CONTENTS

• Rapid Reference 🚀
• Definitions
• Causes of stupor & coma
  • Coma mimics
    • Locked-in syndrome 
    • Pseudocoma
• History
• Coma neuro exam
  • Pupils
  • Spontaneous eye movements
  • Oculocephalic & vestibulo-ocular reflexes
  • Cough & gag reflexes
  • Breathing patterns
  • Muscle tone
  • Motor response to pain
• Coma syndromes
• Tests & investigations
• Airway management
• Emergent therapies to consider
• Podcast
• Questions & discussion
• Pitfalls
• Supplemental media

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rapid reference

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approach to coma ✅

history (if possible)  📖

• Med / neuro / psych hx.
• Outpatient meds & recent changes.
• Preceding symptoms.
• Last known normal.
• History of substance or EtOH use.

exam  📖

• Pupil size & reactivity.📖
• Eye position 📖 & Doll's Eyes reflex 📖.
• Corneal reflex.
• Response to TMJ, sternal, & limb stimulation.📖
• Cough reflex (if intubated).📖
• Patellar reflex, ? ankle clonus.📖
• Babinski Reflex.

labs 📖

• STAT bedside fingerstick glucose.
• Electrolytes including Ca/Mg/Phos.
• CBC with differential.
• Coagulation studies (INR, aPTT).
• Liver function tests & ammonia, lactate level.
• Thyroid Stimulating Hormone (TSH).
• Carboxyhemoglobin if CO poisoning possible.
• Serum salicylate & acetaminophen levels.
• Serum ethanol level.
• ABG or VBG if hypercapnia suspected.
• Creatinine kinase if found down.
• Pregnancy test if relevant.

additional testing 📖

• CT scan
  • Usually obtained if no obvious cause of coma.
  • Consider CTA, CTV if possible stroke (e.g. focality).
• Lumbar puncture
  • If ? infection or no alternative explanation.
• MRI
  • Consider if CT & labs unrevealing.
  • Consider MRA, MRV if possible stroke.
  • Gadolinium helpful to look for tumor, meningitis.
• EEG
  • If concern for seizure (e.g., seizure history, concerning movements, pupillary hippus or dilation, or gaze deviation.)

therapeutic interventions 📖

• IV dextrose (if glucose is low or pending).
• Naloxone (might help avoid intubation and/or extensive diagnostic evaluation).
• IV thiamine (500 mg IV q8hr if alcoholism, eating disorder, s/p bariatric surgery, or malabsorption).
• Empiric therapy for meningitis/encephalitis:
  • Consider if significant concern for meningitis.
  • Don't need to cover for every single possible bacteria!
  • Reasonable regimen: 10 mg dexamethasone IV then ceftriaxone 2 grams q12hr, acyclovir 10 mg/kg IV q8hr.
• Excellent supportive care:
  • Stop any potentially contributory medications (e.g., cefepime).
  • Treat fever.
  • Avoid hypotension or severe hypertension.
  • For intubated patients, ensure adequate ventilation and oxygenation.

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definitions

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basics

• Coma is defined as a state of being unawake (closed eyes), unaware, and unarousable.
• Stupor lacks a clear definition, but usually refers to substantially impaired mental status with preservation of some responsiveness to painful stimuli.
• Vegetative state:  Normal sleep/wake cycles, while otherwise unresponsive.  Patients may open eyes spontaneously, but will not track or fixate.  Reflexive and random movements may occur, but not reproducible purposeful movements. (Shutter 2019)
• Minimally conscious state:  Variable arousal and inconsistent responsiveness, but one or more reproducible behaviors consistent with awareness (e.g., following simple commands, appropriate yes/no responses, or other purposeful behavior). (Shutter 2019)
• Locked in syndrome and other coma mimics: 📖

anatomy

• Coma results from disruption of pathways from the ascending Reticular Activating System.  This system originates in the tegmentum of the upper pons and midbrain, projects to the hypothalamus and bilateral thalami, and subsequently diverges widely throughout the bilateral cortexes.
• For a lesion to cause coma, it must have one of the following locations:
  • (1) Dorsolateral upper-mid pontine lesion
  • (2) Paramedian upper midbrain lesion
  • (3) Bilateral thalamic injury (e.g., artery of Percheron occlusion, or vein of Galen thrombosis).
  • (4) Diffuse bihemispheric damage
• ⚠️ Coma cannot be attributed to a unilateral cortical lesion alone.(33218655)  For example, in order for a unilateral cortical lesion to cause coma it must cause a herniation syndrome that results in damage to the upper midbrain.

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causes of stupor & coma

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Stupor and coma are the final common pathway for most serious neurological injuries, so the list of potential causes is endless.  Below are the more common causes:  

vascular

• Intracranial hemorrhage:
  • Subarachnoid hemorrhage (coma often due to acute hydrocephalus; may improve with external ventricular drain placement).
  • Intracerebral hemorrhage (typically pontine).
  • Large hemorrhage causing herniation.
• Ischemic stroke(s)
  • i) Most commonly, basilar artery stroke.
  • ii) Severe multifocal infarction (e.g., due to endocarditis).
  • iii) Artery of Percheron occlusion involving bilateral thalami (rare).
• PRES.
• Cerebral venous thrombosis (thrombosis of the straight sinus may cause bilateral thalamic dysfunction).

hydrocephalus, e.g.: 

• Intraventricular hemorrhage.
• Colloid cyst.

trauma/surgery

• Hematoma (subdural, epidural, or parenchymal).
• Diffuse axonal injury.
• Edema with elevated intracranial pressure.
• Fat emboli syndrome.

infection/inflammation

• Meningitis.
• Encephalitis
  • Most notably due to HSV or VZV.
  • Autoimmune encephalitis.
• Brain abscess or subdural empyema that exerts mass effect.
• Acute disseminated encephalomyelitis.

severe metabolic derangements

• Hypoxic/anoxic brain injury.
• Hypercapnia (e.g., pCO2 typically over ~80-100 mm).
• Hypothermia or hyperthermia (e.g., temperature <28C or >40C).(27741988)
• Hypoglycemia (glucose below ~40 mg/dL or ~2.2 mM).(20130300)
• Hyperglycemia (rapid rise in glucose above ~900 mg/dL or ~50 mM).(20130300)
• Hyponatremia (e.g., sudden drop below ~110 mM).(20130300)
• Hypernatremia (e.g., sudden rise above ~160 mM).(20130300)
• Hypercalcemia (e.g., ionized calcium above ~3.5 mM).(20130300)
• Hypermagnesemia (e.g., >12 mg/dL, >5 mM, >10 mEq/L).
• Hepatic encephalopathy.
• Severe hyperammonemia.
• Uremia.
• Myxedema coma.
• Wernicke's encephalopathy.
• Adrenal crisis.

toxicologic

• Opioids.
• Alcohols (ethanol, methanol, ethylene glycol).
• Sedatives, including baclofen.
• Serotonin syndrome.
• Sympathomimetic intoxication.
• Salicylate poisoning.
• Lithium.
• Anticholinergics, including tricyclics.
• Carbon monoxide.

seizure

• Nonconvulsive status epilepticus (NCSE)
• Postictal state.

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coma mimics

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catatonia

• Defined roughly as a syndrome of psychomotor disturbance characterized by periods of physical rigidity, negativism, or stupor (although psychomotor hyperactivity may also occur).
• Catatonia may reflect a medical cause of delirium, so it warrants through evaluation for an underlying etiology (e.g., medication review, neuroimaging, laboratory studies, EEG).

abulia and akinetic mutism

• Bilateral medial frontal lesions can cause profound failure of executive function (potentially including failure to speak, move, or eat).
• Patients may respond to questions, but only in a very delayed fashion.(Shutter, 2019)
• Visual tracking may occur, with conjugate eye movements.(Alpert 2019)

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locked-in syndrome

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• Locked-in syndrome is caused by a lesion in the anterior (ventral) pons which damages the bilateral corticobulbar and corticospinal tracts.  This eliminates nearly all afferent motor activity from the brain.
  • Sensory pathways and the reticular activating system in the posterior pons are preserved, so the patient is awake and has preserved sensation.
  • Upper brainstem nuclei controlling vertical eye movements are generally spared.(Nelson, 2020)
• Clinically patients are awake and cognitively intact, but paralyzed (only with the ability to blink or move their eyes vertically).
• Locked-in syndrome is usually caused by an acute ischemic stroke involving the basilar artery territory.  Other causes include pontine hemorrhage or central pontine myelinolysis.

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functional coma (a.k.a. pseudocoma)

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Functional coma may be caused by psychiatric disorder.  When in doubt, it is safest to assume that the patient is in a true coma and evaluate them accordingly.   However, functional coma may often be suspected or diagnosed on the basis of a thorough neurological examination:

• Eyelid movements
  • Patients with functional coma may resist eye opening.
  • In a genuine deep coma, eyes are in a resting closed position.  They may be easily opened.  Subsequently they will close in a smooth, gradual movement that cannot be duplicated by an awake person simulating unconsciousness. (Plum & Posnter 2019; page 69)
• Oculocephalic Reflexes (“Doll's Eyes”)
  • In a conscious person, the forebrain will override brainstem oculocephalic reflexes.  This makes it difficult to simulate the presence of normal oculocephalic reflexes (e.g., acting as if the eyes were fixed on a point in the distance).  Erratic eye movements occurring while moving the head may be a clue to the diagnosis of functional coma. (Plum & Posnter 2019; page 81)
• Demonstration of intact optokinetic nystagmus:
  • Play Video #1 below on your phone, and hold this in front of the patient's eyes.
  • The normal response to this stimulus is optokinetic nystagmus (depicted on Video #2 below).  The presence of optokinetic nystagmus indicates an intact occipital lobe, frontal lobe, and brainstem – suggesting functional coma.
• Cold calorics
  • Patients with pseudocoma display a physiologically normal response:  tonic deviation towards the irrigated ear, followed by rapid nystagmus in the opposite direction.(27741988)  The presence of a normal nystagmus response firmly indicates that the patient is physiologically awake.(Plum & Posnter 2019; page 294)
  • In neurologically intact patients, infusion of cold water can stimulate nausea and vomiting.
• 💡 The diagnosis of pseudocoma involves methodical and thoughtful application of standard neurologic examinations.  Application of extremely aversive or potentially dangerous stimuli should be avoided.

If the diagnosis remains unclear, then further testing may be required.  The emphasis should always be on prompt exclusion of possibly life-threatening processes (e.g., with neuroimaging).  A normal EEG may support the presence of functional coma.

The optimal treatment of functional coma is unclear.  In some patients, this may represent catatonia – which can be a component of an underlying psychiatric disorder.  Patients often have a combination of organic and functional abnormalities, which can create a complex picture.  Consultation with psychiatry may be helpful.

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history

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It may be impossible to obtain any information regarding the history.  If available, the following are notable:

• Prior medical & neurological history.
• Outpatient medication list and any recent medication changes.
• Preceding symptoms (e.g., confusion, headache, abnormal movements, weakness, depression).
• When was the patient last known to be normal?
• History of substance use?

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coma neuro exam

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common pupillary abnormalities

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bilateral fixed & dilated

• Bilateral midbrain damage causing loss of parasympathetic output from CN3.
• Anticholinergic drugs at high dose (especially atropine).
• Extremely deep metabolic coma (e.g., hypothermia, barbiturates, bupropion, lidocaine, sympathomimetics).

bilateral dilated, reactive

• Anticholinergic drugs.
• Withdrawal from alcohol or benzodiazepines.
• Sympathomimetics (e.g., amphetamine, cocaine, methamphetamines, MDMA).
• Serotonin syndrome.
• Generalized seizure, including the postictal period.

unilateral blown pupil (fixed & dilated)

• Oculomotor nerve paralysis (especially suggested if the involved eye is turned downwards and outwards).
  • i) Uncal herniation compressing CN3, which is usually ipsilateral.
  • ii) Posterior communicating artery aneurysm compressing CN3.
• Midbrain lesion affecting the CN3 nucleus.
• Focal seizure.
• Albuterol or oxymetazoline got into the patient's eye (following nebulized or intranasal drug administration).

bilateral mid-position, fixed pupils

• Bilateral midbrain damage with loss of sympathetic and parasympathetic output.
• Profound barbiturate coma.
• Hypothermia.

bilateral mid-position, reactive

• This excludes a lesion around the level of the midbrain (where CN2 and CN3 lie).  Remaining possibilities include, in roughly descending order:
  • (#1) Most likely, this may be toxic/metabolic coma, causing diffuse dysfunction of the cerebral cortex.
  • (#2) Lesions in the dorsolateral upper-mid pons.
  • (#3) Bilateral thalamic dysfunction.
• Neuromuscular blocking drugs are another possibility (note that smooth muscles of the iris don't get paralyzed).

bilateral small pupils

• Medications (e.g., cholinergic agonists, opioids, clonidine, ACE-inhibitors).
• Bilateral central Horner's syndrome:
  • Usually due to extensive pontine hemorrhage (“pontine pupils”).
  • May occur in the early phase of central herniation syndromes (either upwards or downwards herniation).

unilateral small pupil

• Unilateral Horner's syndrome (loss of sympathetic outflow, often due to large hemorrhage affecting the thalamus).

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spontaneous eye movements

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horizontal conjugate deviation

• Cortical injury causes gaze preference.  However, eyes are able to cross the midline during cold calorics or doll's eyes.
  • Damage (e.g., stroke) –> Eyes deviate ipsilateral to the lesion & contralateral to limb paralysis.
  • Focal seizure –> Eyes deviate contralateral to the lesion & ipsilateral to the seizing limb.  Active seizure can be associated with nystagmoid jerks.  This may subsequently be followed by a Todd's paralysis, wherein the eyes deviate in the other direction.
• Pontine injury causes gaze paralysis.  Unlike gaze preference, eyes are unable to cross the midline during doll's eyes or cold calorics.

horizontal conjugate roving eye movements (a.k.a. ping-pong gaze)

• This refers to spontaneous, synchronized movements of the eyes back and forth.  Some texts differentiate between “conjugate roving” versus “ping-pong” movements, but they are fundamentally similar phenomena.
• These movements reveal normal function of midbrain and pons.  Generally, this indicates that the coma is due to bilateral cerebral hemispheric dysfunction (e.g., a toxic/metabolic coma).
• Lesions in the cerebellar vermis may also cause horizontal conjugate roving eye movements, but such lesions wouldn't be expected to cause coma.(28187795)

ocular bobbing or dipping

• Bobbing (rapid down, slow up) suggests a pontine lesion (video below).(28187795)
• Dipping (slow down, rapid up) localizes to bihemispheric dysfunction (e.g., anoxia or a metabolic disorder)(video below).(28187795)

nystagmus (especially if bidirectional, vertical or rotatory, and non-fatiguing)

• Cerebellar or brainstem lesion.
• Intoxication (e.g., phencyclidine).
• Nonconvulsive status epilepticus (NCSE).

skew deviation (one eye looks up, other looks down)

• Suggests a brainstem or cerebellar lesion.

upward gaze

• Suggests bihemispheric damage (e.g., following severe anoxic injury).

downward gaze

• Thalamic injury (e.g., hemorrhage).
• Midbrain dysfunction (e.g., Parinaud syndrome).
• Bilateral hemispheric dysfunction (e.g., anoxic injury).
• Elevated intracranial pressure.

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oculocephalic (doll's eyes) & vestibulo-ocular (cold calorics) reflexes

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definitions

• Both reflexes test a similar neural circuit involving cranial nerves 3, 6, and 8.
• Oculocephalic Reflex (Doll's Eyes):  When the head is rotated, the eyes turn in the opposite direction (thereby staying fixated in roughly the same direction).  This is easily tested, as a front-line evaluation of eye movements.  Intact oculocephalic reflexes argue strongly against a structural cause of coma.  However, this reflex may be muted in deep metabolic coma, so symmetric absence of eye movements doesn't necessarily prove a structural lesion.  If the oculocephalic reflex is absent, cold caloric testing can be used to provide a stronger stimulus and test this more rigorously.
• Vestibulo-ocular Reflex (Cold Calorics) involves flushing the ear with 50 ml of ice water, with the head of the bed inclined at a 30 degree angle (to properly align the semicircular canal).   In a comatose patient with intact brainstem reflexes, this will cause the eyes to rotate towards the stimulated ear.  Cold calorics may elicit nausea and vomiting in awake or mildly somnolent patients.

response seen with intact brainstem and cerebral cortex

• A completely normal response that would be seen in an awake person is deviation of the eyes towards the irrigated side, repeatedly followed by fast-phase nystagmus in the opposite direction.
• If this is found, it suggests:
  • Functional coma (pseudocoma).
  • Akinetic mutism.
  • Less severe toxic/metabolic encephalopathies.

focally abnormal vestibulo-ocular reflexes

• This suggests a focal lesion involving the brainstem, for example:
• (1)  With cold caloric stimulation, isolated failure of the contralateral eye to adduct suggests a lesion in the medial longitudinal fasciculus in the pons.  This can also occur with a CN3 palsy, but CN3 palsy would also cause pupillary dilation.
• (2)  Isolated failure of an eye to abduct (CN6 palsy) may reflect damage to the abducens nucleus in the pons.

symmetrically abnormal vestibulo-ocular reflexes

• This generally indicates brainstem pathology.
• Toxic/metabolic coma can abolish vestibulo-ocular reflexes (e.g., phenytoin, tricyclic antidepressants, or sedatives).

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cough & gag reflexes

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⚠️  please stop gagging patients

• The gag reflex will almost never provide useful information which isn't revealed by other components of the neurologic examination.
  • The presence of a gag reflex does not indicate that the patient is able to protect their airway.  Airway protection involves swallowing reflexes, which are far more complex than a simple gag reflex.
  • Many normal people lack a gag reflex.  Therefore, absence of a gag reflex isn't necessarily pathological, nor does this reveal any definitive information.
• Gagging patients may induce emesis, which could lead to aspiration.
• Further discussion of why gagging patients should be abandoned is here.

cough reflex in intubated patients

• Basics of the cough reflex:
  • The cough reflex involves the vagus nerve (CN10, near the medulla).  This reflex will be preserved in most coma states (which usually involve higher brain centers).
  • Reliably eliciting the cough reflex requires an intubated patient, in whom endobronchial stimulation can be applied by suctioning the endotracheal tube.
  • The cough reflex is one of the most durable reflexes, which is generally preserved even in severe brain injury.  For example, following anoxic brain injury, lack of a cough reflex after 24 hours carries a likelihood ratio of 85 for poor neurologic outcome.(14970067)
• Causes of an absent cough reflex include:
  • Damage to the medulla (e.g., tonsillar herniation, brain death).
  • Extremely profound toxic/metabolic coma (e.g., barbiturate or baclofen overdose).
  • Neuromuscular paralysis (e.g., lingering effects of rocuronium used for intubation).
• 💡 When encountering a patient who lacks a cough reflex without any obvious cause, always consider the possibility of a lingering neuromuscular paralytic agent.  If the patient otherwise appears paralyzed, this should be immediately evaluated at the bedside using a peripheral nerve stimulator (a.k.a. “train of four monitoring”).

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breathing patterns

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how to observe breathing patterns

• Nonintubated patient:  simple observation.
• Intubated patient:  lift sedation (e.g., propofol) and place the patient on a pressure support mode (e.g., 10 cm pressure support with 5 cm PEEP).  This allows patients to drive the rate and depth of respiration without interference, thus revealing their native breathing pattern.

Cheyne-Stokes respiratory pattern

• This is defined as a sinusoidal breathing pattern, reflective of a delayed feedback loop involved in regulating CO2 levels (e.g., commonly seen in severe heart failure with poor cardiac output).  Generation of this pattern requires intact brainstem respiratory reflexes.
• In the context of coma, this pattern may result from bilateral forebrain dysfunction (e.g., metabolic etiologies) or bilateral thalamic injury.

apneustic breathing

• This is a rare pattern that involves end-inspiratory pauses.
• Apneustic breathing suggests pontine dysfunction (especially pontine infarction due to basilar artery occlusion).

ataxic breathing

• Damage to the medulla may cause irregular breathing patterns.
• High medullary lesions may generate irregular clusters of breaths (this may mimic the Cheyne-Stokes pattern, but it lacks any smooth, sinusoidal transition between apnea and hyperventilation).

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muscle tone

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increased motor tone or rigidity

• Intoxication (e.g., serotonin syndrome, neuroleptic malignant syndrome, malignant hyperthermia).
• Seizure.
• May also result from a subacute or chronic brain disorder.

hyperreflexia or clonus

• Suggests serotonin syndrome, neuroleptic malignant syndrome, malignant hyperthermia.
• May also result from a chronic disorder of the brain or spinal cord.

multifocal myoclonus (diffuse, random, asynchronous jerking of various muscle groups)

• Generally, suggests a toxic/metabolic etiology.
• This should be differentiated from diffuse, synchronous or rhythmic movements – that may suggest anoxic brain injury, nonconvulsive status epilepticus (NCSE), lithium intoxication, cephalosporin intoxication, or pesticides.(20130300)

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motor responses to pain

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• How to examine:
  • Apply painful stimuli to four extremities and bilateral face (either supraorbital ridge or temporomandibular joints).
  • Observe for motor response (e.g., purposeful avoidance of the painful stimuli, a “localizing” response to pain) as well as nonfocal grimacing.  For example, grimacing without the ability to withdraw suggests an intact sensory response, but the presence of motor paralysis.
• Asymmetric responses suggest a focal lesion.
• Decorticate posturing is loosely associated with damage at the level of the thalamus.
• Decerebrate posturing is loosely associated with damage at the level of the midbrain.  This is usually associated with downward herniation or compression of the brainstem by posterior fossa lesions.  However, occasionally toxic/metabolic etiologies may also cause decerebrate posturing (e.g., hepatic encephalopathy).

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common coma syndromes

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bilateral hemispheric dysfunction (e.g., most toxic/metabolic comas)

• The key finding is that brainstem reflexes are usually intact.  However, reflexes may be lost in very deep toxic comas (e.g., barbiturate or baclofen overdose).
  • Intact vestibulo-ocular reflexes.
  • Intact pupillary and corneal reflexes.
• Spontaneous eye movements can occur (e.g., roving conjugate gaze, dipping with slow downgaze followed by rapid upgaze, or ping-pong gaze back and forth).(28187795)
• Upward or downward eye deviation can occur.
• Adventitious limb movements may be seen.  If present, multifocal myoclonus, asterixis, or tremor support a metabolic etiology.(28187795)  Any motor signs are usually symmetric.  

uncal herniation

• Ipsilateral blown pupil:
  • Initially, the pupil is dilated and sluggish.  Parasympathetic fibers run along the outside of CN3, so pupillary dilation can occur first.
  • With progression, the pupil becomes fixed and dilated.  Impaired consciousness is almost always present by the time the pupil is fixed and dilated.(Nelson, 2020)
  • With progression, oculomotor paralysis occurs (causing the eye to be fixed in a down-and-out orientation).
  • Ipsilateral ptosis results from denervation of the levator palpebrae superioris.(26704760)
• Contralateral hemiparesis due to compression of the cerebral pedicle
  • Ipsilateral weakness can occur if lateral displacement compresses the opposite cerebral peduncle (Kernohan's notch phenomenon, a false localizing sign).
  • Hemiparesis may be accompanied by hyperreflexia and a positive Babinski's sign.
• If untreated, this may eventually compress the midbrain (e.g., causing bilateral fixed & dilated pupils, with decorticate or decerebrate posturing).

downward central herniation (a.k.a. downward transtentorial herniation)

• Miotic (small) pupils are initially a prominent sign.
  • ⚠️ Initially, this may resemble an intoxication causing small pupils (e.g., cholinergic agonists, opioids, clonidine, ACE-inhibitors).  There may initially be conjugate roving eye movements, simulating a toxic/metabolic coma.
  • Abnormal motor responses (e.g., posturing) may be an early clue to a structural etiology of the coma.
  • Uncommonly, a unilateral Horner's syndrome may occur early on (before transitioning to bilateral small pupils).(Alpert 2019)
• With progression of herniation:
  • Midbrain dysfunction emerges:  pupils may become fixed & mid-position.  Vestibulo-ocular reflexes become abnormal.
  • Pathological breathing patterns may emerge (including Cheyne-Stokes breathing, irregular ataxic breathing, or neurogenic hyperventilation).
  • Decorticate and later decerebrate posturing occur, with bilateral extensor Babinski reflexes.

upward transtentorial herniation

• Vertical gaze palsy may be followed by stupor/coma.(34618757)
• Pupils may be fixed and either midposition or dilated.
• Cerebral aqueduct compression may result in acute hydrocephalus.

brainstem displacement from a cerebellar mass

• Cranial nerves:
  • Pupillary reflexes are often intact (since these are located in the midbrain, which is above the level of compression).
  • Absent corneal reflexes and abnormal vestibulo-ocular reflexes are often seen.  Skew deviation may occur (one eye looks up, the other looks down).
• Ocular bobbing can occur, or nystagmus that may be direction-changing or vertical.(28187795)
• Extensor or flexor posturing can occur.

tonsillar herniation

• Stiff neck may be a very early sign.(Alpert 2019)
• Cranial nerve palsies and stupor/coma result from brainstem compression.
• Quadriparesis occurs due to compression of the medullary pyramids.
• Cushing reflex may occur including hypertension, bradycardia, and slow respirations (which can progress to respiratory arrest).(34618757)
• Acute hydrocephalus may occur.

falcine herniation

• Leg weakness is a central finding.
• Mental status is relatively unaffected compared to other herniation syndromes.
• May progress to central downwards herniation over time (due to increasing edema of herniated tissue).

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tests & investigations

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labs

• Basic labs:
  • Electrolytes, including Ca/Mg/Phos.
  • CBC with differential.
  • Coagulation studies.
• Liver function tests, including ammonia.
• Lactate.
• Thyroid Stimulating Hormone (TSH).
• Urinalysis.
• VBG or ABG, if hypercapnia is suspected and the patient isn't intubated.
• Toxicologic labs, depending on clinical context.  For example:
  • Carboxyhemoglobin level (may be obtained with venous blood).
  • Salicylate & acetaminophen levels.
  • Ethanol level.
  • Urine toxicology screen.
• Blood cultures (if sepsis or meningitis is suspected).
• Creatinine kinase, if the patient is found down with possible rhabdomyolysis.
• Pregnancy test, if relevant.

CT scan

• (1) Most patients will receive a noncontrast head CT to exclude intracranial hemorrhage or other space-occupying lesions.
• (2) CT angiogram (CTA) and CT perfusion:
  • Should be considered if there is suspicion for an acute ischemic stroke (e.g., abnormal brainstem findings on exam suggestive of basilar artery occlusion).
• (3) CT venogram (CTV):
  • Thrombosis of the straight sinus may cause thalamic dysfunction, leading to coma.
  • CT venogram should be considered if there is suspicion of venous sinus thrombosis.

lumbar puncture

• Indications to perform an LP:
  • (1) Suspicion of meningitis or encephalitis (e.g., based on fever, leukocytosis).
  • (2) Lack of any alternative explanations for the coma following review of neurologic examination, labs, and neuroimaging.
• In situations where there is low index of suspicion for meningitis or higher risk from lumbar puncture (e.g., coagulopathy), a contrast-enhanced MRI may be considered as an alternative evaluation for meningitis or encephalitis.(24977138)  
• Basic CSF investigations should include the usual chemistries and cell counts, as well as PCR for both HSV and VZV.  Immunocompromised patients should be tested more broadly (e.g., including cryptococcal antigen).  Cytology should be obtained if leptomeningeal carcinomatosis is suspected.
• Elevated opening pressure may suggest infection (e.g., bacterial or cryptococcal meningitis), venous sinus thrombosis, acute liver failure, or leptomeningeal carcinomatosis.
• Additional fluid should be held for more sophisticated testing if needed (e.g., paraneoplastic or autoimmune antibody screens).

EEG 

• EEG may be indicated if there are reasons to consider nonconvulsive status epilepticus, such as:
  • Seizure history (current or prior).
  • Clinical indications of possible nonconvulsive status, for example:
    • Focal twitching of the hands or face, nystagmus, eye blinking, or chewing movements.
    • Recurrent pupillary hippus (pupils dilating/constricting spontaneously), pupillary dilation.
    • Focal neurologic findings despite a normal CT scan (e.g., gaze deviation).(28187795)

MRI

• MRI is indicated if the above workup fails to reveal a diagnosis.
• Gadolinium contrast may improve the yield for infection or malignancy, so this may be especially useful if a lumbar puncture hasn't already been performed.(24977138)  
• MR angiography (MRA) and/or MR venography (MRV) may be considered, similarly to CT angiography and CT venography (e.g., based on the index of suspicion for cerebral venous sinus thrombosis).
• If the patient isn't already intubated, then intubation should be strongly considered prior to MRI to ensure airway protection.  Additionally, intubation with deep sedation (often with propofol) may facilitate a high-quality MRI, without movement artefact.

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airway management

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noninvasive ventilation (e.g., BiPAP)

• This may sometimes be considered if hypercapnia is believed to be the cause of the altered mental status.
• If COPD is the cause of the hypercapnia, then BiPAP may be trialed under close supervision (more on this in the chapter on COPD).
• If hypercapnia is the result of substance intoxication or neurological disease, BiPAP is contraindicated.  The management of marked hypercapnia in this context is generally intubation.  However, for moderate substance intoxication, if the patient is protecting their airway and they are only moderately hypercapnic, then close observation might be adequate (without either BiPAP or intubation).

consider intubation

• Common indications for intubation in this context:
  • (a) Failure to protect the airway.
  • (b) Intubation may be required to accomplish diagnostic testing safely (e.g., LP, MRI).

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therapies to consider

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dextrose

• Glucose should be checked immediately in any patient with altered mental status.
• If hypoglycemia cannot be excluded immediately, give an ampule of D50W empirically (e.g., while awaiting the return of values from the laboratory).

thiamine

• Wernicke's encephalopathy should be considered in patients with alcoholism, bariatric surgery, eating disorders, or malabsorption.
• When in doubt, treat empirically with 500 mg IV thiamine Q8hr (more on Wernicke's encephalopathy here).

naloxone

• Suspect opioid intoxication primarily if the respiratory rate decreased.
• If opioid intoxication is possible, naloxone may be empirically trialed with increasing doses to a cumulative dose of ~4 mg.(26438464)
• Note that patients on chronic opioid will generally experience pain and agitation after naloxone, due to withdrawal of opioid effects.  This doesn't prove that their stupor/coma is caused solely by opioid, unless they are able to wake up and mentate normally.
  • Increased agitation or pain due to naloxone implies having had exposure to opioid, but doesn't necessarily exclude other pathology.

empiric therapy for meningitis & encephalitis

• If there is a significant concern for meningitis, empiric therapy should be given immediately (even before CT or lumbar puncture).
• A reasonable approach is generally:
  • 10 mg dexamethasone, followed by ceftriaxone 2 grams IV q12hr.
  • Acyclovir 10 mg/kg IV q8hr.
• The added yield of vancomycin and ampicillin here is extremely low, because most of these patients don't actually have meningitis (and the added benefit from vancomycin and ampicillin in meningitis is minimal).
  • More on empiric therapy for meningitis here.

osmotherapy & ICP management

• For patients with evidence of elevated intracranial pressure (e.g., optic disc edema on ultrasonography or clinical features strongly suggestive of a herniation syndrome), the following immediate measures may be considered:
  • Elevation of the head of the bed.
  • Ensuring the neck is in a midposition.
  • One dose of osmotherapy may be considered.  Possible treatment options may include two 50-ml ampules of hypertonic bicarbonate (1 meq/ml), or a bolus of ~250 ml 3% saline.
  • Attention should also be paid to the PaCO2, with a target pCO2 in the low-normal range (e.g., ~35-40 mm).
  • Targeting a higher mean arterial pressure may promote adequate cerebral perfusion pressure (e.g., targeting an initial mean arterial pressure of ~75 mm).

temperature management

• Fever or hyperthermia may pose a threat to the injured brain.
• When possible, target a temperature of 36 C (i.e., avoidance of fever).  This may often be achieved with simple measures (e.g., scheduled acetaminophen 1 gram q6hrs and cooling blankets).  If simple measures fail, more aggressive control measures may be considered (e.g., an external adaptive cooling system, such as the Arctic Sun).
• If you're struggling with temperature management, this should also be a reminder to refocus your differential diagnosis on disorders that cause thermal abnormalities:
  • If the patient has refractory hyperthermia, consider causes of hyperthermia.
  • If the patient has refractory hypothermia, consider causes of hypothermia.

blood pressure management

• Hypotension may be detrimental to the injured brain.  Severe hypotension (e.g., mean arterial pressure below ~60-65 mm) should be treated promptly.  Hemodynamic assessment with ultrasonography can guide optimal management.  In general, immediate correction of critical hypotension will often require vasopressors (rather than attempting fluid loading).
• Hypertension is more challenging:
  • Some patients may have posterior reversible encephalopathy syndrome (PRES), in which the hypertension is the cause of the coma.  This is usually associated with a mean arterial pressure >140 mm.
  • In other patients (e.g., with ischemic stroke), hypertension may be a beneficial physiologic compensatory mechanism that helps perfuse the injured brain.  In these patients, aggressive reduction of the blood pressure can be detrimental.
  • Ultimately, clinical judgement is required to determine optimal management for the undifferentiated patient.  If the blood pressure is profoundly elevated (e.g., mean arterial pressure >140 mm), then gentle reduction may be reasonable.  Ensure that pain and agitation are treated adequately, as these may contribute to hypertension.

antiepileptic therapy

• Status epilepticus may be suspected based on the following findings:
  • History of seizure or abnormal movements prior to coma.
  • Subtle signs of seizure activity (e.g., facial or extremity twitching, eye deviation or nystagmus)
  • Elevated lactate that rapidly normalizes.
• Video EEG (vEEG) should be emergently arranged.  While awaiting vEEG, the following treatments may be considered:
  • For intubated patients:  increase propofol to a relatively high dose (e.g., 50-80 mcg/kg/min), even if this requires vasopressor support with norepinephrine.
  • Levetiracetam loading dose (e.g., 60 mg/kg up to a maximal dose of 4.5 grams).

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Trying to guess the diagnosis and failing to perform a complete evaluation (e.g., skipping a full laboratory panel and missing a diagnosis of carbon monoxide intoxication).
• Satisfaction of search:  one abnormality is found (e.g., positive ethanol level), causing other abnormalities to be overlooked (e.g., subdural hematoma).
• Failure to perform a complete coma neurological examination.  This examination involves only about seven key parts and can be performed in about five minutes.  The examination provides critical information regarding which patients should be risk-stratified for emergent or specialized neuroimaging (e.g., STAT CT angiography to evaluate for basilar artery occlusion).
• There are some rare diagnoses which must be diligently screened for (e.g., primary hyperammonemic disorder, carbon monoxide poisoning), even if they don't seem likely in any particular patient.

Guide to emoji hyperlinks 

•  = Link to online calculator.
•  = Link to Medscape monograph about a drug.
•  = Link to IBCC section about a drug.
•  = Link to IBCC section covering that topic.
•  = Link to FOAMed site with related information.
•  = Link to supplemental media.

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supplemental media

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Optokinetic nystagmus

Video #1: Use this to perform the patient examination.

Video #2: For patients in pseudocoma, you would expect to see intact optokinetic nystagmus, as shown here:

Going further

• EMCrit Podcast 186:  Coma with Eelco Wijdicks
• NeuroEMCrit by Neha Dangayach: Clinical Pearls for Coma