachnoid hemorrhage) - Exudates, hemorrhages, vessel-crossing changes, papilledema (hypertensive encephalopathy) Cutaneous Findings: - Petechiae: Thrombotic thrombocytopenic purpura, meningococcemia, bleeding diathesis with intracerebral hemorrhage - Cyanosis: Indicates underlying systemic disease - Cherry-red coloration: Carbon monoxide poisoning

3.2 Spontaneous Movements and Posturing

Observation Without Intervention: Patient spontaneously moving about bed, reaching toward face, crossing legs, yawning, swallowing, coughing, and moaning reflects drowsy state close to normal awakeness. Using hand to remove offending stimulus indicates even greater responsiveness. Lateralizing Signs: - Lack of restless movements on one side suggests hemiplegia (or hip fracture) - Externally rotated leg suggests hemiplegia (or hip fracture) Movement Disorders: - Subtle intermittent twitching of foot, finger, or facial muscle may be only sign of seizures - Multifocal myoclonus usually indicates metabolic disorder: uremia, hypoxemia, drug intoxication, or rarely prion disease - Bilateral asterixis in drowsy/confused patient indicates metabolic encephalopathy or drug intoxication Posturing: - Decorticate Rigidity: Flexion of elbows and wrists with supination of arm—classically suggests bilateral damage rostral to midbrain - Decerebrate Rigidity: Extension of elbows and wrists with pronation—indicates damage to motor tracts caudal to midbrain - Important Caveat: These localizations from animal work cannot be applied precisely to human coma; acute widespread cerebral disorders of any type, regardless of location, frequently cause limb extension - Posturing may be unilateral and coexist with purposeful movements (reflects incomplete motor system damage)

3.3 Level of Arousal Assessment

A sequence of increasingly intense stimuli determines threshold for arousal and motor response of each side. Stimulus Hierarchy: 1. Tickling nostrils with cotton wisp (moderate stimulus)—all but deeply stuporous/comatose patients move head away and arouse 2. Pressure on bony prominences and pinprick (humane noxious stimuli) 3. Pinching skin causes ecchymoses (generally not performed but may be useful) Response Interpretation: - Posturing to noxious stimuli: Indicates severe damage to corticospinal system - Abduction-avoidance movement: Usually purposeful, denotes intact corticospinal system - Posturing may coexist with purposeful movements reflecting incomplete damage Serial Examinations: Results may vary from minute to minute; serial examinations are useful.

4. BRAINSTEM REFLEXES

Assessment of brainstem function allows localization of the lesion in coma. Patients with preserved brainstem reflexes typically have bihemispheric localization (including toxic/drug intoxication), whereas those with abnormal brainstem reflexes have either primary brainstem lesion or herniation syndrome.

Pupillary Signs in Coma

Pupil Finding	Size	Reactivity	Localization/Etiology
Midsize, round, reactive	2.5-5 mm	Present	Excludes upper midbrain damage; metabolic coma likely
Unilateral dilation	>6 mm	Poor/absent	Third nerve compression (uncal herniation)
Oval, eccentric	Variable	Variable	Early midbrain-third nerve compression (transitional)
Bilateral dilation	>6 mm	Absent	Severe midbrain damage OR anticholinergics/mydria tics/trauma
Bilateral small (not pinpoint)	1-2.5 mm	Present	Metabolic encephalopathy, hydrocephalus, thalamic hemorrhage
Pinpoint	<1 mm	Present	Opioid overdose, pontine hemorrhage
Unilateral miosis	Small	Present	Sympathetic dysfunction (posterior hypothalamus); large thalamic hemorrhage

Ocular Movement Abnormalities in Coma

Finding	Description	Localization
Conjugate horizontal roving	Spontaneous side-to-side movements	Intact midbrain and pons
Conjugate deviation to one side	Eyes deviated laterally	Toward: ipsilateral frontal lesion; Away: contralateral pontine lesion
Wrong-way eyes	Deviation paradoxically away from lesion	Deep hemispheral or thalamic lesion
Downward and inward	Eyes deviated down and toward midline	Thalamic or upper midbrain lesion (thalamic hemorrhage)
Ocular bobbing	Brisk downward, slow upward; absent horizontal	Bilateral pontine damage (basilar artery thrombosis)
Ocular dipping	Slow down, fast up; normal horizontal gaze	Diffuse cortical anoxic damage

4.1 Pupillary Signs

Examined with a bright, diffuse light. Response may be difficult to appreciate in pupils <2 mm; bright room lighting may mute reactivity. Reactive, Round, Midsize Pupils (2.5-5 mm): Essentially exclude upper midbrain damage, either primary or secondary to herniation. Unilaterally Enlarged Pupil (>6 mm), Poorly Reactive: Signifies compression of third nerve from effects of cerebral mass above. Enlargement contralateral to hemispheral mass may occur but is infrequent. Oval and Slightly Eccentric Pupil: Transitional sign accompanying early midbrain-third nerve compression. Bilaterally Dilated and Unreactive Pupils: Indicates severe midbrain damage, usually from compression by supratentorial mass. Other causes include: - Anticholinergic drug ingestion - Mydriatic eye drops - Nebulizer treatments spraying into eye - Direct ocular trauma Reactive, Bilaterally Small Pupils (1-2.5 mm) but Not Pinpoint: Seen in: - Metabolic encephalopathies - Deep bilateral hemispheral lesions (hydrocephalus, thalamic hemorrhage) Very Small Reactive Pupils (<1 mm): Characterize: - Opioid overdoses - Extensive pontine hemorrhage - Distinguish by response to naloxone and presence of reflex eye movements Unilateral Miosis: Attributed to dysfunction of sympathetic efferents originating in posterior hypothalamus and descending through brainstem tegmentum to cervical cord. Occasional finding in large cerebral hemorrhage affecting thalamus.

4.2 Ocular Movements

Resting Position Observations: - Horizontal divergence at rest is normal in drowsiness - As coma deepens, ocular axes may become parallel again Spontaneous Eye Movements: - Conjugate horizontal roving exonerates extensive midbrain and pons damage (same significance as normal reflex eye movements) Conjugate Horizontal Deviation to One Side: - Damage to frontal lobe on same side, OR - Less commonly, pons on opposite side - Maxim: "The eyes look toward a hemispheral lesion and away from a brainstem lesion" - Seizures involving frontal lobe drive eyes to opposite side (simulating pontine lesion) - "Wrong-way eyes": Occasionally turn paradoxically away from deep hemispheral or thalamic lesion Downward and Inward Eye Deviation: Thalamic and upper midbrain lesions, typically thalamic hemorrhage Ocular Bobbing: Brisk downward and slow upward movements with loss of horizontal movements—diagnostic of bilateral pontine damage (usually basilar artery thrombosis) Ocular Dipping: Slower, arrhythmic downward movement followed by faster upward movement with normal reflex horizontal gaze—usually indicates diffuse cortical anoxic damage

4.3 Oculocephalic Reflex ("Doll's Eyes")

Prerequisites: First establish no cervical spinal cord injury. Technique: Move head side to side or vertically, observe eye movements in direction opposite to head movement. Pathway: Depends on integrity of ocular motor nuclei and interconnecting tracts from midbrain to pons and medulla. Interpretation: - Normally suppressed in awake patient with intact frontal lobes - Ability to elicit reflex reflects: (1) reduced cortical influence on brainstem, AND (2) intact brainstem pathways - Absence of reflex eye movements usually signifies brainstem damage, BUT can result from certain drug overdoses - Normal pupillary size and light reaction distinguishes most drug-induced comas from structural brainstem damage

4.4 Oculovestibular Reflex (Caloric Testing)

Provides more intense stimulus than oculocephalic reflex but essentially same information. Technique: Irrigate external auditory canal with cold water to induce convection currents in labyrinths. Response: After brief latency, tonic deviation of both eyes to side of cold water irrigation. In comatose patients, nystagmus in opposite direction may not occur. Mnemonic: "COWS" (Cold Opposite, Warm Same)—describes direction of nystagmus, but since nystagmus is often absent in coma due to frontal lobe dysfunction, this often does not apply.

4.5 Corneal Reflex

Technique: Touch cornea with wisp of cotton, observe bilateral lid closure. Pathway: Pontine pathways between fifth cranial nerve (afferent) and both seventh cranial nerves (efferent). Clinical Utility: Useful test of pontine function. Drug Effects: CNS-depressant drugs diminish or eliminate corneal responses soon after reflex eye movements are paralyzed but BEFORE pupils become unreactive to light. Lateralizing Sign: Corneal response may be lost for a time on side of acute hemiplegia.

4.6 Respiratory Patterns

Less localizing value compared to other brainstem signs. Shallow, Slow, Regular Breathing: Suggests metabolic or drug-induced depression of medullary respiratory centers. Cheyne-Stokes Respiration: Cyclic breathing ending with brief apneic period—signifies bihemispheral damage or metabolic suppression; commonly accompanies light coma. Rapid, Deep (Kussmaul) Breathing: Usually implies metabolic acidosis but may occur with pontomesencephalic lesions. Agonal Gasps: Result of lower brainstem (medullary) damage—terminal respiratory pattern of severe brain damage.

5. DIFFERENTIAL DIAGNOSIS

The causes of coma can be divided into three broad categories based on clinical presentation and CSF findings.

Differential Diagnosis of Coma by Category

Category	CT Findings	CSF	Examples
No focal signs	Often normal	Usually normal	Metabolic, toxic, postictal, infections, shock
Focal brainstem/lateralizing signs	Typically abnormal	Usually normal or bloody	Hemorrhage, infarction, mass lesions, trauma
Meningeal irritation	Variable	Abnormal (WBCs or RBCs elevated)	SAH, meningitis, encephalitis, carcinomatous meningitis

5.1 Coma Without Focal Neurologic Signs

CT scan is often normal in these conditions. Intoxications: Alcohol, sedative drugs, opiates, etc. Metabolic Disturbances: - Anoxia - Hyponatremia, hypernatremia - Hypercalcemia - Diabetic acidosis - Nonketotic hyperosmolar hyperglycemia - Hypoglycemia - Uremia - Hepatic coma - Hypercarbia - Addisonian crisis - Hypo- and hyperthyroid states - Profound nutritional deficiency Severe Systemic Infections: Pneumonia, septicemia, typhoid fever, malaria, Waterhouse-Friderichsen syndrome Shock from Any Cause Seizure-Related: Status epilepticus, nonconvulsive status epilepticus, postictal states Hyperperfusion Syndromes: Hypertensive encephalopathy, eclampsia, posterior reversible encephalopathy syndrome (PRES) Temperature Extremes: Severe hyperthermia, hypothermia Others: Concussion, acute hydrocephalus

5.2 Coma With Focal Brainstem or Lateralizing Signs

CT scan is typically abnormal. Hemispheral Lesions: - Hemispheral hemorrhage (basal ganglionic, thalamic) or infarction (large middle cerebral artery territory) with secondary brainstem compression - Brain abscess, subdural empyema - Epidural and subdural hemorrhage, brain contusion - Brain tumor with surrounding edema - Widespread traumatic brain injury Brainstem Lesions: - Brainstem infarction due to basilar artery thrombosis or embolism - Cerebellar and pontine hemorrhage and infarction Mixed: Metabolic coma in setting of preexisting focal damage

5.3 Coma With Meningeal Irritation

Characterized by fever or stiff neck with excess WBCs or RBCs in CSF. Hemorrhagic: - Subarachnoid hemorrhage from ruptured aneurysm, arteriovenous malformation, trauma Infectious: - Infectious meningitis and meningoencephalitis Inflammatory/Autoimmune: - Paraneoplastic and autoimmune encephalitis Neoplastic: - Carcinomatous and lymphomatous meningitis

5.4 Common Cerebrovascular Causes

Basal Ganglia and Thalamic Hemorrhage: - Acute but not instantaneous onset - Vomiting, headache - Hemiplegia - Characteristic eye signs Pontine Hemorrhage: - Sudden onset - Pinpoint pupils - Loss of reflex eye movements and corneal responses - Ocular bobbing - Posturing - Hyperventilation Cerebellar Hemorrhage: - Occipital headache - Vomiting - Gaze paresis - Inability to stand and walk Basilar Artery Thrombosis: - Neurologic prodrome or TIA warning spells - Diplopia, dysarthria - Vomiting - Eye movement and corneal response abnormalities - Asymmetric limb paresis Subarachnoid Hemorrhage: - Precipitous coma after sudden severe headache and vomiting Middle Cerebral Artery Infarction: - Unilateral infarction does NOT cause coma - However, edema surrounding large infarctions may expand over several days and cause coma from mass effect Acute Hydrocephalus: - Accompanies many intracranial diseases (especially SAH) - Headache, sometimes vomiting - May progress to coma with extensor posturing, bilateral Babinski signs - Small unreactive pupils - Impaired vertical oculocephalic movements - Papilledema often present

5.5 Temporal Course Clues

Sudden Onset Coma: - Drug ingestion - Cerebral hemorrhage - Trauma - Cardiac arrest - Epilepsy - Basilar artery occlusion Subacute Coma: - Usually related to preexisting medical or neurologic problem - Less often due to secondary brain swelling surrounding a mass (tumor, cerebral infarction)

6. INVESTIGATIONS AND DIAGNOSIS

The approach to evaluation requires integration of history, physical examination, laboratory studies, imaging, and electrophysiology.

EEG Patterns in Coma

Pattern	Description	Associated Condition
Generalized slowing	Diffuse slow background	Metabolic encephalopathy (severity correlates with slowing)
Frontal d or triphasic waves	High-voltage slow waves, frontal predominance	Hepatic encephalopathy, other metabolic
Widespread fast (b) activity	Diffuse beta frequencies	Sedative drug overdose (benzodiazepines)
Alpha coma	8-12 Hz, not stimulus-responsive	Pontine or diffuse cortical damage; poor prognosis
Extreme delta brush	Unique adult pattern with delta + fast brush	Anti-NMDA receptor encephalitis
Normal a (stimulus-responsive)	Normal background suppressed by stimulation	Locked-in syndrome, catatonia, functional

6.1 History

The cause may be immediately evident (trauma, cardiac arrest, observed drug ingestion). In remainder, useful points include: 1. Circumstances and rapidity of symptom development 2. Antecedent symptoms: confusion, weakness, headache, fever, seizures, dizziness, double vision, vomiting 3. Use of medications, drugs, or alcohol 4. Chronic medical diseases: liver, kidney, lung, heart Critical Step: Direct interrogation of family, observers, and emergency medical technicians (in person or by telephone) is essential.

6.2 Laboratory Studies

Most Useful Studies: - Chemical-toxicologic analyses of blood and urine - Arterial blood gas (for lung disease and acid-base disorders) - Electrolytes, glucose, calcium, magnesium, osmolarity - Renal function (BUN) - Hepatic function (including NH I ) - Toxicologic analysis (when diagnosis not immediately clear) Important Caveat: Presence of exogenous drugs/toxins (especially alcohol) does NOT exclude other contributing factors (e.g., head trauma). Alcohol Levels: - 43 mmol/L (0.2 g/dL): Causes impaired mental activity in nonhabituated patients - >65 mmol/L (0.3 g/dL): Associated with stupor - >87 mmol/L (0.4 g/dL): Some chronically intoxicated individuals may remain awake at this level

6.3 Neuroimaging

Cranial CT or MRI is essential for detecting hemorrhage, tumor, hydrocephalus, and other structural lesions. Important Limitations—Normal CT does NOT exclude: - Early bilateral hemisphere infarction - Acute brainstem infarction - Encephalitis - Meningitis - Mechanical shearing of axons (closed head trauma) - Sagittal sinus thrombosis - Hypoxic injury - Subdural hematoma isodense to adjacent brain Misleading Findings: Small subdural hematomas or old strokes may be found when coma is actually due to intoxication. Additional Imaging: CT angiography or MRI if acute posterior circulation stroke is considered.

6.4 Electroencephalography (EEG)

Essential Indications: - Reveal coma due to nonconvulsive seizures - Characteristic patterns in herpesvirus encephalitis and prion disease EEG Patterns in Coma: Generalized Slowing: Reflects severity of encephalopathy Predominant High-Voltage Frontal Slow Waves ( δ or triphasic waves): Typical of metabolic coma (especially hepatic failure) Widespread Fast ( β ) Activity: Implicates sedative drug overdose (e.g., benzodiazepines) Alpha Coma: Widespread, variable 8-12 Hz activity superficially resembling normal α rhythm BUT not altered by environmental stimuli. Results from pontine or diffuse cortical damage; associated with poor prognosis. Extreme Delta Brush: Characteristic pattern in adults with anti-NMDA receptor autoimmune encephalitis Normal α Activity (suppressed by stimulation): Alerts clinician to locked-in syndrome, functional disorder, or catatonia

6.5 Lumbar Puncture

Indications: Should be performed if no cause is readily apparent. Indispensable for Diagnosis of: - Various forms of meningitis - Encephalitis Prerequisite: Imaging study generally performed first to exclude large intracranial mass lesion (could lead to herniation with LP). If Infectious Meningitis Suspected: Blood cultures and antibiotics should PRECEDE imaging study.

6.6 Diagnostic Algorithm

Step 1: Stabilize airway, breathing, circulation; address immediate life threats Step 2: Perform rapid neurologic assessment (pupils, eye movements, motor responses) Step 3: Obtain history from available sources Step 4: Laboratory studies (glucose, electrolytes, toxicology, blood gas) Step 5: Administer empiric treatments if indicated (dextrose, thiamine, naloxone) Step 6: Neuroimaging (CT head; consider CT angiography if posterior circulation stroke suspected) Step 7: EEG if unexplained coma or concern for nonconvulsive status epilepticus Step 8: Lumbar puncture if meningitis/encephalitis suspected and no contraindication Step 9: Serial neurologic examinations to monitor for improvement or deterioration

7. MANAGEMENT AND TREATMENT

The immediate goal in a comatose patient is prevention of further nervous system damage through rapid correction of reversible causes and supportive care.

Empiric Treatments in Coma

Agent	Indication	Dose/Route	Cautions
Dextrose	Hypoglycemia	50 mL D50W IV	Give with thiamine if malnourished
Thiamine	Prevent Wernicke's	100 mg IV	Give before or with glucose
Naloxone	Opioid overdose	0.4-2 mg IV	May precipitate withdrawal; short duration
Physostigmine	Anticholinergic toxicity	0.5-2 mg IV slowly	Requires monitoring; reserve for arrhythmias

Agent	Indication	Dose/Route	Cautions
Flumazenil	Benzodiazepine overdose	0.2 mg IV, repeat	Risk of seizures; avoid in mixed overdose
Fomepizole	Ethylene glycol/methanol	15 mg/kg IV loading	Alternative to ethanol

Immediate Treatment Priorities

Parameter	Target	Notes
Airway	Patent and protected	Intubate if GCS £8 or aspiration risk
Oxygenation	SpO2 >94%	Avoid hypoxia
Blood pressure	Adequate cerebral perfusion	Treat hypotension; be cautious with hypertension
Glucose	Normal range	Correct hypoglycemia rapidly
Sodium	Correct slowly	Risk of osmotic demyelination if corrected too fast
Temperature	Normothermia	Correct hyperthermia and hypothermia
ICP	Avoid elevated ICP	Hypocapnia if needed; elevate head of bed

7.1 Initial Stabilization

Immediate Priorities: 1. Airway: Oropharyngeal airway adequate for drowsy patient breathing normally. Tracheal intubation indicated for: - Apnea - Upper airway obstruction - Hypoventilation - Emesis - Risk of aspiration 2. Breathing: Mechanical ventilation required for: - Hypoventilation - Need to induce hypocapnia to lower ICP 3. Circulation: Establish IV access 4. Cervical Spine: Must not be overlooked, particularly before attempting intubation or oculocephalic testing

7.2 Immediate Corrections

Correct Rapidly: - Hypotension - Hypoglycemia - Hypercalcemia - Hypoxia - Hypercapnia - Hyperthermia Correct Slowly: - Hyponatremia (to avoid osmotic demyelination)

7.3 Empiric Treatments

Administer if Indicated: Naloxone: If opioid overdose is possibility Dextrose: If hypoglycemia is possibility Thiamine: Give WITH glucose to avoid provoking Wernicke's encephalopathy in malnourished patients Physostigmine: May awaken patients with anticholinergic-type drug overdose - Use only with careful monitoring - Many physicians reserve for anticholinergic overdose-associated cardiac arrhythmias only Benzodiazepine Antagonists (Flumazenil): Offers some prospect of improvement after overdose but not commonly used empirically (tendency to provoke seizures) Fomepizole: For ethylene glycol ingestion

7.4 Specific Interventions

Suspected Ischemic Stroke (Including Basilar Thrombosis): - IV tissue plasminogen activator (tPA) or mechanical embolectomy - After excluding cerebral hemorrhage - When patient presents within established time windows Suspected Bacterial Meningitis: - Antibiotics should be administered RAPIDLY - Regimen: At least vancomycin AND third-generation cephalosporin - Add dexamethasone - Blood cultures and antibiotics should PRECEDE imaging if meningitis is suspected Raised Intracranial Pressure: Specific management discussed in Chapter 318

7.5 Fluid Management

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

7.6 Fever and Meningismus

These findings indicate urgent need for CSF examination to diagnose meningitis.

8. BRAIN DEATH

Brain death is a state of irreversible cessation of all cerebral and brainstem function with preservation of cardiac activity and maintenance of respiratory and somatic function by artificial means. It is the only type of brain damage recognized as morally, ethically, and legally equivalent to death.

Brain Death Criteria Checklist

Component	Required Finding	Notes
Prerequisites	No confounders (hypothermia, drugs)	Consider 24h delay if cardiac arrest or unknown etiology
Coma	Deep, unresponsive to all stimuli	Demonstrates cortical destruction
Pupillary reflex	Absent bilaterally	Pupils may be mid-position or dilated
Corneal reflex	Absent bilaterally	Brainstem (pontine) function

Component	Required Finding	Notes
Oculovestibular reflex	Absent to cold calorics	Brainstem function
Gag/cough reflex	Absent	Medullary function
Apnea test	No respiratory effort with adequate CO2	PCO2 must rise sufficiently
Deep tendon reflexes	May be present	Spinal cord may remain functional
Diabetes insipidus	Often present	Not a criterion; may appear later

8.1 Diagnostic Criteria

Criteria must adhere to consensus standards due to variability in local practice. Given implications, clinicians must be thorough and precise. Prerequisites: - No confounding factors (hypothermia, drug intoxication) - Consider delaying testing for at least 24 hours if cardiac arrest caused brain death or if inciting disease is unknown - Some centers advocate brief observation period between two examiners' tests Two Essential Elements: 1. Widespread Cortical Destruction: - Deep coma - Unresponsiveness to all forms of stimulation 2. Global Brainstem Damage: - Absent pupillary light reaction - Absent corneal reflexes - Absent oculovestibular reflexes - Complete and irreversible apnea (medullary destruction) Additional Notes: - Diabetes insipidus is often present but may develop hours or days after other signs; NOT used as criterion - Pupils are usually midsized but may be enlarged - Loss of deep tendon reflexes is NOT required (spinal cord remains functional) - Spinal reflexes may occasionally be present and should not preclude diagnosis

8.2 Apnea Testing

Purpose: Demonstrate that apnea is due to medullary damage. Requirement: PCO I must be high enough to stimulate respiration. Technique: 1. Pre-oxygenate with 100% oxygen prior to ventilator removal 2. Continue 100% oxygen during test 3. CO I tension increases ~0.3-0.4 kPa/min (2-3 mmHg/min) during apnea Confirmation: Apnea is confirmed if NO respiratory effort observed in presence of sufficiently elevated PCO I . Stopping Test: Usually stopped if cardiovascular instability occurs; alternative testing methods can be employed.

8.3 Confirmatory Tests

Optional but Useful: - Isoelectric EEG - Radionuclide brain scanning - Cerebral angiography - Transcranial Doppler measurements These may be used to demonstrate absence of blood flow when confirmatory study is desired.

8.4 Ethical and Legal Considerations

It is largely accepted in Western society that: - Ventilator can be disconnected from brain-dead patient - Organ donation is subsequently possible Good communication between physician and family is essential, with appropriate preparation for brain death testing and diagnosis.

9. PROGNOSIS

Prognostication in coma requires careful consideration of etiology, patient age, and clinical findings over time.

Prognostic Factors in Coma

Factor	Better Prognosis	Worse Prognosis
Etiology	Metabolic, drug-induced	Anoxic, traumatic
Age	Children, young adults	Elderly
Pupillary response	Preserved at day 1	Absent at day 1
Motor response	Present, purposeful	Absent or posturing
Comorbidities	None	Multiple
Therapeutic hypothermia	—	Delays reliable prognostication

9.1 General Principles

Important Caveats: - Some patients, especially children and young adults, may have ominous early clinical findings (abnormal brainstem reflexes) yet recover - Early prognostication outside of brain death is therefore unwise - Prognostic systems should be taken as approximations - Medical judgments must be tempered by: - Age - Underlying systemic disease - General medical condition

9.2 Prognosis by Etiology

Metabolic Comas: Far better prognosis than traumatic or ischemic comas. Drug/Toxin-Induced Coma: Typically reversible with no residual damage provided: - No hypoxia occurred - No severe hypotension occurred

9.3 Glasgow Coma Scale

Devised to collect prognostic information from large numbers of patients with head injury. Has predictive value in brain trauma but NOT in most other causes of coma.

9.4 Anoxic Coma Prognosis

Clinical signs have predictive value: - Pupillary responses after 1 day - Motor responses after 1 day, 3 days, and 1 week Important Limitation: In setting of therapeutic hypothermia, these prediction rules are LESS RELIABLE.

9.5 Vegetative and Minimally Conscious States

Persistent Vegetative State: - Prognosis for regaining meaningful mental faculties after several months is poor - After 1 year, almost nil - Most reports of dramatic recovery yield severely disabled conditions - Childhood cases may have somewhat better outcomes Minimally Conscious State: - Better prognosis for some recovery compared to persistent vegetative state - Dramatic recovery after 12 months is unusual even in these patients

9.6 Functional Neuroimaging in Prognosis

Some patients in vegetative and minimally conscious states have demonstrated cerebral activation on functional MRI and EEG that is temporally consistent with verbal and other stimuli. This suggests: - Some patients could potentially communicate using technological advances in the future - Further research may identify treatment approaches targeting preserved brain areas and connections

10. SPECIAL CONSIDERATIONS

Certain clinical scenarios and populations require specific attention in the evaluation and management of coma.

10.1 Trauma

Cervical Spine: Must not be overlooked, particularly before: - Attempting intubation - Evaluation of oculocephalic responses Immobilization is essential when head trauma raises possibility of coexisting spinal cord injury. Detailed approach to coma from cranial trauma is discussed in Chapter 454.

10.2 Pediatric Considerations

Children and young adults may recover from coma despite ominous early clinical findings including abnormal brainstem reflexes. Early prognostication is therefore particularly unwise in this population.

10.3 Therapeutic Hypothermia

In the setting of therapeutic hypothermia (often used after cardiac arrest), traditional clinical prediction rules for anoxic coma are less reliable. Prognostication should be delayed and interpreted with caution.

10.4 Drug Intoxication and Brain Death

Critical Consideration: Barbiturate and other drug intoxications can mimic ALL signs of brain death. Toxic etiologies MUST be excluded prior to making a diagnosis of brain death.

11. KEY POINTS AND CLINICAL PEARLS

Essential clinical takeaways for the diagnosis and management of coma.

Quick Reference: Coma Examination Findings

Finding	Interpretation	Next Step
Reactive midsize pupils	Excludes midbrain damage	Consider metabolic/toxic causes
Unilateral dilated pupil	Third nerve compression (herniation)	Emergent imaging, consider neurosurgery
Bilateral dilated unreactive pupils	Severe midbrain damage OR drugs	Exclude anticholinergics; assess other reflexes
Pinpoint reactive pupils	Opioids or pontine hemorrhage	Give naloxone; check horizontal eye movements
Roving conjugate eye movements	Intact brainstem	Focus on hemispheral/metabolic causes
Ocular bobbing	Pontine damage (basilar thrombosis)	CT angiography; consider thrombolysis
Posturing (decerebrate)	Severe motor pathway damage	Usually poor prognosis
Multifocal myoclonus	Metabolic (uremia, hypoxia, drugs)	Check metabolic panel, toxicology

11.1 Diagnostic Pearls

• "The eyes look toward a hemispheral lesion and away from a brainstem lesion" — helps localize cause of conjugate gaze deviation
• Reactive midsize pupils (2.5-5 mm) essentially exclude upper midbrain damage
• Unilateral pupil dilation is typically the FIRST sign of uncal herniation (third nerve compression)
• Pinpoint pupils with preserved light reflex: Think opioids (responsive to naloxone) or pontine hemorrhage (no response to naloxone, absent horizontal eye movements)
• Normal pupillary responses with absent eye movements: Suggests drug-induced coma rather than structural brainstem damage
• Metabolic comas preserve brainstem reflexes; absent brainstem reflexes suggest structural lesion or herniation
• A normal CT does NOT exclude: early bilateral infarction, brainstem stroke, encephalitis, meningitis, axonal shearing, sagittal sinus thrombosis, hypoxic injury, or isodense subdural hematoma
• EEG is essential to exclude nonconvulsive status epilepticus in unexplained coma

11.2 Management Pearls

• Always give thiamine with glucose to prevent Wernicke's encephalopathy in malnourished patients
• If bacterial meningitis is suspected: Start antibiotics BEFORE imaging (do not delay for CT)
• Hypotonic IV fluids can worsen brain swelling — monitor carefully in acute brain injury
• Check glucose early — hypoglycemia is rapidly reversible but causes permanent damage if prolonged
• Correct hyponatremia SLOWLY — rapid correction causes osmotic demyelination syndrome

11.3 Prognostic Pearls

• Metabolic comas have far better prognosis than traumatic or ischemic comas
• Children may recover despite ominous early brainstem findings — avoid early prognostication
• Therapeutic hypothermia delays reliable prognostication in anoxic coma
• Glasgow Coma Scale predicts outcome in trauma but not in most other causes of coma

11.4 Brain Death Pearls

• Must exclude confounders (hypothermia, drug intoxication) before testing
• Consider 24-hour delay if cardiac arrest or unknown etiology
• Spinal reflexes may persist and do NOT preclude brain death diagnosis
• Barbiturates can mimic all signs of brain death — must be excluded
• Good family communication is essential in preparing for brain death testing