Rudolph's Pediatrics, 22nd Ed.

CHAPTER 104. Acute Neurological Dysfunction

Susan T. Arnold

Acute alterations in the level of consciousness always indicate a serious medical problem, which must be comprehensively evaluated and closely monitored. They may arise from both primary processes within the central nervous system or may be caused by the secondary effects of other systemic disorders. In either case, if the disruption is severe enough, central control of respiratory or cardiovascular function can rapidly deteriorate, leading to a life-threatening emergency. The differential diagnosis for altered consciousness or coma is broad, and imaging studies and laboratory tests alone may not identify an etiology. A careful history of the events leading up to the change in mental status and a full multisystem examination are essential and will help guide the choice of diagnostic tests.

Normal consciousness requires both maintenance of arousal and the ability to focus attention and respond to the environment with a full range of cognitive functions. Maintenance of arousal is mediated by a complex network of interactions within the brain, prominently involving the reticular activating system. This is a poorly delineated brain-stem structure extending from the medulla to the rostral midbrain. It receives input from the cerebral cortex and all major sensory systems and projects to local structures within the brain stem and, via ascending pathways, to the thalamus, the hypothalamus, and the cerebral cortex. Stimulation of the reticular activating system results in increased alertness, and destructive lesions produce unresponsiveness.

The cerebral hemispheres direct conscious response to environmental stimuli. In contrast to the brain stem, where even small lesions affecting the reticular activating system may produce coma, extensive bilateral involvement of the cerebral cortex is necessary to cause severe impairment of consciousness. Focal lesions rarely impair consciousness unless they cause compression or edema of the contralateral hemisphere or when multiple bilateral hemispheric lesions are present. However, both focal and diffuse processes may provoke seizures, which can alter consciousness both during an epileptic attack and in the subsequent postictal state.

Altered consciousness usually begins with mild confusion or lethargy. More severe cases progress to obtundation, where the patient is somnolent but arousable, then to stupor, where a patient responds only to vigorous stimuli and immediately becomes unresponsive when stimulation ceases. Coma refers to true unresponsiveness to external stimuli, although there may be reflexive, nonlocalizing motor responses to pain. Delirium describes a state characterized by confusion, disorientation, and difficulty maintaining attention.¹

Because terminology is used inconsistently among observers, and because a patient’s exam may fluctuate, scoring systems such as the Glasgow Coma Scale (Table 104-1) are useful in documenting a patient’s level of consciousness and changes over time. Although these scales provide prognostic information when the etiology of altered consciousness is known, they do not assist in establishing a diagnosis and are not a substitute for a comprehensive history and examination.

INITIAL EVALUATION

As with all critically ill patients, the initial evaluation of the patient with altered consciousness requires a systematic approach (Table 104-2) that focuses first on correcting life-threatening respiratory and cardiovascular dysfunctions. Airway protection and ventilatory support are usually required in patients with significant respiratory abnormalities. Even if adequate respiratory effort is present, endotracheal intubation is often needed to prevent aspiration due to impairment of airway-protective reflexes. Circulatory disturbances may occur, especially in the setting of hypoxic-ischemic injury, and should be treated with intravenous fluid, vasoactive medications, and inotropic medications as appropriate. Laboratory assessments of arterial blood gases, serum glucose and electrolyte concentrations, renal and liver function, a complete blood count, and comprehensive screening for drug toxicity should be a routine part of the initial evaluation of any patient with decreased responsiveness or coma of unknown cause. The primary focus of care should be to discover and treat conditions that may cause ongoing brain injury.

Table 104-1. Glasgow Coma Scale

Table 104-2. Steps in Management of Acute Alterations of Consciousness

The initial physical evaluation should include a multisystem examination with special attention paid to focal or localizing neurological signs. Indications of elevated intracranial pressure must be searched for specifically, and the condition should be treated aggressively if present. The Cushing response, including arterial hypertension (the systolic pressure usually being more elevated than the diastolic pressure), bradycardia, and significant impairment of consciousness, indicates acute intracranial hypertension and is frequently associated with an irregular breathing pattern (Cheynes-Stokes respiration). Papilledema is a hallmark of chronic intracranial hypertension but is not seen immediately, and its absence does not imply normal intracranial pressure. Unilateral pupillary dilation and hemiparesis (ipsilateral or contralateral) may occur with transtentorial herniation of the temporal lobe. When diffuse cerebral edema occurs, or when the mass effect is in the posterior fossa, these findings may not be present. The management of increased intracranial pressure is discussed (see Chapter 111).

After the patient’s immediate stabilization needs are met, further diagnostic testing should be considered. Neuroimaging is usually performed early in the course of evaluation. CT scans are rapid and readily available in most centers but may not detect acute ischemic injury and are of limited value in assessing subtle cortical changes, brain-stem lesions, and posterior fossa abnormalities. MRI is superior for these purposes, and the use of diffusion-weighted imaging sequences allows for very early identification of ischemic changes, permitting initiation of thrombolytic therapy in acute cerebral infarction. However, the length of time required for MRI and the difficulty involved in monitoring an acutely ill patient during the test limit its use. Examination of the cerebrospinal fluid (CSF) assesses for infection and subarachnoid hemorrhage. Because of the risk of herniation, however, lumbar puncture should never be performed in the unconscious patient until neuroimaging and examination have excluded the possibility of increased intracranial pressure. An electroencephalograph can identify subclinical seizures, which, if present, will cause continued impairment of consciousness. It may also reveal patterns of prognostic significance and is occasionally of value in localizing a lesion not evident on imaging studies. It must be emphasized that, in most cases, none of these studies alone is sufficient to explain coma. Often, their results provide only part of the answer, and the findings must be interpreted in the individual clinical situation.

TYPES OF ENCEPHALOPATHY

Following the patient’s initial stabilization and evaluation, the encephalopathy should be classified in terms of its rapidity of onset and the presence or absence of focal findings. These features help narrow the differential diagnosis and may provide clues to an underlying etiology (see Table 104-3). Hypoxic-ischemic injury, infarction, seizures, and most hemorrhages present acutely over minutes to a few hours at most. In contrast, infections, tumors, and metabolic encephalopathies usually evolve more slowly over hours to days. Even when a presumptive cause is evident from the initial evaluation, variations from the expected pattern should prompt a search for a secondary process. For example, a seizure may be the obvious explanation for a patient’s acute loss of consciousness, but a period of progressive lethargy or confusion in the preceding 24 hours suggests a second pathological process such as an intracranial mass lesion, metabolic derangement, or infection, all of which are likely to require more intensive intervention than the seizure itself. A careful history and a full physical examination are needed to complete the clinical picture and to guide therapy.

The presence or absence of focal features also helps determine etiology. Except for hypoxicischemic injury, most diffuse encephalopathies begin gradually. Brain-stem function is typically preserved, although increased intracranial pressure may cause cranial neuropathies due to compression. Generalized seizures may occur, and movement disorders such as tremor (rhythmic involuntary movement of a body part caused by repetitive contraction of opposing muscle groups), myoclonus (brief involuntary twitch or jerk that can be repetitive and involves a group of fibers, a muscle, or a muscle group), or asterixis (a tremor-like movement, usually involving the wrist, caused by intermittent loss of tone in a muscle group) are characteristic of some specific encephalopathies described later in this chapter. With more severe injury, symmetric motor findings such as hyper- or hypotonia and hyperreflexia may appear. Abnormal posturing and primitive reflexes such as the Babinski reflex develop, reflecting widespread cortical dysfunction.

Table 104-3. Common Presentations of Encephalopathy

In contrast to diffuse processes, focal brain lesions have a wide variety of clinical presentations, depending on the structures involved (Table 104-4). A detailed neurological examination is essential for correctly localizing and diagnosing the pathological process. Neuroimaging studies support the diagnosis but are not a substitute for a careful examination. The most visible lesion on an image may not be the most clinically significant one; for example, brain-stem lesions are difficult to see on some imaging studies, but due to their proximity to vital structures, they may have more serious implications than cerebral hemisphere lesions of much larger size. Common etiologies for focal encephalopathy include hemorrhage, infarction, neoplasm, demyelination, and compression. Infectious and traumatic processes can cause either focal or diffuse injury. The signs and symptoms are more specific to the lesion’s location than to the etiology.

TOXIC-METABOLIC ENCEPHALOPATHY

Toxic ingestions are not uncommon in children and should always be suspected in children who suffer from acute changes in mental status. In young children, the ingestion is usually accidental. In adolescents, it is often intentional, although the individual may not have been fully aware of the danger involved. Screening blood or urine for the presence of toxins may be diagnostic, but the tests take time, and no test will include all possible toxins. A careful history of all medications present in the home should be obtained, even if they are not believed to be accessible to the child. Most intoxications present with global encephalopathy, but physical examination may reveal findings characteristic for a specific ingestion (such as toxidromes; see Chapter 120). For example, pupillary constriction with hypercapnic hypoventilation is typical of opioid intoxication. Salicylate poisoning manifests as hyperpnea with respiratory alkalosis and/or metabolic acidosis. Other common toxins such as alcohol, anticholinergic agents, and carbon monoxide poisoning also have characteristic physical and laboratory findings (see Chapter 120). Intoxication with iron supplements can present with coma at several points in its course and is the most frequent cause of pediatric fatality from accidental ingestion.² Certain chemotherapeutic agents or immunosuppressants such as cyclosporine can induce a posterior reversible encephalopathy syndrome (PRES), with focal symptoms and abnormal neuroimaging findings involving the parietal and occipital lobes. This unusual syndrome, also associated with hypertensive encephalopathy, is a rare instance where a systemic toxin produces a focal encephalopathy.

Table 104-4. Localizing Findings in Coma

Rapid identification of a toxic agent may allow use of specific antidotes. Depending on the ingestion, gastric lavage or administration of activated charcoal may also be appropriate. When there is a depressed level of consciousness, it is important to remember that the airway should be protected with a cuffed endotracheal tube before any attempt is made at gastrointestinal decontamination.

Encephalopathy can also result from endogenous toxins when normal homeostatic mechanisms are disrupted and allow excessive accumulation of metabolic products. In infants with inborn errors of metabolism, this can occur rapidly. In older children, the evolution is usually more gradual. The history may reveal evidence of a preexisting illness or of a genetic disorder causing unexplained infant mortality in the family, such as those affecting amino acid or urea metabolism (see Chapter 134). Examination may reveal characteristic findings such as the odors associated with diabetic ketoacidosis or maple syrup urine disease. Metabolic acidosis with a marked anion gap is prominent in amino and organic acidemias, diabetic ketoacidosis, and renal failure. In contrast, urea cycle defects cause hyperammonemia and coma without metabolic acidosis. Hepatic failure is often associated with hyperpnea and hypocapnia. Certain movement disorders are frequently seen with metabolic encephalopathies. Asterixis, although classically associated with hepatic failure, can occur early in the course of any metabolic brain disease. Multifocal myoclonus is more often seen in deeper states of unresponsiveness. Tremor occurs in hyperthyroidism and in association with the ingestion of many drugs. These bilateral, symmetric movement disorders almost never occur with focal cerebral lesions, unless they are associated with an underlying metabolic disorder. Imaging studies usually show no abnormalities, but the EEG may reveal patterns suggestive of metabolic encephalopathy.

HYPOGLYCEMIA

Hypoglycemia deserves special attention as a common and easily reversible etiology for metabolic encephalopathy. In the newborn, it may occur in the absence of other provoking factors. In older children, it presents more frequently as a complication of an underlying metabolic or endocrine disorder. It should also be suspected when glycogen stores in the liver are deficient (starvation, hepatic disease, very young infant), especially if there is another physical stress such as a concurrent infection. If untreated, it can cause permanent brain injury. The administration of dextrose-containing intravenous solutions is advisable in virtually all cases of unexplained coma unless the serum glucose can be immediately and reliably ascertained to be normal. (If malnutrition is present or suspected, thiamine should be administered at the same time to prevent the rare complication of Wernicke encephalopathy.) Reversible focal neurological signs are occasionally seen in association with hypoglycemia, but their presence should always prompt a search for an underlying focal cerebral lesion.

INFECTIONS OF THE CENTRAL NERVOUS SYSTEM

The approach to diagnosis and management of infections of the central nervous system is discussed in detail in Chapters 231, 232, and 555. The early signs of central nervous system infection may be difficult to recognize in children. Irritability is often attributed to fever, and in children younger than 18 months, typical features of meningeal irritation, such as nuchal rigidity or the Kernig or Brudzinski signs, may be absent. The clinician must suspect meningeal or cerebral infection in the child presenting with seizures or mental status changes, especially if accompanied by fever or leukocytosis. Bacterial meningitis usually presents as a global encephalopathy, without localizing signs. However, later in the course, cranial neuropathies and areas of cortical infarction often result from inflammatory infiltrate in the subarachnoid spaces. In contrast, parameningeal foci of infection present with focal neurological features and meningeal irritation. Bacterial sinusitis is the most common source of parameningeal infections, and initial focal features depend on the site of the infection. If not treated early, intracranial abscesses or cortical venous thromboses may ensue, causing regional cerebral edema and more diffuse cerebral dysfunction.

Diagnosis of meningitis requires lumbar puncture to identify the responsible organism. When antibiotic treatment precedes CSF examination, latex agglutination testing of the CSF or urine may identify a bacterial organism. CSF studies may be unrevealing in parameningeal infections and often cannot be obtained safely, because cerebral edema and increased intracranial pressure preclude performing a spinal tap. Broad-spectrum antibiotic therapy should be initiated, and surgical drainage may be needed for intracranial abscesses.

Management of bacterial meningitis requires the use of antibiotics with good CSF penetration. Inappropriate antidiuretic hormone (ADH) secretion occurs commonly, and fluid balance and serum electrolyte concentrations must be carefully monitored. If a pathological bacterial organism cannot be identified, antibiotic coverage should include antiviral therapy for herpes encephalitis, which may have devastating consequences unless it is treated at an early stage. Focal seizures and an abnormal electroencephalography, especially involving the temporal lobes, are commonly associated with herpes encephalitis but may also be seen with other infections that cause focal destructive lesions of the central nervous system. Children with encephalitis are particularly susceptible to refractory seizures and status epilepticus and should be monitored and treated aggressively for this complication.^3,4

TRAUMA

Trauma to the nervous system is discussed in detail in Chapter 551. Traumatic brain injuries may cause focal or diffuse cerebral lesions, often as a combination of several types of injury. When a localized insult is evident, concurrent signs of diffuse injury may be overlooked, although these have important implications for prognosis. The examiner must also be alert for evidence of cervical injury, and cervical spine radiographs should be obtained on every patient with known or suspected head trauma. A traumatic injury may not be evident in situations involving child abuse, where retinal hemorrhages or the evidence of fractures on a skeletal survey may suggest the diagnosis in the absence of visible external signs of injury (see Chapter 35). Trauma often produces cerebral edema and increased intracranial pressure, which must be carefully managed to prevent causing further injury due to compression of adjacent structures. A deteriorating level of consciousness following an initial more lucid period should always raise the suspicion of intracranial bleeding and should prompt an urgent evaluation for epidural or subdural hematoma, which requires emergent neurosurgical intervention.

HYPOXIC-ISCHEMIC ENCEPHALOPATHY

Hypoxia and ischemia trigger a complex cascade of events. These produce cerebral injury both directly, as the result of arrested aerobic metabolism and accumulation of lactic acid, and via secondary injury from the generation of oxygen free radicals, accumulation of excitotoxins such as glutamate, and disturbance of intra-cellular calcium homeostasis. The secondary processes can lead to neuronal apoptosis (programmed cell death), which can occur in an ongoing fashion from hours to days after the initial injury. Areas of the brain with higher density of amino acid receptors appear to be more vulnerable to hypoxic-ischemic insult. These features, along with changes in cerebral metabolism and vasculature, contribute to the differing appearance of hypoxic-ischemic injury at different ages. Hypoxic-ischemic encephalopathy in the newborn is discussed in detail in Chapter 52.

After the neonatal period, the hippocampus, caudate nucleus, and cerebellar Purkinje cells are particularly at risk, as are the border zones between areas supplied by the major cerebral arteries, especially in the posterior parietal and occipital lobes. With less severe injury, lesions are restricted to these areas, and residual deficits are few. However, in the most severe cases, the injury involves both the cerebrum and the brain stem, and coma is associated with loss of all cranial nerve function. The degree of injury is determined by the extent and duration of the hypoxic or ischemic event and by features individual to the child, such as age, concurrent disease, and body temperature. In particular, hypothermia has a relatively protective effect, and the prognosis after prolonged hypoxia from cold-water immersion may be better than with similar duration exposure under different conditions (see Chapter 117).

Hypoxic-ischemic injury is not always readily evident by history, and particularly with lesser degrees of injury, the diagnosis may be uncertain. Evidence of injury to other hypoxia-sensitive organs such as the heart, liver, or kidneys provides clues to the diagnosis. Seizures are common, particularly early in the course of the disorder, and may be refractory to medical management. CT scans are usually unremarkable in the first 24 hours following ischemic injury. MRI demonstrates changes within a few hours. Diffusion-weighted MR in particular is abnormal very early after ischemic injury. Electroencephalograph is helpful in identifying subclinical seizures and in predicting outcome. Severe suppression or a burst-suppression pattern is indicative of a poor prognosis, unless explained by large doses of central nervous system depressant medication.

SEIZURES

Seizures may be a cause of altered consciousness or may be secondary to a primary neurological process that is itself the cause of the altered consciousness. Most seizures are associated with a postictal period of drowsiness or obtundation that may last from minutes to hours. If the seizure is unwitnessed, the correct diagnosis may be overlooked. If an initial seizure has subtle clinical manifestations, it may also go unrecognized, especially when secondary to an underlying condition in which the patient’s baseline mental status is already impaired.

The possibility of subtle seizures or nonconvulsive status epilepticus should always be entertained whenever a clear explanation for encephalopathy cannot be found. An EEG is usually necessary to make this diagnosis, although careful clinical observation may identify eye movements; brief periods of posturing; or other repetitive, stereotyped movements suggesting the presence of nonconvulsive seizures. This is particularly true following treatment for a prolonged convulsive seizure as continued depression of mental status may be wrongly attributed to medication.⁵

Nonconvulsive seizures or status epilepticus may also occur in the absence of a recognized preceding seizure and are common in acute trauma, hypoxic-ischemic injury, or encephalitis, especially when sedating medications or muscle relaxants masks signs of seizure activity. Studies of comatose patients in intensive care units have demonstrated nonconvulsive seizures on electroencephalograph recording in 10% to 20% of cases; this emphasizes the important role of electroencephalography in evaluating and managing patients with altered consciousness.^4,6,7 The presence of status epilepticus is associated with a higher mortality in the intensive care unit (ICU) and with greater long-term morbidity, and it should be treated aggressively with antiepileptic medication. The evaluation and treatment of epilepsy is reviewed in greater detail in Chapters 557 through 564.

SUPRATENTORIAL CEREBRAL LESIONS

Supratentorial lesions involving the cerebral hemispheres or basal ganglia are often associated with focal signs on examination. Headache and behavioral changes are common early in the course of an enlarging supratentorial mass lesion. Unilateral weakness, visual field deficits, hemineglect, and aphasia may occur, providing clues to localization. Seizures are frequent and typically have focal features. Consciousness is not usually impaired unless extensive bilateral lesions are present or a unilateral lesion compresses the contralateral hemisphere either by direct extension or by causing edema and shifting of adjacent structures, as occurs in the herniation syndromes (see Brain Herniation Syndromes in this section).

Table 104-5. Etiologies of Intracranial Hypertension

INFRATENTORIAL CEREBRAL LESIONS

The posterior fossa contains the brain stem and the cerebellum, which are separated from the more rostral structures by an unyielding dural membrane, the tentorium cerebelli. Clinical findings from lesions in this space may include multiple cranial nerve palsies, ataxia, and abnormal pupillary responses. In contrast to supratentorial processes, where extensive bilateral injury is required to produce alteration of consciousness, relatively small infratentorial lesions can produce coma by injuring or compressing the brain stem reticular activating system. Lesions in the posterior fossa require particular vigilance, as even small amounts of edema in this confined area may lead to compression and infarction of brain-stem respiratory and autonomic centers. More extensive swelling, as often occurs with cerebellar lesions, can produce herniation downward through the foramen magnum or upward through the tentorium. In either case, there is a high risk of developing hydrocephalus due to obstruction of cerebrospinal fluid flow through the cerebral aqueduct and fourth ventricle; this compounds the infratentorial process by causing compression and injury to supratentorial structures. Emergent surgical decompression of the posterior fossa may be indicated to halt this chain of events.

INTRACRANIAL HYPERTENSION

The causes of intracranial hypertension are outlined in Table 104-5. The nature of the pathological process dictates the probable time course of intracranial hypertension and may help guide therapy. Cerebral hemorrhages cause acute, often catastrophic increases in intracranial pressure. Brain infarcts produce edema that usually reaches its maximum after 48 hours and then gradually improves. Abscesses and metastatic tumors are typically associated with extensive surrounding edema of longer duration and slow progression. Recognizing the risk and likely time course for developing increased intracranial pressure allows the clinician to anticipate this serious complication and initiate timely, appropriate therapy.

In the newborn period, the open fontanel and cranial sutures allow for sudden increases in intracranial volume, as occurs, for example, after an intraventricular hemorrhage. (In these instances, a bulging fontanel and split sutures provide valuable signs of the increased pressure within.) Beyond this period, however, the cranial vault becomes a relatively fixed container for the brain parenchyma, cerebrospinal fluid, and cerebral blood volume. An increase in any of these components raises the intracranial pressure, causing headache, nausea, and somnolence, which can rapidly progress to stupor or coma. The neurological examination often reveals associated ocular palsies (especially abducens palsy), and papilledema becomes evident over time. As the intracranial pressure increases, it interferes with cerebral blood flow, causing further cerebral injury and edema. The classic Cushing response with raised systolic blood pressure and bradycardia may not occur until late in the course, when medullary compression occurs.

Management of intracranial hypertension is discussed in Chapter 111.

BRAIN HERNIATION SYNDROMES

Herniation is the process by which rapidly expanding cerebral lesions or massive regional edema displaces surrounding brain tissue into an adjacent cranial compartment. In the process, local blood vessels, cranial nerves, or adjacent brain parenchyma may be further injured (Table 104-6). Unilateral edema, especially in the frontal lobe, may force the cingulate gyrus under the midline falx cerebri, compressing the ipsilateral anterior cerebral artery. Uncal herniation occurs when an expanding temporal or frontotemporal lesion forces the medial temporal lobe downward over the edge of the tentorium, compressing the third nerve, midbrain, and posterior cerebral artery (see Fig. 104-1).¹ This produces the characteristic clinical sign of ipsilateral pupillary dilation, which is always associated with profound coma and often with an irregular breathing pattern (Cheynes-Stokes respirations) and the Cushing response.

Table 104-6. Cerebral Herniation Syndromes

Central or transtentorial herniation is the result of caudal displacement of the diencephalon (thalamus and hypothalamus) through the tentorial notch, compressing the structures below. As the herniation progresses, injury extends from the diencephalon to the midbrain and lower portions of the brain stem. A pattern of progressive loss of higher-level functioning may be evident (see Table 104-6). Diencephalic injury is characterized by preservation of conjugate oculocephalic responses. The pupils are small but if carefully examined still show constriction to light (unless the ipsilateral third nerve has been injured in concurrent uncal herniation). A Cheyne-Stokes respiratory pattern is often present, and noxious stimuli provoke nonpurposeful decorticate posturing with flexion of the arms and leg extension. As the midbrain and upper pons become involved, oculomotor movements become disconjugate and may be difficult to elicit. The pupils are midposition and unresponsive to light. The respiratory pattern shifts to sustained tachypnea, and decerebrate posturing (with extension of all extremities) replaces decorticate posturing in response to stimulation.¹

The development of these signs is associated with a grim prognosis. In most cases, medullary compression soon follows, announced by loss of oculovestibular responses; flaccid muscle tone; and slow, irregular breathing, which eventually progresses to apnea. In clinical situations, the progression from higher to lower stages of functioning is often less distinct, and findings are commonly asymmetric, but the ominous implications of the later stages are the same.

ASSESSMENT OF BRAIN DEATH

Brain death occurs when all cerebral functions are irreversibly absent. Accordingly, its diagnosis implies an evaluation of physical findings and a judgment that brain function has no chance of recovery. It is particularly the latter that puts an onerous responsibility in the hands of the physician. To help the process and provide uniformity, several expert bodies have elaborated guidelines, which provide a valuable framework for conducting the diagnostic procedures described below. The guidelines are by nature nonbinding and need to be complemented by careful consideration of the circumstances and mechanism of the neurological injuries, the age of the patient, and the presence of other organ or system dysfunctions. Hospitals may also have their own established protocols to guide medical staff in this complex situation.

FIGURE 104-1. The floor of the anterior and middle cerebral fossae, illustrating the tentorial notch (dark gray) and the contents that pass through it. Note that the sections of the circle of Willis (dotted blue line) that is most at risk during downward tentorial herniation are the posterior cerebral arteries (red). These run adjacent to both branches of the oculomotor nerve (cranial nerve III, yellow) that controls pupillary dilatation. (Source: Adapted by Dr. Steven G. Kernie from Plum F, Posner JB. The Diagnosis of Stupor and Coma. 3d ed. New York: Oxford University Press; 2000.)

It is commonly accepted that the diagnosis of brain death requires at least two careful and detailed examinations by an experienced clinician, followed by formal documentation of apnea as described below.^9-11 Every effort must be made to eliminate confounding factors that could suppress evidence of brain activity. These factors include hypothermia, systemic hypotension, and the presence of medications that suppress central nervous system function. To confirm brain death, all central motor and autonomic responses to external stimuli must be absent, including reflexive decorticate or decerebrate posturing. Spinal motor reflexes may persist. Lack of brain-stem function is documented by careful testing of individual cranial nerves. Vestibular and oculomotor functions are examined by testing caloric responses. If the water is cold, relative to body temperature, the eyes turn toward the ipsilateral ear, with horizontal nystagmus (quick horizontal eye movements) to the contralateral ear. If the water is warm (44°C or above) the eyes turn toward the contralateral ear. Respiratory control is assessed by performing an oxygenated apnea test that confirms the absence of any respiratory drive to hypercarbia at least 20 mmHg above the baseline PCO₂ level.

Clinical guidelines published in 1987 recommended using the EEG as a confirmatory test in children under 1 year of age.⁹ According to these guidelines, from age 7 days to 2 months, two examinations and electroencephalographies (EEGs) should be performed with an interval of at least 48 hours. (No guidelines have been specified for the first week after birth.) Between the ages of 2 months and 1 year, the examinations should be separated by 24 hours, and the interval may be decreased and the second EEG eliminated if radionuclide angiography shows no cerebral blood flow. After 1 year of age, laboratory testing is not required, and the exams should be separated by 12 hours when an irreversible condition exists, or by 24 hours if the reversibility is difficult to assess, as in acute hypoxic-ischemic injury. Laboratory testing in children over 1 year of age is most helpful when the ability to perform a clinical examination is impaired, when there is a desire to reduce the observation interval between examinations, or when such testing is necessary to help the patient’s family come to terms with the clinical situation.¹⁰

Despite the recommendation for EEG testing in infants, the test is of limited usefulness and may yield contradictory results. Specifically, there may be traces of cerebral activity on the test when all other signs are consistent with brain death.¹² EEG is also influenced by the presence of sedative medications and is difficult to perform in an ICU environment where environmental artifacts may obscure the findings. Recognition of the EEG’s limitation has led to greater use of other ancillary tests to determine brain death. Brain-stem auditory or somato-sensory-evoked potential testing is sometimes helpful in establishing loss of brain-stem function, but the available techniques test only a limited number of brain-stem pathways and are not readily available in all settings. Auditory-evoked potentials can be useful to establish absence of eighth cranial nerve function when facial trauma prevents normal performance of caloric testing.¹³ Studies of cerebral blood flow (including transcranial Doppler ultrasonography of intracranial vessels, magnetic resonance or CT angiography, and conventional cerebral angiography) may be of particular value in the definition of pediatric brain death.¹³ These tests are less likely than EEG to be influenced by sedative medications and with newer imaging modalities are easier to perform and available at most medical centers.