CONTENTS

• Front matter: Most clinically relevant:
  • Rapid Reference – Clinical approach 🚀
  • Causes of stupor & coma
• Definitions
• Distinctive states that mimic coma:
  • Locked-in syndrome
  • Abulia and akinetic mutism
  • Hypokinetic catatonia
  • Functional unresponsiveness
  • Malingering
• Management – some additional comments
  • Airway management
• Related
  • Coma syndromes (section of Exam chapter)
• Podcast
• Questions & discussion
• Pitfalls

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rapid reference

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diagnostic approach

history (if possible)

• Med / neuro / psych history.
• Outpatient meds & recent changes.
• Preceding symptoms: ?
  • Gradual onset vs. immediate?
  • Headache, fever?
  • Abnormal movements/seizure?
  • Weakness / focal deficits?
• Last known normal.
• History of substance or EtOH use.

coma exam

1. Pupil size & reactivity. 📖
2. Eye position & Doll's Eyes reflex. 📖
3. Corneal reflex. 📖
4. Response to TMJ, sternal, & limb stimulation. 📖
5. Cough reflex (if intubated). 📖
6. Patellar reflex, ? ankle clonus. 📖
7. Babinski sign. 📖
8. Nuchal rigidity.

labs to consider

• Basic labs
  • STAT fingerstick glucose.
  • Electrolytes including Ca/Mg/Phos.
  • CBC with differential.
  • Coagulation studies (INR, PTT).
  • Liver function tests & ammonia.
  • TSH (thyroid stimulating hormone).
• Other labs to consider:
  • ABG/VBG, if hypercapnia suspected.
  • Creatinine kinase, if found down.
  • Pregnancy test, if relevant.
• Toxicology evaluation as appropriate, e.g.: 📖
  • Serum salicylate & acetaminophen levels.
  • Carboxyhemoglobin level.
  • Serum ethanol level.
• Infectious workup as appropriate: 📖
  • Blood cultures (if sepsis or meningitis is suspected).
  • Chest X-ray, urinalysis.
  • HIV screen.

consider neuroimaging

• CT scan
  • Most patients will receive a noncontrast head CT to exclude intracranial hemorrhage or other space-occupying lesions.
  • 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).
  • CT venogram (CTV) should be considered if there is suspicion for venous sinus thrombosis (thrombosis of the straight sinus or Vein of Galen may cause thalamic dysfunction, leading to coma).
• MRI
  • MRI is indicated if the above workup fails to reveal a diagnosis.
  • 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).

consider lumbar puncture

• Indications include:
  • (1) Clinical suspicion of meningitis or encephalitis.
  • (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)
• Elevated opening pressure may suggest infection (e.g., bacterial or cryptococcal meningitis), venous sinus thrombosis, acute liver failure, or leptomeningeal carcinomatosis.

consider EEG, especially if: 📖

• 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)
• Elevated lactate that rapidly normalizes.

therapeutic approach

modified “coma cocktail”

• IV dextrose (only if glucose is low or pending). 📖
• IV thiamine: 500 mg IV q8hr if Wernicke encephalopathy 📖 is possible (e.g., alcoholism, eating disorder, s/p bariatric surgery, malabsorption, or merely a patient with unknown medical history who could be thiamine deficient).
• Naloxone:
  • Naloxone might help avoid intubation and/or extensive diagnostic evaluation.
  • 🛑 Anyone on chronic opioids 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.
  • Strategies for naloxone use & dosing here: 📖
• Stop problematic medications: Review the medication list for any drugs that may suppress mental status.

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. Immediate correction of critical hypotension will often require vasopressors (rather than 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 MAP >140 mm.
  • In other patients (e.g., with ischemic stroke), hypertension may be a 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 often contribute to hypertension.

temperature management

• Fever may pose a threat to the injured brain.
• Normothermia should generally be targeted. This may often be achieved with simple measures (e.g., scheduled acetaminophen 1 gram q6hrs and cooling blankets). If simple measures fail, more aggressive intervention may be needed (e.g., an external adaptive cooling system).
• If the temperature is significantly abnormal, broaden the differential diagnosis to include causes of hyperthermia 📖 or causes of hypothermia 📖.

empiric therapy for meningitis & encephalitis

• If there is a significant concern for CNS infection, empiric therapy should be given following blood cultures (before CT or lumbar puncture).
• A reasonable regimen is often 10 mg dexamethasone, ceftriaxone 2 grams IV q12hr, and acyclovir 10 mg/kg IV q8hr. The added benefit of vancomycin and ampicillin here is usually low, because most of these patients don't actually have meningitis. Further discussion here: 📖

antiepileptic therapy

• Potential signs of nonconvulsive status epilepticus are listed above and discussed further here: 📖
• If there is a high index of suspicion for ongoing seizures:
  • For intubated patients: increase propofol to a relatively high dose (e.g., ~80 mcg/kg/min), even if this requires vasopressor support with norepinephrine.
  • Consider a levetiracetam loading dose (e.g., 60 mg/kg up to a maximal dose of 4.5 grams).

ICP management & osmotherapy

• Potential indications for semi-empiric therapy: 📖
  • Suggestive history (e.g., coma after neurotrauma). 📖
  • Neurologic examination suggestive of a herniation syndrome. 📖
  • Optic disc nerve sheath diameter is unequivocally elevated. 📖
• Management may include: 📖
  • Ensuring the neck is in midposition.
  • Osmotherapy. 📖 Treatment options may include two 50-ml ampules of hypertonic bicarbonate (1 meq/ml) over ~10 minutes, or a bolus of ~250 ml 3% saline.
  • Attention should be paid to the PaCO2, with a target pCO2 in the low-normal range (e.g., ~35-40 mm).

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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:

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/hyperglycemia (glucose below ~40 mg/dL or 2.2 mM, or rapid rise over roughly ~900 mg/dL or 50 mM).(20130300)
• Hyponatremia/hypernatremia (e.g., sudden drop below ~110 mM or 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 (in absence of liver failure).
• Uremia.
• Myxedema coma.
• Wernicke's encephalopathy.
• Adrenal crisis.
• Shock (especially septic shock).

toxicologic

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

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)
  • Most commonly, basilar artery stroke.
  • Severe multifocal infarction (e.g., due to endocarditis).
  • Artery of Percheron occlusion involving bilateral thalami (rare).
• PRES (posterior reversible encephalopathy syndrome).
• Cerebral venous thrombosis:
  • i) Thrombosis of the straight sinus may cause bilateral thalamic dysfunction.
  • ii) Extensive thrombus burden may cause diffuse cerebral edema.

hydrocephalus, e.g.:

• Intraventricular hemorrhage.
• Colloid cyst.

trauma/surgery

• Hematoma (subdural, epidural, or parenchymal).
• Multifocal contusion causing edema and elevated intracranial pressure.
• DAI (diffuse axonal injury).
• 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.
• ADEM (acute disseminated encephalomyelitis).

seizure

• Nonconvulsive status epilepticus (NCSE)
• Postictal state.

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definitions

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basics

• Two dimensions of consciousness:
  • Arousal: Wakefulness, eye opening.
  • Awareness: Processing information from environment (e.g., follows commands, responds to stimuli, eyes track objects, purposeful behavior).
• Coma is defined as a state of being unawake, unaware, and unarousable.
• Stupor/obtundation lacks a clear definition, but usually refers to substantially impaired mental status with preservation of some responsiveness to painful stimuli.
• Vegetative state, or unaware wakeful state (UWS): Intact arousal (e.g., sleep/wake cycles), but without awareness. 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 awareness, but one or more reproducible behaviors reveal some awareness (e.g., following simple commands, appropriate yes/no responses, or other purposeful behavior). (Shutter 2019)
• Locked in syndrome and other coma mimics: 📖
• 💡 When in doubt, it's best to simply describe exactly what the patient can or cannot do.

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 via the central tegmental tract to the bilateral reticular nuclei of the thalami, and subsequently diverges widely throughout the bilateral cortexes.(Flemming 2022)
• 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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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.
  • Vertical eye movements and blinking are usually spared (since these are controlled by the midbrain tegmentum).
• 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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abulia and akinetic mutism

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clinical presentation

• 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)

causes

• Often reflects damage to the medial frontal lobe(s).
• May result from infarction of the ACA 📖 (anterior cerebral artery), or vasospasm involving the ACA territory.

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hypokinetic catatonia

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• Patients generally appear obtunded, rather than completely comatose.(Posner 2019)
• Common symptoms include immobility, mutism, and staring. Less commonly rigidity and posturing may be seen. Other distinctive features of catatonia may be useful if observed (e.g., cataplexy, waxy flexibility).
• Patients can be unresponsive to painful stimuli.(19884605)
• Patients may be incontinent of urine or stool, or may retain urine and require catheterization.(Posner 2019)
• Rarely, this may progress to malignant catatonia wherein autonomic instability occurs (e.g., hyperthermia, diaphoresis, labile blood pressures, and tachypnea).
• Further discussion of the diagnosis of catatonia here: 📖

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functional unresponsiveness

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This condition has been referred to under a broad variety of names including “psychogenic unresponsiveness,” “psychogenic coma,” and “functional coma.”

key characteristics of functional unresponsiveness (27719852)

• Time-limited state that resembles stupor or coma, with impaired responsiveness to external stimuli such as pain, lasting longer than 30 minutes.
• Unequivocal evidence that brain function is analogous to a waking state during this time.
• Experienced by the patient as a genuine and involuntary problem (this is not factitious/malingering).
• Not better explained by catatonia.
• Fundamentally a similar state as functional (non-epileptic) seizures, which are more common.

epidemiology & triggers

• Functional unresponsiveness is uncommon, with only sparse reported cases in the medical literature.
• Common triggers may include psychological stress, or procedures involving anesthesia.(27719852)
• Recurrence is common, with patients often experiencing multiple similar episodes.

diagnosis of functional unresponsiveness: overall approach

• The diagnosis is generally based on two features:
  • (1) Exclusion of alternative medical/neurologic emergencies (e.g., hypoglycemia).
  • (2) Demonstration of positive features on neurological examination. The use of positive features is extremely important to secure a confident diagnosis.
• EEG may be quite helpful. A normal EEG supports the presence of functional unresponsiveness. However, normal EEG may also be seen in some patients with catatonia or brainstem lesions (e.g., locked in syndrome).

examination features supportive of functional unresponsiveness

• Gently open the eyelids and look for three signs of functional unresponsiveness:
  • (#1) Tightly shut eyelids. Patients with functional unresponsiveness may resist eye opening, whereas in organic coma the eyes can be easily opened. However, some patients with anti-NMDA receptor encephalitis may have dissociative responses to stimuli (with resistance to eye opening, yet unresponsiveness to painful stimuli).(24381709)
  • (#2) Eye movements. Patients with functional unresponsiveness may move their eyes in usual ways (e.g., eyes roll upwards). In organic coma, the eyes should often remain still or move in a stereotyped fashion (e.g., conjugate horizontal roving, ocular bobbing, or ocular dipping 📖).
  • (#3) Rapid eyelid closure may occur in functional unresponsiveness. Alternatively, in organic coma the eyes will close in a smooth, gradual movement that cannot be duplicated by an awake person simulating unconsciousness. (Plum & Posner 2019)
• 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 unresponsiveness. (Plum & Posner 2019)
• Optokinetic nystagmus
  • Expose to the patient to an optokinetic stimulus (e.g., play Video #1 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 unresponsiveness. 🌊
• Cold calorics (vestibulo-ocular reflex testing)
  • Patients with functional unresponsiveness 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 implies that the patient is physiologically awake.(Plum & Posnter 2019)
  • In neurologically intact patients, infusion of cold water can stimulate nausea and vomiting. Further discussion of vestibulo-ocular reflex testing: 📖
• Response to stimuli
  • Eyelash tickling or gentle nasal swabbing may elicit eyelid opening or fluttering in a patient with functional unresponsiveness.
• Pitfalls
  • ⚠️ Patients with functional unresponsiveness may fail to respond to highly painful stimuli, so avoid the repeated use of highly aversive stimuli (e.g., sternal rub and nailbed pressure).
  • ⚠️ Dropping the patient's hand over their face is a popular technique, but this carries a risk of trauma and may be ambiguous to interpret.

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

Video #2: For patients with functional unresponsiveness, you would expect to see intact optokinetic nystagmus, as shown here:

management

• The optimal management of functional unresponsiveness is unclear.
• The natural history of functional unresponsiveness is to improve, but this may take several days in some cases.(27719852)
• Approaches similar to those for functional seizure may be reasonable (e.g., gentle non-judgemental explanation of the diagnosis to the patient, along with calm reassurance that they are safe and will recover).
• Consultation with psychiatry may be helpful.

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malingering

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• Malingering refers to intentionally faking a coma for the purpose of secondary gain (e.g., avoiding an uncomfortable situation).
• Neurological examination may appear similar to functional unconsciousness (as above).  A clue may be that patients look around or move when they think nobody is paying attention.

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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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podcast

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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.

Acknowledgement: Thanks to Dr. Casey Albin (@caseyalbin) for thoughtful comments on this chapter.

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