Clinical Vignette

A 57-year-old man with coronary artery disease develops severe chest pain and heaviness on exertion and then loses consciousness while working in the garden with his wife. Emergency Medical Service is called immediately and arrives at the scene within minutes. The man is found pale, unresponsive, and flaccid. The systolic blood pressure is low, about 70–85 mm Hg, and he is found to be in ventricular tachycardia, but he promptly reverts to sinus rhythm with electroconversion. In the hospital, he is found to have roving eyes, grimaces and withdraws his limbs to painful stimuli, but has no directed responses to verbal commands. Over a 3-day period, he is awake and conversant but has poor short-term memory and ataxia. These symptoms gradually resolve over a 3-week period.

Clinical Vignette

A 76-year-old man was found unconscious in bed at home. His wife informed the emergency physician that he had a history of prostate cancer but no risk factors for vascular disease. She denied knowledge of any recent head injury. He was totally unresponsive to verbal and painful stimuli. Neurologic examination showed he was comatose with pinpoint pupils. Eye movements to doll’s-eyes maneuvers were full and conjugate, and cold caloric stimulation of the ear canals produced ipsilateral tonic deviation of the eyes without nystagmus. There were bilateral withdrawal responses of his extremities to noxious stimuli, and bilateral Babinski signs.

Intravenous administration of 0.4 mg naloxone produced dramatic change, with full awakening within a few minutes. Results of a subsequent brain computed tomography (CT) were normal, confirming that there was no evidence of intracerebral, subarachnoid, or subdural hemorrhage, cerebral infarction, or mass lesions. When asked about narcotic use, the patient stated that he was no longer able to tolerate the pain of metastatic prostate cancer; he had taken an overdose of an opioid analgesic.

The first vignette reflects a common scenario for anoxic–ischemic brain injury secondary to cardiac arrest. The degree of recovery usually depends on a number of factors that include age, extent, or duration of the ischemic insult and the initial presenting neurologic examination. A detailed history, review of in-field records, and serial examinations is an essential first step in guiding prognostic predications and determining the need for further workup. The second vignette illustrates the classic case of “toxic-metabolic” induced coma. Despite profound unresponsiveness and very miotic pupils, neurologic examination demonstrated retained brainstem reflexes and CT results were normal. Although pontine hemorrhage is often suspected in a comatose septuagenarian with pinpoint pupils, intact reflexive eye movement strongly indicated a metabolic cause. The prognosis in such cases, in the absence of secondary hypoperfusion or anoxia, is overwhelmingly favorable.

Consciousness is the state of awareness of internal and external stimuli and is manifested by the ability to react to these stimuli through thought or by directed physical movement. Coma is the loss of awareness of stimuli and the ability to react voluntarily to them. Full consciousness of one’s self and the surroundings can be disrupted partially without total loss of arousal or wakefulness and is sometimes referred to as a state of stupor. Varying degrees of consciousness can therefore be roughly delineated by the specificity or accuracy of the response to a particular stimulus, and terms such as confusion, obtundation, or stuporous are used to reflect this. However, the most useful tool in following patients with altered mentation remains the exact description of patient behavior and reactions to specific stimuli. For example, it is preferable to indicate that a patient stays alert without stimulation but is unable to give the exact date and location or follow two sequential commands than to only say that the patient is confused or clouded. Nevertheless, defining terms may provide uniformity in meaning when encountered in patient records. Obtundation describes a condition in which repeated stimuli are needed to draw the patients’ attention back to a task. Stupor is a state of extreme inattention in which wakefulness and minimal interaction with the examiner can be achieved only by repeated or constant stimulation. Delirium is an acute confusional state often involving sympathetic nervous system overactivity with attention marred by hyperexcitability. Tachycardia, perspiration, hypertension, and hallucinations may all be features of delirium.

Because the examining physician can only infer thought from patients’ actions (e.g., speech or movement), a reliable and reproducible physical examination is essential in evaluating the comatose or stuporous patient. The neurologist must make every effort to establish the presence or absence of a directed nonreflexive response and judge its quality. For example, in basilar occlusion when the lesion is restricted to the basis pontis a “locked-in” syndrome occurs with the patient seemingly having no directed response to stimuli, yet on close examination may blink in an exact fashion to instructions and indirectly answer questions appropriately. Partially preserved voluntary vertical eye movements may also be present. Similarly, in patients with severe acute polyneuropathies such as Guillain–Barré syndrome, consciousness is preserved but difficult to assess and quantify secondary to profound peripheral weakness.

The Glasgow Coma Scale assesses and quantifies the degree of consciousness across three measures: response to verbal commands, response of eye opening, and the nature of motor movements in response to verbal or physical stimuli. Those not responding to verbal commands or opening their eyes with a Glasgow Coma Scale score of 8 or less are defined as being in a coma (Fig. 16-1). The Glasgow Coma Scale is one of the primary predictors of long-term outcomes, especially in cases of head trauma.

Figure 16-1 Glasgow Coma Scale.

Prevalence of the different etiologies of coma varies depending on the population surveyed. For example, head trauma and intoxicants are the major causes in registries based on densely populated high-crime areas. Stroke and cardiac events are the leading etiologies in suburban areas with retirement communities. Overall, trauma, stroke, diffuse anoxic–ischemic brain insult (secondary to cardiorespiratory arrest), and intoxicants are the leading mechanisms for coma. Infections, seizures, and metabolic–endocrine disorders account for the remaining cases (Fig. 16-2).

Figure 16-2 Differential Diagnosis of Coma.

States that affect cognition and attention without affecting wakefulness such as the various degenerative dementias (characterized by progressive cognitive deterioration) and focal brain lesions (which cause restricted cortical dysfunction) do not fit the definition of coma. Sleep is a normal patterned physiologic disconnection of the cortex from external stimuli and is discussed elsewhere (Chapter 15).

Clinical Vignette

A 23-year-old woman was an unrestrained driver in a “head-on” automobile accident. She was ejected 30 feet through the windshield and sustained major head trauma. On arrival in the emergency department, she was totally unresponsive, hypotensive, and tachycardic. Brain CT demonstrated generalized cerebral edema and diffuse subarachnoid hemorrhage. Neurologic examination showed her to be unresponsive even to painful stimuli, other than some rare nonpurposeful right leg movements. Pupils were minimally and inconsistently reactive, and she had a dense left hemiplegia. Subsequent magnetic resonance imaging (MRI) demonstrated bilateral focal contusions of the cerebral hemispheres, shear injury of the splenium of the corpus callosum and brainstem edema. Four months later, after no improvement in her clinical state, she was diagnosed with persistent vegetative state (PVS).

Cases of PVS frequently involve young individuals with healthy cardiovascular and pulmonary systems. Before the recognition of these patients’ hopeless outcomes after a few months of no improvement, some were maintained in chronic care facilities or their parents’ homes for years, with the unrealistic hope that they might someday regain the ability to meaningfully interact.

The vegetative state, minimally conscious states, or post-coma unawareness are terms that describe a state of preserved brainstem and hypothalamic functions with absent or insufficient cortical function to sustain awareness of environment and self. Wakefulness is by definition preserved, and patients may cycle through sleep stages. There is no behavioral evidence of even the simplest reproducible response. Patients may startle, look about, occasionally move a limb, shift position, or yawn, but none of these actions are consistently in response to a specific stimulus (Fig. 16-5). Even the most basic voluntary actions, such as chewing and swallowing, are lost. Once reversible metabolic or exogenous causes have been eliminated, the condition is called persistent when it lasts without change for more than 1 month. It is considered permanent when lasting more than 12 months for traumatic brain injury and more than 3 months for nontraumatic causes. After these time limits, the chance of recovery is exceedingly low and at best progresses to severe disability.

Figure 16-5 Persistent Vegetative State.

As with coma, individuals in a posttraumatic PVS have better chances of recovery than cases due to medical causes. Nevertheless, one third of all these patients die within the first year. Of patients with head trauma, one third regains consciousness after 3 months and approximately one half in a year. Overall, one fourth of all patients with traumatic PVS recover to a level of moderate disability, mostly those who regain awareness within 3 months.

Of patients with nontraumatic PVS, more than 50% die within a year and only approximately 10–15% regain consciousness by the third month. Most remain severely disabled, with rare improvement in functional status. If the condition persists longer, there is minimal chance of any significant functional recovery. Neither age nor cause seems to correlate with eventual recovery, but of those recovering, the younger patients show somewhat better outcomes than older patients, at least in locomotion and self-care. After 3 months, once PVS is considered permanent, withdrawal of nutritional support and hydration can be discussed with the family. Many physicians consider such withdrawal acceptable, based on the contention that nutritional support in such cases constitutes medical treatment that is neither alleviating suffering nor improving the overall condition. When viewed as a human or legal rights issue, such reasoning becomes more complex and less applicable as a general principle.

Clinical Vignette

A 46-year-old man was found lying on the floor at home. Examination in the emergency department (ED) demonstrated a left hemiplegia, with conjugate eye deviation to the right. He was awake but had profound neglect for his left arm and denied any difficulties with his limbs. Brain CT demonstrated a large right middle cerebral artery and anterior cerebral artery territory stroke, with incipient potential for significant brain edema and increased ICP (“malignant brain swelling”). During the next 2 days, the patient became obtunded and progressively less responsive to external stimulation. Repeat brain CT scan showed loss of sulcal markings and a right cerebral shift across the midline falx and downward through the cerebellar tentorium, with distortion of the midbrain.

The patient underwent intubation for airway protection and, soon afterward, could not be aroused. He had right-sided flexed arm posturing and left-sided extension, with tonic leg extension and plantar flexion. His pupils were irregular and sluggishly reactive to light. Conjugate eye movements to the doll’s-eyes maneuver were lost. He did not respond to osmotic agents or hyperventilation. A hemicraniectomy was performed, and during the following week, he awakened gradually and underwent extubation. He could eventually interact with his family and perform simple tasks, but he remained disabled, with a dense right hemiplegia, hemianopsia, and cognitive difficulties.

Anatomic Considerations

The skull is a rigid closed cavity that serves as a basin in which the brain is suspended and protected from traumatic injury. The brain comprises approximately 90% of intracranial volume, with the remaining 10% blood and CSF. The ability to compensate for increased intracranial volume is therefore limited, and when maximum accommodation occurs, any further volume increase causes an exponential increase in ICP. Eventually, arterial and arteriolar perfusion is compromised, and ischemic tissue damage with swelling ensues, causing an even greater increase in ICP. If the exerted force on the brain is asymmetric (e.g., focal brain tumor, lobar bleed, or a unilateral stroke), then shifts in brain tissue against or across fixed structures may occur. Extrusion of shifted brain across fixed intracranial structures (falx cerebri, cerebellar tentorium, and the skull) is called herniation. Whether brain dysfunction occurs as a result of shift without actual herniation is unclear. Shift and herniation likely represent progressive stages in an evolving continuum, starting with reversible tissue dysfunction and ending with eventual cell ischemia and death.

Rostrocaudal Signs of Brain Compromise

As pressure from a hemispheric lesion increases, patients gradually move from being easily roused, but inattentive, to sleepy and unable to maintain wakefulness, then to coma—a state of absent voluntary or directed response to external or internal stimuli.

The ascending reticular formation, excited by sensory input, mediates arousal and consciousness to the cortex via the thalamic nuclei. Lesions that cause coma are at one of three levels along the neuraxis: bilateral cerebral cortex, the thalami, or the upper brainstem. The classic concept of herniation and coma produced by brain mass lesions pertains to a hemispheric process that ultimately causes “rostrocaudal” deterioration of function, gradually coursing down the hemispheres into the medulla. Although these “stages” rarely manifest symmetrically in a strict and clearly delineated sequential pattern, this paradigm remains useful for evaluating deteriorating patients with evolving neurologic signs. In addition to the level of consciousness, important physical examination elements include pupillary size and reactivity, reflexive eye movements, limb posturing, and breathing pattern (Fig. 16-4, Table 16-1).

Pupillary Reactivity and Eye Movements

When pressure onto or across the diencephalon exists, loss of wakefulness results, but patients may transiently continue to withdraw appropriately from uncomfortable stimuli and to resist passive limb movements. Pupils are small and retain reactivity, although at times blunted and subtle to detect. Although there is no visual fixation, eye movements are conjugate and full. As pressure mounts across the thalami onto the mesencephalon, pupillary and eye movement abnormalities appear. Involvement of CN-III or its nucleus initially causes irregular and poorly reactive pupils (corectopia). Eventually, eye movements are disrupted by CN-III or CN-VI lesions or from involvement of the medial longitudinal fasciculus (MLF). The MLF, a paracentral dorsally located tract coursing up the vestibular nuclei to the CN-III nucleus, maintains conjugate eye movements either initiated voluntarily in the waking state or induced reflexively from cervical or vestibular inputs in comatose patients. This pathway provides the basis of doll’s-eyes testing or caloric stimulation testing of the semicircular canals. An intact MLF system keeps the eyes from moving passively when the examiner rolls the head to one side. The eyes remain in their primary position in relation to the examiner or seem to move to the opposite side in relation to the head rolling. With unilateral caloric stimulation of the ears, the eyes deviate conjugately to one side or another, depending on the water temperature used for irrigation. The direction of the convection current induced in the semicircular canals by different temperatures determines the direction of eye movement. With the head maintained in the neutral position, cold water causes the eye to deviate to the side of the stimulated ear while warm water causes deviation away from the stimulated ear. Disruption of the MLF system causes an abnormal or absent responses of these reflexive eye movements (Fig. 16-6). Therefore oculocephalic testing checks the integrity of a large portion of the brainstem from the vestibular nuclei to the mesencephalic third-nerve nucleus.

Figure 16-6 Eye Movements in Coma.

Breathing

Respiratory patterns also change with worsening levels of consciousness in coma (Fig. 16-7). The earliest breathing alterations are Cheyne–Stokes respirations. Hemispheric forebrain structures serve to regulate breathing by mechanisms independent of CO₂ accumulation. With bilateral cerebral cortex damage, this breathing control is lost, and CO₂-driven breathing is accentuated with only modest CO₂ accumulations, thus inducing an increased rate and depth of respiration. This reactive hyperpnea leads to an eventual decrease in arterial CO₂ and, again without forebrain control, loss of respiratory drive. The ensuing apnea then allows CO₂ to reaccumulate and the cycle to repeat itself, resulting in hyperpnea of a crescendo–decrescendo pattern, alternating with intervening episodes of brief apnea.

Figure 16-7 Respiratory Exchange in Head Injury.

Midbrain and upper pons lesions cause hyperventilation with a constant rate and amplitude, without periods of apnea. The reasons for the so-called “central neurogenic hyperventilation” are unclear but are unlikely to be of purely neuronal origin. Lung congestion caused by immobility and poor airway protection likely play a major role. Hypothalamic and midbrain lesions engender increased sympathetic activity, which in turn promotes capillary fluid seepage, worsening lung congestion and, in extreme cases, pulmonary edema.

Injury to the lower half of the pons damages the respiratory control system, possibly generating apneustic breathing; a pattern of prolonged end inspiratory pauses alternating with end-expiratory pauses of several seconds, without the crescendo–decrescendo pattern of Cheyne–Stokes breathing. Further damage causes this pattern to fragment into an irregular, unpredictable rhythm of varying amplitude, intermixed with pauses of variable length. Ultimately, destruction of the centrally located dorsomedial medullary respiratory center causes total cessation of breathing, even before circulatory collapse occurs.

Variation from the Classic Rostrocaudal Paradigm

Unilateral cerebral lesions can cause asymmetric pressures leading to medial temporal lobe (uncal) herniation through the tentorial incisure, with direct compression of the midbrain (Fig. 16-8). In this case, the diencephalic features described above are not seen; instead, rapid loss of consciousness is immediately followed by a decerebrate posture. This is usually heralded by a compressive palsy of CN-III as it exits the ventral aspect of the midbrain and runs between the superior cerebellar and posterior cerebral arteries across the top of the tentorium. The initial sign is pupillary dilation, followed by ophthalmoplegia and ptosis with downward displacement of the abducted globe. Hemiplegia ipsilateral to the lesion may result from compression of the contralateral anteriorly located pyramidal tract against the anterior edge of the tentorium (Kernohan notch phenomenon). Further increase in pressure causes stretching of the pontine penetrators off the basilar artery or venous congestion with paramedian hemorrhages and usually irreversible worsening (Fig. 16-8). A sudden worsening and increase in ICP may also result from posterior cerebral artery compression with occipital lobe infarction. Finally, the cingulate gyrus may herniate beneath the falx cerebri, compressing the ipsilateral or contralateral anterior cerebral artery and causing infarction in its distribution (Fig. 16-8).

Figure 16-8 MR and CT Images Showing Cerebral Herniation Patterns.

Infratentorial lesions within the brainstem tegmentum or secondary to brainstem compression, such as with cerebellar mass lesions, cause coma abruptly as a result of the almost immediate involvement of the reticular activating system. Lesions involving the midbrain result in oculomotor- or infranuclear-type ophthalmoplegia or both, with fixed irregular or midposition dilated pupils. If the lesion involves the pons without the midbrain, sympathetic fibers running up to the CN-III nucleus are destroyed, and pupils are pinpoint in size but still reactive to light. An internuclear ophthalmoplegia occurs from bilateral MLF lesions, but vertical oculocephalic movements, controlled by the tectal midbrain, are preserved. Cerebellar mass lesions can cause forward brainstem displacement and may produce findings similar to those described for isolated pontine lesions or may cause cerebellar tissue crowding and herniation upward around the midbrain through the tentorium or downward around the medulla through the foramen magnum. Cerebellar tonsillar herniation down through the foramen magnum causes sudden respiratory and circulatory arrest, without gradual signs of evolving brainstem dysfunction.

Coma from metabolic disease rarely conforms to the typical rostrocaudal stages and often shows concurrent findings pertaining to different nervous system levels. For example, hypoglycemia can cause unconsciousness with decerebrate posturing but preserved oculocephalic responses and pupillary reactivity. In metabolic comas from opioid overdose, pupils are tiny but reactive, even though respiratory drive may be obliterated. Also, the oculocephalics are intact, despite drug-induced pinpoint pupillary changes mimicking a pontine hemorrhage, as the vignette at the beginning of this chapter illustrates. Finally, pupillary reactivity remains relatively resistant to metabolic effects; when other brainstem signs are absent, the presence of brisk pupillary reactivity suggests a nonstructural metabolic or toxic cause.

Treatment of Increased Intracranial Pressure

When signs of increased ICP are evident, emergent treatment is needed to halt progressive obtundation or coma and to avoid herniation and irreversible brain injury. Delaying treatment to first determine the underlying pathophysiologic mechanism is of minimal benefit. An invasive, but highly effective, method to decrease ICP is CSF drainage through an external ventricular drain if applicable. Noninvasive therapeutic modalities available to acutely control increasing ICP act mainly by three mechanisms: vascular, osmotic, and metabolic. With induced vasoconstriction, cerebral blood flow (CBF) diminishes, reducing total cerebral blood volume with a subsequent decrease in ICP. Agents that create a hyperosmolar intravascular compartment in relation to brain tissue induce water movement down a gradient from cells and the interstitium into plasma, reducing total brain water content, volume, and pressure. This affects both normal and, likely to a lesser extent, damaged edematous brains. Osmotic agents may have other beneficial actions, such as preserving cerebral perfusion pressure (CPP), decreasing blood viscosity, decreasing CSF production, and the scavenging of free radicals.

Increased metabolic demand from injury or illness may increase blood flow and enhance the delivery of oxygen, which, in turn, may cause increased free radical production and cell injury. Decreasing the metabolic drive helps limit blood flow and decreases the need for tissue oxygen delivery.

Clinical Vignette

A 56-year-old man suddenly collapsed at home after experiencing severe chest pain. His wife called the emergency technicians, who found him pulseless and cyanotic. ECG demonstrated ventricular fibrillation, but he was successfully defibrillated. After an airway was established and 100% oxygen was given, he was transported to the ED. There, neurologic evaluation showed that he was unresponsive to any form of communication. His pupils were dilated and not reactive to light stimulation. Decerebrate posturing was noted to suctioning and to noxious stimulation. Bilateral Babinski signs were present. He eventually became flaccid, and cold caloric vestibular stimulation showed no ocular response. The next day, he developed generalized myoclonus and continued to require cardiac and full respiratory support. Three days later, there was no change in his neurologic status. An apnea test showed no respiratory response to induced hypercarbia. Although he was declared brain dead, his wife asked that further testing be performed to confirm the clinical diagnosis. An EEG demonstrated electrocerebral silence, and she agreed to have life support withdrawn.

This vignette is the classic example of a patient with prolonged cardiorespiratory arrest resulting in devastating diffuse cerebral ischemic damage. Until a precise determination of brain death is established, there are many medical and legal issues to address in caring for individuals who have no effective residual brain function despite cardiopulmonary function maintained with modern intensive care therapies.

In most medical communities, a person is considered dead once there is irreversible and total cessation of all brain function, regardless of a continuing functional circulatory system. The cause of brain damage must be clearly elucidated by history, examination, or medical tests before the diagnosis of brain death is entertained. Intoxicants, sedatives, and hypothermia may present similarly to brain death but are potentially reversible and must always be considered if the cause is not clear and well documented. In many countries, including the United States, “brain death” constitutes a legal definition of death, and all life support measures can be halted.

When caring for an individual, it is best to respect the family’s wishes, religious or personal, regarding the timing of discontinuing life support. It is important to continue to explain the situation’s finality and that circulatory collapse will invariably occur within hours to days of the onset of this clinical picture. The widespread difficulty in obtaining organs for an ever-growing list of patients awaiting transplant procedures makes it of paramount importance to broach the subject of organ donation as soon as possible as it is vital to harvest organs early. The physician who has an established relationship with the patient’s family is perhaps the one best to initiate such discussion before involving the transplant team.

Brain Death Criteria

The criteria for brain death vary among states and countries. Usually the determination is clinical, with testing used only as an ancillary or confirmatory measure. The following are generally accepted principles of brain death determination:

Figure 16-9 Hypoxic Brain Damage and Brain Death.

Mitigating Factors

When a severe cerebral insult is suspected but brain death determination cannot be confirmed because of confounding issues, the utmost should be done to correct for these specific factors before brain death assessment can proceed. For example, hypothermia is treated with a warming blanket to bring and maintain core body temperature above 36.5°C. Fluid, and at times vasopressor agents, are administered for patients with systolic blood pressures lower than 90 mm Hg.

Patients with chronic hypercapnia secondary to lung disease such as chronic obstructive pulmonary disease have a higher respiratory center PCO₂ threshold, and a PCO₂ of approximately 60 mm Hg may not necessarily drive the chemoreceptors, even with a functioning brainstem. The CO₂ level may be allowed to climb to approximately 80 mm Hg, but such levels risk ensuing acidosis with direct cardiodepressor effects as well as arrhythmias and hypotension. Therefore, it is preferable in these instances to obtain confirmatory tests to bolster the diagnosis without risking untoward iatrogenic complications.

Although most centers in the United States uphold the general outline of the principles mentioned above, there are numerous variations and differences concerning how best to ensure diagnostic certainty. Most medical centers do not require confirmatory tests. The number of evaluations and the time span between them also differ. Many institutions require a brain death evaluation by two attending neurologists at different times and their presence at the apnea test. The specific brain death criteria and protocol for each medical center must be consulted before the evaluation is begun and a diagnosis is substantiated.