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Altered States of Consciousness
The terms used to describe states of decreased consciousness are listed in Table 2.1 . With the exception of coma, these definitions are not standard. However, they are more precise and therefore more useful than such terms as semicomatose and semistuporous . The term encephalopathy describes a diffuse disorder of the brain in which altered states of consciousness, altered cognition or personality, and seizures may occur. Encephalitis is an encephalopathy accompanied by inflammation and usually cerebrospinal fluid pleocytosis.
Table 2.1
States of Decreased Consciousness
| Term | Definition |
|---|---|
| Lethargy | Difficult to maintain the aroused state |
| Obtundation | Responsive to stimulation other than pain a |
| Stupor | Responsive only to pain a |
| Coma | Unresponsive to pain |
a Responsive indicates cerebral alerting, not just reflex withdrawal.
Lack of responsiveness is not always lack of consciousness. For example, infants with botulism (see Chapter 6 ) may have such severe hypotonia and ptosis that they cannot move their limbs or eyelids in response to stimulation. They appear to be in a coma or stupor, but are actually alert. The locked-in syndrome (a brainstem disorder in which the individual can process information but cannot respond due to paralysis) and catatonia are other examples of diminished responsiveness in the alert state. Lack of responsiveness is also common in psychogenic spells, and transient lack of responsiveness may be seen in children with inattentiveness or obsessive-compulsive traits.
Either increased or decreased neuronal excitability may characterize the progression from consciousness to coma. Patients with increased neuronal excitability (the high road to coma ) become restless and then confused; next, tremor, hallucinations, and delirium (an agitated confusional state) develop. Myoclonic jerks may occur. Seizures herald the end of delirium, and stupor or coma follow. Box 2.1 summarizes the differential diagnosis of the high road to coma. Tumors and other mass lesions are not expected causes. Instead, metabolic, toxic, and inflammatory disorders are likely.
Box 2.1
Causes of Agitation and Confusion
Epileptic
Infectious Disorders
Metabolic and Systemic Disorders
-
Disorders of osmolality
-
Endocrine disorders
-
Hepatic encephalopathy
-
Inborn errors of metabolism
-
Renal disease
Migraine
Psychological
-
Panic disorder a
-
Schizophrenia
Toxic
Vascular
-
Congestive heart failure a
-
Embolism a
-
Hypertensive encephalopathy a
-
Lupus erythematosus a
-
Anti-NMDA antibody encephalitis
-
Subarachnoid hemorrhage a
-
Vasculitis a
a Denotes the most common conditions and the ones with disease-modifying treatments
NMDA, N-methyl-D-aspartate
Decreased neuronal excitability (the low road to coma ) lacks an agitated stage. Instead, awareness progressively deteriorates from lethargy to obtundation, to stupor, and to coma. The differential diagnosis is considerably larger than that with the high road and includes mass lesions and other causes of increased intracranial pressure ( Box 2.2 ). Box 2.3 lists conditions that cause recurrent encephalopathies. A comparison of Box 2.1 and Box 2.2 shows considerable overlap between conditions whose initial features are agitation and confusion and those that begin with lethargy and coma; therefore the disorders responsible for each are described together to prevent repetition.
Box 2.2
Causes of Lethargy and Coma
Epilepsy
Hypoxia-Ischemia
-
Cardiac arrest
-
Cardiac arrhythmia
-
Congestive heart failure
-
Hypotension
-
Autonomic dysfunction
-
Dehydration
-
Hemorrhage
-
Pulmonary embolism
-
-
Near drowning
-
Neonatal (see Chapter 1 )
Increased Intracranial Pressure
-
Cerebral abscess (see Chapter 4 )
-
Cerebral edema (see Chapter 4 )
-
Cerebral tumor (see Chapters 4 and 10 )
-
Herniation syndromes (see Chapter 4 )
-
Hydrocephalus (see Chapters 4 and 18 )
-
Intracranial hemorrhage
-
Spontaneous (see Chapter 4 )
-
Traumatic
-
Infectious Disorders
-
Bacterial infections
-
Postimmunization encephalopathy
-
Rickettsial infections
-
Viral infections
-
Arboviruses
-
Aseptic meningitis
-
Herpes simplex encephalitis
-
Measles encephalitis
-
Postinfectious encephalomyelitis
-
Reye syndrome
-
Metabolic and Systemic Disorders
-
Disorders of osmolality
-
Diabetic ketoacidosis (hyperglycemia)
-
Hypoglycemia
-
Hypernatremia
-
Hyponatremia
-
-
Endocrine disorders
-
Adrenal insufficiency
-
Hypoparathyroidism
-
Thyroid disorders
-
-
Hepatic encephalopathy
-
Inborn errors of metabolism
-
Renal disorders
-
Acute uremic encephalopathy
-
Chronic uremic encephalopathy
-
Dialysis encephalopathy
-
Hypertensive encephalopathy
-
-
Other metabolic disorders
-
Burn encephalopathy
-
Hypomagnesemia
-
Parenteral hyperalimentation
-
Vitamin B complex deficiency
-
-
Migraine coma
-
Toxic
-
Trauma
-
Concussion
-
Contusion
-
Intracranial hemorrhage
- ▪
Epidural hematoma
- ▪
Subdural hematoma
- ▪
Intracerebral hemorrhage
- ▪
-
Neonatal (see Chapter 1 )
-
-
Vascular
-
Hypertensive encephalopathy a
-
Lupus erythematosus a (see Chapter 11 )
-
Neonatal idiopathic cerebral venous thrombosis (see Chapter 1 )
-
Vasculitis a
a Denotes the most common conditions and the ones with disease-modifying treatments
(see Chapter 11 )
-
Box 2.3
Causes of Recurrent Encephalopathy
-
Burn encephalopathy
-
Epileptic encephalopathies a
-
Hashimoto encephalopathy a
-
Hypoglycemia a
-
Increased intracranial pressure a
a Denotes the most common conditions and the ones with disease-modifying treatments
(recurrent)
-
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
-
Mental disorders
-
Migraine
-
Mitochondrial disorders
-
Pyruvate metabolism disorders
-
Substance abuse
-
Urea cycle disorder
Diagnostic approach to delirium
Delirium is characterized by diffuse cognitive dysfunction, altered sleep-wake cycle, perceptual disturbances, thought and language disturbance, altered mood and affect. The symptom onset is characteristically acute and the intensity of symptoms fluctuates for the duration of the delirium.
Assume that any child with the acute behavioral changes of delirium (agitation, confusion, delusions, or hallucinations) has an organic encephalopathy until proven otherwise. Some of the most frequent etiologies include central nervous system (CNS) infection, medication induced (anticholinergics, opioids, etc.), autoimmune disease (anti-NMDA [N-methyl-D-aspartate receptor], lupus, polyarteritis nodosa), CNS neoplasm, organ failure (respiratory, cardiac, kidney, liver) following transplant or surgery, sepsis, illicit drugs, and trauma. The usual causes of delirium are toxic or metabolic disorders diffusely affecting both cerebral hemispheres. Schizophrenia should not be a consideration in a prepubertal child with acute delirium. Fixed beliefs, unalterable by reason, are delusions . The paranoid delusions of schizophrenia are logical to the patient and frequently part of an elaborate system of irrational thinking in which the patient feels menaced. Delusions associated with organic encephalopathy are less logical, not systematized, and tend to be stereotyped.
Hallucination is the perception of sensory stimuli that is not present. Organic encephalopathies usually cause non-formed visual more than auditory hallucinations, whereas psychiatric illness usually causes formed auditory more than visual hallucinations, especially if the voices are accusatory. Stereotyped auditory hallucinations that represent a recurring memory are an exception and suggest temporal lobe seizures.
History and Physical Examination
Delirious children, even with stable vital function, require rapid assessment because the potential for deterioration to a state of diminished consciousness is real. Mortality has been reported to be as high as 20%. Obtain a careful history of the following: (1) the events leading to the behavioral change; (2) drug or toxic exposure (prescription drugs are more often at fault than substances of abuse, and a medicine cabinet inspection should be ordered in every home the child has visited); (3) a personal or family history of migraine or epilepsy; (4) recent or concurrent fever, infectious disease, or systemic illness; and (5) a previous personal or family history of encephalopathy.
Examination of the eyes, in addition to determining the presence or absence of disk edema, provides other etiological clues. Small or large pupils that respond poorly to light, nystagmus, or impaired eye movements suggest a drug or toxic exposure. Fixed deviation of the eyes in one lateral direction may indicate seizure or a significant loss of function in one hemisphere. The general and neurological examinations should specifically include a search for evidence of trauma, needle marks on the limbs, meningismus, lymphadenopathy, and cardiac disease.
Laboratory Investigations
Individualize laboratory evaluation; not every test is essential for each clinical situation. Studies of potential interest include culture; complete blood count; sedimentation rate; urine drug screening; blood concentrations of glucose, electrolytes, calcium and phosphorus, urea nitrogen, ammonia, liver enzymes, thyroid-stimulating hormone, thyroid, NMDA receptor and lupus antibodies, and liver enzymes. If possible, obtain computed tomography (CT) or rapid-sequence MRI while the results of these tests are pending. If sedation is required to perform the study, a short-acting benzodiazepine is preferred. Nondiagnostic blood studies and normal imaging results are an indication for lumbar puncture to look for infection or increased intracranial pressure. A manometer should always be available to measure cerebrospinal fluid pressure.
An electroencephalogram (EEG) is useful in the evaluation of altered mentation. Acute organic encephalopathies will show a decreased speed in the occipital dominant rhythm during the waking state. The EEG is often normal in psychiatric illnesses. Diffuse theta and delta activity, absence of faster frequencies, and intermittent rhythmic delta activity are characteristic of severe encephalopathies. Specific abnormalities may include epileptiform activity consistent with absence or complex partial status; triphasic waves indicating hepatic, uremic, or other toxic encephalopathy; and periodic lateralizing epileptiform discharges in one temporal lobe, suggesting herpes encephalitis.
Diagnostic approach to lethargy and coma
The diagnostic approach to states of diminished consciousness in children is similar to that suggested for delirium, except for greater urgency. The causes of progressive decline in the state of consciousness are diffuse or multifocal disturbances of the cerebral hemispheres or focal injury to the brainstem. Physical examination reveals the anatomical site of abnormality in the brain.
History and Physical Examination
Obtain the same historical data as for delirium, except that mass lesions are an important consideration. Inquire further concerning trauma or preceding symptoms of increasing intracranial pressure. Direct the physical examination to determining both the anatomical site of disturbed cerebral function and its cause. The important variables in locating the site of abnormality are state of consciousness, pattern of breathing, pupillary size and reactivity, eye movements, and motor responses. The cause of lethargy and obtundation is usually mild depression of hemispheric function. Stupor and coma are characteristic of much more extensive disturbance of hemispheric function, or involvement of the diencephalon and upper brainstem. Derangements of the dominant hemisphere may have a greater effect on consciousness than derangements of the non-dominant hemisphere.
Cheyne-Stokes respiration , in which periods of hyperpnea alternate with periods of apnea, is usually caused by bilateral hemispheric or diencephalic injuries, but can result from bilateral damage anywhere along the descending pathway between the forebrain and upper pons. Alertness, pupillary size, and heart rhythm may vary during Cheyne-Stokes respiration. Alertness is greater during the waxing portion of breathing. Lesions just ventral to the aqueduct or fourth ventricle cause a sustained, rapid, deep hyperventilation (central neurogenic hyperventilation). Abnormalities within the medulla and pons affect the respiratory centers and cause three different patterns of respiratory control: (1) apneustic breathing, a pause at full inspiration; (2) ataxic breathing, haphazard breaths and pauses without a predictable pattern; and (3) Ondine curse, failure of automatic breathing when asleep.
In metabolic encephalopathies, retention of the pupillary light reflex is usual. Absence of the pupillary reflex in a comatose patient indicates a structural abnormality. The major exception is drugs; the cause of fixed dilation of pupils in an alert patient is topical administration of mydriatics. In comatose patients, hypothalamic damage causes unilateral pupillary constriction and Horner syndrome; midbrain lesions cause mid-position fixed pupils; pontine lesions cause small but reactive pupils; and lateral medullary lesions cause Horner syndrome.
Tonic lateral deviation of both eyes indicates a seizure originating in the frontal lobe opposite to the direction of gaze (saccade center); the parietal lobe is ipsilateral to the direction of gaze (pursuit center); or a destructive lesion is present in the ipsilateral frontal lobe in the direction of gaze. The assessment of ocular motility in comatose patients is the instillation of ice water sequentially 15 minutes apart in each ear to chill the tympanic membrane. Ice water in the right ear causes both eyes to deviate rapidly to the right and then slowly return to the midline. The rapid movement to the right is a brainstem reflex, and its presence indicates that much of the brainstem is intact. Abduction of the right eye with failure of left eye adduction indicates a lesion in the medial longitudinal fasciculus (see Chapter 15 ). The slow movement that returns the eyes to the left requires a cortico-pontine pathway originating in the right hemisphere and terminating in the left pontine lateral gaze center. Its presence indicates unilateral hemispheric function. Skew deviation, the deviation of one eye above the other (hypertropia), usually indicates a lesion of the brainstem or cerebellum.
Carefully observe trunk and limb position at rest, spontaneous movements, and response to noxious stimuli. Spontaneous movement of all limbs generally indicates a mild depression of hemispheric function without structural disturbance. Monoplegia or hemiplegia suggests a structural disturbance of the contralateral hemisphere, except when in the postictal state. An extensor response of the trunk and limbs to a noxious stimulus is termed decerebrate rigidity . The most severe form is opisthotonos . The neck is hyperextended and the teeth clenched; the arms adducted, hyperextended, and hyperpronated; and the legs extended with the feet plantar flexed. Decerebrate rigidity indicates brainstem compression and is considered an ominous sign whether present at rest or in response to noxious stimuli. Flexion of the arms and extension of the legs is termed decorticate rigidity . It is uncommon in children except following head injury and indicates hemispheric dysfunction with brainstem integrity.
Laboratory Investigations
Laboratory investigations are similar to those described for the evaluation of delirium. Perform head CT with contrast enhancement promptly in order to exclude the possibility of a mass lesion and herniation. It is a great error to send a child, whose condition is uncertain, for CT without someone in attendance who knows how to monitor deterioration and intervene appropriately.
Hypoxia and ischemia
Hypoxia and ischemia usually occur together. Prolonged hypoxia causes personality change first and then loss of consciousness; acute anoxia results in immediate loss of consciousness.
Prolonged Hypoxia
Clinical features
Prolonged hypoxia can result from severe anemia (oxygen-carrying capacity reduced by at least half), congestive heart failure, chronic lung disease, and neuromuscular disorders.
The best-studied model of prolonged, mild hypoxia involves ascent to high altitudes. Mild hypoxia causes impaired memory and judgment, confusion, and decreased motor performance. Greater degrees of hypoxia result in obtundation, multifocal myoclonus, and sometimes focal neurological signs such as monoplegia and hemiplegia. Children with chronic cardiopulmonary disease may have an insidious alteration in behavioral state as the arterial oxygen concentration slowly declines.
The neurological complications of cystic fibrosis result from chronic hypoxia and hypercapnia leading to lethargy, somnolence, and sometimes coma. Neuromuscular disorders that weaken respiratory muscles, such as muscular dystrophy, often produce nocturnal hypoventilation as a first symptom of respiratory insufficiency. Frequent awakenings and fear of sleeping are characteristic (see Chapter 7 ).
Diagnosis
Consider chronic hypoxia in children with chronic cardiopulmonary disorders who become depressed or undergo personality change. Arterial oxygen pressure ( P a o 2 ) values below 40 mm Hg are regularly associated with obvious neurological disturbances, but minor mental disturbances may occur at P a o 2 concentrations of 60 mm Hg, especially when hypoxia is chronic.
Management
Encephalopathy usually reverses when P a o 2 is increased, but persistent cerebral dysfunction may occur in mountain climbers after returning to sea level, and permanent cerebral dysfunction may develop in children with chronic hypoxia. As a group, children with chronic hypoxia from congenital heart disease have a lower IQ than non-hypoxic children. The severity of mental decline relates to the duration of hypoxia. Treat children with neuromuscular disorders who develop symptoms during sleep with overnight, intermittent positive-pressure ventilation (see Chapter 7 ).
Acute Anoxia and Ischemia
The usual circumstance in which acute anoxia and ischemia occur is cardiac arrest or sudden hypotension. Anoxia without ischemia occurs with suffocation (near drowning, choking). Prolonged anoxia leads to bradycardia and cardiac arrest. In adults, hippocampal and Purkinje cells begin to die after 4 minutes of total anoxia and ischemia. Exact timing may be difficult in clinical situations when ill-defined intervals of anoxia and hypoxia occur. Remarkable survivals are sometimes associated with near drowning in water cold enough to lower cerebral temperature and metabolism. The pattern of hypoxic-ischemic brain injury in newborns is different, and depends largely on brain maturity (see Chapter 1 ).
Clinical features
Consciousness is lost within 8 seconds of cerebral circulatory failure, but the loss may take longer when anoxia occurs without ischemia. Presyncopal symptoms of lightheadedness and visual disturbances sometimes precede loss of consciousness. Initially, myoclonic movements due to lack of cortical spinal inhibition may occur. Seizures may follow.
Prediction of outcome after hypoxic-ischemic events depends on age and circumstances. Only 13% of adults who have had a cardiac arrest regain independent function in the first year after arrest. The outcome in children is somewhat better because the incidence of preexisting cardiopulmonary disease is lower. Absence of pupillary responses on initial examination is an ominous sign; such patients are less likely to recover independent function. Twenty-four hours after arrest, lack of motor responses in the limbs and eyes identifies patients with a poor prognosis. Persistent early-onset myoclonus is a negative prognostic sign. In contrast, a favorable outcome is predictable for patients who rapidly recover roving or conjugate eye movements and limb withdrawal from pain. Children who are unconscious for longer than 60 days are very unlikely to regain language skills or the ability to walk.
Two delayed syndromes of neurological deterioration follow anoxia. The first is delayed postanoxic encephalopathy, the appearance of apathy or confusion 1–2 weeks after apparent recovery. Motor symptoms follow, usually rigidity or spasticity, and may progress to coma or death. Demyelination is the suggested mechanism. Diffuse restricted diffusion weighted signal in all while matter extending to subcortical regions with sparing of U-fibers is a common finding. The other syndrome is postanoxic action myoclonus . This usually follows a severe episode of anoxia and ischemia caused by cardiac arrest. All voluntary activity initiates disabling myoclonus (see Chapter 14 ). Symptoms of cerebellar dysfunction are also present.
Diagnosis
Cerebral edema is prominent during the first 72 hours after severe hypoxia. CT during that time shows decreased density with loss of the differentiation between gray and white matter. Severe, generalized loss of density on the CT correlates with a poor outcome. An EEG that shows a burst-suppression pattern or absence of activity is associated with a poor neurological outcome or death; lesser abnormalities typically are not useful in predicting the prognosis. Magnetic resonance imaging (MRI) is a more sensitive imaging modality that shows the extent of hypoxia very well in diffusion weighted T 2 and FLAIR images; however, some of the changes noted with this technique may be reversible.
Management
The principles of treating patients who have sustained hypoxic-ischemic encephalopathy do not differ substantially from the principles of caring for other comatose patients. Maintaining oxygenation, circulation, and blood glucose concentration is essential. Regulate intracranial pressure to levels that allow satisfactory cerebral perfusion (see Chapter 4 ). Anticonvulsant drugs manage seizures (see Chapter 1 ). Anoxia is invariably associated with lactic acidosis. Restoration of acid-base balance is essential.
The use of barbiturate coma to slow cerebral metabolism is common practice, but neither clinical nor experimental evidence indicates a beneficial effect following cardiac arrest or near drowning. Hypothermia prevents brain damage during the time of hypoxia and ischemia, and it has some value after the event. Whole body and head cooling are now standard of care for perinatal hypoxic-ischemic encephalopathy. Corticosteroids do not improve neurological recovery in patients with global ischemia following cardiac arrest. Postanoxic action myoclonus sometimes responds to levetiracetam, zonisamide, or valproate.
Persistent Vegetative State or Unresponsive Wakefulness Syndrome
The term persistent vegetative state (PVS) or unresponsive wakefulness syndrome (UWS) describes patients who, after recovery from coma, return to a state of wakefulness without signs of awareness of the self or the environment. PVS is a form of eyes-open permanent unconsciousness with loss of cognitive function and awareness of the environment but preservation of sleep-wake cycles and vegetative function. Survival is indefinite with good nursing care. The usual causes, in order of frequency, are anoxia and ischemia, metabolic or encephalitic coma, and head trauma. Anoxia-ischemia has the worst prognosis. Children who remain in a PVS for 3 months do not regain functional skills.
The American Academy of Neurology has adopted the policy that discontinuing medical treatment, including the provision of nutrition and hydration, is ethical in a patient whose diagnosed condition is PVS, when it is clear that the patient would not want maintenance in this state, and the family agrees to discontinue therapy.
Brain death
The guidelines for brain death suggested by the American Academy of Neurology (1995 reviewed in 2012 ) are generally accepted. Box 2.4 summarizes the important features of the report. Absence of cerebral blood flow is the earliest and most definitive proof of brain death.
Box 2.4
Diagnostic Criteria for the Clinical Diagnosis of Brain Death
Prerequisites
-
Cessation of all brain function
-
Proximate cause of brain death is known
-
Condition is irreversible
Cardinal Features
-
Coma
-
Absent brainstem reflexes
-
Pupillary light reflex
-
Corneal reflex
-
Oculocephalic reflex
-
Oculovestibular reflex
-
Oropharyngeal reflex
-
-
Apnea (established by formal apnea test)
Confirmatory Tests (Optional)
-
Cerebral angiography
-
Electroencephalography
-
Radioisotope cerebral blood flow study
-
Transcranial Doppler ultrasonography
Determination of brain death in term newborns (> 37 weeks' gestational age), infants, and children is a clinical diagnosis based on the absence of neurological function with a known irreversible cause of coma. Hypotension, hypothermia, and metabolic disturbances should be corrected, and medications that can interfere with the neurological examination and apnea testing should be discontinued allowing for adequate clearance before proceeding with these evaluations. Two exams including apnea test by different attending physicians separated by an observation period are required. Apnea testing may be performed by the same physician. An observation period of 24 hours for term newborns up to age 30 days and 12 hours for infants and children up to 18 years is recommended. Apnea testing requires documentation of an arterial PaC o 2 20 mm Hg above the baseline and > 60 mm Hg with no respiratory effort during the testing period. Ancillary testing is required (EEG, radionucleotide cerebral blood flow) if an apnea test cannot be safely completed, if the observation period needs to be abbreviated, if the clinical findings are uncertain, or if a medication effect may be present.
Infectious disorders
Bacterial Infections
Cat-Scratch Disease
The causative agent of cat-scratch disease is Bartonella ( Rochalimaea ) henselae, a gram-negative bacillus transmitted by a cat scratch or cat bite contaminated by flea feces, or less frequently ticks may act as vectors. It is the most common cause of chronic benign lymphadenopathy in children and young adults. The estimated incidence in the United States is 22,000 per year, and 80% of cases occur in children less than 12 years of age.
Clinical features
The major feature is lymphadenopathy proximal to the site of the scratch. Fever is present in only 60% of cases. The disease is usually benign and self-limited. Unusual systemic manifestations are oculoglandular disease, erythema nodosum, osteolytic lesions, and thrombocytopenic purpura. The most common neurological manifestation is encephalopathy. Transverse myelitis, radiculitis, cerebellar ataxia, and neuroretinitis are rare manifestations. Neurological manifestations when present occur 2 or 3 weeks after the onset of lymphadenopathy.
Neurological symptoms occur in 2% of cases of cat-scratch disease, and 90% of them manifest as encephalopathy. The mechanism is unknown, but the cause may be either a direct infection or vasculitis. The male-to-female ratio is 2:1. Only 17% of cases occur in children less than 12 years old and 15% in children 12–18 years old. The frequency of fever and the site of the scratch are the same in patients with encephalitis compared to those without encephalitis. The initial and most prominent feature is a decreased state of consciousness ranging from lethargy to coma. Seizures occur in 46%–80% of cases and combative behavior in 40%. Focal findings are rare, but neuroretinitis, Guillain-Barré syndrome, and transverse myelitis can be seen.
Diagnosis
The diagnosis requires local lymphadenopathy, contact with a cat, and an identifiable site of inoculation. Enzyme-linked immunosorbent assay (ELISA) tests and polymerase chain reaction (PCR) amplification from infected tissues are available for diagnosis. The cerebrospinal fluid is normal in 70% of cases. Lymphocytosis in the cerebrospinal fluid, when present, does not exceed 30 cells/mm . The EEG is diffusely slow. Only 19% of patients have abnormal findings on CT scan or MRI of the brain, and these include lesions of the cerebral white matter, basal ganglia, thalamus, and gray matter.
Management
All affected children recover completely, 50% within 4 weeks. For neuroretinitis, doxycycline is preferred because of its excellent intraocular and CNS penetration. For children younger than 8 years of age in whom tooth discoloration is a concern, azithromycin is a good substitute. When coupled with rifampin, these antibiotics seem to promote disease resolution, improve visual acuity, decrease optic disk edema, and decrease the duration of encephalopathy. We use the combination of doxycycline and rifampin for 2–4 weeks in immunocompetent patients, and 4 months for immunocompromised patients in cases of encephalopathy or neuroretinitis.
Gram-Negative Sepsis
Clinical features
The onset of symptoms in gram-negative sepsis may be explosive and characterized by fever or hypothermia, chills, hyperventilation, hemodynamic instability, and mental changes (irritability, delirium, or coma). Neurological features may include asterixis, tremor, and multifocal myoclonus. Multiple organ failure follows: (1) renal shutdown caused by hypotension; (2) hypoprothrombinemia caused by vitamin K deficiency; (3) thrombocytopenia caused by nonspecific binding of immunoglobulin; (4) disseminated intravascular coagulation with infarction or hemorrhage in several organs; and (5) progressive respiratory failure.
Diagnosis
Always consider sepsis in the differential diagnosis of shock, and obtain blood cultures. When shock is the initial feature, gram-negative sepsis is the likely diagnosis. In Staphylococcus aureus infections shock is more likely to occur during the course of the infection and not as an initial feature. The cerebrospinal fluid is usually normal or may have an elevated concentration of protein. MRI or CT of the brain is normal early in the course and shows edema later on.
Management
Septic shock is a medical emergency. Promptly initiate antibiotic therapy at maximal doses (see Chapter 4 ). Treat hypotension by restoration of intravascular volume, and address each factor contributing to coagulopathy. Mortality is high even with optimal treatment.
Hemorrhagic Shock and Encephalopathy Syndrome
Bacterial sepsis is the presumed cause of the hemorrhagic shock and encephalopathy syndrome.
Clinical features
Most affected children are younger than 1 year of age, but cases occur in children up to 26 months. Half of children have mild prodromal symptoms of a viral gastroenteritis or respiratory illness. In the rest, the onset is explosive; a previously well child is found unresponsive and having seizures. Fever of 38°C or higher is a constant feature. Marked hypotension with poor peripheral perfusion is the initial event. Profuse watery or bloody diarrhea with metabolic acidosis and compensatory respiratory alkalosis follows. Disseminated intravascular coagulopathy develops, and bleeding occurs from every venipuncture site. The mortality rate is 50%; the survivors have mental and motor impairment.
Diagnosis
The syndrome resembles toxic shock syndrome, gram-negative sepsis, heat stroke, and Reye syndrome. Abnormal renal function occurs in every case, but serum ammonia concentrations remain normal, hypoglycemia is unusual, and blood cultures yield no growth.
Cerebrospinal fluid is normal except for increased pressure. CT shows small ventricles and loss of sulcal marking caused by cerebral edema. The initial EEG background is diffusely slow or may be isoelectric. A striking pattern called electric storm evolves over the first hours or days. Runs of spikes, sharp waves, or rhythmic slow waves that fluctuate in frequency, amplitude, and location characterize the pattern.
Management
Affected children require intensive care with ventilatory support, volume replacement, correction of acid–base and coagulation disturbances, anticonvulsant therapy, and control of cerebral edema.
Rickettsial Infections
Lyme disease
A spirochete ( Borrelia burgdorferi ) causes Lyme disease. The vector is hard-shelled deer ticks: Ixodes dammini in the eastern United States, I. pacificus in the western United States, and I. ricinus in Europe. Lyme disease is now the most common vector-borne infection in the United States. Six northeastern states account for 80% of cases.
Clinical features
The neurological consequences of disease are variable and some are uncertain. Those associated with the early stages of disease enjoy the greatest acceptance. The first symptom (stage 1) in 60%–80% of patients is a skin lesion of the thigh, groin, or axillae (erythema chronicum migrans), which may be associated with fever, regional lymphadenopathy, and arthralgia. The rash begins as a red macule at the site of the tick bite and then spreads to form a red annular lesion with partial clearing, sometimes appearing as alternating rings of rash and clearing.
Neurological involvement (neuroborreliosis) develops weeks or months later when the infection disseminates (stage 2). Most children only have a headache, which clears completely within 6 weeks; the cause may be mild aseptic meningitis or encephalitis. Fever may not occur. Facial palsy, sleep disturbances, and papilledema are rare. Polyneuropathies are uncommon in children. Transitory cardiac involvement (myopericarditis and atrioventricular block) may occur in stage 2.
A year or more of continual migratory arthritis begins weeks to years after the onset of neurological features (stage 3). Only one joint, often the knee, or a few large joints are affected. During stage 3, the patient feels ill. Encephalopathy with memory or cognitive abnormalities and confusional states, with normal cerebrospinal fluid results, may occur. Other psychiatric or fatigue syndromes appear less likely to be causally related.
Diagnosis
The spirochete grows on cultures from the skin rash during stage 1 of the disease. At the time of meningitis, the cerebrospinal fluid may be normal at first but then shows a lymphocytic pleocytosis (about 100 cells/mm ), an elevated protein concentration, and a normal glucose concentration. B. burgdorferi grows on culture from the cerebrospinal fluid during the meningitis. A two-test approach establishes the diagnosis of neuroborreliosis. The first step is to show the production of specific IgG and IgM antibodies in cerebrospinal fluid. Antibody production begins 2 weeks after infection, and IgG is always detectable at 6 weeks. The second step, used when the first is inconclusive, is PCR to detect the organism.
Management
Either ceftriaxone (2 g once daily intravenously) or penicillin (3–4 mU intravenously every 3–4 hours) for 2–4 weeks treats encephalitis. Examine the cerebrospinal fluid toward the end of the 2- to 4-week treatment course to assess the need for continuing treatment and again 6 months after the conclusion of therapy. Intrathecal antibody production may persist for years following successful treatment, and in isolation it does not indicate active disease. Patients in whom cerebrospinal fluid pleocytosis fails to resolve within 6 months, however, should be retreated.
The treatment of peripheral or cranial nerve involvement without cerebrospinal fluid abnormalities is with oral agents, either doxycycline 100 mg twice daily for 14–21 days, or amoxicillin 500 mg every 8 hours for 10–21 days. An effective vaccine against Lyme disease is available and may be used for children who live in endemic areas.
A subcommittee from the American Academy of Neurology concluded in 2007 that some evidence supports the use of penicillin, ceftriaxone, cefotaxime, and doxycycline in both adults and children with neuroborreliosis.
Rocky Mountain spotted fever
Rocky Mountain spotted fever is an acute tick-borne disorder caused by Rickettsia rickettsii. Its geographic name is a misnomer; the disease is present in the northwestern and eastern United States, Canada, Mexico, Colombia, and Brazil.
Clinical features
Fever, myalgia, and rash are constant symptoms and begin 2–14 days after a tick bite. The rash first appears around the wrist and ankles 3–5 days after onset of illness and spreads to the soles of the feet and forearms. It may be maculopapular, petechial, or both. Headache is present in 66% of affected individuals, meningitis or meningoencephalitis in 33%, focal neurological signs in 14%, and seizures in 6%. The focal abnormalities result from microinfarcts.
Diagnosis
R. rickettsii are demonstrable by direct immunofluorescence or immunoperoxidase staining of a skin biopsy specimen of the rash. Other laboratory tests may indicate anemia, thrombocytopenia, coagulopathy, hyponatremia, and muscle tissue breakdown. Serology retrospectively confirms the diagnosis. The cerebrospinal fluid shows a mild pleocytosis.
Management
Initiate treatment when the diagnosis is first suspected. Delayed treatment results in 20% mortality. Oral or intravenous tetracycline (25–50 mg/kg/day), chloramphenicol (50–75 mg/kg/day) in four divided doses, or oral doxycycline (100 mg twice a day for 7 days) is effective. Continue treatment for 2 days after the patient is afebrile.
Toxic Shock Syndrome
Toxic shock syndrome is a potentially lethal illness caused by infection or colonization with some strains of Staphylococcus aureus.
Clinical features
The onset is abrupt. High fever, hypotension, vomiting, diarrhea, myalgia, headache, and a desquamating rash characterize the onset. Multiple organ failure may occur during desquamation. Serious complications include cardiac arrhythmia, pulmonary edema, and oliguric renal failure. Initial encephalopathic features are agitation and confusion. These may be followed by lethargy, obtundation, and generalized tonic-clonic seizures.
Many pediatric cases have occurred in menstruating girls who use tampons, but they may also occur in children with occlusive dressings after burns or surgery, and as a complication of influenza and influenza-like illness in children with staphylococcal colonization of the respiratory tract.
Diagnosis
No diagnostic laboratory test is available. The basis for diagnosis is the typical clinical and laboratory findings. Over half of the patients have sterile pyuria, immature granulocytic leukocytes, coagulation abnormalities, hypocalcemia, low serum albumin and total protein concentrations, and elevated concentrations of blood urea nitrogen, transaminase, bilirubin, and creatine kinase. Cultures of specimens from infected areas yield S. aureus.
Management
Hypotension usually responds to volume restoration with physiological saline solutions. Some patients require vasopressors or fresh-frozen plasma. Initiate antibiotic therapy promptly with an agent effective against S. aureus.
Viral Infections
Because encephalitis usually affects the meninges as well as the brain, the term meningoencephalitis is more accurate. However, distinguishing encephalitis from aseptic meningitis is useful for viral diagnosis because most viruses cause primarily one or the other, but not both. In the United States, the most common viruses that cause meningitis are enteroviruses, herpes simplex virus (HSV), and arboviruses. However, despite the best diagnostic effort, the cause of 70% of cases of suspected viral encephalitis is unknown. Some of these cases represent autoimmune disease.
Routine childhood immunization has reduced the number of pathogenic viruses circulating in the community. Enteroviruses and HSV are now the most common viral causes of meningitis and encephalitis in children. However, specific viral identification is possible in only 15%–20% of cases.
The classification of viruses undergoes frequent change, but a constant first step is the separation of viruses with a DNA nucleic acid core from those with an RNA core. The only DNA viruses that cause acute postnatal encephalitis in immunocompetent hosts are herpes viruses. RNA viruses causing encephalitis are myxoviruses (influenza and measles encephalitis), arboviruses (St. Louis encephalitis, eastern equine encephalitis, western equine encephalitis, La Crosse-California encephalitis), retroviruses (acquired immunodeficiency syndrome encephalitis), and rhabdoviruses (rabies). RNA viruses (especially enteroviruses and mumps) are responsible for aseptic meningitis.
Some viruses, such as HSV, are highly neurotropic (usually infect the nervous system) but rarely neurovirulent (rarely cause encephalitis), whereas others, such as measles, are rarely neurotropic but are highly neurovirulent. In addition to viruses that directly infect the brain and meninges, encephalopathies may also follow systemic viral infections. These probably result from immune-mediated responses triggered by the infection.
Aseptic Meningitis
The term aseptic meningitis defines a syndrome of meningismus and cerebrospinal fluid leukocytosis without bacterial or fungal infection. Drugs or viral infections are the usual cause. Viral meningitis is usually a benign, self-limited disease from which 95% of children recover completely.
Clinical features
The onset of symptoms is abrupt and characterized by fever, headache, and stiff neck, except in infants who do not have meningismus. Irritability, lethargy, and vomiting are common. “Encephalitic” symptoms are not part of the syndrome. Systemic illness is uncommon, but its presence may suggest specific viral disorders. The acute illness usually lasts less than 1 week, but malaise and headache may continue for several weeks.
Diagnosis
In most cases of aseptic meningitis, the cerebrospinal fluid contains 10–200 leukocytes/mm 3 , but cell counts of 1000 cells/mm 3 or greater may occur with lymphocytic choriomeningitis. The response is primarily lymphocytic, but polymorphonuclear leukocytes may predominate early in the course. The protein concentration is generally between 50 and 100 mg/dL (0.5 and 1 g/L) and the glucose concentration is normal, although it may be slightly reduced in children with mumps and lymphocytic choriomeningitis.
Aseptic meningitis usually occurs in the spring or summer, and enteroviruses are responsible for most cases in children. Non-viral causes of aseptic meningitis are rare but considerations include Lyme disease, Kawasaki disease, leukemia, systemic lupus erythematosus, and migraine.
Individuals with a personal or family history of migraine may have attacks of severe headache associated with stiff neck and focal neurological disturbances, such as hemiparesis and aphasia. Cerebrospinal fluid examination shows a pleocytosis of 5–300 cells/mm 3 that is mainly lymphocytes, and a protein concentration of 50–100 mg/dL (0.5–1 g/L). Unresolved is whether the attacks are migraine provoked by intercurrent aseptic meningitis or represent a “meningitic” form of migraine. The recurrence of attacks in some people suggests that the mechanism is wholly migrainous. Nonsteroidal anti-inflammatory drugs may also contribute to pleocytosis.
Bacterial meningitis is the major concern when a child has meningismus. Although cerebrospinal fluid examination provides several clues that differentiate bacterial from viral meningitis, initiate antibiotic therapy for every child with a clinical syndrome of aseptic meningitis until cerebrospinal fluid culture is negative for bacteria (see Chapter 4 ). This is especially true for children who received antibiotic therapy before examination of the cerebrospinal fluid.
Management
Treatment for herpes encephalitis with acyclovir is routine in children with viral meningitis or encephalitis until excluding that diagnosis by PCR analysis of CSF. Treatment of viral aseptic meningitis is symptomatic. Bed rest in a quiet environment and mild analgesics provide satisfactory relief of symptoms in most children.
Arboviral (Arthropod-Borne) Encephalitis
The basis of arbovirus classification is ecology rather than structure. Ticks and mosquitoes are the usual vectors, and epidemics occur in the spring and summer. Each type of encephalitis has a defined geographic area. Arboviruses account for 10% of encephalitis cases reported in the United States.
La Crosse-California encephalitis
The California serogroup viruses, principally La Crosse encephalitis, are the most common cause of arboviral encephalitis in the United States. The endemic areas are the Midwest and western New York State. Most cases occur between July and September. Small woodland mammals serve as a reservoir and mosquitoes as the vector.
Clinical features
Most cases of encephalitis occur in children, and asymptomatic infection is common in adults. The initial feature is a flu-like syndrome that lasts for 2 or 3 days. Headache heralds the encephalitis. Seizures and rapid progression to coma follows. Focal neurological disturbances are present in 20% of cases. Symptoms begin to resolve 3–5 days after onset, and most children recover without neurological sequelae. Death is uncommon and occurs mainly in infants.
Diagnosis
Examination of cerebrospinal fluid shows a mixed pleocytosis with lymphocytes predominating. The count is usually 50–200 cells/mm 3 , but it may range from 0–600 cells/mm 3 . The virus is difficult to culture, and diagnosis depends on showing a 4-fold or greater increase in hemagglutination inhibition and neutralizing antibody titers between acute and convalescent sera.
Management
Treatment is supportive. No effective antiviral agent is available.
Eastern equine encephalitis
Eastern equine encephalitis is the most severe type of arboviral encephalitis with a mortality rate of 50%–70%. Fewer than 10 cases occur per year in the United States.
Clinical features
Eastern equine encephalitis is a perennial infection of horses from New York State to Florida. Human cases do not exceed five each year, and they follow epidemics in horses. The mortality rate is high. Wild birds serve as a reservoir and mosquitoes as a vector. Consequently, almost all cases occur during the summer months.
Onset is usually abrupt and characterized by high fever, headache, and vomiting, followed by drowsiness, coma, and seizures. A long duration of non-neurological prodromal symptoms predicts a better outcome. In infants, seizures and coma are often the first clinical features. Signs of meningismus are often present in older children. Children usually survive the acute encephalitis, but expected sequelae include mental impairment, epilepsy, and disturbed motor function.
Diagnosis
The cerebrospinal fluid pressure is usually elevated, and examination reveals 200–2000 leukocytes/mm 3 , of which half are polymorphonuclear leukocytes. MRI shows focal lesions in the basal ganglia and thalamus. Diagnosis relies on showing a 4-fold or greater rise in complement fixation and neutralizing antibody titers between acute and convalescent sera.
Management
Treatment is supportive. No effective antiviral agent is available.
Japanese B encephalitis
Japanese B encephalitis is a major form of encephalitis in Asia and is an important health hazard to nonimmunized travelers during summer months. The virus cycle is among mosquitoes, pigs, and birds.
Clinical features
The initial features are malaise, fever, and headache or irritability lasting for 2–3 days. Meningismus, confusion, and delirium follow. During the second or third week, photophobia and generalized hypotonia develop. Seizures may occur at any time. Finally, rigidity, a mask-like facies, and brainstem dysfunction ensue. Mortality rates are very high among indigenous populations and lower among Western travelers, probably because of a difference in the age of the exposed populations.
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