Stupor and Coma

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Chapter 5 Stupor and Coma

Joseph R. Berger

Definitions

Consciousness may be defined as a state of awareness of self and surroundings. Alterations in consciousness are conceptualized into two types. The first type affects arousal and is the subject of this chapter. The second type involves cognitive and affective mental function, sometimes referred to as the “content” of mental function. Examples of the latter type of alteration in consciousness are dementia (see Chapter 6), delusions, confusion, and inattention (see Chapter 9). These altered states of consciousness, with the exception of advanced dementia, do not affect the level of arousal. Sleep, the only normal form of altered consciousness, is discussed in Chapter 68.

The term delirium describes a clouding of consciousness with reduced ability to sustain attention to environmental stimuli. Diagnostic criteria for delirium from the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-R) include at least two of the following: (1) perceptual disturbance (misinterpretations, illusions, or hallucinations), (2) incoherent speech at times, (3) disturbance of sleep/wake cycle, and (4) increased or decreased psychomotor activity. Delirium is a good example of a confusional state in which a mild decline in arousal may be clinically difficult to separate from a change in cognitive or affective mental function. In clinical practice, the exact boundary between different forms of altered consciousness may be vague. Alterations in arousal, though often referred to as “altered levels of consciousness,” do not actually form discrete levels but rather are made up of a continuum of subtly changing behavioral states that range from alert to comatose. These states are dynamic and thus may change with time. Four points on the continuum of arousal are often used in describing the clinical state of a patient: alert, lethargic, stuporous, and comatose. Alert refers to a perfectly normal state of arousal. Lethargy lies between alertness and stupor. Stupor is a state of baseline unresponsiveness that requires repeated application of vigorous stimuli to achieve arousal. Coma is a state of complete unresponsiveness to arousal in which the patient lies with the eyes closed. The terms lethargy and stupor cover a broad area on the continuum of behavioral states and thus are subject to misinterpretation by subsequent observers of a patient when used without further qualification. In clinical practice, in which relatively slight changes in arousal may be significant, only the terms alert and comatose (the endpoints of the continuum) have enough precision to be used without further qualification.

Conditions That May Mimic Coma

Several different states of impaired cognition or consciousness may appear similar to coma or be confused with it (Table 5.1). Moreover, patients who survive the initial coma may progress to certain of these syndromes after varying lengths of time. Once sleep/wake cycles become established, true coma is no longer present. Differentiation of these states from true coma is important to allow administration of appropriate therapy and help determine prognosis.

Table 5.1 Behavioral States Confused with Coma

In the locked-in syndrome (de-efferented state), patients are alert and aware of their environment but are quadriplegic, with lower cranial nerve palsies resulting from bilateral ventral pontine lesions that involve the corticospinal, corticopontine, and corticobulbar tracts. These patients are awake and alert but are voluntarily able only to move their eyes vertically or blink. The locked-in syndrome most often is observed as a consequence of pontine infarction due to basilar artery thrombosis. Other causes include central pontine myelinolysis and brainstem mass lesions. A state similar to the locked-in syndrome also may be seen with severe polyneuropathy—in particular, acute inflammatory demyelinating polyradiculoneuropathy, myasthenia gravis, and poisoning with neuromuscular blocking agents.

In the persistent vegetative state (PVS), patients have lost cognitive neurological function but retain vegetative or noncognitive neurological function such as cardiac action, respiration, and maintenance of blood pressure. This state follows coma and is characterized by absence of cognitive function or awareness of the environment despite a preserved sleep/wake cycle. Spontaneous movements may occur, and the eyes may open in response to external stimuli, but the patient does not speak or obey commands. Diagnostic criteria for PVS are provided in Box 5.1. Diagnosis of this condition should be made cautiously and only after extended periods of observation. A number of poorly defined syndromes have been used synonymously with PVS, including apallic syndrome or state, akinetic mutism, coma vigil, alpha coma, neocortical death, and permanent unconsciousness. These terms, used variously by different authors, probably are best avoided because of their lack of precision.

Box 5.1

Criteria for Diagnosis of Persistent Vegetative State

1. No evidence of awareness of themselves or their environment; they are incapable of interacting with others

2. No evidence of sustained, reproducible, purposeful, or voluntary behavioral responses to visual, auditory, tactile, or noxious stimuli

3. No evidence of language comprehension or expression

4. Intermittent wakefulness manifested by the presence of sleep/wake cycles

5. Sufficiently preserved hypothalamic and brainstem autonomic functions to survive if given medical and nursing care

6. Bowel and bladder incontinence

7. Variably preserved cranial nerve (pupillary, oculocephalic, corneal, vestibulo-ocular, and gag) and spinal reflexes

Data from The Multi-Society Task Force on PVS, 1994. Medical aspects of the persistent vegetative state. N Engl J Med 330, 1499-1508, 1572-1579.

A condition that has been estimated to be 10 times more common than PVS is the minimally conscious state, in which severe disability accompanies minimal awareness. A set of diagnostic criteria for the minimally conscious state has been proposed (Box 5.2). Abulia is a severe apathy in which patients have blunting of feeling, drive, mentation, and behavior such that they neither speak nor move spontaneously.

Box 5.2

Criteria for the Minimally Conscious State

To diagnose a minimally conscious state, limited but clearly discernible evidence of self- or environmental awareness must be demonstrated on a reproducible or sustained basis by one or more of the following behaviors:

1. Follows simple commands

2. Gestural or verbal yes/no responses (regardless of accuracy)

3. Intelligible verbalization

4. Purposeful behavior, including movements or affective behaviors that occur in contingent relationship to relevant environmental stimuli and are not due to reflexive activity

Data from Giacino, J.T., Ashwal, S., Childs, N., et al., 2002. The minimally conscious state: definition and diagnostic criteria. Neurology 58, 349-353.

Catatonia may result in a state of muteness with dramatically decreased motor activity. The maintenance of body posture, with preserved ability to sit or stand, distinguishes it from organic pathological stupor. It generally is a psychiatric manifestation but may be mimicked by frontal lobe dysfunction or drug effect.

Pseudocoma is the term for a condition in which the patient appears comatose (i.e., unresponsive, unarousable, or both) but has no structural, metabolic, or toxic disorder.

Approach to the Patient in Coma

The initial clinical approach to the patient in a state of stupor or coma is based on the principle that all alterations in arousal constitute acute life-threatening emergencies until vital functions such as blood pressure and oxygenation are stabilized, potentially reversible causes of coma are treated, and the underlying cause of the alteration in arousal is understood. Urgent steps may be necessary to avoid or minimize permanent brain damage from reversible causes. In view of the urgency of this situation, every physician should develop a diagnostic and therapeutic routine to use with a patient with an alteration in consciousness. A basic understanding of the mechanisms that lead to impairment in arousal is necessary to develop this routine. The anatomical and physiological bases for alterations in arousal are discussed in Chapter 68.

Although it is essential to keep in mind the concept of a spectrum of arousal, for the sake of simplicity and brevity only the term coma is used in the rest of this chapter. Table 5.2 lists many of the common causes of coma. More than half of all cases of coma are due to diffuse and metabolic brain dysfunction. In Plum and Posner’s landmark study (1980, see 2007 revision) of 500 patients initially diagnosed as having coma of unknown cause (in whom the diagnosis was ultimately established), 326 patients had diffuse and metabolic brain dysfunction. Almost half of these had drug poisonings. Of the remaining patients, 101 had supratentorial mass lesions, including 77 hemorrhagic lesions and 9 infarctions; 65 had subtentorial lesions, mainly brainstem infarctions; and 8 had psychiatric coma.

Table 5.2 Causes of Coma

I. SYMMETRICAL-NONSTRUCTURAL

Toxins

Drugs

Monoamine oxidase inhibitors

II. SYMMETRICAL-STRUCTURAL Supratentorial

Bilateral internal carotid occlusion

Bilateral anterior cerebral artery occlusion

III. ASYMMETRICAL-STRUCTURAL Supratentorial

Thrombotic thrombocytopenic purpura ^†

Disseminated intravascular coagulation

Nonbacterial thrombotic endocarditis marantic endocarditis

Subacute bacterial endocarditis

Fat emboli

Unilateral hemispheric mass (tumor, bleed) with herniation

Metabolic

Aminoacidemia

Wernicke encephalopathy

Porphyria

Hepatic encephalopathy *

Uremia

Dialysis encephalopathy

Addisonian crisis

Subarachnoid Hemorrhage

Thalamic hemorrhage *

Trauma—contusion, concussion *

Hydrocephalus

Subdural Hemorrhage, Bilateral

Intracerebral bleed

Pituitary apoplexy ^†

Massive or bilateral supratentorial infarction

Multifocal leukoencephalopathy

Creutzfeldt-Jakob disease

Adrenal leukodystrophy

Infections

Postinfectious encephalomyelitis

Waterhouse-Friderichsen syndrome

Psychiatric Catatonia Other

Postictal

Diffuse ischemia (myocardial infarction, congestive heart failure, arrhythmia)

Hypotension

Fat embolism

Hypertensive encephalopathy

Hypothyroidism

Infratentorial

Basilar occlusion *

Midline brainstem tumor

Pontine hemorrhage *

Subdural Empyema

Thrombophlebitis ^†

Multiple sclerosis

Leukoencephalopathy associated with hemotherapy

Acute disseminated encephalomyelitis

Infratentorial

Brainstem infarction

Brainstem hemorrhage

* Relatively common asymmetrical presentation.

† Relatively symmetrical.

Data from Plum, F., Posner, J.B., 1980. The Diagnosis of Stupor and Coma, third ed. F.A. Davis, Philadelphia; and from Fisher, C.M., 1969. The neurological examination of the comatose patient. Acta Neurol Scand 45, 1-56.

A logical decision tree often used in searching for the cause of coma divides the categories of diseases that cause coma into three groups: structural lesions, which may be above or below the tentorium; metabolic and toxic causes; and psychiatric causes. The history and physical examination usually provide sufficient evidence to determine the presence or absence of a structural lesion and quickly differentiate the general categories to either decide what further diagnostic tests are needed or allow for immediate intervention if necessary.

Serial examinations are needed, with precise description of the behavioral state at different points in time to determine whether the patient is improving or—a more ominous finding—worsening, and to decide whether a change in therapy or further diagnostic testing is necessary. Subtle declines in the intermediate states of arousal may herald precipitous changes in brainstem function, which may affect regulation of vital functions such as respiration or blood pressure. The dynamic quality of alterations of consciousness and the need for accurate documentation at different points in time cannot be overemphasized.

Rapid Initial Examination and Emergency Therapy

A relatively quick initial assessment is conducted to ensure that the comatose patient is medically and neurologically stable before a more detailed investigation is undertaken. This rapid initial examination is essential to rule out the need for immediate medical or surgical intervention. In addition, various supportive or preventive measures may be indicated.

Urgent and sometimes empirical therapy is given to prevent further brain damage. Potential immediate metabolic needs of the brain are supplied by empirical use of supplemental oxygen, intravenous (IV) thiamine (at least 100 mg), and IV 50% dextrose in water (25 g). A baseline serum glucose level should be obtained before glucose administration.

The use of IV glucose in patients with ischemic or anoxic brain damage is controversial. Extra glucose may augment local lactic acid production by anaerobic glycolysis and may worsen ischemic or anoxic damage. Clinically, however, we currently recommend empirical glucose administration when the cause of coma is unknown. There are two reasons for this approach: (1) the frequent occurrence of alterations in arousal due to hypoglycemia and the relatively good prognosis for coma due to hypoglycemia when it is treated expeditiously; and (2) the potentially permanent consequences if it is not treated. By comparison, the prognosis for anoxic or ischemic coma generally is poor and probably will remain poor regardless of glucose supplementation.

Thiamine must always be given in conjunction with glucose to prevent precipitation of Wernicke encephalopathy. Naloxone hydrochloride may be given parenterally, preferably IV, in doses of 0.4 to 2 mg if opiate overdose is the suspected cause of coma. An abrupt and complete reversal of narcotic effect may precipitate an acute abstinence syndrome in persons who are physically dependent on opiates.

Initial examination should include a check of general appearance, blood pressure, pulse, temperature, respiratory rate and breath sounds, best response to stimulation, pupil size and responsiveness, and posturing or adventitious movements. The neck should be stabilized in all instances of trauma until cervical spine fracture or subluxation can be ruled out. The airway should be protected in all comatose patients and an IV line placed.

In coma, however, the classic sign of an acute condition in the abdomen—namely, abdominal rigidity—may be subtle or absent. In addition, the diagnosis of blunt abdominal trauma is difficult in patients with a change in mental status. Therefore, in unconscious patients with a history of trauma, peritoneal lavage by an experienced surgeon may be warranted.

Hypotension, marked hypertension, bradycardia, arrhythmias causing depression of blood pressure, marked hyperthermia, and signs of cerebral herniation mandate immediate therapeutic intervention.

Hyperthermia or meningismus prompts consideration of urgent lumbar puncture (LP). Examination of the fundus of the eye for papilledema and a computed tomography (CT) scan of the brain should be performed before LP in any comatose patient. Although the only absolute contraindication to LP is the presence of an infection over the site of puncture, medicolegal considerations make a CT scan mandatory before LP. To avoid a delay in therapy required to perform a CT scan, some authorities recommend initiating antibiotics immediately when acute bacterial meningitis is strongly suspected, though this may prevent subsequent identification of the responsible organism.

The risk of herniation from an LP in patients with evidence of increased intracerebral pressure is difficult to ascertain from the literature; estimates range from 1% to 12%, depending on the series (Posner et al., 2007). It is important to recognize that both central and tonsillar herniation may increase neck tone.

Despite an elevated intracranial pressure (ICP), sufficient cerebrospinal fluid (CSF) should always be obtained to perform the necessary studies; bacterial culture and cell count, essential in cases of suspected bacterial meningitis, requires but a few milliliters of fluid. Intravenous access and IV mannitol should be ready in the event unexpected herniation begins after the LP. When the CSF pressure is greater than 500 mm H₂O, some authorities recommend leaving the needle in place to monitor the pressure and administering IV mannitol to lower the pressure. If focal signs develop during or after the LP, immediate intubation and hyperventilation also may be necessary to reduce intracerebral pressure urgently until more definitive therapy is available.

Ecchymosis, petechiae, or evidence of ready bleeding on general examination may indicate coagulation abnormality or thrombocytopenia. This increases the risk of epidural hematoma after an LP, which may cause devastating spinal cord compression. Measurements of prothrombin time, partial thromboplastin time, and platelet count should precede LP in these cases, and the coagulation abnormality or thrombocytopenia should be corrected before proceeding to LP.

Common Presentations

Coma usually manifests in one of three ways. Most commonly, it occurs as an expected or predictable progression of an underlying illness. Examples are focal brainstem infarction with extension; chronic obstructive pulmonary disease in a patient who is given too high a concentration of oxygen, thereby decreasing respiratory drive and resulting in carbon dioxide narcosis; and known barbiturate overdose when the ingested drug cannot be fully removed and begins to cause unresponsiveness. Second, coma occurs as an unpredictable event in a patient whose prior medical conditions are known to the physician. The coma may be a complication of an underlying medical illness, such as in a patient with arrhythmia who suffers anoxia after a cardiac arrest. Alternatively, an unrelated event may occur, such as sepsis from an IV line in a cardiac patient or stroke in a hypothyroid patient. Finally, coma can occur in a patient whose medical history is totally unknown to the physician. Sometimes this type of presentation is associated with a known probable cause such as head trauma incurred in a motor vehicle accident, but often the unknown comatose patient presents to the physician without an obvious associated cause. Although the patient without an obvious cause of coma may seem most challenging, thorough objective systematic assessment must be applied in every comatose patient. Special care must be taken not to be lulled or misled by an apparently predictable progression of an underlying illness or other obvious cause of coma.

History

Once the patient is relatively stable, clues to the cause of the coma should be sought by briefly interviewing relatives, friends, bystanders, or medical personnel who may have observed the patient before or during the decrease in consciousness. Telephone calls to family members may be helpful. The patient’s wallet or purse should be examined for lists of medications, a physician’s card, or other information.

Attempts should be made to ascertain the patient’s social background and prior medical history and the circumstances in which the patient was found. The presence of drug paraphernalia or empty medicine bottles suggests a drug overdose. Newer recreational drugs, such as γ-hydroxybutyrate (GHB), must be considered in the differential diagnosis. An oral hypoglycemic agent or insulin in the medicine cabinet or refrigerator implies possible hypoglycemia. Antiarrhythmic agents such as procainamide or quinidine suggest existing coronary artery disease with possible myocardial infarction (MI) or warn that an unwitnessed arrhythmia may have caused cerebral hypoperfusion, with resulting anoxic encephalopathy. Warfarin, typically prescribed for patients with deep venous thrombosis or pulmonary embolism, those at risk for cerebral embolism, and those with a history of brainstem or cerebral ischemia, may be responsible for massive intracerebral bleeding. In patients found to be unresponsive at the scene of an accident such as a car crash, the unresponsive state may be due to trauma incurred in the accident, or sudden loss of consciousness may have precipitated the accident.

The neurologist often is called when patients do not awaken after surgery or when coma supervenes following a surgical procedure. Postoperative causes of coma include many of those listed in Table 5.4. In addition, the physician also must have a high index of suspicion for certain neurological conditions that occur in this setting, including fat embolism, addisonian crisis, hypothyroid coma (precipitated by acute illness or surgical stress), Wernicke encephalopathy from carbohydrate loading without adequate thiamine stores, and iatrogenic overdose of a narcotic analgesic.

Attempts should be made to ascertain whether the patient complained of symptoms before onset of coma. Common signs and symptoms include headache preceding subarachnoid hemorrhage, chest pain with aortic dissection or MI, shortness of breath from hypoxia, stiff neck in meningoencephalitis, and vertigo in brainstem stroke. Nausea and vomiting are common in poisonings. Coma also may be secondary to increased ICP. Observers may have noted head trauma, drug abuse, seizures, or hemiparesis. Descriptions of falling to one side, dysarthria or aphasia, ptosis, pupillary dilatation, or dysconjugate gaze may help localize structural lesions. The time course of the disease as noted by family or friends may help differentiate the often relatively slow, progressive course of toxic-metabolic or infectious causes from abrupt catastrophic changes seen most commonly with vascular events.

Finally, family members or friends may be invaluable in identifying psychiatric causes of unresponsiveness. The family may describe a long history of psychiatric disease, previous similar episodes from which the patient recovered, current social stresses on the patient, or the patient’s unusual idiosyncratic response to stress. Special care must be taken with psychiatric patients because of the often biased approach to these patients, which may lead to incomplete evaluation. Psychiatric patients are subject to all the causes of coma listed in Table 5.4.

General Examination

A systematic, detailed general examination is especially helpful in the approach to the comatose patient who is unable to describe prior or current medical problems. This examination begins in the initial rapid examination with evaluation of blood pressure, pulse, respiratory rate, and temperature.

Blood Pressure Evaluation

Integument Examination

Systematic examination of the integument includes inspection of the skin, nails, and mucous membranes. A great deal of information can be gained by a brief examination of the skin (Table 5.3). Hot, dry skin is a feature of heatstroke. Sweaty skin is seen with hypotension or hypoglycemia. Drugs may cause macular-papular, vesicular, or petechial-purpuric rashes or bullous skin lesions. Bullous skin lesions most often are a result of barbiturates but also may be caused by imipramine, meprobamate, glutethimide, phenothiazine, and carbon monoxide. Kaposi sarcoma, anogenital herpetic lesions, or oral candidiasis should suggest the acquired immunodeficiency syndrome (AIDS), with its plethora of CNS abnormalities.

Table 5.3 Skin Lesions and Rashes in Coma

Lesion or Rash	Possible Cause
Antecubital needle marks	Opiate drug abuse
Pale skin	Anemia or hemorrhage
Sallow, puffy appearance	Hypopituitarism
Hypermelanosis (increased pigment)	Porphyria, Addison disease, chronic nutritional deficiency, disseminated malignant melanoma, chemotherapy
Generalized cyanosis	Hypoxemia or carbon dioxide poisoning
Grayish-blue cyanosis	Methemoglobin (aniline or nitrobenzene) intoxication
Localized cyanosis	Arterial emboli or vasculitis
Cherry-red skin	Carbon monoxide poisoning
Icterus	Hepatic dysfunction or hemolytic anemia
Petechiae	Disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, drugs
Ecchymosis	Trauma, corticosteroid use, abnormal coagulation from liver disease or anticoagulants
Telangiectasia	Chronic alcoholism, occasionally vascular malformations of the brain
Vesicular rash	Herpes simplex, varicella, behçet disease, drugs
Petechial-purpuric rash	Meningococcemia, other bacterial sepsis (rarely), gonococcemia, staphylococcemia, pseudomonas, subacute bacterial endocarditis, allergic vasculitis, purpura fulminans, Rocky Mountain spotted fever, typhus, fat emboli
Macular-papular rash	Typhus, candida, cryptococcus, toxoplasmosis, subacute bacterial endocarditis, staphylococcal toxic shock, typhoid, leptospirosis, pseudomonas sepsis, immunological disorders: Systemic lupus erythematosus Dermatomyositis Serum sickness
Other skin lesions:
Ecthyma gangrenosum	Necrotic eschar often seen in the anogenital or axillary area in Pseudomonas sepsis
Splinter hemorrhages	Linear hemorrhages under the nail, seen in subacute bacterial endocarditis, anemia, leukemia, and sepsis
Osler nodes	Purplish or erythematous painful, tender nodules on palms and soles, seen in subacute bacterial endocarditis
Gangrene of digits, extremities	Emboli to larger peripheral veins or arteries

Data on diseases associated with rashes from Corey, L., Kirby, P., 1987. Rash and fever. In: Braunwald, E., Isselbacher, K.J., Petersdorf, R.G. (Eds.), Harrison’s Principles of Internal Medicine, eleventh ed. McGraw-Hill, New York, pp. 240-244.

Examination of Lymph Nodes

Generalized lymphadenopathy is nonspecific; it may be seen with neoplasm, infection (including AIDS), collagen vascular disease, sarcoid, hyperthyroidism, Addison disease, and drug reaction (especially that due to phenytoin). Local lymph node enlargement or inflammation, however, may provide clues to a primary tumor site or source of infection.

Cardiac Examination

Cardiac auscultation will confirm the presence of arrhythmias such as atrial fibrillation, with its inherent increased risk of emboli. Changing mitral murmurs are heard with atrial myxomas and papillary muscle ischemia, which is seen with current or impending MI. Constant murmurs indicate valvular heart disease and may be heard with the valvular vegetation of bacterial endocarditis.

Abdominal Examination

Possibly helpful findings on abdominal examination include abnormal bowel sounds, organomegaly, masses, and ascites. Bowel sounds are absent in an acute abdominal condition, as well as with anticholinergic poisoning. Hyperactive bowel sounds may be a consequence of increased gastrointestinal (GI) motility from exposure to an acetylcholinesterase inhibitor (a common pesticide ingredient). The liver may be enlarged as a result of right heart failure or tumor infiltration. Nodules or a rock-hard liver may be due to hepatoma or metastatic disease. The liver may be small and hard in cirrhosis.

Splenomegaly is caused by portal hypertension, hematological malignancies, infection, and collagen vascular diseases. Intraabdominal masses may indicate carcinoma. Ascites occurs with liver disease, right heart failure, neoplasms with metastasis to the liver, or ovarian cancer.

Miscellaneous Examinations

Examination of the breasts in the female and of the testicles in the male and rectal examination may reveal common primary tumors. A positive result on tests for blood in stool obtained at rectal examination is consistent with GI bleeding and, possibly, bowel carcinoma. Large amounts of blood in the GI tract may be sufficient to precipitate hepatic encephalopathy in the patient with cirrhosis.

Neurological Examination

Neurological signs may vary depending on the cause of the impaired consciousness and its severity, and they may be partial or incomplete. For example, the patient may have a partial third nerve palsy with pupillary dilation, rather than a complete absence of all third nerve function, or muscle tone may be decreased but not absent. This concept is especially important in the examination of the stuporous or comatose patient, because the level of arousal may also influence the expression of neurological signs. In the stuporous or comatose patient, even slight deviations from normal should not be dismissed as unimportant. Such findings should be carefully considered to discover their pattern or meaning.

The neurological examination of a comatose patient serves three purposes: (1) to aid in determining the cause of coma, (2) to provide a baseline, and (3) to help determine the prognosis. For prognosis and localization of a structural lesion, the following components of the examination have been found to be most helpful: state of consciousness, respiratory pattern, pupillary size and response to light, spontaneous and reflex eye movements, and skeletal muscle motor response.

State of Consciousness

The importance of a detailed description of the state of consciousness is worth reemphasizing. It is imperative that the exact stimulus and the patient’s specific response be recorded. Several modes of stimulation should be used, including auditory, visual, and noxious. Stimuli of progressively increasing intensity should be applied, with the maximal state of arousal noted and the stimuli, the site of stimulation, and the patient’s exact response described. The examiner should start with verbal stimuli, softly and then more loudly calling the patient’s name or giving simple instructions to open the eyes. If there is no significant response, more threatening stimuli such as taking the patient’s hand and advancing it toward the patient’s face are applied. However, a blink response to visual threat need not indicate consciousness (Vanhaudenhuyse et al., 2008). Finally, painful stimuli may be needed to arouse the patient. All patients in apparent coma should be asked to open or close the eyes and to look up and down; these voluntary movements are preserved in the locked-in syndrome but cannot be elicited in coma—an important distinction.

Supraorbital pressure evokes a response even in patients who may have lost afferent pain pathways as a result of peripheral neuropathy or spinal cord or some brainstem lesions. Pinching the chest or extremities may help localize a lesion when it evokes asymmetrical withdrawal responses. Care must be taken to avoid soft-tissue damage. Purposeful movements indicate a milder alteration in consciousness. Vocalization to pain in the early hours of a coma, even if only a grunt, indicates relatively light alteration in consciousness. Later, primitive vocalization may be a feature of the vegetative state.

The Glasgow Coma Scale (GCS; Table 5.4) is used widely to assess the initial severity of traumatic brain injury. This battery assesses three separate aspects of a patient’s behavior: the stimulus required to induce eye opening, the best motor response, and the best verbal response. Degrees of increasing dysfunction are scored. Its reproducibility and simplicity make the GCS an ideal method of assessment for non-neurologists involved in the care of comatose patients, such as neurological intensive care nurses. Its failure to assess other essential neurological parameters, however, limits its utility. Additionally, in patients who are intubated or who have suffered facial trauma, assessment of certain components of the GCS, such as eye opening and speech, may be difficult or impossible. Wijdicks and colleagues (1998) have suggested two new tools—the continuous performance test and the hand position test—that may serve as substitutes for the GCS in such patients, as well as in those with fluctuating levels of consciousness. The continuous performance test monitors level of alertness and requires the patient to raise a hand every time he or she hears a certain letter sound in a standardized sentence spoken by the examiner. The hand position test is a test of praxis in which the patient must mimic three different hand positions demonstrated by the examiner.

Table 5.4 The Glasgow Coma Scale

BEST MOTOR RESPONSE	M
Obeys	6
Localizes	5
Withdraws	4
Abnormal flexion	3
Extensor response	2
Nil	1
VERBAL RESPONSE	V
Oriented	5
Confused conversation	4
Inappropriate words	3
Incomprehensible sounds	2
Nil	1
EYE OPENING	E
Spontaneous	4
To speech	3
To pain	2
Nil	1

Respiration

Normal breathing is quiet and unlabored. The presence of any respiratory noise implies airway obstruction, which must be dealt with immediately to prevent hypoxia. Normal respiration depends on (1) a brainstem mechanism, located between the midpons and cervical medullary junction, that regulates metabolic needs; and (2) forebrain influences that subserve behavioral needs such as speech production. The organization and function of brainstem mechanisms responsible for respiratory rhythm generation, as well as forebrain influences, are complex and beyond the scope of this chapter. Neuropathological correlates of respiration are presented in Fig. 5.1.

Fig. 5.1 Abnormal respiratory patterns associated with pathologic lesions (shaded areas) at various levels of the brain. The tracings were obtained by chest-abdomen pneumograph; inspiration reads up. A, Cheyne-Stokes respiration—diffuse forebrain damage. B, Central neurogenic hyperventilation—lesions of low midbrain ventral to aqueduct of Sylvius and of upper pons ventral to the fourth ventricle. C, Apneusis—dorsolateral tegmental lesion of middle and caudal pons. D, Cluster breathing—lower pontine tegmental lesion. E, Ataxic breathing—lesion of the reticular formation of the dorsomedial part of the medulla.

(Reprinted from Plum, F., Posner, J.B., 1995. The Diagnosis of Stupor and Coma, third ed. Oxford University Press, New York. Copyright 1966, 1972, 1980, 1996, Oxford University Press, Inc. Used by permission of Oxford University Press, Inc.)

Respiratory patterns that are helpful in localizing levels of involvement include Cheyne-Stokes respiration, central neurogenic hyperventilation, apneustic breathing, cluster breathing, and ataxic respiration. Cheyne-Stokes respiration is a respiratory pattern that slowly oscillates between hyperventilation and hypoventilation. In 1818, Cheyne described his patient as follows: “For several days his breathing was irregular; it would entirely cease for a quarter of a minute, then it would become perceptible, though very low, then by degrees it became heaving and quick and then it would gradually cease again. This revolution in the state of his breathing occupied about a minute during which there were about 30 acts of respiration.”

Cheyne-Stokes respiration is associated with bilateral hemispheric or diencephalic insults, but it may occur as a result of bilateral damage anywhere along the descending pathway between the forebrain and upper pons. It also is seen with cardiac disorders that prolong circulation time. Alertness, pupillary size, and heart rhythm may vary during Cheyne-Stokes respiration (Posner et al., 2007). Patients are more alert during the waxing portion of breathing.

A continuous pattern of Cheyne-Stokes respiration is a relatively good prognostic sign, usually implying that permanent brainstem damage has not occurred. However, the emergence of Cheyne-Stokes respiration in a patient with a unilateral mass lesion may be an early sign of herniation. A change in pattern from Cheyne-Stokes respiration to certain other respiratory patterns, described next, is ominous.

Two breathing patterns similar to Cheyne-Stokes respiration should not be confused with it. Short-cycle periodic breathing is a respiratory pattern with a shorter cycle (faster rhythm) than Cheyne-Stokes respiration, with one or two waxing breaths followed by two to four rapid breaths, then one or two waning breaths. It is seen with increased ICP, lower pontine lesions, or expanding lesions in the posterior fossa (Posner et al., 2007). A similar type of respiration, in which there are short bursts of seven to ten rapid breaths, then apnea without a waning and waxing prodrome, has been erroneously referred to as Biot’s breathing. Biot, in fact, described an ataxic respiratory pattern, which is described later.

Central neurogenic hyperventilation refers to rapid breathing, from 40 to 70 breaths per minute, usually due to central tegmental pontine lesions just ventral to the aqueduct or fourth ventricle (Posner et al., 2007). This type of breathing is rare and must be differentiated from reactive hyperventilation due to metabolic abnormalities of hypoxemia secondary to pulmonary involvement. Large CNS lesions may cause neurogenic pulmonary edema with associated hypoxemia and increased respiratory rate. Increased intracerebral pressure causes spontaneous hyperpnea. Hyperpnea cannot be ascribed to a CNS lesion when arterial oxygen partial pressure is less than 70 to 80 mm Hg or carbon dioxide partial pressure is greater than 40 mm Hg.

Kussmaul breathing is a deep, regular respiration observed with metabolic acidosis. Apneustic breathing is a prolonged inspiratory gasp with a pause at full inspiration. It is caused by lesions of the dorsolateral lower half of the pons (Posner et al., 2007). Cluster breathing, which results from high medullary damage, involves periodic respirations that are irregular in frequency and amplitude, with variable pauses between clusters of breaths.

Ataxic breathing is irregular in rate and rhythm and usually is due to medullary lesions. The combination of ataxic respiration and bilateral sixth nerve palsy may be a warning sign of brainstem compression from an expanding lesion in the posterior fossa. This is an important sign because brainstem compression due to tonsillar herniation (or other causes) may result in abrupt loss of respiration or blood pressure. Ataxic and gasping respirations are signs of lower brainstem damage and often are preterminal respiratory patterns.

Pupil Size and Reactivity

Normal pupil size in the comatose patient depends on the level of illumination and the state of autonomic innervation. The sympathetic efferent innervation consists of a three-neuron arc. The first-order neuron arises in the hypothalamus and travels ipsilaterally through the posterolateral tegmentum to the ciliospinal center of Budge at the T1 level of the spinal cord. The second-order neuron leaves this center and synapses in the superior cervical sympathetic ganglion. The third-order neuron travels along the internal carotid artery and then through the ciliary ganglion to the pupillodilator muscles. Parasympathetic efferent innervation of the pupil arises in the Edinger-Westphal nucleus and travels in the oculomotor nerve to the ciliary ganglion, from which it innervates the pupillosphincter muscle (see Figs. 16.1 and 16.2 in Chapter 16).

Afferent input to the papillary reflex depends on the integrity of the optic nerve, optic chiasm, optic tract, and projections into the midbrain tectum and efferent fibers through the Edinger-Westphal nucleus and oculomotor nerve. Abnormalities in pupil size and reactivity help delineate structural damage between the thalamus and pons (Fig. 5.2), act as a warning sign heralding brainstem herniation, and help differentiate structural causes of coma from metabolic causes.

Fig. 5.2 Pupils in comatose patients.

Thalamic lesions cause small, reactive pupils, often referred to as diencephalic pupils. Similar pupillary findings are noted in many toxic-metabolic conditions resulting in coma. Hypothalamic lesions or lesions elsewhere along the sympathetic pathway result in Horner syndrome. Midbrain lesions produce three types of pupillary abnormality, depending on where the lesion occurs:

1. Dorsal tectal lesions interrupt the pupillary light reflex, resulting in midposition pupils, which are fixed to light but react to near vision; the latter is impossible to test in the comatose patient. Spontaneous fluctuations in size occur, and the ciliospinal reflex is preserved.

2. Nuclear midbrain lesions usually affect both sympathetic and parasympathetic pathways, resulting in fixed, irregular midposition pupils, which may be unequal.

3. Lesions of the third nerve fascicle in the brainstem, or after the nerve has exited the brainstem, cause wide pupillary dilation unresponsive to light. Pontine lesions interrupt sympathetic pathways and cause small, so-called pinpoint pupils which remain reactive, although magnification may be needed to observe this feature. Lesions above the thalamus and below the pons should leave pupillary function intact, except for Horner syndrome in medullary or cervical spinal cord lesions. The pathophysiology of pupillary response is discussed further in Chapters 16 and 36.

Asymmetry in pupillary size or reactivity, even of minor degree, is important. Asymmetry of pupil size may be due to dilation (mydriasis) of one pupil, such as with third nerve palsy, or contraction (miosis) of the other, as in Horner syndrome. This may be differentiated by the pupillary reactivity to light and associated neurological signs. A dilated pupil due to a partial third nerve palsy is less reactive and usually is associated with extraocular muscle involvement. The pupil in Horner syndrome is reactive; if the syndrome results from a lesion in the CNS, it may be associated with anhidrosis of the entire ipsilateral body. Cervical sympathetic chain lesions produce anhidrosis of only face, neck, and arm. A partial or complete third nerve palsy causing a dilated pupil may result from an intramedullary lesion, most commonly in the midbrain (e.g., intramedullary glioma or infarction), uncal herniation compressing the third nerve, or a posterior communicating artery aneurysm. A sluggishly reactive pupil may be one of the first signs of uncal herniation, followed soon thereafter by dilation of that pupil, and later complete third nerve paralysis.

Several caveats are important in examining the pupil or assessing pupillary reflexes. A common mistake is using insufficient illumination. The otoscope may be useful in this regard, because it provides both adequate illumination and magnification. Rarely, preexisting ocular or neurological injury may fix the pupils or result in pupillary asymmetry. Seizures may cause transient anisocoria. Local and systemic medications may affect pupillary function. Topical ophthalmological preparations containing an acetylcholinesterase inhibitor, used in the treatment of glaucoma, produce miosis. The effect of a mydriatic agent placed by the patient or a prior observer may wear off unevenly, resulting in pupillary asymmetry. Some common misleading causes of a unilateral dilated pupil include prior mydriatic administration, old ocular trauma or ophthalmic surgery, and (more rarely) carotid artery insufficiency.

Ocular Motility

Normal ocular motility (see Chapters 16 and 35) depends on the integrity of a large portion of the cerebrum, cerebellum, and brainstem. Preservation of normal ocular motility implies that a large portion of the brainstem from the vestibular nuclei at the pontomedullary junction to the oculomotor nucleus in the midbrain is intact. Voluntary ocular motility cannot be judged in the comatose patient, so the examiner must rely on reflex eye movements that allow for assessment of the ocular motor system. The eye movements normally are conjugate, and eyes are in the midposition in the alert person. Sleep or obtundation alone may unmask a latent vertical or horizontal strabismus, resulting in dysconjugacy; therefore, patients must be examined when maximally aroused. The eyes return to the midposition in brain-dead patients.

Evaluation of ocular motility consists of (1) observation of the resting position of the eyes, including eye deviation; (2) notation of spontaneous eye movements; and (3) testing of reflex ocular movements.

Abnormalities in Resting Position

Careful attention must be paid to the resting position of the eyes. Even a small discrepancy in eye position may represent a partial extraocular nerve palsy. Partial nerve palsies or combined nerve palsies predictably result in a more complex picture on examination. Unilateral third nerve palsy from either an intramedullary midbrain lesion or extramedullary compression causes the affected eye to be displaced downward and laterally. A sixth nerve palsy produces inward deviation. Isolated sixth nerve palsy, however, is a poor localizer because of the extensive course of the nerve and because this palsy may be caused by nonspecific increases in ICP, presumably from stretching of the extramedullary portion of the nerve. A fourth nerve palsy is difficult to assess in the comatose patient because of the subtle nature of the deficit in ocular motility. Extraocular nerve palsies often become more apparent with the “doll’s eye maneuver” or cold caloric testing in the comatose patient.

Pontaneous eye deviation may be conjugate or dysconjugate. Conjugate lateral eye deviation usually is due to an ipsilateral lesion in the frontal eye fields but may be due to a lesion anywhere in the pathway from the ipsilateral eye fields to the contralateral parapontine reticular formation (see Chapter 35). Dysconjugate lateral eye movement may result from a sixth nerve palsy in the abducting eye, a third nerve palsy in the adducting eye, or an internuclear ophthalmoplegia. An internuclear ophthalmoplegia may be differentiated from a third nerve palsy by the preservation of vertical eye movements.

Downward deviation of the eyes below the horizontal meridian usually is due to brainstem lesions (most often from tectal compression); however, it also may be seen in metabolic disorders such as hepatic coma. Thalamic and subthalamic lesions produce downward and inward deviation of the eyes. Patients with these lesions appear to be looking at the tip of the nose. Sleep, seizure, syncope, apnea of Cheyne-Stokes respiration, hemorrhage into the vermis, and brainstem ischemia or encephalitis cause upward eye deviation, making this a poor localizing sign. Skew deviation is a maintained deviation of one eye above the other (hypertropia) that is not due to a peripheral neuromuscular lesion or a local extracranial problem in the orbit. It usually indicates a posterior fossa lesion (brainstem or cerebellar). Dysconjugate vertical eye position sometimes may occur in the absence of a brainstem lesion in the obtunded patient.

Spontaneous Eye Movements

Spontaneous eye movements (see Chapter 16) are of many types. Purposeful-appearing eye movements in a patient who otherwise seems unresponsive should lead to consideration of the locked-in syndrome, catatonia, pseudocoma, or PVS. Roving eye movements are slow, conjugate, lateral to-and-fro movements. For roving eye movements to be present, the ocular motor nuclei and their connections must be intact. Generally when roving eye movements are present, the brainstem is relatively intact and coma is due to a metabolic or toxic cause or bilateral lesions above the brainstem. Detection of roving eye movements may be complicated by ocular palsies or internuclear ophthalmoplegia. These superimposed lesions produce relatively predictable patterns but often obscure the essential roving nature of the movement for the inexperienced observer.

Nystagmus occurring in comatose patients suggests an irritative or epileptogenic supratentorial focus. An epileptogenic focus in one frontal eye field causes contralateral conjugate eye deviation. Nystagmus due to an irritative focus may rarely occur alone without other motor manifestations of seizures. In addition, inconspicuous movements of the eye, eyelid, face, jaw, or tongue may be associated with electroencephalographic status epilepticus. An electroencephalogram (EEG) is required to ascertain the presence of this condition.

Spontaneous conjugate vertical eye movements are separated into different types according to the relative velocities of their downward and upward phases. In ocular bobbing, rapid downward jerks of both eyes are observed, followed by a slow return to the midposition (Leigh and Zee, 2006). In the typical form, there is associated paralysis of both reflex and spontaneous horizontal eye movements. Monocular or paretic bobbing occurs when a coexisting ocular motor palsy alters the appearance of typical bobbing. The term atypical bobbing refers to all other variations of bobbing that cannot be explained by an ocular palsy superimposed on typical bobbing. Most commonly, this term is used to describe ocular bobbing when lateral eye movements are preserved. Typical ocular bobbing is specific but not pathognomonic for acute pontine lesions. Atypical ocular bobbing occurs with anoxia and is nonlocalizing. Ocular dipping, also known as inverse ocular bobbing, refers to spontaneous eye movements in which an initial slow downward phase is followed by a relatively rapid return. Reflex horizontal eye movements are preserved. It usually is associated with diffuse cerebral damage. In reverse ocular bobbing, there is a slow initial downward phase followed by a rapid return that carries the eyes past the midposition into full upward gaze. Then the eyes slowly return to the midposition. Reverse ocular bobbing is nonlocalizing.

Vertical nystagmus due to an abnormal pursuit or vestibular system is slow deviation of the eyes from the primary position, with a rapid (saccadic) immediate return to the primary position. It is differentiated from bobbing by the absence of latency between the corrective saccade and the next slow deviation. Ocular-palatal myoclonus (the palatal movement also is called palatal tremor) occurs after damage to the lower brainstem involving the Guillain-Mollaret triangle, which extends between the cerebellar dentate nucleus, red nucleus, and inferior olive. It consists of a pendular vertical nystagmus in synchrony with the palatal movements. Ocular flutter is back-to-back saccades in the horizontal plane and usually is a manifestation of cerebellar disease.

Reflex Ocular Movements

Examination of ocular movement is not complete in the comatose patient without assessment of reflex ocular movements, including the oculocephalic reflex (“doll’s eye phenomenon”) and, if necessary, caloric (thermal) testing. In practice, the terms doll’s eye phenomenon and doll’s eye maneuver are used synonymously to refer to the oculocephalic reflex, but these terms are often confusing to the neophyte neurologist. It is better to use the term oculocephalic reflex followed by a description of the response. To test for this reflex, the examiner briskly rotates the patient’s head in both directions laterally, then flexes and extends the neck, continually observing the motion of the eyes. When supranuclear influences on the ocular motor nerves are removed, the eyes move in the orbit opposite to the direction of the head turn and maintain their position in space. This maneuver should not be performed on any patient until the stability of the neck has been adequately assessed. If there is any question of neck stability, a neck brace should be applied and caloric testing substituted. In the normal oculocephalic reflex (normal or positive doll’s eye phenomenon), the eyes move conjugately in a direction opposite to the direction of movement of the head. Cranial nerve palsies predictably alter the response to this maneuver (Table 5.5).

Table 5.5 Oculocephalic Reflex *

Method	Response	Interpretation
Lateral head rotation	Eyes remain conjugate, move in direction opposite to head movement and maintain position in space	Normal
	No movement in either eye on rotating head to left or right	Bilateral pontine gaze palsy, bilateral labyrinthine dysfunction, drug intoxication, anesthesia
	Eyes move appropriately when head is rotated in one direction but do not move when head is rotated in opposite direction	Unilateral pontine gaze palsy
	One eye abducts, the other eye does not adduct	Third nerve palsy
		Internuclear ophthalmoplegia
Vertical head flexion and extension	Eyes remain conjugate, move in direction opposite to head movement and maintain position in space	Normal
	No movement in either eye	Bilateral midbrain lesions
	Only one eye moves	Third nerve palsy
	Bilateral symmetrical limitation of upgaze	Aging

* To be performed only after neck stability has been ascertained.

Clinical caloric testing (as distinct from quantitative calorics, used to assess vestibular end-organ disorders; see Chapter 37) is commonly done by applying cold water to the tympanic membrane. With the patient supine, the head should be tilted forward 30 degrees to allow maximal stimulation of the lateral semicircular canal, which is most responsible for reflex lateral eye movements. After the ear canal is carefully checked to ensure that it is patent and the tympanic membrane is free of defect, 10 mL of ice-cold water is slowly instilled into one ear canal. For purposes of the neurological examination, irrigation of each ear with 10 mL of ice water generally is sufficient.

Cold water applied to the tympanic membrane causes currents to be set up in the endolymph of the semicircular canal. This results in a change in the baseline firing of the vestibular nerve and slow (tonic) conjugate deviation of the eyes toward the stimulated ear. In an awake person, the eye deviation is corrected with a resulting nystagmoid jerking of the eye toward the midline (fast phase). Warm-water irrigation produces reversal of flow of the endolymph, which causes conjugate eye deviation with a slow phase away from the stimulated ear and a normal corrective saccadic fast phase toward the ear. By tradition, the nystagmus is named by the direction of the fast phase. The mnemonic COWS (cold, opposite; warm, same) refers to the fast phases. Simultaneous bilateral cold water application results in slow downward deviation, whereas simultaneous bilateral warm water application causes upward deviation.

Oculocephalic or caloric testing may elicit subtle or unsuspected ocular palsies. Abnormal dysconjugate responses occur with cranial nerve palsies, intranuclear ophthalmoplegia, or restrictive eye disease. Movements may be sluggish or absent. Sometimes reinforcement of cold caloric testing with superimposed passive head turning after injection of cold water into the ear may reveal eye movement when either test alone shows none.

False-negative or misleading responses on caloric testing occur with preexisting inner ear disease, vestibulopathy such as that due to ototoxic drugs like streptomycin, vestibular paresis caused by illnesses such as Wernicke encephalopathy, and drug effects. Subtotal labyrinthine lesions decrease the response; there is no response when the labyrinth is destroyed. Lesions of the vestibular nerve cause a decreased or absent response. Drugs that suppress either vestibular or ocular motor function (or both) include sedatives, anticholinergics, anticonvulsants, tricyclic antidepressants, and neuromuscular blocking agents. If the response from one ear is indeterminate, both cold- and warm-water stimuli should be applied to the other ear. If the test remains equivocal, superimposition of the doll’s eye maneuver is recommended. Interpretation of abnormal cold caloric responses is summarized in Table 5.6. An unusual ocular reflex that has been observed in the setting of PVS is reflex opening of both eyes triggered by flexion of an arm at the elbow. This reflex is distinct from reflex eye opening in the comatose patient induced by raising the head or turning it from side to side.

Table 5.6 Caloric Testing

Method	Response	Interpretation
Cold water instilled in right ear	Slow phase to right, fast (corrective) phase to the left	Normal
	No response (make sure canal is patent, apply warm-water stimulus to opposite ear)	Obstructed ear canal, “dead” labyrinth, eighth nerve or nuclear dysfunction, false-negative result (see text)
	Slow phase to right, no fast phase	Toxic-metabolic disorder, drugs, structural lesion above brainstem
	Downbeating nystagmus	Horizontal gaze palsy
Cold water instilled in left ear	Responses should be opposite those for right ear	Peripheral eighth nerve or labyrinth disorder on right (provided that right canal is patent)
Warm water instilled in left ear after no response from cold water in right ear	Slow phase to right, fast phase to left

Motor System

Examination of the motor system of a stuporous or comatose patient begins with a description of the resting posture and adventitious movements. Purposeful and nonpurposeful movements are noted and the two sides of the body compared. Head and eye deviation to one side and contralateral hemiparesis suggests a supratentorial lesion, whereas ipsilateral paralysis indicates a probable brainstem lesion. External rotation of the lower limb is a sign of hemiplegia or hip fracture.

Decerebrate posturing is bilateral extensor posture with extension of the lower extremities and adduction and internal rotation of the shoulders and extension at the elbows and wrist. Bilateral midbrain or pontine lesions usually are responsible for decerebrate posturing. Less commonly, deep metabolic encephalopathies or bilateral supratentorial lesions involving the motor pathways may produce a similar pattern.

Decorticate posturing is bilateral flexion at the elbows and wrists, with shoulder adduction and extension of the lower extremities. It is a much poorer localizing posture, because it may result from lesions in many locations, although usually above the brainstem. Decorticate posture is not as ominous a sign as decerebrate posture, because the former occurs with many relatively reversible lesions.

Unilateral decerebrate or decorticate postures also are less ominous. Lesions causing unilateral posturing may be anywhere in the motor system from cortex to brainstem. Unilateral extensor posturing is common immediately after a cerebrovascular accident, followed in time by a flexor response.

Posturing may occur spontaneously or in response to external stimuli such as pain, or may even be set off by such minimal events as the patient’s own breathing. These postures, though common, may also be variable in their expression because of other associated brainstem or more rostral brain damage.

Special attention should be given to posturing because it often signals a brainstem herniation syndrome. Emergency room personnel and inexperienced physicians may mistake these abnormal postures for convulsions (seizures) and institute anticonvulsant therapy, resulting in an unfortunate delay of appropriate therapy for the patient.

Adventitious movements in the comatose patient may be helpful in separating metabolic from structural lesions. Tonic-clonic or other stereotyped movements signal seizure as the probable cause of decreased alertness. Myoclonic jerking, consisting of nonrhythmical jerking movements in single or multiple muscle groups, is seen with anoxic encephalopathy or other metabolic comas such as hepatic encephalopathy. Rhythmic myoclonus, which must be differentiated from epileptic movements, usually is a sign of brainstem injury. Tetany occurs with hypocalcemia. Cerebellar fits result from intermittent tonsillar herniation and are characterized by deterioration of level of arousal, opisthotonos, respiratory rate slowing and irregularity, and pupillary dilatation.

The motor response to painful stimuli should be tested, but the pattern of response may vary depending on the site stimulated. Purposeful responses may be difficult to discriminate from more primitive reflexes. Flexion, extension, and adduction may be either voluntary or reflex in nature. In general, abduction is most reliably voluntary, with shoulder abduction stated to be the only definite nonreflex reaction. This is tested by pinching the medial aspect of the upper arm. Reflex flexor response to pain in the upper extremity consists of adduction of the shoulder, flexion of the elbow, and pronation of the arm. The triple flexion response in the lower extremities refers to reflex withdrawal, with flexion at the hip and knee and dorsiflexion at the ankle, in response to painful stimulation on the foot or lower extremity. Such reflexes seldom are helpful in localizing a lesion.

Spinal reflexes are reflexes mediated at the level of the spinal cord and do not depend on the functional integrity of the brain or brainstem. Most patients with absent cortical or brainstem function have some form of spinal reflex.

The plantar reflex may be extensor in coma from any cause, including drug overdoses and postictal states. It becomes flexor on recovery of consciousness if there is no underlying structural damage.

Muscle tone and asymmetry in muscle tone are helpful in localizing a focal structural lesion and may help differentiate metabolic from structural coma. Acute structural damage above the brainstem usually results in decreased or flaccid tone. In older lesions, tone usually is increased. Metabolic insults generally cause a symmetrical decrease in tone. Finally, generalized flaccidity is ultimately seen after brain death.

Coma and Brain Herniation

Herniation syndromes are explained in Chapter 50. Knowledge of some of the clinical signs of herniation is especially important in the clinical approach to coma. Traditional signs of herniation due to supratentorial masses usually are variations of either an uncal or a central pattern. Classically, the uncal pattern includes early signs of third nerve and midbrain compression. The pupil initially dilates as a result of third nerve compression but later returns to the midposition with midbrain compression that involves the sympathetic as well as the parasympathetic tracts. In the central pattern, the earliest signs are mild impairment of consciousness, with poor concentration, drowsiness, or unexpected agitation; small but reactive pupils; loss of the fast component of cold caloric testing; poor or absent reflex vertical gaze; and bilateral corticospinal tract signs, including increased tone of the body ipsilateral to the hemispheric mass lesion responsible for herniation (Posner et al., 2007).

Signs of herniation tend to progress generally in a rostrocaudal manner. An exception occurs when intraventricular bleeding extends to the fourth ventricle and produces a pressure wave, compressing the area around the fourth ventricle. Also, when an LP reduces CSF pressure suddenly in the face of a mass lesion that produced increased ICP, sudden herniation of the cerebellar tonsils through the foramen magnum may result (Posner et al., 2007). Both of these clinical scenarios may be associated with sudden unexpected failure of medullary functions that support respiration or blood pressure. In patients with herniation syndromes, the clinical picture may be confusing because of changing signs or the expression of scattered, isolated signs of dysfunction in separate parts of the brain. In addition, certain signs may be more prominent than others.

Increased ICP invariably accompanies brainstem herniation and may be associated with increased systolic blood pressure, bradycardia, and sixth nerve palsies. These signs, however, as well as many of the traditional signs of herniation described, actually occur relatively late. Earlier signs of potential herniation are decreasing level of arousal, slight change in depth or rate of respiration, and the appearance of a Babinski sign. Tonsillar herniation may be suggested by an altered level of consciousness, opisthotonic posturing, dilated pupils, and irregular breathing. It is important to suspect herniation early, because once advanced changes develop, structural injury is likely to have occurred; subsequently, there is less chance of reversal.

Differential Diagnosis

Differentiating Toxic-Metabolic Coma from Structural Coma

Many features of the history and physical examination help differentiate structural from metabolic and toxic causes of coma. Some features have already been mentioned. When the history is available, the patient’s underlying illnesses and medications or the setting in which they are found often help guide the physician to the appropriate cause. The time course of the illness resulting in coma can be helpful. Generally, structural lesions have a more abrupt onset, whereas metabolic or toxic causes are more slowly progressive. Multifocal structural diseases such as vasculitis or leukoencephalopathy are an exception to this rule, as they may exhibit slow progression, usually in a stepwise manner. Supratentorial or infratentorial tumors characterized by slow growth and surrounding edema may also mimic metabolic processes.

The response to initial emergency therapy may help differentiate metabolic or toxic causes of coma. The hypoglycemic patient usually awakens after administration of glucose, the hypoxic patient responds to oxygen, and the patient experiencing an opiate drug overdose responds to naloxone.

In general, structural lesions have focal features or at least notable asymmetry on neurological examination. Toxic, metabolic, and psychiatric diseases are characterized by their symmetry. Bilateral and often multilevel involvement frequently is seen with metabolic causes. Asymmetries may be observed but generally are of small degree and tend to fluctuate over time.

Many features of the neurological examination differentiate metabolic or toxic causes from structural lesions:

• State of consciousness. Patients with metabolic problems often have milder alterations in arousal, typically with waxing and waning of the behavioral state. Patients with acute structural lesions tend to stay at the same level of arousal or progressively deteriorate. Toxins may also cause progressive decline in level of arousal.

• Respiration. Deep, frequent respiration most commonly is due to metabolic abnormalities, though rarely it is caused by pontine lesions or by neurogenic pulmonary edema secondary to acute structural lesions.

• Funduscopic examination. Subhyaloid hemorrhage or papilledema are almost pathognomonic of structural lesions. Papilledema due to increased ICP may be indicative of an intracranial mass lesion or hypertensive encephalopathy. Papilledema does not occur in metabolic diseases except hypoparathyroidism, lead intoxication, and malignant hypertension.

• Pupil size. The pupils usually are symmetrical in coma from toxic-metabolic causes. Patients with metabolic or toxic encephalopathies often have small pupils with preserved reactivity. Exceptions occur with methyl alcohol poisoning, which may produce dilated and unreactive pupils, or late in the course of toxic or metabolic coma if hypoxia or other permanent brain damage has occurred. In terminal asphyxia, the pupils dilate initially and then become fixed at midposition within 30 minutes. The initial dilation is attributed to massive sympathetic discharge.

• Pupil reactivity. Assessment of the pupillary reflex is one of the most useful means of differentiating metabolic from structural causes of coma. Pupillary reactivity is relatively resistant to metabolic insult and usually is spared in coma from drug intoxication or metabolic causes, even when other brainstem reflexes are absent. Hypothermia may fix pupils, as does severe barbiturate intoxication. Neuromuscular blocking agents produce midposition or small pupils, and glutethimide and atropine dilate them.

• Ocular motility. Asymmetry in oculomotor function typically is a feature of structural lesions.

• Spontaneous eye movements. Roving eye movements with full excursion are most often indicative of metabolic or toxic abnormalities.

• Reflex eye movements. Reflex eye movements normally are intact in toxic-metabolic coma, except rarely in phenobarbital or phenytoin intoxication or deep metabolic coma from other causes.

• Adventitious movement. Periods of motor restlessness, tremors, or spasm punctuating coma often are due to drugs or toxins such as chlorpromazine or lithium. Brainstem herniation or intermittent CNS ischemia also may produce unusual posturing movements. Myoclonic jerking generally is metabolic and often anoxic in origin.

• Muscle tone. Muscle tone usually is symmetrical and normal or decreased in metabolic coma. Structural lesions cause asymmetrical muscle tone. Tone may be increased, normal, or decreased by structural lesions.

The examiner should be aware of common structural lesions that mimic toxic-metabolic causes and, conversely, toxic or metabolic causes of coma that may be associated with focal abnormalities on examination. Structural lesions that may mimic toxic-metabolic causes include subarachnoid hemorrhage, sinus vein thrombosis, chronic or bilateral subdural hemorrhage, and other diffuse or multifocal disorders such as vasculitis, demyelinating diseases, or meningitis. Any toxic-metabolic cause of coma may be associated with focal features; however, such features most often are observed with barbiturate or lead poisoning, hypoglycemia, hepatic encephalopathy, and hyponatremia. Old structural lesions such as prior stroke may be the origin of residual abnormalities found on neurological examination in a patient who is comatose from toxic or metabolic causes. Moreover, metabolic abnormalities such as hypoglycemia may unmask relatively silent structural abnormalities. Detailed descriptions of the toxic and metabolic encephalopathies are provided in Chapter 56.

Differentiating Psychiatric Coma and Pseudocoma from Metabolic or Structural Coma

The patient who appears unarousable as a result of psychiatric disease and the patient who is feigning unconsciousness for other reasons may be difficult to differentiate from each other. In such instances, the history, when available, and findings on the physical examination may suggest to the physician that a nonphysiological mechanism is at work. Multiple inconsistencies are present on examination, and abnormalities that are found do not fit the pattern of usual neurological syndromes. Examinations of the eyelid, pupil, adventitious eye movements, and vestibulo-oculogyric reflex by cold caloric testing are especially useful to confirm the suspicion of pseudocoma.

Eyelid tone is difficult to alter voluntarily. In the patient with true stupor or coma, passive eyelid opening is easily performed and is followed by slow, gradual eyelid closure. The malingering or hysterical patient often gives active resistance to passive eye opening and may even hold the eyes tightly closed. It is nearly impossible for the psychiatric or malingering patient to mimic the slow, gradual eyelid closure. Blinking also increases in psychiatric and malingering patients but decreases in patients in true stupor.

The pupils normally constrict in sleep or (eyes-closed-type) coma but dilate with the eyes closed in the awake state. Passive eye opening in a sleeping person or a truly comatose patient (if pupillary reflexes are spared) results in pupillary dilation. Opening the eyes of an awake person produces constriction. This principle may help differentiate coma from pseudocoma.

Roving eye movements cannot be mimicked and thus also are a good sign of true coma. Finally, if during cold caloric testing, the eyes do not tonically deviate to the side of the caloric instillation, and the fast phases are preserved, stupor or true coma is essentially ruled out. Moreover, cold caloric testing with the resultant vertigo usually “awakens” psychiatric and malingering patients.

Helpful Laboratory Studies

Laboratory tests that are extremely helpful in evaluating the comatose patient are listed in Table 5.7. Arterial blood gas determinations rule out hypoxemia and carbon dioxide narcosis and help differentiate primary CNS problems from secondary respiratory problems. Liver disease, myopathy, and rhabdomyolysis all elevate alanine aminotransferase and aspartate aminotransferase levels. Liver function test results may be misleading in end-stage liver disease, as values may be normal or only mildly elevated with markedly abnormal liver function. Although the blood ammonia level does not correlate well with the level of hepatic encephalopathy, it often may be markedly elevated and thus helpful in cases of suspected liver disease with relatively normal liver function studies. Hepatic encephalopathy may continue for up to 3 weeks after liver function values return to normal.

Table 5.7 Laboratory Tests Helpful in Differential Diagnosis for Coma

Laboratory Study	Result	Associated Disorders
Electrolytes (Na, K, Cl, CO₂)		See Chapters 49A and 56 for discussion of disorders associated with abnormalities of electrolytes, glucose, BUN, calcium, and magnesium
Glucose
BUN
Creatinine
Calcium
Magnesium
Complete blood count with differential	Hematocrit:
	Increased	Volume depletion, underlying lung disorder, myeloproliferative disorder, cerebellar hemangioblastoma; may be associated with vascular sludging (hypoperfusion)
	Decreased	Anemia, hemorrhage
	White blood cell count:
	Increased	Infection, acute stress reaction, steroid therapy, after epileptic fit, myeloproliferative disorder
	Decreased	Chemotherapy, immunotherapy, viral infection, sepsis
	Lymphocyte count:
	Decreased	Viral infection, malnutrition, AIDS
Platelet count	Decreased	Sepsis, disseminated intravascular coagulation, thrombotic thrombo-cytopenic purpura, idiopathic thrombocytopenic purpura, drugs; may be associated with intracranial hemorrhage
PT	Increased	Coagulation factor deficiency, liver disease, anticoagulants, disseminated intravascular coagulation
PTT	Increased	Heparin therapy, lupus anticoagulant
Arterial blood gases		See text
Creatine phosphokinase		See text
Liver function studies		See text
Thyroid function studies		See text
Plasma cortisol level		See text
Drug and toxin screen		See text
Serum osmolality		See text

AIDS, Acquired immunodeficiency syndrome; BUN, blood urea nitrogen; PT, prothrombin time; PTT, partial thromboplastin time.

Thyroid function studies are necessary to document hypothyroidism or hyperthyroidism. When addisonian crisis is suspected, a serum cortisol level should be obtained. A low or normal level in the stressful state of coma or illness strongly suggests adrenal insufficiency. Further testing of adrenal function should be performed as appropriate.

When the cause of coma is not absolutely certain, or in possible medicolegal cases, a blood alcohol level and a drug and toxin screen are mandatory. The results of these tests usually are not available immediately but may be invaluable later. Serum osmolality can usually be measured rapidly by the laboratory and may be used to estimate alcohol level because alcohol is an osmotically active particle and increases the osmolar gap in proportion to its blood level. Serum osmolality can be calculated using the following:

The osmolar gap, which is the difference between the measured serum osmolality and the calculated serum osmolality, represents unmeasured osmotically active particles.

Creatine kinase levels should routinely be measured in comatose patients initially and then at least daily for the first several days because of the great risk of rhabdomyolysis and subsequent preventable acute tubular necrosis in these patients. Measuring creatine kinase MB isoenzyme levels every 8 hours for the first 24 hours helps rule out an MI.

Other Useful Studies

Electrocardiography

The electrocardiogram is useful to show MI, arrhythmia, conduction blocks, bradycardia, or evidence of underlying hypertension or atherosclerotic coronary vascular disease. Hypocalcemia causes QT prolongation. Hypercalcemia shortens the QT interval. The heart rate is slow in hypothyroid patients with low-voltage QRS, flat or inverted T waves, and flattened ST segments. Hyperthyroid patients are generally tachycardic.

Neuroradiological Imaging

Once the patient is stabilized, necessary treatment is given, the initial examination is complete, and appropriate laboratory studies are ordered, the next test of choice is a CT scan of the brain, without contrast but with 5-mm cuts of the posterior fossa. Alternatively, magnetic resonance imaging (MRI) may be performed, depending on the clinical setting and the stability of the patient’s condition. MRI provides superb visualization of the posterior fossa and its contents, an extremely useful feature when structural disease of the brainstem is suspected. MRI is not as specific as CT scanning for visualizing early intracranial hemorrhage, however, and it is limited at present by the length of time required to perform the imaging, image degradation by even a slight movement of the patient, and the relative inaccessibility of the patient during the imaging process. The CT scan, when performed as described, is currently the most expedient imaging technique, giving the physician the most information about possible structural lesions with the least risk to the patient. Repeating the scan with IV dye may be necessary later to better define lesions seen on the initial scan.

The value of the CT scan in demonstrating mass lesions and hemorrhage is undeniable. Furthermore, it may demonstrate features of brain herniation. Uncal herniation is characterized on CT scan by (1) displacement of the brainstem toward the contralateral side, with increase in width of subarachnoid space between the mass and ipsilateral free edge, (2) medial stretching of the posterior cerebral and posterior communicating arteries, (3) obliteration of the interpeduncular cistern, (4) occipital lobe infarction, and (5) distortion and elongation of the U-shaped tentorial incisura. The clinician should be aware that the CT scan may miss early infarction, encephalitis, and isodense subdural hemorrhage. Special caution must be taken in evaluating CT scans in comatose patients, especially before LP, to rule out isodense subdural or bilateral subdural hemorrhage. Interpretation of CT scans is discussed in Chapter 33A.

In severe head injury, studies of cerebral metabolism employing single photon emission computed tomography (SPECT) may be of prognostic value (Della Corte et al., 1997). Although cerebral blood flow in the first 48 hours after trauma does not appear to correlate with severity or prognosis, the cerebral metabolic rate of oxygen (CMRo₂), like the GCS, may be useful in predicting prognosis.

Electroencephalography

The EEG is helpful in many situations and disorders: confirming underlying cortical structural damage in patients too unstable to travel to the CT scanner; postictal states in patients slow to wake after a presumed seizure; partial complex seizures; electroencephalographic or nonconvulsive status epilepticus, such as is seen in comatose patients after anoxic ischemic damage; and toxic-metabolic disturbances. With metabolic disorders, the earliest EEG changes typically are a decrease in the frequency of background rhythms and the appearance of diffuse theta activity that progresses to more advanced slowing in association with a decrease in the level of consciousness. In hepatic encephalopathy, bilaterally synchronous and symmetrical, medium- to high-amplitude, broad triphasic waves, often with a frontal predominance, may be observed. Herpes simplex encephalitis may be suggested by the presence of unilateral or bilateral periodic sharp waves with a temporal preponderance. The EEG also can help confirm a clinical impression of catatonia, pseudocoma, the locked-in syndrome, PVS, and brain death (Brenner, 2005). EEGs are discussed further in Chapter 32A.

Evoked Potentials

Evoked potentials may help in evaluating brainstem integrity and assessing prognosis for comatose patients. A study of 50 hemodynamically stable patients remaining in coma 4 hours after resuscitation from cardiopulmonary arrest with short-latency somatosensory evoked potentials within 8 hours after arrest found that none of the 30 patients without cortical potentials recovered cognition. Five of the 20 patients with cortical potentials recovered. Forty percent of the patients who did not recover had preserved brainstem reflexes, allowing some evaluation of prognosis in a group of patients in whom prognosis is difficult to assess by other means. Event-related potentials may prove particularly useful as an objective assessment of cognitive function in patients with the locked-in syndrome (Onofrj et al., 1997). The N100 component of the auditory evoked potential and cognitive evoked potentials (mismatch negativity obtained after novel stimuli) appear to have predictive value for awakening from coma, but the pupillary reflex remains the strongest prognostic variable (Fischer et al., 2004). Absence of evoked potentials in response to somatosensory stimuli also is highly predictive of nonawakening from coma (Robinson et al., 2003).

Intracranial Pressure Monitoring

ICP measurements provide an index of the degree of brain swelling and are particularly useful in the management of patients who have suffered severe head injury. Postmortem studies of fatal head injuries demonstrate a direct correlation between very elevated ICP and death due to tentorial herniation. In the absence of intracranial hematomas, however, comatose patients with normal findings on brain imaging studies have a low frequency of increased ICP and almost never develop uncontrolled intracranial hypertension.

Prognosis

In view of the current state of knowledge, outcome in any comatose patient cannot be predicted with 100% certainty unless that patient meets the criteria for brain death, as described later in the chapter. The available evidence is insufficient to permit a definitive statement that a particular non–brain-dead patient will not recover from coma, nor does it allow prognostication regarding how much recovery may occur in specific cases. However, based on serial examinations at various times after the onset of coma, general statistics on the outcome of coma have been compiled and give the examiner a general idea of how patients may do.

The natural history of coma can be considered in terms of three subcategories: drug-induced, nontraumatic, and traumatic coma. Drug-induced coma usually is reversible unless the patient has not had appropriate systemic support while comatose and has sustained secondary injury from hypoperfusion, hypoxia, or lack of other necessary metabolic substrates.

Nontraumatic Coma

Only about 15% of patients in nontraumatic coma make a satisfactory recovery. Functional recovery is related to the cause of coma. Diseases causing structural damage, such as cerebrovascular disease including subarachnoid hemorrhage, carry the worst prognosis; coma from hypoxia-ischemia due to such causes as cardiac arrest has an intermediate prognosis; coma due to hepatic encephalopathy and other metabolic causes has the best ultimate outcome. Age does not appear to be predictive of recovery. The longer a coma lasts, the less likely the patient is to regain independent functioning. Factors that adversely impact brain injury following cardiac arrest include cerebral edema, pyrexia, hyperglycemia, and seizures (Neumar et al., 2008).

In the early days after the onset of nontraumatic coma, it is not possible to predict with certainty which patients will ultimately enter or remain in a vegetative state. Although rare cases have been reported of patients awakening after prolonged vegetative states, patients with nontraumatic coma who have not regained awareness by the end of 1 month are unlikely to do so. Even if they do regain consciousness, they have practically no chance of achieving an independent existence. A large multi-institutional study determined that within 3 days of cardiac arrest, evaluation in the intensive care unit is sufficiently predictive of neurological outcome to allow for informed decisions regarding life support. Absence of pupillary light or corneal reflexes, and motor response to noxious stimuli no greater than extension, suggest a poor prognosis for recovery. Other poor prognostic signs are myoclonic status epilepticus, bilateral absence of the N20 response from the somatosensory cortex, and several neuroimaging signs (Young, 2009).

Traumatic Coma

The prognosis for traumatic coma differs from that for nontraumatic coma in many ways. First, many patients with head trauma are young. Second, prolonged coma of up to several months does not preclude a satisfactory outcome in traumatic coma. Third, in relationship to their initial degree of neurological abnormality, traumatic coma patients do better than nontraumatic coma patients.

The prognosis for coma from head trauma may be considered in terms of survival. However, because many more patients survive traumatic coma than nontraumatic coma, it is equally important to consider the ultimate disabilities of the survivors; many who survive are left with profound disabilities. The GCS is a practical system for describing outcome in traumatic coma. As originally proposed, this scale includes five categories: (1) death, (2) PVS, (3) severe disability (conscious but disabled and dependent on others for activities of daily living), (4) moderate disability (disabled but independent), and (5) good recovery (resumption of normal life even though there may be minor neurological and psychiatric deficits).

In their landmark 1979 report, Jennett and colleagues studied 1000 patients in coma longer than 6 hours from severe head trauma: 49% of these patients died, 3% remained vegetative, 10% survived with severe disability, 17% survived with moderate disability, and 22% had good recovery. The most reliable predictors of outcome 6 months later were depth of coma as evaluated by the GCS; pupil reaction, eye movements, and motor response in the first week after injury; and patient age.

In summary, early predictors of the outcome of posttraumatic coma include patient’s age, motor response, pupillary reactivity, eye movements, and depth and duration of coma. The prognosis worsens with increasing age. Cause of injury, skull fracture, lateralization of damage to one hemisphere, and extracranial injury appear to have little influence on the outcome.

Persistent Vegetative State

As a rule, PVS can be reliably diagnosed 12 months after a traumatic brain injury and 6 months after other cerebral insults. Recovery after 3 years for patients in PVS has not been reported (Wijdicks and Cranford, 2005). Those patients who have been reported to “improve” remain severely disabled, bed- or wheelchair-bound, and fully dependent on care. At 5 years, the mortality rate for PVS is in excess of 80%. Prolonged survival is rare and requires exquisite medical attention. Death typically results from untreated infection or overwhelming sepsis. “Miracle awakenings,” such as with the sudden appearance of communicative speech, have been observed rarely in patients in the minimally conscious state but not in those in PVS (Wijdicks and Cranford, 2005).

Brain Death

Clinical Approach to Brain Death

A thorough knowledge of the criteria for brain death is essential for the physician whose responsibilities include evaluation of comatose patients. Despite differences in state laws, the criteria for the establishment of brain death are fairly standard within the medical community. These criteria include the following:

• Coma. The patient should exhibit an unarousable unresponsiveness. There should be no meaningful response to noxious, externally applied stimuli. The patient should not obey commands or demonstrate any verbal response, either reflexively or spontaneously. Spinal reflexes, however, may be retained.

• No spontaneous respirations. The patient should be removed from ventilatory assistance, and carbon dioxide should be allowed to build up because of the respiratory drive that hypercapnia produces. The diagnosis of absolute apnea requires the absence of spontaneous respiration at a carbon dioxide tension of at least 60 mm Hg. A safe means of obtaining this degree of carbon dioxide retention involves the technique of apneic oxygenation, in which 100% oxygen is delivered endotracheally through a thin sterile catheter for 10 minutes. Arterial blood gas levels should be obtained to confirm the arterial carbon dioxide pressure.

• Absence of brainstem reflexes. Pupillary, oculocephalic, corneal, and gag reflexes all must be absent, and there should not be any vestibulo-ocular responses to cold calorics.

• Electrocerebral silence. An isoelectric EEG should denote the absence of cerebrocortical function. Some authorities do not regard the performance of an EEG as mandatory in assessing brain death, and instances of preserved cortical function despite irreversible and complete brainstem disruption have been reported.

• Absence of cerebral blood flow. Cerebral contrast angiography or radionuclide angiography can substantiate the absence of cerebral blood flow, which is expected in brain death. These tests are considered confirmatory rather than mandatory. On rare occasions, in the presence of supratentorial lesions with preserved blood flow to the brainstem and cerebellum, findings on cerebral radionuclide angiography may be misleading.

• Absence of any potentially reversible causes of marked CNS depression. Such causes include hypothermia (temperature 32°C [89.6°F] or less), drug intoxication (particularly barbiturate overdose), and severe metabolic disturbance.

Brain Death Survival

Despite aggressive therapeutic measures, survival of “brain-dead” persons for more than 1 week has been considered unlikely. Shewmon (1998) reviewed a series of 175 cases surviving longer than 1 week after diagnosis of “brain death.” Survival potential decreased exponentially, with an initial half-life of 2 to 3 months, followed at 1 year by a slow decline. One patient survived for more than 14 years. Survival was found to correlate inversely with age, and prolonged survival was more common with primary brain pathology. The tendency to cardiovascular collapse in brain death may be transient and is more likely to be attributable to systemic than to brain pathology.

References

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Della Corte F., Galli G., Campioni P., et al. Quantitative cerebral blood flow and metabolism determination in the first 48 hours after severe head injury with a new dynamic SPECT device. Acta Neurochir (Wien). 1997;139:636-641.

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Leigh R.J., Zee D.S. The Neurology of Eye Movements, fourth ed. New York: Oxford University Press; 2006.

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