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Chapter 8
Abstract
Coma has many causes but there are a few urgent ones in clinical practice. Management must start with
establishing the cause and an attempt to reverse or attenuate some of the damage. This may include early
neurosurgical intervention, efforts to reduce brain tissue shift and raised intracranial pressure, correction of
markedly abnormal laboratory abnormalities, and administration of available antidotes. Supporting the
patient’s vital signs, susceptible to major fluctuations in a changing situation, remains the most crucial
aspect of management.
Management of the comatose patient is in an intensive care unit and neurointensivists are very often
involved. This chapter summarizes the principles of caring for the comatose patient and everything a neu-
rologist would need to know. The basic principles of neurologic assessment of the comatose patient have
not changed, but better organization can be achieved by grouping comatose patients according to specific
circumstances and findings on neuroimaging. Ongoing supportive care involves especially aggressive
prevention of medical complications associated with mechanical ventilation and prolonged immobility.
Waiting for recovery—and many do- is often all that is left. Neurorehabilitation of the comatose patient
is underdeveloped and may not be effective. There are, as of yet, few proven options for neurostimulation
in comatose patients.
*Correspondence to: Eelco F.M. Wijdicks, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester MN 55905, USA.
E-mail: wijde@mayo.edu
118 E.F.M. WIJDICKS
healthcare workers involved. This chapter provides the epidemic” and many survivors have long-term anoxic
main essentials for care and treatment, not only in the brain injury. The presentation of a comatose patient in spe-
acute stage, but also in the weeks and sadly sometimes cialized hospital wards and units may also narrow the dif-
months or years ahead. ferential diagnosis of acute coma. It is highly unusual for
patients who have been admitted to general medical or sur-
CAUSES OF COMA AND PREVALENCE gical wards to suddenly deteriorate and become comatose.
Acute coma in the hospital is occasionally a reason for a
For the physician trying to make sense of it all, there
rapid response team call, and acute metabolic disturbances
are multifarious causes of coma, but, after an initial eval-
or an unintentional drug overdose (e.g. post operative opi-
uation, physicians often have narrowed the range of pos-
oid treatment) remain most likely. Acute hypo- or hyper-
sibilities. In the initial evaluation of the comatose patient
glycemia is also often a cause for immediate alarm, but is
with no apparent cause, the medical history becomes more
usually recognized quickly and corrected. In our experi-
important and often cues the physician towards a possible
ence, only a small fraction of comatose patients have no
explanation. Questions that should be asked to family
clear explanation on computed tomography (CT) scan
members or bystanders – when appropriate – are shown
or after lumbar puncture (Edlow et al., 2014). In some
in Table 8.1. However, the cause of coma clearly depends
patients, early magnetic resonance imaging (MRI) has
on where the patient is seen first. Assessing a patient in a
been diagnostic in demonstrating posterior reversible
transplant intensive care unit (ICU) is a different environ-
encephalopathy syndrome, fat embolization syndrome
ment than consulting in a medical ICU or coronary care
(Mijalski et al., 2015), infarcts in the brainstem and
unit. Consultation in surgical ICUs for coma is relatively
thalamus, or acute demyelination disease such as acute
frequent and involves questions about failure to awaken or
disseminated encephalomyelitis (ADEM) or osmotic
acute coma in the setting of critical illness. Moreover, the
demyelination. In many others, coma may be a result of
nature of the primary illness for which the patient is admit-
an unwitnessed seizure, illicit drug use, or other toxins.
ted may provide sufficient leads. It is likely to be true that
intoxications are the predominant cause of coma in
patients arriving in the emergency department. Neverthe- NEUROPATHOPHYSIOLOGY
less, comatose patients may present to the emergency
Coma is a result of dysfunction or damage of structures
department with no known cause, clinical course and little
that allow normal wakefulness and awareness. Wakeful-
documentation (Stevens et al., 2015). Many emergency
ness is mostly driven by the ascending reticular forma-
departments in the world are in the midst of a “fentanyl
tion in the brainstem. Becoming aware and thus
understanding content requires the thinking parts of
Table 8.1 the cortex, including the associative parietal areas and
frontal lobe. Comatose patients are neither awake nor
Questions to ask in coma of uncertain etiology
aware (even if sporadic functional MRI signals may sug-
Could there have been trauma or assault? gest otherwise). Coma may deteriorate to brain death in
Was the patient breathing when the response team arrived? about 5–10% and simply implies that all brainstem
Was there noticeable blood loss? reflexes are permanently lost, including the ability to
Did the patient use antibiotics for infection? generate a breath. Hypotension almost always occurs,
Was there a rapid onset of fever and headache?
but the spinal cord may increase sympathetic tone just
Was a cardiac arrest documented? How long did the efforts last
enough to maintain a pressure which allows circulation.
before resumption of circulation?
Has the patient had prior episodes of diabetic ketoacidosis, or The clinical diagnosis of brain death is conservative and
severe hypoglycemia, and has there been a recent change in defines a clear point of no return. Once all brainstem
insulin medications? reflexes are absent in a demonstrably apneic comatose
Is the patient known to have atrial fibrillation or other cardiac patient, with no confounding circumstances, recovery
disease and be using anticoagulation or has it recently been does not occur and then fullfills criteria for a neurologic
discontinued? determination of death (Wijdicks 2001, 2011, 2017). In
Was hypertension poorly controlled? comatose patients with preserved brainstem reflexes,
What other pills or over-the-counter drugs does the patient have long-term support with a gastrostomy tube for feeding
access to? and possibly a tracheostomy and mechanical ventilator
Has the patient had prior suicide attempts, a psychiatric
is feasible. Patients in a persistent vegetative state
consultation, and are there problems at work?
(PVS) may be kept alive for decades with no improve-
Has anyone complained about the patient’s drinking habits?
Has the patient used medications that may increase heat ment in awareness. Patients in a minimally conscious
production, such as salicylate drugs with sympathicomimetics state may stay in this condition for years or improve mar-
such as cocaine, amphetamines, or ecstasy? ginally. Each of these conditions can be linked to certain
degrees of brain injury, but a neuropathologist cannot
MANAGEMENT OF THE COMATOSE PATIENT 119
Table 8.2
Classification and causes of coma
predict the clinical state after grading the degree of injury. overwhelming ischemia, necrosis of all cortical layers
The neuropathology associated with coma is summa- is seen. In most patients, hypoxic-ischemic injury spares
rized in Table 8.2. the brainstem clinically, but necrosis may occur, espe-
The neuropathology associated with disorders caus- cially in the inferior colliculi and tegmental nuclei. Sus-
ing acute or prolonged coma has been well characterized. tained absence of brainstem reflexes after cardiac arrest is
Several fatal neurologic disorders causing coma have relatively uncommon.
come to autopsy and -mostly in the past-have allowed Few patients with CT-proven catastrophic stroke
detailed description of the underlying pathology. come to autopsy. The destruction and mass effect are evi-
The neuropathology of hypoxic-ischemic injury is a dent. In patients with large thalamic hemorrhage, blood
result of damage to the most vulnerable sites, including has tracked deep into the brainstem. In other patients,
the first and second frontal gyrus, globus pallidus, cornu edema may have caused further deterioration. Edema
ammonis, and the cerebellar cortex affecting predomi- around an intracerebral hematoma peaks after several
nantly the Purkinje cells. The ischemic alterations in days. Edema is a multiphase event and is caused by clot
the cornu ammonis involve the CA1 and CA4 sectors. retraction, movement of serum into ambient tissue, fol-
The hippocampus becomes ischemic in CA1 areas after lowed by activation of coagulation cascade and throm-
several minutes of global ischemia. The CA4 region bus, and finally erythrocyte lysis with toxicity from
requires only minimal ischemic insult for these cells to hemoglobin. Edema is perpetuated by disruption of the
become damaged. Necrosis of the globus pallidus points blood–brain barrier, as well as inflammation and
to major anoxic-ischemic injury, and is also a common activation of the complement system. Increased produc-
manifestation of carbon monoxide poisoning. tion of matrix metalloproteinase iron may also exacer-
The pathologic changes of anoxic-ischemic injury bate cerebral edema.
are typically in the watershed zones and therefore The neuropathology of traumatic brain injury is
also involve the posterior cerebral regions. With diverse but often multiple contusions and subdural
120 E.F.M. WIJDICKS
hematomas are identified at autopsy, localized on cortical Fungal encephalitis may be difficult to detect micro-
surfaces. Diffuse axonal injury is caused by rotational scopically on routine stains, and the fungus may also be
acceleration following an impact to the head. On gross challenging to culture. Aspergillus fumigatus infection of
examination, hemorrhages of the corpus callosum and the CNS is aggressive and destructive. At autopsy, both
cerebellar peduncle region are often seen, and there infarcts and hemorrhages can be found due to
may also be hemorrhages in the deeper structures. angioinvasion.
So-called “gliding contusions” can sometimes be found In acute demyelinated leukoencephalopathies, the
in the parasagittal white matter. Small hemorrhagic shear acute changes are edema with fibrinoid necrosis of blood
lesions are also commonly found in the hemispheric vessels, and also infiltration of neutrophils, mononuclear
white matter, perpendicular to the cortical ribbon. Tissue inflammatory cells, sometimes with regions of hemor-
tear hemorrhages are mostly concentrated in the midline rhage (particularly in acute hemorrhagic leukoencepha-
structures, such as the corpus callosum, septum pelluci- lopathy). Another inflammatory demyelinating disease
dum, fornix, midbrain, pons, and hippocampus. Trau- is ADEM, resulting in symmetric subcortical white-
matic brain injury is often in the medial basal cortical matter lesions. Multiple sclerosis may present with an
areas of the temporal lobes, in the margins of the base acute mass (tumefactive form of Marburg syndrome).
of the cerebellar peduncles, due to pressure on the tentor- Next to marked demyelinization, the neuropathology
ial ridge, and on top of the corpus callosum, due to inden- findings in this variant are characterized by macro-
tation by the free edge of the falx cerebri. phages, large glial cells with mitosis, and chromatin frag-
The neuropathology of bacterial meningitis is fairly mentation (Creutzfeldt cells).
characteristic and immediately apparent. At autopsy, Coma due to intoxication or poisoning is usually acci-
purulent meningitis is revealed by pus and yellow and dental, but can occur intentionally in the setting of suicide
green deposits on the leptomeninges. Generally, the pus or homicide. Many neurotoxins produce no apparent neu-
follows the distribution of the meningeal blood vessels. ropathologic changes in the CNS. In some, such as lithium
Depending on the time elapsed before death, microscopic poisoning, more specific abnormalities are seen, such as
features include neutrophils, macrophages, and fibrin in spongiform changes in the thalamus, midbrain, and cere-
the subarachnoid space. Arteritis associated with severe bellum, with significant damage to the Purkinje cells
forms of meningitis has now been recognized as one of (explaining cerebellar ataxia during presentation). Thal-
the most important secondary complications leading to lium (used in many rat poisons) produces cerebral edema
ischemic strokes and much worse outcome, including with multiple white matter and cerebellar hemorrhages,
prolonged coma. Fulminant meningitis may show cere- but also degenerative changes in the cerebral cortex, hypo-
bral edema and relatively little exudate. Acute bacterial thalamic nuclei, and olivary complex. An important foren-
meningitis may be a surprising finding in patients who sic question is whether death occurred from carbon
died rapidly, when no real opportunity for the physician monoxide poisoning. The morphology is fairly character-
existed to obtain cerebrospinal fluid. istic, with bright redness of brain sections at autopsy that
Similarly, fulminant viral encephalitis may cause remain after fixation. Often a significant brightness of the
early demise and can be confirmed at autopsy. The find- dura is seen at exposure of the brain. There is bilateral
ings are generally nonspecific, showing clusters of necrosis of the globus pallidus and pars reticulata of the
inflammatory changes. In some regions, there is perivas- substantia nigra. Cortical laminar necrosis and involve-
cular chronic inflammation with microglial nodules and ment of both hippocampi are expected.
neuronophagia. The most common etiology is herpes Acute fatal alcohol intoxication remains nonspecific,
simplex virus encephalitis, which is characterized by but brain edema and congestion can be found. Equally
hemorrhagic necrosis, specifically involving the tempo- rare is documented neuropathologic confirmation of
ral lobes, insula, and posterior orbitofrontal cortex. Cow- Wernicke–Korsakoff syndrome, with its characteristic
dry A intranuclear inclusions can be found in herpes changes that involve atrophy of the mammillary bodies,
simplex virus encephalitis. When ultrastructural findings periventricular hemorrhages, and also astrogliosis and
are examined, viral particles with hexagonal features and capillary proliferation in more chronic cases. Far more
a central nucleoid are found. Polymerase chain reaction likely in alcoholics are multiple intracranial hemorrhages,
amplification of viral DNA in cerebrospinal fluid has particularly subdural and parenchymal hemorrhages.
long replaced brain biopsy in making the diagnosis.
Cytomegalovirus encephalitis is more commonly seen
NEUROLOGIC EXAMINATION OF THE
in patients who have been infected with the human
COMATOSE PATIENT
immunodeficiency virus. Cytomegalovirus has typical
microscopic findings of scattered cytomegalic cells with The primary goal of the neurologic examination in an
intracytoplasmic viral inclusion. The absence of an unresponsive patient is to localize the lesion and thereby
inflammatory infiltrate is notable in these infections. narrow the differential diagnosis. The examination
MANAGEMENT OF THE COMATOSE PATIENT 121
should proceed in a stepwise fashion and is familiar to involving the CNs or the pathways connecting them
the neurologist. and thus are indicative of brainstem functioning. Pupil
Pending a more comprehensive neurologic examina- size, shape and reactivity should be examined. Small
tion, the depth of coma can be assessed using a coma scale. pupils could be secondary to a pontine lesion that inter-
The Glasgow Coma Scale (GCS) is the most common of rupts descending sympathetic outflow. The most com-
such scales and originally developed for victims of trau- mon cause of small pupils is prior use of opioids (on
matic brain injury, and to improve transfer of patients, it the streets, it is most often heroin; in the hospital, it is
consists of three parts: eye opening, best motor response, overuse of opioids and can be related to errors with
and best verbal response (Teasdale and Jennett, 1974). patient-controlled analgesia pumps or opioid patches).
Each component is graded on a different scale (maximum Dilated (>8 mm) pupils are due to disruption of CN
4 for eyes, 5 for verbal, and 6 for motor) and the summation III, secondary to either a mesencephalic injury or lesion
of the scores is used to communicate the depth of coma. of the peripheral nerve. Drugs and other toxins such as
The minimum score is 3 and the maximum 15. Although amphetamines or lidocaine can also result in bilaterally
not useful in the diagnosis of coma, the GCS has been dilated pupils, and must be excluded through the
shown to have acceptable interobserver reliability through patient’s history and laboratory testing. Midsize, fixed
a wide range of trained providers, and has predictive value pupils are seen in severe midbrain lesions that can be sec-
for outcomes in aneurysmal subarachnoid hemorrhage, ondary to herniation and are frequently the first sign of
traumatic brain injury, and comatose survivors of cardiac impending loss of all brainstem reflexes (Fig. 8.2).
arrest. However, the GCS does not account for the presence In addition to pupil size and reactivity, any deviation
or absence of brainstem reflexes and does not detect other of one or both eyes should also be noted. Spontaneous
highly relevant changes in the neurologic examination, eye movements, including “ping-pong” eyes or ocular
findings that could be instrumental in determining a dipping, generally indicate bihemispheric dysfunction.
patient’s prognosis. GCS is reduced to a raw motor scale Ocular bobbing, described as a rapid downward devia-
if a patient is intubated and has facial injury with swelling. tion of the eyes followed by a slow upward movement,
To address the shortcomings of the GCS, the Full Out- typically implies a pontine lesion. Bihemispheric dys-
line of UnResponsiveness (FOUR) score was developed function can also lead to the classic “roving eye
(Fig. 8.1). To simplify scoring, the FOUR score includes movements,” though metabolic processes and various
four components – eyes, motor, brainstem, and toxicities can also be responsible. Rather than support-
respiratory – that are each graded on a scale from 0 to ing particular localization or a specific disease process,
4, producing a maximum combined total score of 16. roving eye movements indicate that the brainstem is
With an equal to higher interrater reliability than the relatively intact (Table 8.3). The oculocephalic reflex
GCS, as well as validation in multiple patient popula- deserves special mention as several brainstem structures
tions, the FOUR score has proven to be an important ini- are assessed simultaneously. In a patient with a nor-
tial tool in the evaluation of comatose patients. Perhaps mally functioning brainstem, eyes will move in a direc-
because of its greater emphasis on brainstem reflexes tion opposite the head movement and appear to remain
and respiratory patterns, the FOUR score has also been fixated on a point in space (much like a doll’s eyes). If a
shown to have greater predictive value in terms of even- lesion disrupts any of the structures or pathways
tual progression towards more severe injury, especially involved in the reflex, including CNs III, IV, and VI,
in patients with low GCS scores, or the relatively ubiq- or the medial longitudinal fasciculus, the eyes will
uitous GCS score of 3 T, which is commonly reported move along with the head, remaining in midposition
by paramedics following intubation in the field after sed- with respect to the orbits.
atives and paralytics have been given. Brainstem damage Tonic deviation of the eyes, typically in the horizontal
and failure to maintain adequate ventilation are reflec- plane, may indicate an ipsilateral hemispheric lesion
tions of injury severity. The FOUR score does not con- affecting the frontal eye fields or a contralateral pontine
tain a verbal component, and can be measured with lesion. Differentiation between a hemispheric lesion and a
equal accuracy in intubated and nonintubated ICU pontine lesion can be difficult in comatose patients as
patients. The FOUR score can be used to evaluate for hemiparesis is typically not apparent. However, the oculo-
clinical progression with serial examinations in patients cephalic maneuver will be able to overcome gaze
with intracranial mass lesions. preference from a cortical lesion, since the pontine and
midbrain structures responsible for the reflex remain intact.
Horizontal deviation can also be seen with noncon-
Cranial nerves
vulsive status epilepticus, and may be one of the few
A more formal neurologic evaluation of an unresponsive signs to indicate the need for an emergent electroenceph-
patient typically begins with the cranial nerves (CNs). alogram (EEG). Skew deviation implies a brainstem
Dysfunction of any of these reflexes implies a lesion injury.
122 E.F.M. WIJDICKS
Fig. 8.1. The Full Outline of UnResponsiveness (FOUR) score. Used with the permission of Mayo foundation for Medical
Education and Research. All rights reserved.
Eye response (E) Brainstem reflexes (B)
4 ¼ eyelids open or opened, tracking, or blinking to command 4 ¼ pupil and corneal reflexes present
3 ¼ eyelids open but not tracking 3 ¼ one pupil wide and fixed
2 ¼ eyelids closed but open to loud voice 2 ¼ pupil or corneal reflexes absent
1 ¼ eyelids closed but open to pain 1 ¼ pupil and corneal reflexes absent
0 ¼ eyelids remain closed with pain 0 ¼ absent pupil, corneal, and cough reflex
Motor response (M) Respiration (R)
4 ¼ thumbs-up, fist, or peace sign 4 ¼ not intubated, regular breathing pattern
3 ¼ localizing to pain 3 ¼ not intubated, Cheyne–Stokes breathing pattern
2 ¼ flexion response to pain 2 ¼ not intubated, irregular breathing pattern
1 ¼ extension response to pain 1 ¼ breathes above ventilatory rate
0 ¼ no response to pain or generalized myoclonus status 0 ¼ breathes at ventilator rate or apnea
A fundoscopic examination should also be performed Further testing of the CNs is accomplished through
once the external examination of the eyes has been the various reflexes, including the corneal, gag, and
completed. Vitreous hemorrhage, often subhyaloid in cough, but these are the least helpful with localization.
location, can be indicative of subarachnoid hemor- Midbrain and pontine lesions can cause central neuro-
rhage. Fundoscopy may also reveal the presence of genic hyperventilation. Pontine lesions can cause cluster
papilledema. Though often cited as a manifestation of breathing (brief episodes of tachypnea punctuated by
acutely increased intracranial pressure in subarachnoid brief spells of apnea). Lower pontine and medullary
hemorrhage or acute meningitis, papilledema is more lesions can produce ataxic breathing or apnea. Sighs
commonly seen with slowly progressive processes such or yawns can herald a decrease in level of consciousness
as an enlarging intracranial mass, and may also be seen resulting from rapidly increasing intracranial pressure.
with severe hypertensive crisis causing posterior revers-
ible encephalopathy syndrome. The presence of venous
Motor responses
pulsations suggests normal intracranial pressure, but
their absence is less useful. Measuring the optic nerve Testing of the motor system in an unresponsive patient
sheath with bedside ultrasound using a high-frequency typically involves applying a noxious stimulus to the
probe is reported to estimate intracranial pressure with supraorbital nerve or the temporomandibular joint, and
some accuracy. This method could be a noninvasive assessing the patient’s reaction. Possible responses
way to detect raised intracranial pressure, allowing ear- include a localizing response, in which the patient reaches
lier and more rational therapeutic interventions, but bet- towards the stimulus, reflexive responses such as decorti-
ter validation is needed. cate or decerebrate posturing, or no response at all.
MANAGEMENT OF THE COMATOSE PATIENT 123
Fig. 8.2. Pathways of commonly used brainstem reflexes in assessment of coma. Used with the permission of Mayo foundation for
Medical Education and Research. All rights reserved.