Part 3. Acute Deterioration of Neurologic Function

The statement that children are not small adults particularly applies when considering the developing nervous system. The nervous system is constantly changing throughout childhood. Thus the way trauma to the developing nervous system affects the child depends on where along the neuraxis the trauma occurs, at what age and developmental stage, and the mechanism of the trauma. These specifics are important to consider in the context of the most frequent causes of trauma, the implications, and the outcomes. Trauma usually results in acute deterioration in neurologic function but late sequelae or delayed effects must also be anticipated. In this section, discussion will focus on the most commonly encountered scenarios of trauma to the nervous system in pediatrics. This includes accidental traumatic brain injury, inflicted neurotrauma, spinal cord injury, and associated injury to adjacent tissues, such as bone in skull fractures and blood vessels in hemorrhage. The acute management of these injuries is further discussed in Chapter 104. Trauma to the brachial plexus during delivery will be briefly discussed.

Under normal circumstances, the skull protects the brain from minor trauma by cushioning the sensitive contents from external blows. The surrounding cerebrospinal fluid (CSF) assists in reducing any force by providing a fluid layer in which the brain may “float.” However, with more severe trauma, the differential rate of movement of the skull, brain, CSF, and blood vessels causes acute injury to the contents. Traumatic brain injury results from the sudden acceleration or deceleration of the brain relative to the skull or from penetrating injury. The degree of injury manifests along a spectrum from mild functional impairment without obvious visible injury (either on physical examination or neuroimaging) to severe, generalized, or focal/multifocal injury.

Head injury is one of the most common neurologic disorders in pediatrics. Millions of children and adolescents suffer an injury to the head each year but most do not seek medical attention or are seen by a primary physician well after the event. Thus, the incidence and characteristics of these head injuries are not fully known. Of those who seek care in a hospital-based setting, each year, approximately 475,000 traumatic brain injuries (TBIs) occur in children ages 0 to 14 years.1 More than 90% of these (435,000) present to emergency rooms for immediate care, 37,000 are hospitalized, and 2685 are fatal. The rate of TBI-related emergency room (ER) visits, hospitalizations and deaths is greater than 50% more common in boys than girls ages 0 to 14. Across all ages in children and adolescents, TBI is more common in males than in females. Falls are the most common cause of TBI from ages 0 to 14, accounting for 39% of all TBIs in that age range. After age 14, motor vehicle accidents become the most common cause, followed by assaults and falls. Most fall-related TBIs are evaluated in the emergency room and more than 90% of patients are released to their home. However, after age 4 years, motor vehicle accidents (usually as passenger but also as pedestrian or pedal-powered operator) increasingly account for TBI-related hospitalizations and deaths. These statistics have several implications for mechanisms and severity of injury, and prevention of TBI (discussed below).

Mild Traumatic Brain Injury

It is clear from the statistics that the most common form of pediatric head injury results in mild traumatic brain injury (mTBI).2 Also known as concussion, minor head injury, minor head trauma, or minor TBI, mTBI had been diagnosed based on scores of 13 to 15 on the Glasgow Coma Scale. However, most recently, mTBI has been defined clinically by the brief presence of altered mental status after injury from impact or forceful linear or rotational motion of the head with or without loss of consciousness.3,4 This alteration in mental status is characterized by confusion or disorientation, trauma induced retrograde and/or anterograde amnesia, or loss of consciousness less than 30 minutes. By contrast, moderate or severe TBIs are associated with loss of consciousness longer than 30 minutes, amnesia longer than 24 hours, penetrating skull injury, or visible signs of focal/multifocal brain injury on physical examination or neuroimaging (see below).

Pathophysiology

Neurologic sequelae of mild traumatic brain injury (mTBI) are not the result of localization-related injury but of widespread neuronal metabolic dysfunction involving a cascade of subcellular ionic, metabolic, and local physiologic events. These involve neuronal depolarization with release of excitatory neurotransmitters, potassium release from the intracellular compartment, increased energy utilization by ion pumps to restore homeostasis, leading to increased glycolysis and lactate accumulation. This leads to changes in cerebral blood flow and axonal function (Fig. 551-1). During brain development, the excitatory neurotransmitter glutamate predominates, meaning there is an increased probability of excitotoxicity in the developing brain. The widespread activation of glutamate receptors also results in downregulation of the receptors and changes in inhibitory circuitry with increased the chance for seizures.5

Clinical Features and Associated Injuries

Clinically, mild traumatic brain injury (mTBI) manifests as disruption of one or more of four domains: physical, cognitive, emotional, and sleep patterns. Acutely, children suffering mTBI may experience symptoms of vomiting, headache, emotional lability or inconsolability, restlessness, irritability, mental confusion, amnesia, dizziness, transient loss of vision (often confused with malingering), seizure, or change in personality. Physical signs are often lacking but should be considered as with any trauma-related injury. This includes monitoring of airway, breathing, and circulation. Further management depends on recovery of function and persistence of symptoms. Thus, immediate evaluation on site should document level of functioning after injury such as assessment of retrograde and anterograde amnesia and loss of consciousness. In school age children, mTBI often occurs in sports-related activities so that assessment on the field may be made by coaches or certified athletic trainers using standardized instruments such as the Standardized Assessment of Concussion. When a child is seen by a clinician, the Acute Concussion Evaluation (ACE) form available from the CDC4 helps to document and subsequently track symptoms thus assisting in planning recovery management. In preschool or preverbal children, clinicians must have a low threshold of suspicion for concussion after head injury because these individuals will not be able to report symptoms, even though they may have headache, crying, irritability, restlessness, dizziness, confusion, seizure, or change in personality. Emergency room evaluation is warranted if these symptoms worsen in a preverbal child.

Diagnostic Evaluation

Medical evaluation of any child with mild traumatic brain injury (mTBI) first documents the nature or cause and circumstances of the injury including type and strength of force and location on the head and position of the head at the time of impact. A greater force causing the injury correlates with greater potential for more severe symptoms. However, when the history suggests the symptoms are out of proportion to the force of the injury, malingering should not be assumed but increased susceptibility to mTBI (especially if there is a history of multiple mTBI) or other physical or psychological factors should be considered. Whiplash type injury occurs when a blow to the body or to a vehicle results in acceleration and deceleration forces on the brain, leading to coup and contrecoup injuries. Physical examination should first assess airway, breathing, and circulation. It is important to rule out any bleeding including hematoma or petechiae. Neuroimaging is not necessary in most cases of mTBI, particularly in children older than age 2 years. However, if there is a history of loss of consciousness longer than a few seconds, or deteriorating neurologic function, worsening of initial symptoms, or new symptoms, imaging should be considered. Head computed tomography (CT) is optimal for detecting skull fracture and intracranial blood; it is also ideal for rapid assessment and detection of brain edema.

Neuropsychologic testing using standardized tests establishes quantifiable measures of self-reported or observed impairments in the cognitive domain. This testing can be repeated over the subsequent 6 to 12 months in order to guide recommendations for return to full activity after mTBI.

Complications

After the initial symptoms of mild traumatic brain injury (mTBI), a child may continue to complain of headache, dizziness, and cognitive impairment, and exhibit behavioral disorders such as irritability for days, weeks, and even months. These symptoms constitute postconcussive syndrome and are treated symptomatically.

Treatment and Management

Most likely due to the general neuronal metabolic and physiologic dysfunction, during recovery from mTBI, symptoms may worsen or reemerge with physical or mental exertion. Thus treatment is symptomatic and preventive. Immediately after a concussion, rest is essential. There should be no physical exertion until there are no signs or symptoms of mTBI at rest. The decision to return to full activity should be guided and planned. Return to full activity should be gradual and graded as, for example, those involved in sports. The recommended return to sport guidelines6,7 include (1) complete rest, especially on the day of injury (thus removal from the competition); (2) light aerobic exercise, such as walking, without weight training; (3) sport-specific activity such as running with some weight lifting; (4) training drills without contact; (5) training drills with full contact; and (6) competitive game play. At each of these steps, physical and mental monitoring and comparison with initial Acute Concussion Evaluation status should guide ongoing and increasing level of activity.

Minimal TBI affects cognitive abilities and experience-dependent learning. For this reason, the child’s academic performance should be monitored and return to full academic participation should be gradual. Initially after concussion, lighter school and homework loads should be considered. If necessary, more formal Section 504 plans (designed to accommodate the unique needs of an individual with a disability) or Individualized Education Plans should be instituted.

Second Impact Syndrome

The risk of returning to full activity after mTBI is the possibility of further mTBI with resultant worsening of postconcussive symptoms. With the impairment in cognitive ability and reaction time after an initial mTBI, the risk of repeat injury is higher than baseline. A more dangerous, albeit less common occurrence with repeated mTBI, is second impact syndrome. If full recovery from the first impact has not occurred and cerebrovascular autoregulation is still impaired, a second episode of head trauma may trigger diffuse cerebral edema secondary to hyperemia, vasogenic edema, or cytotoxic edema. This may lead to increased intracranial pressure and brain herniation. Unrecognized after minor head trauma and untreated, this can be fatal.

Prognosis and Prevention

Most children recover completely after mTBI and do not have lasting postconcussive symptoms. Treatment of any effects of concussion should be symptomatic with rest, over-the-counter analgesics for headaches and medication for attention deficit symptoms or other behavioral problems. Effects of mTBI may be slightly worse for the younger child. For example, some evidence suggests longer times to recover from the cognitive deficits after concussions in high school athletes compared with college athletes.

Because the mechanisms of mTBI involve direct force on the brain, measures to avoid or dissipate potential forces on the head decrease the likelihood of mTBI. This involves the use of appropriate car seats and seatbelts in motor vehicles to decrease the chance of whiplash injuries, and the use of helmets during sporting and physical activities such as bicycle and scooter riding or winter snow and ice activities. For parents of toddlers, anticipatory guidance against use of walkers is warranted.

Traumatic Brain Injury (Moderate to Severe)

Clinically, moderate traumatic brain injury (TBI) has been classified based on Glasgow Coma Scale (GCS) score of 9 to 12 and severe TBIs with scores less than 8. These somewhat artificial distinctions are meant to reflect severity of injuries causing unconsciousness longer than 30 minutes, amnesia longer than 24 hours, or penetrating skull injuries. In pediatric patients with severe TBI, lower GCS scores correlate with worse outcome. There may also be associated intracranial injuries based on neuroimaging. These may include skull fractures, brain contusions, and intracranial hemorrhages (see below).

Biomechanics and Pathophysiology

With child development, muscles strengthen, skull thickness and tensile strength increase, and the motor repertoire expands and becomes more adept. The mechanisms of injury and implications of accidental injury change with the age of the child. Infants tend to suffer accidental injury most frequently due to low-level falls (ie, less than 3–4 feet), for example from cribs and beds. Skull thickness increases with age from 1 mm in infants to 4 mm in a young child and 10 mm in adults.8 With impact injury, the skull of an infant is more likely to fracture compared with that of an adult, particularly in the thinnest part of the calvarium—the parietal region. The infant skull is able to deform and absorb a significant amount of the energy of the fall thus protecting the brain from more severe injury. Much more energy is required to cause intracranial injury (ie, bleeding) and axonal damage in the infant and young child compared with the adult. Still, intracranial injury may occur (see below) even without any clinical signs and symptoms. As the child begins to ambulate, falls from heights, such as off furniture or down stairs, become more common.

The neurometabolic cascade discussed above also operates after a more forceful head injury. Additionally, diffuse axonal injury from shear forces, disconnection, and necrotic and apoptotic cell death may occur. The resultant effects on the developing brain have delayed and lasting implications for prognosis and outcome (see below). Other than the initial TBI, second insults such as hypoxia and hypotension exacerbate brain injury and are associated with poorer outcome. Diffuse cerebral edema, which may lead to decreased cerebral perfusion, is more common in infants and children compared with adults, after severe TBI.9

Diagnostic Evaluation

After stabilizing and securing the airway, breathing, and circulation, the diagnostic evaluation of a child with moderate to severe TBI begins with physical examination for associated injuries and neurologic examination followed by neuroimaging. In infants in whom specific symptoms are difficult to elicit early, imaging of the cranium for signs of skull fracture must be included. Underlying intracranial bleeding is quickest and best seen using computed tomography (CT scanning). If magnetic resonance imaging (MRI) is available, sequences to detect blood can be used. An advantage of MRI is the ability to detect signs of brain edema early and without exposure to radiation. Also, any child with a change in level of consciousness or focal neurologic deficit on examination should undergo neuroimaging using brain MRI.

Treatment

Hospital-based treatment of acute moderate to severe TBI in children aims to reduce the likelihood of second insult and maintain adequate cerebral perfusion pressure and tissue oxygenation. Thus, management of airway, breathing, and circulation is paramount, as is decreasing brain edema to guard against increased intracranial pressure. There is no clear treatment standard but algorithms for tiered management of acute TBI exist (Fig. 551-2).10 Strategies including prophylactic use of antiepileptics and antipyretics are instituted to decrease metabolic demand of the brain and possible second insult. Hypothermia therapy is another means of reducing the metabolic demands of the brain. Observations of improved survival and recovery after cold water drowning have led to trials of therapeutic brain cooling after TBI. However, speed of initiation of hypothermia, degree of cooling, length of cooling time, and rapidity of rewarming have yet to be established. The most recent multicenter trial of hypothermia for pediatric TBI initiated within 8 hours and lasting for 24 hours failed to show any improvement in either neurologic outcome or survival benefit.11 Further large-scale trials to establish standards for hypothermia in pediatric TBI are needed.

Prognosis and Outcome

Children who suffer focal brain lesions often show remarkable neurologic recovery because of developmental plasticity. In fact, the earlier in development a lesion is acquired, the better the neurologic outcome will be. However, this same capacity for plasticity and reorganization may belie a propensity for worse outcome after the more global insult of TBI in children compared with adults. Because a majority of cognitive and adaptive behavior neural systems continue to develop throughout childhood to young adulthood, injury to these frontal, subcortical, distributed systems leads to significant developmental and cognitive delay and behavioral impairment. In one study12 children who suffered accidental TBI prior to age 2 on average performed at least one standard deviation below the mean on standardized cognitive developmental testing at age 3. Those with nonaccidental TBI fared worse (see below). Posttraumatic headaches and seizures may also occur. Seizures occurring within 7 days of injury are termed acute and are the result of immediate effects of the injury such as glutamate release, stretch induced neuronal depolarization, and local irritation from blood products. Late seizures (occurring after 7 days postinjury) may be secondary to infection, neuronal death, gliosis, and aberrant neuronal circuit development.

The same physical protective measures described for mild traumatic brain injury (mTBI) (vehicle safety and helmet use) apply for more serious TBI.

Inflicted Childhood Neurotrauma

Physical abuse of children by adults results in many types of injury (see also Chapter 35). The most severe and fatal injuries affect the nervous system, especially the brain and cervical spinal cord. Over the past few decades, various terminologies have been used to describe the method of injury including battered child syndrome, shaken baby syndrome, shaken impact syndrome, trauma X, nonaccidental trauma, inflicted TBI, and inflicted childhood neurotrauma. An adult or older child may inflict injury on an infant or younger child by shaking, hitting, throwing down onto the floor or against a wall, or asphyxiation in attempts to quiet by smothering or strangulating. Each of these mechanisms causes significant and multifocal injuries to the child’s neuraxis.

Epidemiology

Traumatic brain injury due to child abuse is the leading cause of infant death secondary to accidental injury. It is also a leading cause of moderate to severe traumatic brain injury (TBI) in children. Accurate estimates of the incidence of abuse are difficult to obtain and represent only those with physical injuries serious enough to come to medical attention. These statistics are likely underestimates of head injuries from abuse. In a population-based study of inflicted childhood neurotrauma,13 the incidence of inflicted moderate to severe TBI of children under age 2 years was 17.0 per 100,000 person-years. Infants were almost 10 times more often affected than children age 1 to 2 years and boys over 50% more likely than girls to suffer inflicted TBI. Young maternal age (⩽ 21 years old) and limited social support were identified risk factors for inflicted neurotrauma.14

Biomechanics and Pathophysiology

The larger head-to-body ratio, undeveloped shoulder and neck musculature, and laxity of the atlanto-occipital joints of infants compared with adults lead to greater impulsive or rotational forces on the infant head during periods of shaking. Force exerted through the held torso during shaking causes repeated acceleration/deceleration of the head leading to significant shear force on the brain, resulting in axonal damage and intracranial bleeding. Shaking alone does not account for the severity of most injuries. Accompanying impact and/or suffocation (as from restriction on the thoracic cage) are often necessary to explain the intracranial pathology of inflicted neurotrauma.

Head injury associated with inflicted neurotrauma includes skull fractures, subgaleal hematoma, subdural hematoma, subdural effusions, subarachnoid hemorrhage, cerebral contusions, and cerebral edema. These injuries are not unique to child abuse but, if present, consideration of child abuse in the differential diagnosis is warranted (see below).

Associated Injury

Although neurotrauma is the most frequent cause of fatality in child abuse, injury may have been inflicted on other parts of the body and signs of injury should be sought elsewhere. Facial injury is associated with inflicted neurotrauma especially around the mouth and teeth. Retinal hemorrhages frequently occur with repeated shaking. Scalp and soft tissue hematoma and bruising, ruptured ear drums, long and rib bone fractures, and pattern bruising (indicating a mechanism of holding or impact, as with an open hand or object) may also be seen.

Evaluation and Differential Diagnosis

Children suffering abusive head injuries are usually first brought to medical attention with relatively minor and nonspecific symptoms such as vomiting and irritability. In fact, in one study of cases of abusive head trauma not initially diagnosed, symptoms at first presentation included facial injury, seizures, altered mental status, abnormal respiratory pattern, vomiting, and irritability.15 Suspicion of inflicted neurotrauma should be raised when no explanation or history of trauma is given.16 Also, if the given history frequently changes from caregiver to caregiver or from the same caregiver, or if the history given is inconsistent with the developmental level of the child, the possibility of inflicted neurotrauma should be considered.

With suspicion of inflicted neurotrauma, there should be a thorough documentation of the history provided, not only of the events leading up to symptoms or injury, but also birth history and family medical history. Physical examination should include thorough evaluation of all skin surfaces to document any bruising, especially pattern bruising. Assessment of Glasgow Coma Scale or the equivalent for infants should be documented. Because abused infants and children may also be neglected, laboratory evaluation and assessment of fluid balance or signs of dehydration should be obtained. Clotting defects and bleeding may lead to anemia and thus should be evaluated. There are promising laboratory measures suggestive of inflicted neurotrauma. Elevated serum and/or cerebrospinal fluid (CSF) levels of the neuronal and CNS glial markers, neuron specific enolase (NSE), and myelin basic protein (MBP) may serve as screening markers of inflicted neurotrauma.17 Further evaluation by neuroimaging starts with a head computed tomography (CT) scan, which can be performed immediately and can assess skull fracture and intracranial bleeding. Subsequently magnetic resonance imaging (MRI) may possibly be indicated for more accurate assessment of injuries and dating of intracranial bleeding.

There is often concern for false accusation of child abuse, but the safety of the child is of paramount importance. The primary caregiver or accompanying adult may not have perpetrated the abuse or even be aware of it. The observation that households with young, single mothers are most often associated with child abuse may simply reflect the difficulty in finding suitable caregivers.13 Missed cases of inflicted neurotrauma often represent within a week to months of the first episode with more serious injury.15 Thus, erring on the side of caution to consider and investigate suspicious injuries in an infant or child may be lifesaving. Investigation of accidental injuries may also reveal deficiencies in the home or childcare setting. Investigations should not be pursued as punitive but as a means of offering assistance and guidance so that further accidents do not occur.

The differential diagnosis of nonaccidental neurotrauma includes accidental injury such as falls and susceptibility to injury secondary to genetic or metabolic disorder. Falls are distinguished based on height as a surrogate for force of impact. Short, low impact falls of less than 4 feet may lead to skull fracture in infants but rarely to intracranial pathology. Falls from heights greater than 4 feet may lead to more serious skull and intracranial injury. However, the pattern of brain injury differs from that of abusive injury. Additionally, with inflicted neurotrauma, there is often associated cervical spinal cord and nerve root injury. Multiple bone fractures and subdural effusions or hematoma from abuse must be distinguished from injuries that are secondary to rare genetic syndromes such as osteogenesis imperfecta or glutaric aciduria type I.

Treatment

Treatment of inflicted neurotrauma is supportive care with monitoring for posttraumatic seizures. Longer-term, careful follow-up is important as children suffering abusive head injury are at greatly increased risk of cognitive and behavioral difficulties. Family- and school-based support with appropriate accommodations should be anticipated.

Outcome and Prevention

The range of subsequent difficulties and sequelae following inflicted TBI is similar to accidental TBI. However, inflicted TBI results in more severe injury than injuries caused by accident. Overall, children with inflicted TBI have a worse prognosis than do those with TBI caused by accidents. Estimates of mortality from inflicted neurotrauma range from 15% to 38% and neurologic morbidity up to 68%. The range of morbidity following inflicted TBI includes motor deficits, visual deficits, epilepsy, speech and language impairment, and behavioral problems.18 Most victims of inflicted neurotrauma have only mild disability by age 2 years with 45% functioning at age appropriate levels.19

Adults rarely inflict serious injury on infants and children in a premeditated fashion. These unfortunate events often occur at times of emotional upset, stress, and anger over unexpected and uncontrollable situations, such as crying and toileting accidents. Prevention of abuse in specific situations is difficult but assistance and guidance to help prepare for these unexpected times is needed. Social intervention and childcare assistance need to be made available to those at risk. If pediatric neurotrauma does occur, the child will need ongoing monitoring of development, academic abilities, and behavior so that assistance may be provided at school to prevent significant and long-lasting effects.

Cranial and Intracranial, Extra-Axial Injuries

Skull Fracture

Trauma to the head may result in skull fractures which may be (1) simple linear or diastatic, causing abnormal suture separation; (2) simple depressed; (3) comminuted; or (4) ping-pong (pond). More than 80% of skull fractures are simple linear and usually occur in the parietal region. In infants the cranium is not well calcified, allowing for displacement without fracture. This results in a ping-pong or pond fracture. Skull-base fractures are associated with bilateral orbital or retroauricular ecchymoses (Battle sign). Skull fracture with accompanying otorrhea or rhinorrhea is of concern because it suggests basilar fracture with associated risk of infection. This can be detected by testing the fluid for the presence of glucose, which is found in cerebrospinal fluid (CSF) but not in nasal secretions.

Skull fracture are evaluated by skull radiograph or computed tomography (CT) scan with bone windows. In infants, a skeletal survey should be strongly considered to search for other signs of injury. In children under age 8 years, cervical spine films are also recommended, particularly if there is neck pain or tenderness.

No treatment is required for uncomplicated simple linear skull fracture or pond fracture. Healing should occur within 6 to 12 months. However, migration of the meninges through the fracture site with brain herniation may give rise to an expanding leptomeningeal cyst and bony erosion. Repeat skull radiograph at 3-month intervals to demonstrate union is recommended.

Epidural Hematoma

Head trauma may lead to the acute collection of blood in the potential space between the skull and dura, causing an epidural hematoma. With trauma and fracture of the temporal bone, the source of this blood may be the middle meningeal artery. However, in young children bleeding is often from the bridging veins; because venous pressure is low, blood accumulates slowly. The loss of blood may lead to anemia, which may be the first indication of pathology. However, faster accumulation from arterial bleeding leads to compression of underlying brain tissue and more acute presentation. Prompt detection of this blood by CT or MRI scan allows for surgical evacuation and complete recovery without residual deficit.

Subdural Hematoma

Subdural hematomas (SDH) result from the tearing of cortical bridging veins. They are commonly seen after accidental and inflicted head trauma. Appearance on CT imaging is of a crescent shaped hyperdensity beneath the skull. Subdural hematoma may develop with apparent neurologic symptoms within 3 days of trauma—acute subdural hematoma. Symptoms may develop within 4 to 20 days (subacute) or after 20 days (chronic). Surgical treatment by evacuation is sought for acutely symptomatic SDH. The child should also be monitored for any signs of increased intracranial pressure. Cerebrospinal fluid (CSF) removal (10–20 mL per day) relieves this pressure and also helps to reduce the size of the hematoma. Removal of larger amounts may lead to reaccumulation of the hematoma. Outcome after treatment of traumatic SDH is good if there are no other parenchymal injuries; up to 75% of infants achieve normal developmental milestones.

Contusions

Cerebral contusions occur when the surface of the brain directly affects the bony surface of the skull. This is rare in children but may occur in the frontal or temporal regions, usually along gyri. Treatment is usually unnecessary unless bleeding or edema become symptomatic.

Spinal Cord Injury

Epidemiology

Isolated traumatic spinal cord injury (SCI) in children is rare, with approximately 1000 pediatric SCI annually in the United States. Sixty to eighty percent of pediatric SCI affects the cervical spinal cord.20 The incidence of pediatric spinal cord injury was 18.2 per million among those ages 1 to 12 year in one population-based study. Motor vehicle accidents and falls are the two most frequent causes of pediatric SCI. Motor vehicle accidents usually involve young children as pedestrians or on bicycles, whereas older children suffer SCI as passengers in motor vehicle accidents. Sports-related injuries increase in frequency in adolescence.

Obstetrical trauma is the most common cause of SCI in infancy occurring in approximately 1 in 60,000 births. Most injuries result from breech presentations and usually involve the cervical or cervicothoracic region. Birth-related spinal cord injuries after cephalic presentation most frequently involve the upper cervical region.

Biomechanics and Pathophysiology

The infant and child’s head to body ratio is approximately 25% compared with an older child’s and adult’s ratio of 10%. The change in this ratio occurs gradually, reaching the adult ratio at about 8 to 10 years of age. Additionally, the undeveloped shoulder and neck musculature, ligamentous laxity, C2 weakness, and shallowness and horizontal orientation of the facet joints of infants and young children compared with adults and older children place the upper cervical spine at relatively greater risk for injury. In infants, abuse leads to fracture of the upper and lower cervical and upper thoracic vertebral bodies by the mechanisms of hyperflexion/hyperextension from shaking. Thus 80% of spine injuries in children under age 8 years occur in the cervical spinal cord. In children under age 3 years, 50% of those injuries occur in the C1-2 region.

The spinal cord is well protected by the spinal column. However, trauma to the spine may result in spinal cord injury when there is (1) spinal fracture; (2) fracture with subluxation; (3) subluxation alone; and (4) hyperflexion, hyperextension, or rotation without obvious radiographic features. After pediatric spinal trauma, spinal cord injury without radiographic abnormalities (SCIWORA) has been described21 potentially associated with significant morbidity. However, consensus on the use of the term has not been reached.22 With more advanced MRI techniques such as diffusion weighted imaging, and spinal cord abnormalities are more frequently detected.23 Clinical spinal cord injury without neuroimaging accompaniment may be similar to minimal traumatic brain injury in which functional change occurs secondary to neuronal metabolic dysfunction involving subcellular ionic, metabolic, and local physiologic events.

Clinical Features

In the neonatal period, clinical features of spinal cord injury (SCI) after birth trauma may be subtle. Signs include apnea, intercostal paralysis, a weak cry, and flaccid paralysis. The latter is evidenced by a flaccid, abducted, and motionless limb. Decreased sensation is evident as decreased response to pain. A Gallant reflex, in which the infant is held suspended in the palm in a prone position and the paraspinal region is scratched, leads to reflex curvature of the spine toward the stimulus. Absence of this reflex at a position along the back helps determine the cord level of injury. The differential diagnosis of SCI in the neonatal period includes neonatal asphyxia, intracranial injury, congenital defects, or progressive infantile spinal muscular atrophy.

In the infant who has been subjected to inflicted neurotrauma, it is important to recognize that SCI (particularly of the cervical and upper thoracic spinal cord) may also occur. In the older child with a history of trauma, the diagnosis of SCI is self-evident. Pain and tenderness are typical presenting features. Physical examination should delineate the spinal cord level based on motor, sensory, and deep tendon reflex function.

Evaluation

In the case of suspected birth injuries, spinal radiographs are often normal. Fractures and subluxation may be detected but radiographs are best interpreted by those familiar with the normal variations of the cervical spine in infancy. Spine MRI will allow detection of soft tissue and ligamentous injury, as well as myelopathy.

In the older child with suspected spine injury from blunt trauma, particularly with altered mental status, antero-posterior and lateral radiographs will quickly assess the bony elements for fracture or dislocation. Whereas radiographs are a minimum requirement for suspected spinal trauma, the addition of MRI is useful for detection of ligamentous injury, bleeding, disc herniation, and myelopathy.

Treatment

Spinal cord injury in the neonatal period often involves the upper cervical cord and thus diaphragmatic control may be compromised. Careful and immediate attention to ensure adequate and safe ventilation is essential. Mask ventilation may be sufficient and effective so as to avoid intubation with manipulation of the neck and worsening of spinal cord injury.

Children involved in trauma with suspected spinal cord injury must have complete stabilization of the entire spine by immobilization. At the scene of injury, the child should be placed on a rigid board, which can accommodate the occiput and maintain the child’s head in neutral position without cervical flexion. Rolls placed under the shoulders can help achieve this.24

After stabilization and acute care, subsequent treatment is supportive. Whereas trials of intravenous methylprednisolone have demonstrated some recovery of motor and sensory function, the degree of functional recovery has been minimal. Furthermore, complications from high-dose steroid administration should be anticipated and avoided. If steroid therapy is used, an intravenous bolus of 30 mg/kg of methylprednisolone is given no later than 8 hours after the injury followed by maintenance intravenous infusion of 5.4 mg/kg per hour. If steroid therapy is begun within 3 hours of injury, total steroid therapy is recommended for 24 hours; if begun 3 to 8 hours after injury, it is recommended for 48 hours.

Complications

Injury to the cervical spine and spinal cord, especially in the first year of life, may lead to ligamentous laxity and development of a syrinx. After spinal cord injury, pain spasms and autonomic dysfunction may develop and are treated symptomatically. The sequelae of spinal cord injury depend on the level at which injury occurs and the functions affected. Motor and sensory function of the lower extremities is often impacted significantly with resultant paralysis and anesthesia. Without proper care, this may lead to decubitus ulcers and serious infection. Bowel and bladder function are also affected, requiring catheterization. This introduces a lifelong risk of infection. The psychologic impact of the loss of independent mobility is difficult for the child and adolescent and may be mitigated by ensuring that support networks and counseling are provided.

Outcome and Prevention

With rapid immobilization and appropriate traction, infants and children may recover from spinal cord injury. After the initial recovery period, long-term care and rehabilitation are needed. The child should be cared for at an established pediatric rehabilitation center with expertise in spinal cord injury. During recovery, efforts focus on reestablishing bowel and bladder function or teaching bowel, bladder, and skin care.

As with all accidental injuries, prevention of injury by protective means is paramount. Because children under age 10 years are at increased risk of cervical cord trauma as a result of the anatomical differences described above, it is appropriate to restrict their participation in contact sports, which may lead to head trauma with forces transmitted to the cervical spinal column. Additionally, the use of proper restraints in motor vehicles (car seats and seat belts) and headgear in sporting activities should be recommended at every opportunity.

Obstetrical Brachial Plexus Palsy (BPP)

During birth, injuries to the brachial plexus may occur. Incidence has ranged from 0.38 to 3 per 1000 deliveries.25 Obstetric brachial plexus lesions may result in root syndromes affecting the upper root (C5-6 +/– C7) in 70 to 90% of brachial plexus palsy (BPP) lesions, global brachial plexus injuries (C5-T1) in approximately 20%, or rarely lower root (C8-T1) in less than 1% of patients. Risk factors include increasing birth weight, assisted delivery, macrosomia, breech presentation, and shoulder dystocia. Most (70–90%) upper root injuries recover full function by 3 months of age. The remainder may have some functional recovery of antigravity movement of biceps, triceps, and deltoid by 6 months. Surgical evaluation and repair at a center with experience in obstetrical brachial plexus injury should be sought.

Stroke denotes the sudden onset of a focal neurologic deficit and most often includes the abrupt appearance of weakness. Interruption of blood flow to a part of the central nervous system (CNS) usually underlies the resultant weakness. Because most strokes in children are related to focal cerebral involvement, the most common clinical manifestation is the abrupt appearance of hemiparesis. Less frequently, the cause of stroke involves the brainstem, cerebellum, or spinal cord. The functional consequences always reflect the neuroanatomic features of the affected CNS region. Either focal cerebral ischemia or hemorrhage may cause the clinical manifestations of stroke. Further, ischemic stroke in children is attributable to either arterial ischemic stroke (AIS) or to cerebral sinovenous thrombosis (CSVT). This chapter addresses these causes of focal cerebral injury in children. First, epidemiologic features of stroke in children will be presented. Consideration will then be directed to the occurrence of pediatric cerebrovascular disease in neonates as well as in older children. Emphasis will be placed on the pathogenetic, clinical, diagnostic, and therapeutic aspects of the varied causes of strokes in children.

Stroke in children follows a biphasic pattern of occurrence. Its occurrence is highest among newborns and occurs less frequently in children greater than 30 days of age. Among neonates, studies indicate an occurrence of stroke that approximates a frequency of 1 in 4000 births.1-3 Arterial ischemic stroke accounts for 80% of these occurrences, although 20% are due tocerebral sinovenous thrombosis (CSVT) and hemorrhage (excluding intraventricular and subarachnoid hemorrhages).4,5

Several studies of stroke in children older than age 1 month, performed over the last three decades have reported an occurrence of stroke at a rate of approximately 2 in 100,000 per year.6-8 However, recent studies suggest that the frequency may be greater and as high as 13 in 100,000 per year.5,9 Strokes occur more often in males than in females and more frequently in African Americans and Caucasians.

Ischemic injury to the brain occurs as a result of one of three different mechanisms: embolism, thrombosis, or diminished systemic perfusion. Embolic damage to the brain occurs when material formed at a site in the vascular system proximal to the brain lodges in a blood vessel, blocking cerebral perfusion. Emboli originate most commonly from the heart, arising from clots on cardiac chamber walls or from vegetations on valve leaflets. Congenital heart disease that includes right-to-left shunt predisposes to such embolus formation. Artery-to-artery emboli are composed of clot or platelet aggregates that originate in vessels proximal to the brain but ultimately come to rest and to occlude flow in vessels critical for cerebral perfusion. Intravascular embolus formation is promoted by some forms of thrombophilia (see below). Thrombosis denotes vascular occlusion resulting from a localized process within a blood vessel or vessels. Although atherosclerosis underlies most thrombotic processes affecting adults, it is a very uncommon cause of thrombosis in children. Localized luminal clot formation occurs in polycythemia or in a hypercoaguable state. Alternatively, anatomic abnormalities may lead to clot formation or mechanical obstruction in fibromuscular dysplasia, focal arteriopathies, or vascular malformations. Should systemic pressure decline enough to compromise cerebral perfusion, the central nervous system may suffer injury as a result of diminished systemic perfusion. Cardiac pump failure (related to congenital heart disease and its surgical repair), as well as systemic hypotension due to hypovolemia, represents common causes of hypotensive cerebral ischemic injury. Often, in the circumstance of diminished cerebral perfusion, brain injury is much more diffuse than that found in the more focal injuries characteristic of thrombotic and embolic cerebral events. Cerebral ischemia serves as the final common pathway leading to brain injury irrespective of whether an embolic, thrombotic, or hypoperfusive mechanism has caused the stroke.

Both thrombotic and embolic strokes may be heralded by the occurrence of transient ischemic attacks (TIAs). Transient ischemic attacks are brief episodes of focal, nonconvulsive neurologic deficit attributable to interruptions of cerebral perfusion. Similar to stroke, the onset is abrupt. However, a TIA episode lasts less than 24 hours and recovery is complete. Despite full recovery, the TIA can serve as a sentinel event of subsequent episodes that may result in fixed deficits. Importantly, signal correlates of a TIA may not be present on magnetic resonance imaging (MRI) of the brain.10

Hemorrhage occurs when blood is released into the extravascular, intracranial, or intraspinal space. In this circumstance, focal injury of brain or spinal tissue occurs as a result of pressure exerted by the space-occupying mass of blood, as well as hemorrhage-related ischemia. Such injury can be exacerbated by the damaging effects upon neural tissue of substances released in the blood. Epi- and subdural hemorrhages represent intracranial collections of blood separated from brain parenchyma by dural or arachnoid membranes. Subarachnoid hemorrhage occurs when blood flows out of the intracranial vascular bed and onto the surface of the brain to admix with cerebrospinal fluid in the subarachnoid space. Intracerebral hemorrhage denotes bleeding into the parenchyma of the brain.

Stroke in neonates may be considered as perinatal stroke, which has been defined to occur during the fetal or neonatal periods but before 28 days after birth.4,11 Stroke differs from the intraventricular hemorrhage observed in premature infants and discussed in Chapter 58. Eighty percent of strokes in neonates are arterial and ischemic (AIS). The remaining 20% are attributable to either cerebral sinovenous thrombosis (CSVT) or hemorrhage. Interestingly, a left hemispheric location has been noted to be the most common in neonatal AIS, a lateralization for which no proven explanation has been found.12 Neonatal CSVT may cause focal infarction or hemorrhage. Cerebral veins conduct deoxygenated blood from the parenchyma to the dural sinuses. These sinuses—the sagittal, straight, transverse, cavernous, and petrous—convey the blood to the jugular vein for return to the cardiopulmonary circulation. Thrombotic occlusion of flow anywhere in these venous conduits can lead to increased venous pressure, ischemia, and sometimes, infarction that can be hemorrhagic (Fig. 552-1).13

Risk factors associated with perinatal stroke have received limited investigation but include maternal and placental disorders, perinatal asphyxia, blood disorders including polycythemia, congenital cardiac disorders, infection, trauma, and drug exposures. In particular, the role of hypercoaguable states associated with prothrombotic risk factors such as factor V Leiden (FVL), prothrombin 20210 mutations, elevated concentrations of lipoprotein (a), homocysteine, factor VIIIC, anticardiolipin antibodies (ACA), and deficiencies of protein C and protein S have been implicated14 (see also Chapter 438). Although recurrent thromboembolic stroke is not common in infants, abnormality of lipoprotein (a), hyperhomocysteinemia, and protein C deficiency in the setting of underlying systemic disease may increase the chance of recurrence. Both maternal and infant characteristics may be related to the occurrence of cerebral sinovenous thrombosis (CSVT). Maternal risk factors may include preeclampsia, gestational diabetes, and chorioamnionitis.15,16 Frequent association between systemic illness and CSVT has been recognized in infants and includes dehydration, sepsis, congenital cardiac defects, extracorporeal membrane oxygenation, and meningitis.13,16,17 Although the role of thrombophilia in neonatal CSVT has not been proven, factor V Leiden (FVL), prothrombin 20210, and methylene tetrahydrofolate reductase (MTHFR) mutations have been suggested as factors that may promote the occurrence of CSVT in neonates.15,18 Importantly, more than one risk factor has been found simultaneously among many infants with CSVT.16,19 Thus, a combinatorial or synergistic mechanism may underlie many occurrences.

Seizure often is the first indication of AIS in the neonate.20,21 However, seizure may also be accompanied by signs of encephalopathy in newborns with AIS.22 Neonatal CSVT also commonly presents as seizure.15,23,24 However, other symptoms can include apnea, respiratory distress, feeding difficulty, hypotonia, and apnea. Indeed, CSVT can present in an infant as unexplained lethargy, alone.24

Because both AIS and CSVT in the newborn commonly present as seizure, an electroencephalogram (EEG) is often obtained. Evidence of localized dysfunction of the brain found on an EEG consists of focal persistent voltage reduction or of marked focal slowing and sharp wave activity. Periodic lateralized epileptiform discharges (PLEDS) may be present. In some instances electrographic evidence of clinically observed seizures may be found. Each of these findings may exist while the EEG remains relatively less affected over other regions of the brain. The areas of electrical abnormality should correspond to the affected areas of the brain revealed by neuroimaging.

Head ultrasound (HUS) serves as a noninvasive method of neuroimaging that offers the considerable advantage of bedside use. The sensitivity of head ultrasound is low and acute stroke in the neonate can be missed.25 Cranial computerized tomography (CCT) provides good fidelity in the identification of focal ischemia. However, magnetic resonance imaging (MRI) provides superior ability to identify ischemic foci in brain. The addition of diffusion tensor MR imaging provides superior sensitivity to that of CCT for identification of early focal ischemia. Moreover, MRI imparts no exposure to ionizing radiation, a considerable advantage of this modality over CCT.26 A combination of T1-weighted (T1W), T2-weighted (T2W), and diffusion weighted imaging (DWI) is most effective in the early identification of focal stroke in the neonate.27

Treatment is supportive and symptomatic. Anticonvulsant treatment is given if seizures have occurred. Phenobarbital remains the preferred drug and is administered as a loading dose of 20 mg/kg. Maintenance therapy of 3 to 5 mg/kg/day can be divided into twice daily doses. Attention should be given to hydration state, acid-base balance, and hematocrit. Deficits should be corrected. Treatment of underlying infection, metabolic disarray, or coagulopathy is necessary. Anticoagulation therapy with low molecular weight heparin (LMWH) or unfractionated heparin (UFH) is not used as a matter of routine in this age group but can be considered in selected neonates with severe thrombophilic disorders, multiple emboli to brain, or evidence of propagating CSVT despite supportive therapy (see below).28 Further investigation on the use of anticoagulation in neonates with focal stroke is needed.

Both motor and cognitive disabilities have been associated with perinatal stroke. Seizure during the neonatal period or neurologic abnormality on discharge have been associated with both these deficits.12 Infants with perinatal stroke due to thrombophilia have been identified to be at risk for long-term neurologic deficit.29 Cognitive deficits often manifest by two years of age.30 Magnetic resonance imaging appears to be helpful in predicting outcome. Concomitant involvement of ipsilateral basal ganglia, corpus callosum, and the posterior limb of the internal capsule has been found to predict lasting hemiparesis.31 Further work is needed concerning neurodevelopmental outcome.

Stroke occurs less frequently in older children than it does in newborns. Despite its relative infrequency in this age group, myriad etiologies exist. Nonetheless, the etiologies may be grouped according to whether the stroke is attributable to an embolic, thrombotic, or hemorrhagic cause. Causes of stroke in children are listed in Table 552-1 and are discussed below

Thrombosis

Vascular Dysplasia

Moyamoya disease is observed most commonly in children under the age of 15 years. This chronic condition is characterized by stenosis or occlusion of the terminal internal carotid arteries resulting in a characteristic development of an abnormal vascular network in the vicinity of the arterial occlusion (Fig. 552-2). The Japanese word moyamoya (meaning “puff of cigarette smoke”) was selected to describe this condition because of the characteristic appearance of this reactive vascular network on angiography. The network of collateral vessels arises principally from the external carotid circulation in response to relative tissue hypoxia. This phenomenon has been associated with increased central nervous system concentrations of angiogenic factors and creates an intricate latticework of compensatory blood flow.32,33 Most commonly, moyamoya disease presents bilaterally, but unilateral presentations have been reported.34 Affected children most commonly come to medical attention due to stroke or transient ischemic attacks (TIA). Commonly, Moyamoya disease causes acute hemiplegia resulting from uncompensated occlusion of the internal carotid artery. When the condition is present bilaterally, bilateral motor deficits may be found. Both fine motor and extrapyramidal motor function can be adversely affected. It has been found as a sequela to a diverse array of conditions in children including sickle cell disease, neurofibromatosis, postcranial irradiation vasculopathy, Down syndrome, and Williams syndrome. Recently, genetic linkage analyses have revealed associations between Moyamoya disease and loci at 3p24-p26.1, 8q23, and 17q25.3.35 No specific medical therapy has been identified to halt progression of this disorder. However, aspirin has been used to prevent thrombotic events. Importantly, two surgical revascularization techniques have been employed to treat this condition (see below).

Fibromuscular dysplasia may involve multiple sites throughout the systemic arterial tree, most commonly the renal arteries. However, cervicocephalic vasculature comprises the second most common site of this vasculopathy.36 Pathologic or radiologic evidence of fibromuscular dysplasia has been found in carotid, vertebral, and intracranial arteries. Commonly, fibromuscular dysplasia involves irregularly spaced focal zones of dysplastic fibrous tissue in the media muscularis of the arterial wall. These findings can extend to the intima, as well.37 The resulting constricted regions of vascular fibrosis alternate with regions of lumenal dilation to create the characteristic beaded appearance on angiography. Its association with alpha-1-anti-trypsin disease has led to speculation about its possible relationship to other connective tissue disorders. Fibromuscular dysplasia is more common in adult females who range in age from the third decade to middle age, but has been found in adolescent and younger children. Familial occurrence has also been described. If renal arteries are affected, hypertension may be present. Neurologic symptoms signifying cerebrovascular involvement consist of headache, TIA, and stroke. A thrombotic mechanism for stroke has been postulated but has not been proven.

Vasculopathy

Acute hemiplegia due to stroke may occur in children with sickle cell disease. By age 14, up to 11% of children with sickle cell disease will have had clinical stroke and 22% will have had silent cerebral infarction. Low hemoglobin concentration and saturation, high hemoglobin S concentration, and chronically increased cerebral blood flow have all been observed to bear a relationship to the increased occurrence of stroke among children with sickle cell disease.38-41 However, large and middle-sized vessel vasculopathy comprises an important mechanism related to stroke in this patient population. Cerebral vessels can reveal endothelial proliferation, disruption of the elastic lamina, fibrin deposition, and stenosis. Stenosis is found most commonly in the distal internal carotid artery at the site where it bifurcates into the middle cerebral and anterior cerebral arteries.42 The stenoses may be severe in this region producing Moyamoya disease detectable by magnetic resonance imaging (MRI) or catheter angiography (Fig. 552-2).43 Indeed, among children with sickle cell disease, the presence of Moyamoya disease is associated with a twofold increase in the risk of stroke as compared to children undergoing transfusion therapy but who do not have this finding.44

The neurologic signs of stroke in this patient group often consist of hemiparesis, aphasia or visual disturbances. Magnetic resonance imaging studies reveal that clinically evident infarction frequently involves both gray matter and white matter although silent cerebral infarction most commonly involves white matter alone.45 Not only motor but cognitive deficits found among children with sickle cell disease correlate with MRI findings.46 Blood transfusion therapy has proven effective for the prevention of stroke in patients with sickle cell disease. The goal of therapy has become reduction of the hemoglobin S concentration to below 30% with transfusions given roughly monthly. Chronic transfusion therapy imparts increased risk for iron overload. Recently, encouraging results have been obtained with hydroxyurea therapy as an adjunct to transfusion therapy.47-49

A transient form of cerebral vasculopathy unrelated to atherosclerosis has emerged as an important clinical associate of stroke in children. Neurovascular imaging reveals stenoses of the distal internal carotid artery or of the proximal anterior, middle, or posterior cerebral arteries. The arteriopathy is monophasic and reversible. It has been associated with viral pathogens, such as parvovirus, enterovirus, and cytomegalovirus. In addition, mycoplasma pneumoniae and borrelia burgdorferii have been suspected as etiologic agents.50 When neuroimaging prompted by the occurrence of stroke in a child leads to the discovery of such a pattern of mulitfocal stenoses and has been preceded in the previous 12 months by the occurrence of varicella, postvaricella arteriopathy can be contemplated as the cause of the cerebrovascular event.51 The recurrent association of cerebral vasculopathy and stroke with viral infection underscores the importance of these agents in the pathogenesis of stroke in children.

Cervical vessel injury caused by head, neck, or intraoral trauma may cause stroke. Neurologic symptoms may be delayed more that 24 hours relative to the time of inciting trauma. Stroke due to carotid artery injury has been well documented. A typical presentation follows intraoral trauma to the internal carotid artery in a toddler who falls with a pencil or other object in the mouth. In older children, these cerebrovascular events occur after head/neck trauma sustained during motor vehicle or bicycle accidents, or following fights or falls. Conventional angiography may reveal internal carotid artery occlusion. Neuropathologic findings vary from an intimal tear with resulting thrombus formation leading, to arterial occlusion or frank arterial dissection. Vertebral artery injury may also lead to stroke in the posterior circulation of the brain. The serpentine course of the vertebral arteries through the cervical spine imparts vulnerability to traction injury. Thus, neurologic signs referable to brainstem, cerebellar, thalamic, temporal, or occipital lesions should lead to consideration of a vertebrobasilar etiology of stroke. Indeed, spontaneous arterial dissection of vessels in the anterior and posterior cerebral circulations have been reported in children.52-55 Finally, cranial radiation therapy, received as part of cancer therapy, may induce an occlusive vasculopathy leading to focal cerebral ischemia.56,57

Vasculitis

Bacterial infection constitutes an important and treatable cause of stroke in children. Inflammation of cerebral arteries and veins may occur in the course of bacterial meningitis. The subarachnoid arteries become immersed in purulent exudate and smaller vessels are affected as exudate moves down the Virchow-Robin spaces. Autopsy studies have revealed white cell invasion beneath the arterial intima; focal necrosis and mural thrombi have been observed in veins.58 Stroke may occur due to occlusion of either arteries or veins. Antibiotic treatment early in the course of the infection forms the cornerstone of therapy. Viral infections may promote vascular inflammation that may involve the cerebral vessels and culminate in stroke (see above). Indeed, cerebral vasculitis and stroke have been described in association with HIV infection in children.

Autoimmune disorders can include vasculitis that may involve the central nervous system (Table 552-2). Cerebrovascular involvement is well documented. Central nervous system symptoms of abrupt onset have long been associated with systemic lupus erythematosus (SLE). A CNS vasculitis had been presumed to underlie the brain cerebrovascular manifestations of SLE. However, autopsy study of patients suffering from SLE revealed a virtual absence of cerebrovascular inflammation. Rather, small areas of infarction relate to proliferative changes in cerebral arterioles leading to luminal occlusion.59 Large areas of infarction are sometimes found and may be related to anitphospholipid antibody related thromboembolism or to lupus-related embolism from sterile cardiac leaflet vegetations associated with SLE.60

Stroke may occur in the course of polyarteritis nodosa. Involvement of the CNS is found in 20% to 40% of patients.61,62 Mixed connective tissue disease (MCTD), which clinically overlaps with polymyositis, SLE, and progressive systemic sclerosis, can involve the CNS. Cranial neuropathy, most commonly trigeminal nerve dysfunction has been the most frequently cited deficit. However, stroke has been reported in children afflicted with MCTD.63 Necrotizing arteritis with inflammatory infiltrate has been found in both meningeal and cerebral vessels of children suffering from Henoch-Schoenlein purpura. Both fixed and transient central neurologic deficits may occur in this disorder. Treatment with steroid or with other immunosuppressive agents may prove helpful. Long-term anticoagulation has not been studied. Neurologic complications have been reported to accompany Kawasaki disease. Hemiplegia and neuroimaging findings indicative of focal cerebral infarction have been observed.64-66 Takayasu arteritis involving the aorta and its principal branches has been associated with thrombotic stroke. Inflammation-induced luminal constriction leading to thrombosis is thought to cause cerebral ischemia in these children. Angiographic improvement of vessels in the carotid tree has been observed following immunosuppressive therapy. The central nervous system may be involved in children with hemolytic-uremic syndrome (HUS). Stroke accompanied by radiographic evidence of focal CNS injury has been observed in 5% of children with HUS. Focal infarction is found primarily in cerebral hemisphere and basal ganglia. Damage to endothelial vascular lining due to Shiga toxin produced by Escherichia coli O157:H7 is thought to activate platelets and coagulation cascades to culminate in thromboembolic stroke.67,68

Vasospasm

Stroke may occur in the setting of migraine headache. The occurrence of focal deficits during migraine headache denotes a complicated migraine and is believed to reflect the involvement of either the carotid or vertebrobasilar circulation. Symptoms may include hemiparesis, ataxia, cortical blindness, and cranial nerve dysfunction and may be either fixed or transient. Angiographic studies have been performed on patients suffering focal deficits consistent with stroke in the setting of migraine headache. Vasoconstriction of vessels in either the vertebrobasilar or carotid circulations has been documented. In these cases, the neuroanatomic position of the constricted vessels correlated with the location of the observed deficits. As a result, ischemia provoked by vasoconstriction during prolonged migraine has been hypothesized as a mechanism of stroke in these patients.

Drug abuse may promote thrombotic stroke. Cerebral infarction and peripheral neuropathy have been associated with glue sniffing in children. Cerebral infarction and subarachnoid hemorrhage have both been observed in association with cocaine use. Cocaine blocks the reuptake of catecholamines at the synaptic cleft. As a result of elevated synaptic concentration of epinephrine and norepinephrine, the neural activity of adrenergic systems is markedly enhanced. Tachycardia, hypertension, and vasoconstriction result. The probability of subarachnoid hemorrhage is higher in cocaine users with occult intracranial vascular abnormalities than in those with normal cerebral vasculature. The resultant sudden rise in systemic blood pressure is thought to precipitate subarachnoid hemorrhage. Ischemic lesions have also been found in patients who have used cocaine or who have been exposed to it prenatally. The physiologic evidence favors vasoconstriction as the underlying etiology of ischemic stroke found after cocaine use.69

Hematologic Etiologies

Several disorders of coagulation have been associated with embolic or thrombotic stroke. Adverse consequences of antiphospholipid antibodies including the lupus anticoagulant (LAC) and anticardiolipin antibody (aCL) have been identified in all age groups. However, cerebrovascular consequences of these antibodies are found in children, adolescents, and young adults. Antiphospholipid antibodies are polyclonal antibodies in serum which can bind to both neutral and negatively charged phospholipids. Recently, antibodies to beta-2-glycoprotein-1, a plasma cofactor that facilitates the binding of anticardiolipin antibodies to phospholipid, has also been demonstrated to be elevated in young children with cerebral thrombosis.70-72 Antiphospholipid antibodies prolong the partial thromboplastin time (PTT) in vitro, but act as a procoagulant in vivo. In addition to a prolonged PTT, its presence is indicated by a falsely positive serum Venereal Disease Research Laboratory (VDRL) test result and can be confirmed by functional and immunologic tests for antiphospholipid antibodies. Its presence has been associated with up to a six-fold increase in risk of stroke in children.73 Further, transplacental passage of the antibody from mother to infant has been invoked as a cause of presumed prenatal, perinatal, and neonatal stroke.74

Absence of specific serum proteins that act as inhibitors of coagulation may lead to stroke in children. Deficiencies of protein S and protein C have been associated with thrombotic or embolic cerebrovascular disease in the young. Protein C and its cofactor protein S act as anticoagulants and synergistically attenuate coagulation by deactivating the thrombin-activated forms of factors V and VIII. Absence of either of these proteins may tip the scale of balanced coagulation toward increased spontaneous clotting and can result in stroke. Antithrombin-III inhibits serine esterase activity and opposes not only the action of thrombin but also the activated forms of II, IX, X, XI, and XII. Deficiencies of protein S or C or of antithrombin-III may cause arterial thrombotic or embolic stroke or venous infarction.14,75,76 Although these deficiencies are often congenital, they may be acquired through liver disease (reduced synthesis), inflammatory bowel disease, or nephritic syndrome (protein wasting).77 Screening tests, including prothrombin time (PT), partial thromboplastin time (PTT), and specific immunologic and functional testing of the proteins suspected of being deficient are essential for diagnosis.

Elevation of lipoprotein (a) represents a recently identified characteristic that has been suggested as a risk factor for stroke in both neonates and older children. Lipoprotein (a) is a low-density lipoprotein with apolipoprotein (a) as a substituent. Bearing regions of homology very similar to the fibrin binding sites of plasminogen, lipoprotein (a) appears to compete with plasminogen and thereby contributes to a procoaguable state. It has been associated with stroke in neonates and in older children.78-80

Cancer and its treatment may predispose children to cerebrovascular ischemic events. Promyelocytic leukemia and its treatment have been observed to provoke disseminated intravascular coagulation leading to stroke. Lymphoreticular cancers, more than solid tumors, have been linked to thrombotic and embolic strokes. Transient ischemic attacks (TIAs) following induction chemotherapy for acute lymphoblastic leukemia have been reported. In addition, dural sinus and cerebral sinovenous thrombosis (CSVT) have been found after therapy with L-asparaginase.81

Oral contraceptives continue to engender concern as a risk factor for stroke among young women, especially those with migraine. Migraine in young women is associated with increased risk for ischemic stroke. This risk is higher in migraine with aura and is further increased by tobacco smoking and use of oral contraceptives. As a result, among young women who are prescribed oral contraceptives, abstinence from tobacco use and use of low-estrogen-content oral contraceptive pills, or those with progestogens only, has been advised.82 Pregnancy and the post partum state have been considered periods of hypercoaguability. In addition, venous stasis increases. These two factors are believed to promote the occurrence of cerebral venous thrombosis and cerebral infarction, often venous in nature, in pregnant and immediately postpartum females. Frequently, the initial manifestation is headache. Seizures, either focal or generalized, are common. Acute hemiparesis is the most common focal finding on the neurologic examination. Papilledema can appear as a consequence of increased intracranial pressure resulting from obstruction of cerebral venous outflow. The appearance of these signs or symptoms in a gravid or postpartum adolescent should raise suspicion about the existence of the underlying cerebral venous thrombosis. Finally, insect stings have caused focal cerebral infarction in children. Wasp and scorpion venom activate platelets, promoting thrombogenesis, which can culminate in focal infarction.

Genetic and Metabolic Etiologies

Table 552-3 provides a summary of the genetic and metabolic causes of stroke. Three genetic mutations have been found to lead to protein dysfunction that has been associated with prothrombotic features that may culminate in stroke. These are the factor V Leiden mutation (FVL), the prothrombin 20210 mutation, and deficiency of methylene tetrahydofolate reductase (MTHFR). The factor V Leiden mutation, due to a single nucleotide G→A transition in exon 10 of the factor V gene, results in replacement of arginine by glutamine at amino acid 506 in the protein. This substitution imparts striking resistance of the factor to inactivation by protein C and consequently abnormally sustained ability to advance coagulation. It accounts for greater than 95% of activated protein C resistance. Neonatal stroke and stroke in older children has been associated with this mutation.83,84

The prothrombin 20210 (PTG20210A) mutation, like the FVL mutation, involves a G→A transition and occurs at nucleotide 20210 in the prothrombin gene. Although this occurs in the terminal untranslated portion of the gene, it nonetheless imparts an increased level of activity to the prothrombin protein. The prothrombin 20210 mutation has been associated with childhood and neonatal stroke.78,79,85 In addition, it has been associated with recurrence of stroke in children.86

Genetically determined dysfunction of cystathionine reductase is widely recognized for consequent elevation of serum homocysteine level (see below). However, the level of this amino acid can become abnormally high by other means. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the regeneration of fully reduced methyl tetrahydrofolate, the major circulating form of folate. Folate participates in the remethylation of homocysteine to methionine. A mutation at the 677 position of the MTHFR gene causes an alanine to valine substitution in the resulting protein and impairs enzyme function that results in elevated plasma homocysteine levels in the setting of folate deficiency. Although increased risk for childhood stroke has been associated with both homozygosity and heterozygosity for this mutation, it remains unclear whether this increased risk relates to elevation of the homocysteine level or to some other consequence of the genetic mutation itself.87-92

Homocystinuria, a disorder of homocysteine metabolism, can cause thrombotic stroke in children. Abnormal homocysteine metabolism results from one of three heritable enzymatic defects. The most striking phenotype results from deficiency of cystathionine synthetase, the enzyme that catalyzes the catabolism of homocysteine to cystathionine. In this disorder, accumulation of both homocysteine and methionine result. Children affected by this autosomal recessive disorder manifest marfanoid habitus, global developmental delay, lens dislocation, and thromboembolism. Serum hyperhomocystinemia injures the vascular endothelium. The denuded vessel wall then becomes a site for thrombosis. The resulting thrombus may remain at its site of origin or it may embolize to a distal location. Therefore, stroke may have thrombotic or embolic characteristics and both arterial and venous infarcts may result. Treatment is dietary, aimed principally at reduction of homocysteine levels in serum.

Sulfite oxidase deficiency, an autosomal recessive disorder of sulfur amino acid metabolism, results in the accumulation of serum sulfites. The associated phenotype may result from deficiency of either the enzyme or its associated and essential pterin-containing molybdenum cofactor. The clinical picture of this disorder consists of mental retardation, seizures, lens displacement, and can include acute onset of hemiparesis. The cause of hemiparesis is not determined; it is possible that ischemic mechanisms are not involved but that direct metabolic neurotoxicity accounts for sudden onset of deficits that resemble those of stroke.

Fabry disease, a lipid storage disease attributable to ceramide trihexosidase deficiency, results in accumulation of sphingolipid, globotriaosylceramide in kidney, vascular endothelium, and cornea. Symptoms include angiokeratomas and painful paresthesiae, often first apparent in adolescence. Due to endothelial accumulation of sphingolipid in vessel walls, cerebrovascular occlusion may occur and culminate in stroke. Recurrent stroke is not uncommon in this rare X-linked disorder.

Mitochondrial disorders may be manifested by recurrent and sometimes catastrophic strokelike episodes. The clinical constellation of mitochondrial encephalomyopathy, lactic acidosis, and stroke (MELAS) presents in childhood and most commonly derives from a mutation of mitochondrial DNA. The most common biochemical finding is a deficiency of complex I of the electron transport chain. An elevated serum lactate concentration, or more consistently CSF lactate level, supports the diagnosis. Molecular diagnosis may be secured from blood. While Leigh syndrome and myoclonic epilepsy and red ragged fibers (MERRF) syndrome may also feature strokelike events, hemiparesis of abrupt onset, often accompanied by hemianopia is characteristic of MELAS. Seizures, sensorineural hearing loss, dementia, and short stature are frequently present. Neuropathologic study of brain from patients with MELAS has revealed cystic cavities and necrosis of cortex, especially of posterior cerebrum with relative sparing of white matter. Interestingly, cerebrovascular degeneration associated with mitochondrial encephalopathy has been described and offers an alternative mechanism for stroke-like episodes observed in these patients.93

Other metabolic disorders have been associated with stroke in childhood. Urea cycle defects, especially ornithine transcarbamylase deficiency presenting in hemizygous girls, can cause stroke. Organic acidemia has also been associated with stroke. Methylmalonic, propionic, and type 2 glutaric acidemia have been associated with striatal necrosis. In addition, both methylmalonic and propionic academia have been associated with intracranial hemorrhage. Both 3-methyl crotonyl-CoA carboxylase deficiency and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency have been associated with stroke.94

Embolus

Congenital heart disease is a very common cause of stroke in childhood. Children with cyanotic congenital heart disease face the greatest risk. An embolic stroke constitutes the most common cerebrovascular event. Cardiac defects involving right-to-left shunts allow emboli originating in the peripheral circulation to bypass filtration and removal by the pulmonary vascular bed. Thus, emboli entering the heart via venous return may be shunted to the peripheral arterial circulation, only to lodge in the cerebrovascular tree (Fig. 552-3).

Patent foramen ovale (PFO) is associated with the occurrence of stroke in children and young adults. Echocardiographic evaluation of young patients who have suffered stroke reveal patent foramen ovale or evidence of right-to-left shunting in greater than 3-fold more patients suffering stroke relative to control patients. Notably, PFO is the most commonly detected cardiac anomaly in patients studied with echocardiography. Transesophageal echocardiography conducted with Valsalva bubble studies for evidence of direct right-to-left conduction is the most useful diagnostic test. Treatment possibilities include PFO closure, anticoagulation or antiplatelet therapy. Data from adult studies indicate treatment equivalence between anticoagulation and antiplatelet therapy. Further, while the presence of right to left shunt across the PFO at rest has been associated with stroke recurrence, the effect of PFO size upon outcome or stroke recurrence rate has been questioned.95-97

Congenital valvular defects such as aortic stenosis and mitral stenosis can result in stroke. Rheumatic valve disease, once a common cause of embolic stroke, has become infrequent. However, infected valves found in subacute bacterial endocarditis (SBE) still pose considerable risk for the occurrence of embolic stroke. Infective mitral and aortic valvular vegetations may dislodge, travel distally, and, ultimately, occlude cerebral arteries. Even after vegetations have been successfully sterilized they may still embolize and cause stroke. Emboli from infected valvular vegetations may also lead to other vascular lesions. For example, emboli may travel to the cerebral vasculature and there seed the adventitia of the cerebral vessel. The resultant infection and inflammation result in weakening of the vessel and development of a mycotic aneurysm. Typically located in distal cerebral vasculature, they may lie dormant for some time before their rupture leads to subarachnoid or intraparenchymal hemorrhage and the possibility of lasting neurologic deficit.

Fat or air emboli can ramify in cerebral vasculature. Most commonly found in patients with long bone fractures or following surgery, including procedures that employ cardiopulmonary bypass, these emboli have been observed with nontraumatic conditions such as pancreatitis, sickle cell disease, connective tissue diseases, and intravenous lipid administration. Because fat or air emboli occur as showers, multiple sites in the central nervous system may be involved leading to generalized symptoms such as impaired consciousness, delirium, or coma. Focal or lateralized neurologic signs are found in only one third of patients.

Clinically explicit recurrence of stroke is rare in neonates but has been reported to occur in up to 25% of older children. Both vasculopathy and prothrombotic mutations, especially, have been reported to impart increased likelihood of stroke recurrence.86,98 Among these, deficient protein C, elevated lipoprotein (a), the presence of at least one prothrombotic genetic defect, and antecedent TIAs have emerged as clinical characteristics associated with stroke recurrence. Importantly, the possibility of synergy between features associated with stroke occurrence and constitutional features such as systemic inflammation or dehydration to culminate in stroke is of increasing interest, as this has emerged as a clinical profile of many children who present with stroke. Among children with sickle cell disease, stroke recurrence is increased among those who are not adequately treated with exchange transfusion and those with Moyamoya disease.44,99

Hemorrhage

Nontraumatic intracranial hemorrhage occurs more commonly in males than females. Hemorrhage may be subdural, subarachnoid, intraparenchymal, or intraventricular in location. Recent data indicate that the most common cause of nontraumatic hemorrhage is vascular abnormality (arteriovenous malformation, cavernous malformation, venous angioma, aneurysm, and Moyamoya disease). However, brain tumor and hemorrhage associated with congenital heart disease contribute significantly to its occurrence. Whereas younger children present with nonspecific symptoms such as mental status change, seizure, and vomiting, older children may manifest focal neurologic symptoms in addition to nausea and vomiting. Blood pressure may be greater than the 90th percentile for age. Investigation has revealed that approximately 50% of children with nontraumatic intracranial hemorrhage have no lasting deficit. However, children with intraparenchymal hemorrhage resulting from vascular abnormality appear to have a better prognosis than other groups.100,101

Arteriovenous malformation (AVM) of the brain is a common cause of intracranial hemorrhage in preadolescent children. The malformation represents a developmental anomaly that presents with hemorrhage more frequently in children than in adults. The AVM consists of dilated vascular channels some of which exhibit the highly muscularized walls of arterioles. Gliotic neural tissue resides in and among the vascular branches of the malformation. More common in males, the most frequently observed events associated with AVM in children are seizures and hemorrhage. The vast majority of AVMs are located in the cerebral hemispheres, whereas 10% to 15% arises in the posterior fossa. The clinical features of hemorrhage due to AVM may consist of acute onset of focal neurologic deficit, features of which depend upon the area of brain in which the hemorrhage has occurred. Mortality is higher in children than in adults.102

Intracranial aneurysm constitutes an important cause of hemorrhagic stroke in patients less than 20 years of age. Mycotic aneurysm found in association with subacute bacterial endocarditis (SBE) has already been discussed. Saccular aneurysms are more frequent in males than in females. Unlike aneurysms in adults, the most common site of aneurysmal bleeding in children is along the intracranial portion of the internal carotid artery. The vertebral and basilar arteries are other common sites of intracranial aneurysm in children. In addition, intracranial aneurysms discovered in children tend to be larger than those found in adults. While most aneurysms constitute vascular developmental anomalies, other associations exist. These include disorders of connective tissue (such as Ehler-Danlos and Marfan syndromes), children with polycystic renal disease, and those with aortic coarctation.

Some coagulation disturbances may predispose to intracranial bleeding. The hemophilias, both A and B, are X-linked disorders that may result in intracranial bleeding (Table 552-3). Bleeding may occur in either intraparenchymal or subarachnoid locations. Hemophilia A arises because of factor VIII deficiency. Males affected by this disorder may experience intracranial bleeding in association with head trauma. However, hemorrhage may also occur spontaneously. The risk of spontaneous hemorrhage increases as the severity of factor VIII deficiency rises. Hemophilia B derives from a deficiency of factor IX. Intracranial bleeding is seen less frequently in these patients than in those with hemophilia A. Hemophilia B is encountered much less frequently than hemophilia A and this may account for the less frequent observation of intracranial bleeding. If the bleeding occurs in the subarachnoid space, symptoms of severe headache, nuchal rigidity, and meningismus can be found; mental status change may also occur. If parenchymal brain bleeding occurs, focal and central signs may be evident.

Severe thrombocytopenia leads to cerebral hemorrhage in very few patients. Significant risk of intraparenchymal hemorrhage appears to occur only after platelet counts of 20,000 per mm3 or less are reached. Small petechial hemorrhages into white matter are more common than parenchymal hemorrhage. Causes of thrombocytopenia include idiopathic thrombocytopenic purpura, infection, and malignancy.

Intracranial hemorrhage, often with subarachnoid involvement, occurs among children with sickle cell disease. Hemorrhage may be subarachnoid, intraparenchymal, or intraventricular. Recently, intracranial bleeding in children with sickle cell disease has been observed to be related to hypertension or to treatment with transfusion or corticosteroids.103

Clinical suspicion of stroke in a patient with suggestive symptoms constitutes the most salient element of diagnosis. Despite presentation of focal symptoms including hemiparesis, headache, aphasia, dysarthria, diplopia, and mental status change, the diagnosis of stroke is often not considered during initial assessment of children who ultimately prove to have sustained a stroke. Mean time to accurate diagnosis from onset of symptoms has been found to be more than 35 hours.104

Once stroke has been suspected, diagnostic efforts concentrate on documentation of its occurrence and discovery of its underlying cause. Neuroradiologic and laboratory evaluations are conducted simultaneously. A suggested approach to diagnostic evaluation is provided in Figure 552-4. Cranial computerized tomography (CCT) and magnetic resonance imaging (MRI) provide rapid and topographic evidence of infarction or intracranial hemorrhage. Cranial CT images are more rapidly acquired than MRI at many centers, particularly during nighttime hours and provide clear evidence of acute intracranial hemorrhage. Magnetic resonance imaging, which provides greater resolution and structural detail than CCT, demonstrates infarctions that are smaller and newer than those detected with CCT. Diffusion weighted MR imaging permits visualization of CNS infarction very early in its course. Magnetic angiography (MRA) yields reliable information about blood flow in and structure of large cervicocephalic and intracranial vessels. Small intracranial vessels still are poorly resolved by MRA. Invasive angiography remains the neuroradiologic procedure of choice when detailed knowledge of the cerebral vasculature is required.

Laboratory testing should screen for conditions that predispose a child to stroke. In addition, laboratory evidence of inflammation should be sought. Serum electrolytes will provide initial evidence of a metabolic acidosis that may accompany a mitochondrial disorder or an organic acid disturbance. Toxicology screen should be performed if drug-induced stroke is suspected. A lumbar puncture should be considered if CNS infection, inflammation, or neoplastic involvement is suspected. However, a lumbar puncture should not be performed if either physical examination or neuroimaging indicates the presence of a focal space-occupying abnormality causing increased intracranial pressure. Performance of this procedure in a patient with a unilateral intracranial lesion could precipitate transtentorial or transmagnal herniation.

If a stroke is clinically or radiologically documented and the aforementioned laboratory studies yield normal results, further investigation is warranted. Evidence of coagulopathy, systemic inflammation, antiphospholipid antibodies, rheumatologic diseases, and elevated serum lipoprotein (a) should be sought. In addition, serum or CSF lactate and pyruvate and urine organic acids concentrations should be determined. DNA and functional assays should be considered for mutations in FVL, PT20210, and MTHFR. If the patient’s clinical picture suggests Fabry disease or urinary sulfite oxidase deficiency, the appropriate blood or urine tests should be obtained for diagnosis. Echocardiography should be performed in a child who has sustained a stroke and in whom a cardiac murmur is heard or in whom mural or valvular thrombus is suspected. If concern exists regarding the possibility of a right-to-left cardiac shunt, an echocardiogram bubble study should be included in hope of documenting an existing intracardiac shunt. Either transesophageal or transthoracic echocardiography may be employed though the transesophageal method will often provide the best view of intracardiac anatomy.

The axis of treatment for stroke consists of two arms: acute response and prophylactic response. In neonates, supportive elements of treatment in the acute phase consist of correction of thrombocytopenia, anemia, and dehydration, if present. Similarly, low levels of coagulation factors and vitamin K deficiency should be corrected in an age-appropriate fashion. External ventricular drain or shunt placement should be considered for infants with intracranial hemorrhage and consequent intractable hydrocephalus. Although thrombolytic therapy has been studied and used in adult patients, there are few data regarding its safety and efficacy in children with stroke and virtually none available in neonates. Use of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) has been studied to some extent in this patient population.18,24,105 Consideration of anticoagulation treatment with UFH or LMWH has been suggested for neonates with cerebral sinovenous thrombosis (CSVT) and radiologic evidence of clot propagation, with severe thrombophilia disorders or with evidence of multiple cerebral and systemic embolic events.28

There is keen interest in the safety and efficacy of thrombolytic therapy for older children who present in the acute phase of stroke. Currently, data on use of thrombolytic agents (tissue plasminogen activator (tPA) or urokinase) in children are available by case report only. These case reports suggest that use of these agents may provide benefit to children with stroke if diagnosed early enough in the course of the event. However, the lack of uniformity in choice of agent, time of thrombolytic administration after stroke onset, and method of administration prevent any conclusion to be drawn regarding the safest and best use of these agents in children.106-111

Anticoagulation with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) is appropriate for certain children after presentation with acute stroke resulting from the comparatively high occurrence of embolism in complex congenital heart disease, arterial dissection, and hypercoaguable states among children relative to adults.28,105 Warfarin is chosen for long-term anticoagulation. Although LMWH can be used for this purpose, warfarin dosing is oral and offers an alternative to the subcutaneous injection needed for LMWH administration. Warfarin has been used for prophylactic treatment in children with substantial risk of recurrence of embolic events, such as those with complex congenital heart disease. Although effective, the benefit of the drug must be considered relative to the risk of hemorrhage which occurs at a rate of less than 3.2% per patient-year as found in children treated for mechanical prosthetic cardiac valve placement.If cardioembolic stroke and arterial dissection are ruled out as a cause of stroke, treatment with aspirin is often instituted.105

Prophylactic therapy remains the cornerstone of therapy in thrombotic stroke. Exchange transfusion diminishes the fraction of blood composed of hemoglobin S-containing RBCs and reduces the risk of recurrent strokes in children with sickle cell anemia.39,99,112,113 Hydroxyurea may well reduce the occurrence of stroke among sickle cell patients and is of great interest as a prophylactic therapy.48,49,114 Stroke due to coagulation factor deficit can be treated with anticoagulation or with factor replacement. Similarly, patients symptomatic from the presence of antiphospholipid antibodies may be treated with anticoagulation using either LMWH or warfarin.60

Metabolic diseases that may lead to recurrent stroke generally lack effective therapy and carry a poor prognosis. However, homocystinuria may be treated with oral vitamin B6 therapy.92 If serum homocysteine level is elevated and is related to a documented mutation in the MTHFR gene, treatment with folate may be instituted.91 Patients with Fabry disease may benefit from enzyme replacement therapy for defective ceramide trihexosidase.115,116

Vascular abnormalities may be treated prophylactically to prevent stroke. Arteriovenous malformations (AVMs) may be partly or selectively embolized. Embolization may constitute definitive treatment or may represent preliminary treatment prior to surgical extirpation. Ischemic injury to brain due to Moyamoya disease can be prevented through surgical revascularization techniques. Two types of revascularization procedures are in use; “direct” procedures anastamose arteries from the external cranial circulation to those of the internal cranial circulation while indirect procedures mobilize the superficial temporal artery or other vascularized tissue to the surface of the brain to induce revascularization.34,117-119 Both have demonstrated clinical efficacy. Each procedure is designed to reconstitute cerebral perfusion distal to the critical stenosis. Clinical trials to determine which may be most effective have not yet been conducted.

Hydrocephalus is a condition in which there is an accumulation of cerebrospinal fluid (CSF) within the ventricles, leading to increased intracranial pressure. Hydrocephalus may be caused by increased production, decreased absorption, or obstruction to flow of CSF. By contrast, ventricular dilatation due to loss of brain tissue or atrophy is not considered to be hydrocephalus.

Cerebrospinal Fluid Dynamics

Typically, cerebrospinal fluid (CSF) is produced at a volume of 20 mL/hour, or more than 500 mL per day, in the adult. Total CSF volume in infants is approximately 50 mL, as compared to approximately 150 mL in normal adults. Cerebrospinal fluid is produced by active secretion and diffusion predominantly in the choroid plexus, located in the lateral ventricles and the roof of the fourth ventricle. Cerebrospinal fluid passes from the lateral ventricles into the paired foramina of Monro to reach the third ventricle and then along the cerebral aqueduct into the fourth ventricle. Once in the fourth ventricle, CSF flows through the midline foramen of Magendie or laterally through the paired foramina of Luschka into focally enlarged areas of subarachnoid space known as the basal cisterns, which connect the spinal and intracranial subarachnoid spaces (Fig. 553-1). Cerebrospinal fluid is in continual flow around the brain and spinal cord and within the ventricles in a cephalad direction. Production of CSF is regulated by the enzyme carbonic anhydrase, and reabsorption occurs within the arachnoid villi in the meninges into the venous channels of the sagittal sinus. Smaller amounts of CSF absorption also occurs across the ependymal lining of the ventricles. Typically, there is a delicate balance between CSF production and reabsorption; hydrocephalus results when that balance is disrupted. However, CSF production rarely fluctuates in normal circumstances and even in the face of rising intracranial pressure, unless extremely elevated pressures are reached.

Potential Etiologies

Hydrocephalus is generally classified as communicating, obstructive, and external, depending on the underlying etiology.1 Communicating hydrocephalus refers to a situation in which cerebrospinal fluid (CSF) flows freely into the subarachnoid space, but the total volume of CSF is increased secondary to either impaired reabsorption or overproduction. Impaired reuptake of CSF may result from blood within the ventricular system (as occurs with subarachnoid hemorrhage) increased protein content (resulting from meningitis) or an increased cell content from malignant cells such as leukemia. Some tumors, such as choroid plexus tumors, may increase CSF production thereby contributing to hydrocephalus (Fig. 553-2).2

Obstructive, or noncommunicating hydrocephalus, results from obstruction to the outflow of CSF. Aqueductal stenosis is the most frequent cause, accounting for about 20% of cases, with an incidence of 0.5 to 1 per 1000 births.3 Anatomically, the cerebral aqueduct is vulnerable to external compression because of its long, narrow tract connecting the third and fourth ventricles. Stenosis may be congenital, often associated with spina bifida, or may result from inflammatory or neoplastic processes. The Chiari malformation describes a condition in which the inferior poles of the cerebellum protrude caudally into the foramen magnum, resulting in compression of the medulla (Fig. 553-3). These malformations, either alone or in combination with other congenital abnormalities, account for 40% of cases of hydrocephalus.4,5

Any decrease in cerebral venous drainage (and resultant increase in cerebral venous pressure), as seen with cerebral or jugular vein thromboses, can result in increased intracranial pressure (ICP) and hydrocephalus. In addition, superior mediastinal obstruction compromising superior vena cava flow has been reported as a cause of increased ICP.6,7

Benign enlargement of the subarachnoid space, otherwise referred to as benign extra-axial fluid, external hydrocephalus, idiopathic external hydrocephalus, or extraventricular hydrocephalus, is relatively common, occurring in approximately 16% of infants.8,9 Head circumference typically increases to greater than the 90th percentile and then parallels the normal curve. The head growth velocity then slows to normal by the age of 6 months. Typically these children experience normal development and have normal neurologic examination; nonetheless, their development should be monitored closely.10 This benign increase in the size of the subarachnoid space should be contrasted with the extra-axial fluid collections that are observed in children who spent extensive periods of time in the neonatal intensive care unit or on extracorporeal membrane oxygenation. In these circumstances, the increased head size and fluid collections may be associated with adverse neurologic sequelae and/or poor developmental outcomes.11

Clinical Signs and Symptoms

The clinical signs and symptoms of hydrocephalus are nonspecific and independent of underlying etiology. In young children, the most obvious sign of hydrocephalus is a rapid increase in head size, often accompanied by a bulging, enlarged anterior fontanel, conspicuous scalp veins, and/or frontal bossing.3 Other symptoms may include irritability, increased sleepiness, vomiting, seizures, and downward eye deviation—the “setting sun sign”—in which the sclerae are visible above the iris.12 In older children, symptoms of hydrocephalus reflect the increased intracranial pressure and include headaches, nausea, vomiting, and, occasionally, changes in vision with double vision and/or blurry vision. Headaches that are the result of increased intracranial pressure often occur early in the morning and may be associated with nausea and vomiting. Prolonged increases in intracranial pressure (ICP) may be accompanied by changes on ophthalmological examination, such as papilledema, as well as changes in balance or walking and increased sleepiness. Physical examination may also demonstrate palsies of the third or sixth cranial nerves.

Evaluation and Management of Hydrocephalus: Cerebrospinal Fluid Diversion

Evaluation for hydrocephalus includes imaging studies to assess the ventricular size and to assess for signs of anatomical obstruction, the presence of mass lesions, or signs of impending herniation. In young infants, ultrasonography is the preferred imaging modality, because it is portable and avoids ionizing radiation. In older children, computerized tomography (CT) or magnetic resonance imaging (MRI) should be performed.13 In addition, direct ophthalmoscopy is useful to evaluate for signs of papilledema, reflecting increased intracranial pressure (Fig. 553-4).12

The goal of therapy is to relieve the increased intracranial pressure, restore flow of cerebrospinal fluid (CSF), and prevent irreversible neurologic deterioration. This can be achieved by several approaches. Often, mechanical shunts are placed as soon as the hydrocephalus is recognized in order to drain excess accumulation of CSF. Although this does not address the cause of the hydrocephalus, it does effectively treat the symptoms and stops progression of the ventricular dilatation and minimizes neurologic deterioration. Shunt placement involves placement of a plastic catheter directly into the ventricle, typically on the right. The catheter can be connected to a one-way valve system to better regulate pressure; alternatively, a reservoir can be placed to administer chemotherapy. The catheter is tunneled under the skin and the distal end of the system is then connected and placed into the right atrium of the heart (ventriculoatrial shunt) or into the peritoneal cavity (ventriculoperitoneal shunt). This allows a bypass of the site of obstruction, either mechanical or functional, into a site where the fluid can be reabsorbed into the systemic circulation. Externalized shunt devices, also referred to as external ventricular drains (EVDs) are often placed in the setting of acute hydrocephalus for pressure monitoring and temporary CSF diversion. They may also be placed during management of a shunt infection.

Endoscopic third ventriculostomy (ETV) is a procedure in which a perforation is placed in the floor of the third ventricle, creating a direct connection to the subarachnoid space and thus bypassing the obstruction.14,15 This procedure has been used for the initial treatment of select cases of obstructive hydrocephalus and as an alternative to shunt revision. ETV may avoid the issues related to foreign body implantation and establishes a more “physiologic” cerebrospinal fluid circulation, thus avoiding the need for future shunt-related complications and/or the need for revisions.16 The overall success of ETV depends on the age of the patient and the etiology of the hydrocephalus; shunt failure and/or webbing along the ventriculostomy site may occur, leading to secondary obstruction and the need for a repeat procedure.14,17 Medical therapy, such as diuretics and serial lumbar punctures, can be used as a temporizing measure if the underlying etiology is thought to be transient and the child is stable clinically (see section below on treatment of pseudotumor cerebri).18,19 For further management of hydrocephalus in the preterm and newborn infant, see Chapter 52.

Shunt Malfunctions

Complications of shunts implanted for hydrocephalus typically result from mechanical malfunction of the shunt or to infection.20 Mechanical failure is more likely during the first year after shunt placement, and primarily results from obstruction at the ventricular site, due to broken tubing or migration of all or a portion of the shunt.

Shunt infection is often caused by skin flora, such as staphylococcus epidermidis, followed less frequently by infections with Staphylococcus aureus, enteric bacteria, and Streptococcus species.20 This may occur at the time of surgery or in the postoperative period due to breakdown of the overlying skin. The incidence of shunt infection is highest during the month after initial placement and in patients requiring multiple revisions, and ranges from 5% to 15%.21 Infection must be considered in any child with a mechanical shunt who develops a persistent fever. Shunt infections can present with few or no symptoms; in some cases, symptoms develop only when subsequent obstruction occurs, leading to increased intracranial pressure. Ventriculoperitoneal shunts may also present with symptoms of peritonitis, including fever, abdominal pain, and anorexia. Ventriculoatrial infections can also present with fever and bacteremia. Diagnostic evaluation includes plain radiographs of the skull, neck, chest, and abdomen (shunt series) to look for mechanical breaks, kinks, and disconnections in the shunt, and a cranial computed tomography (CT) scan to evaluate for signs of increased ventricular size, blood culture and cerebrospinal fluid (CSF) analysis, preferably through direct aspiration of the shunt. Antibiotic therapy is guided by the results of the CSF analysis. In most cases, the shunt must then be removed; if the underlying hydrocephalus remains an issue, another drainage procedure would be indicated with replacement of the shunt once the CSF is sterile.

Pseudotumor cerebri, also known as idiopathic or benign intracranial hypertension (IIH), is a syndrome of increased intracerebral pressure in the absence of change in ventricular size, with normal cerebrospinal fluid (CSF) fluid analysis and normal neuroimaging.

Epidemiology/Populations at Risk

The incidence of idiopathic or benign intracranial hypertension (IIH) is 0.9 per 100,000 persons in the general population, including children; the risk is thought to be higher in adolescents compared to children, and in women ages 20 to 44 years, who are more then 20% above ideal body weight.22 In one meta-analysis of studies evaluating IIH in childhood, there was an even gender distribution in children less than 12 years; however, in children 12 to 17 years, more than 70% were female, and the rates of obesity were significantly higher.23 Idiopathic or benign intracranial hypertension has been associated with numerous underlying secondary comorbidities, including endocrine, rheumatologic, and immunologic conditions.24 In addition, medications such as corticosteroids, nitrofurantoin, and vitamin A derivatives have been associated with secondary IIH. Some of these are well supported, whereas others are cited in case reports. Up to 84% of prepubertal children have an identifiable cause of the IIH.

Pathophysiology

The pathophysiology of IIH remains poorly defined. Based on the current understanding of cerebrospinal fluid (CSF) flow, proposed contributors may include CSF overproduction or underabsorption, cerebral edema, or vascular congestion resulting in elevated cerebral venous pressure and resistance to the outflow of CSF.25

Clinical Features

Presenting symptoms vary with age of onset, yet are similar to those associated with hydrocephalus and typically include headache and changes in vision. As noted above, headaches that occur in the setting of increased intracranial pressure (ICP) are often worse at night and may lead to nighttime awakenings. Valsalva maneuvers, during coughing or defecation, may worsen the headache. Some patients experience blurry or double vision, as with hydrocephalus, in addition to pulsatile tinnitus. Ataxia, torticollis, paresthesias, facial numbness or pain, and dizziness have also been described.

By definition, the neurologic examination is typically normal, although there may be falsely localizing palsy of the abducens or facial nerves. Patients with IIH should be referred to an ophthalmologist for full acuity and visual field testing, including the perimetry. Papilledema, characterized by optic disc edema with elevation of the optic nerve head, blurring of the disc margin, loss of venous pulsations, and venous congestion, is almost always noted in adults, but may be inconsistent in children and adolescents (Fig. 553-4). Papilledema is typically not observed in infants, because the increased intracranial pressure (ICP) is at least in part relieved by the splitting of the sutures and bulging of the fontanel. Loss of vision may either occur before the definitive diagnosis has been made, or may occur after several years. Typical changes in visual field include enlargement of the physiologic blind spot and presence of scotomas and other abnormalities.26 One study demonstrated visual field changes in 85% of prepubertal children at time of presentation.27 Visual acuity testing and detailed visual field evaluation is necessary at baseline and after initiation of treatment to evaluate for progressive optic atrophy.

Diagnosis

The diagnosis of idiopathic or benign intracranial hypertension (IIH) is made by demonstration of cerebrospinal fluid (CSF) pressure greater than 25 cm H2O, a normal CSF composition, and the exclusion of any structural, anatomical or vascular lesions that might otherwise result in increased intracranial pressure. By definition, no other cause of increased intracranial pressure (ICP) should be identified. The diagnosis requires a thorough medication history to determine possible drug exposures and recent weight gain that might represent risk factors.

Neuroimaging studies should be performed in any person who presents with headache and papilledema to exclude the presence of an underlying mass lesion or hydrocephalus. Although computerized tomography (CT) scan is often the first imaging modality utilized in many children, magnetic resonance imaging (MRI) is preferable.13 Up to 70% of persons with IIH are found to have an empty sella on neuroimaging; this is thought to result from the longstanding effects of pulsatile high-pressure CSF that leads to downward herniation of the arachnocele through a defect in the sella.28 In addition, flattening of the posterior sclera is commonly observed in up to 80% of patients, without other associated ocular abnormalities such as enhancement of the prelaminar optic nerve, tortuosity of the orbital optic nerve, or distension of the perioptic subarachnoid space.29 Evaluation of the venous sinus system using magnetic resonance venography is important to exclude cerebral venous thrombosis, which can mimic IIH in children and adults.

Lumbar puncture is performed after imaging studies confirm the lack of space-occupying lesion. Ideally, opening pressure of CSF is measured with the patient lying relaxed with both legs extended in the lateral decubitus position. The pressure is then measured and CSF sent for analysis of cell count, glucose, protein, cytology, and infectious studies. When the opening pressure is elevated, CSF should be removed until the closing pressure approximates normal levels.

Treatment

The goal for therapy of idiopathic or benign intracranial hypertension (IIH) is to treat the symptoms such as headaches and to prevent deterioration of vision and subsequent permanent visual impairment. Treatment should be coordinated between a neurologist and an ophthalmologist with regular evaluations to assess for progressive vision loss.30

In patients for whom a precipitating factor or contributor has been identified, withdrawal of that agent or treatment of the underlying condition may itself lead to resolution of the symptoms. For example, weight loss may lead to recovery of papilledema and improvement in visual fields. Thus, supervised weight loss may be the first line treatment for overweight children with IIH.31

As noted above, the production of CSF is controlled in large part by the enzyme carbonic anhydrase. The diuretic agents acetazolamide and furosemide decrease CSF production by inhibition of choroid plexus carbonic anhydrase; acetazolamide is much more potent in terms of specific inhibition of choroid plexus carbonic anhydrase, however, and is recommended for the first line medical therapy.32,33 Possible side effects include gastrointestinal upset, extremity tingling, anorexia, and drowsiness. Furosemide is less potent when given alone, but has been used as an adjunct to acetazolamide. Steroids may also be effective, but are not recommended for long-term use because of potential side effects, which include elevation of intracranial pressure (ICP).

Repeated lumbar punctures have been used as a temporizing measure. However, the long-term efficacy is probably poor, because CSF is replenished within several hours after the intervention. Patients who experience progressive optic atrophy or visual field deterioration despite maximal medical therapy may benefit from optic nerve fenestration to relieve the papilledema.34,35 The procedure involves creating a window, or fenestration, into the optic nerve sheath just proximal to the globe. Unilateral fenestration ultimately leads to improvement bilaterally in many patients as well as reduction in severity of headache. Efficacy has been shown primarily in adults, with stabilization or improvement in vision in up to 85% to 100% of patients and concomitant improvement of visual function. Experience in children is more limited but results are thought to be comparable. Although this does not relieve the increased ICP, it may spare vision.

Surgery, such as placement of lumboperitoneal or ventriculoperitoneal shunt, is reserved for children in whom visual function is severely compromised and/or continues to deteriorate despite maximal medical management.36

By convention, the cerebral palsies (CP) are nonprogressive disorders of tone, strength, movement, and posture due to central nervous system (CNS) injury, the consequences of which become apparent in infancy. The CNS lesions variously involve pyramidal (cortical, subcortical, brainstem, spinal cord), extrapyramidal, or cerebellar motor systems. The static nature of the CNS lesion and public misunderstanding of the nature of CP has prompted the coining of the not entirely synonymous alternative designation static encephalopathy (SE). A cerebral palsy (CP) is a static encephalopathy (SE) in which motor dysfunction must be present, although individuals may also manifest disorders of intellect, attention, memory, sensory, autonomic, and other neurologic modalities. They may also be at risk for epilepsy and for dysfunction of respiratory, gastrointestinal, and other nonneural systems.1-6

Cerebral palsies are a subgroup of SE, a category that also includes individuals whose static CNS injury may involve various patterns of intellectual dysfunction unaccompanied by central motor system deficits. Where only one or a few specific relatively mild cognitive modalities are impaired, the qualifier learning disabled may be applied, whereas more severe conditions affecting many or all cognitive domains suggests the qualifier intellectually disabled rather than the older term mentally retarded. Limitations of variable degree in the social-pragmatic functions of daily life may or may not be found in individuals with CP.

The combination and degree of deficits in individuals with SE or the large subgroup comprising CP is dependant on the location and extent of underlying CNS injury. The clinical pattern is often predictive of the site of lesions and may be predictive of underlying cause. However, the deficits of most individuals with CP or SE remain of uncertain pathogenesis, although rapid progress in the elucidation of genetically determined developmental disorders is reducing this uncertainty and replacing these generic labels with specific conditions. The importance of labels is that they designate cause with increasing accuracy. The increasing specificity of labels that should be permitted to replace the generic labels of CP or SE results in increasing accuracy of formulation of heritability, risks, prognosis, and treatment.7-9 Postnatal neural development may impart a pseudoprogressive appearance to the static deficits of CP, or of conditions within the wider spectrum of SE, due to the fact that damage to various systems may not become fully apparent until such systems “come on line” during postnatal development.3,4,7 It is important to note that despite the possible infantile worsening of manifestations, most children with CP will experience, at varied rates and degrees, improvement over the course of their development.3,8,9

The incidence of CP is approximately 0.1% to 0.25% of all live births, with little international variation among countries with modern medical facilities.10,11 Modern neonatology has greatly increased the survival of very low birth weight babies, whose risk for CP is approximately eight-fold greater than for larger neonates.12 Interestingly, increases in utilization of electronic fetal monitoring and cesarean section rates, advances in neonatal management, and declining rates of acute neonatal encephalopathy have not appreciably altered CP prevalence in term infants. In fact, the prevalence and severity of CP in term infants may have increased, possibly due to increased survival of very ill neonates.11,13,14

These data place in question the magnitude of the effect of presumed perinatal hypoxic-ischemic stress in increasing risk for CP. The uncertainty is in large part the result of a lack of a reliable biological marker for any of the several possible types of hypoxic-ischemic encephalopathy (HIE) to which the neonate is potentially subjected and the difficulty that exists concerning identification of the timing, degree, and duration of such stress. Neonatal encephalopathy and other possible indices of hypoxic-ischemic encephalopathy (HIE), such as acidemia, seizures, and so forth, may result not only from HIE, but also from inherited metabolic disease, intrauterine infectious or vascular events, developmental brain anomalies, and so forth.15,16 The best available data suggest that perinatal hypoxic ischemic stress may account for 6% to 28% of all cases of CP. More than half of all term infants who experience severe neonatal encephalopathy may develop CP.12,17

Determination of the efficacy of neonatal interventions that may prevent or ameliorate CP (eg, acute mild brain cooling) will require refinement of clinical and biologic markers for the various subtypes of HIE (hypoxemic, ischemic, hypoxic-ischemic, asphyxial; each further qualified by developmental maturity at birth, time of onset, intrauterine/peripartum duration) that set specific HIE syndromes apart from other causes of neonatal encephalopathy.15,16,18 Cerebral palsy syndromes that are most likely to have resulted from various forms of perinatal HIE and their characteristic patterns will be considered. It remains particularly unclear what role HIE may play in the leukencephaloclastic or hemorrhagic forms of CNS injury that are the most commonly encountered structural abnormalities found in very low birth weight infants who develop CP.

Various other risk factors for CP have been identified. These include African-American ancestry, absence of prenatal care, and maternal smoking. The increased rate of prematurity associated with these conditions may in part explain the elevation of risk, although mechanisms of injury are otherwise little understood. Other important and incompletely understood risk factors include male sex, intrauterine growth retardation, maternal chorioamnionitis, insulin dependant diabetes, hyperthyroidism, and epilepsy. Postnatal causes of cerebral palsy include kernicterus, infection, intoxication, and trauma.2-5,17,19,20

The National Collaborative Perinatal Project (NCPP), which evaluated the outcome of 40,000 live births between 1959 and 1966, somewhat demonstrated that cerebral palsy developed in only a minority of neonates who had manifested Apgar scores of 3 or below during the first 15 minutes of life. As markers and definitions of the various forms of hypoxic-ischemic encephalopathy (HIE) became more refined, it remained surprising that evidence for perinatal HIE was found in less than 15% of NCPP children who ultimately developed CP. The Western Australia Cerebral Palsy register, which considered infants born between 1975 and 1980, could assign HIE as the most probable cause of CP in less than 10% of the infants. The Cummins study of all normal birth weight live-birth infants in four northern California counties from 1983 to 1995 could assign HIE as the probable cause of ensuing cerebral palsy in only 6% of cases. Thus, other, often unknown causes appear to be of greater statistical importance.

Conventionally, the cerebral palsies are subclassified on the basis of the type and distribution of the predominant motor findings. The subgroups include hemiparetic (HP), double hemiparetic/quadriparetic (QP), diplegic (DP), extrapyramidal (EP), ataxic (ATx), and hypotonic/atonic (Hyp) cerebral palsies.2-4,19,21 The groups are not entirely discrete from one another and the terminology is not universally standardized. Proper classification serves as an important indicator of localization within the nervous system, of likely cause (including phase of neurological development during which the abnormality is likely to have arisen), of pertinence of particular treatment strategies, and of ultimate prognosis. Cerebral palsy syndromes have variable patterns of associated nonmotoric deficits.

Hemiparetic cerebral palsy (HP CP) is usually found in children who have experienced large vessel (especially middle cerebral artery, left more commonly than right) strokes.3,19,22,23 In approximately half of such cases the stroke is thought to have occurred prior to delivery, while in the other half they are thought to have occurred in the perinatal interval. The latter cases may be identified perinatally upon the basis of contralateral hand or arm clonic seizure activity occurring during the first few days after birth. Weakness and encephalopathy are more likely to be present in the perinatal interval where multiple large artery territories (unilaterally or bilaterally) are found to be involved. The resulting hemiparesis is often not apparent until 4 to 8 weeks later. The cause of these strokes is seldom identified, although clotting disturbances and cardiac sources of emboli must be excluded.

The clinical course is one of spastic hemiparesis (arm > leg > face) that very gradually improves. Comparative stunting of the growth of the affected limbs (especially arm and hand) ensues in proportion to weakness. A very helpful clinical sign is the finding of a smaller thumbnail on the affected as compared to the unaffected hand. Cortical sensory abnormalities may be found in older children.24 A visual field cut may be detected (ipsilateral to the hemiparesis) although even if found this often improves within the first year of life.2,3,5 Epilepsy (usually localization related seizures, often partial-complex) develops in at least one-third of these full-term infants. Onset is typically within 2 to 10 years after birth and may be associated with mental retardation, the severity of which correlates with difficulty controlling seizures.1,5,8 In individuals who do not have epilepsy, intellect is well preserved in as many as two-thirds of children with HP CP.

The designation quadriplegic cerebral palsy (QP CP) is the commonly employed term for infants who actually manifest double hemiparetic CP (DHP CP). Whereas all four limbs are involved, one side of the body manifests greater degree of spastic weakness than the other and on each side the arm is more involved than the leg or face. This is the form of CP that is most commonly associated with birth asphyxia of term or near-term infants. It may also be found in infants who experienced bilateral large vessel strokes. In such cases, as with bilateral asphyxial insults, epilepsy, motor, and intellectual deficits are significantly more likely and severe than in individuals with HP CP.1,3

Bilateral spastic rigidity is a characteristic finding, with associated clonus, hyperreflexia, and asymmetric scissoring of the legs. Over time contractures tend to develop, rendering care, such as diapering, difficult. In severe cases there is little movement of the limbs. Supranuclear bulbar palsy or injury to brainstem and cerebellum may result in cranial nerve abnormalities and impairments of coordination, breathing, swallowing, and vision. The deficits may be due to selective neuronal necrosis of particularly vulnerable neurons due to various forms of hypoxic-ischemic encephalopathy (HIE) or to acute severe hypoglycemia. Because of the large volume of brain that may be injured in DHP CP, intellectual deficits are often marked. Complications of DHP CP often include drooling, feeding problems, inanition, aspiration pneumonia, constipation, and significant risk for bedsores. Head turning may evoke opisthotonus and decerebrate posturing, which may disturb onset or maintenance of sleep.3-5,7,8 The combination of deficits results in greater risk for early death in children with QP CP.25

Epilepsy is found in at least half of these children.1,3 Intermittent irritability of unclear etiology is often encountered. Care is aimed at prevention or treatment of the complications noted above. Common surgical interventions include placement of feeding tubes and orthopedic intervention to improve function. Medical management includes treatment of epilepsy as well as prevention of aspiration, inanition, and osteopenia. Nutritional approaches should scrupulously avoid excessive weight gain, which may further compromise movement, increasing risk for aspiration, bedsores, and other complications. Overtreatment of spasticity may worsen function, as rigidity to some extent compensates for weakness. Tenotomies may improve function. Ill-considered surgery may worsen function and result in unfortunate outcomes such as “wind-swept hips.” Muscle relaxant medications may prove useful, although they often do so at the expense of alertness. Benzodiazepines may dampen the sleep-onset dystonia or posturing that interferes with sleep. Asymmetrical leukoencephalomalacia with acquired microcephaly is the most common pathologic finding. Involvement of forebrain deep gray tissues is the cause of associated dystonia. In milder cases, sclerosis may largely be confined to the cortical mantle, whereupon the clinical findings are largely pyramidal (spastic weakness) rather than extrapyramidal.

Spastic diplegia (SD) is the most common form of cerebral palsy (CP) encountered after premature birth, accounting for as many as 80% to 90% of cases. Spastic diplegic CP prevalence has increased in association with increased survival of very low birth weight children.26 Legs are more strikingly involved than arms and ankle clonus is an early important sign of the underlying leukoencephalomalacia. In milder cases, toe walking associated with ankle clonus may be the first clues to diplegic (DP) CP. Although the motor involvement of arms tends to be of lesser degree than legs, fine motor dysfunction of the hands may impair daily living activities. Even with mild arm involvement, a forearm clasp-knife response to passive rotation is usually found.27

Periventricular leukomalacia (PVL) is the characteristic pathologic landmark of SD CP, although injuries to cerebral and cerebellar gray matter are recognized with increasing frequency. Intraventricular hemorrhage (IVH) with ventricular enlargement may be associated with SD CP of greater degree. Grade IV IVH may be associated with severe motor and intellectual abnormalities, with the combination of QP CP and SD CP.27 There is evidence that low-birth-weight (LBW) male infants are at greater risk for PVL and for IVH than LBW girls.28 There is increasing evidence that antenatal intrauterine infection and the ensuing inflammatory response may, by several mechanisms, increase the risk for SD CP as well as for associated visual defects (see Chapter 58).29

Problems associated with SD CP include abnormalities of intellect, vision, and feeding, though these tend to be milder than those encountered in children with QP CP. Drooling may be troublesome, which together with gait abnormalities may lead to underestimation of the intellect of children with SD CP, which in many instances may be normal. Orthopedic intervention may prove beneficial in improving stance and gait in children with SD CP. Spastic diplegia CP may be associated with diminished limb growth and stature and is occasionally complicated by ataxia.3,5-8,19

Extrapyramidal (EP) or dystonic cerebral palsy (CP) is most commonly manifested by dystonia or by involuntary and uncontrollable slow writhing movements (athetosis), particularly of the distal limbs. In more severe cases shoulder and trunk dystonia or abnormal movements may be found. Athetosis includes rotation of the limb about the long axis in association with choreic (dancelike) intermittent extension of fingers and toes. To a lesser degree, asymmetric chorea of the face and limbs, sudden, fleeting, nonrepetitive postured movements, may be intercalated with the athetosis. The various postures may at times coalesce into a sustained peculiar dystonic posture, At times, sudden shocklike myoclonus (much more rapid and less graceful than chorea) may be observed, as well as briefly sustained tremors.

Extrapyramidal system dysfunction tends to become increasingly apparent late in the first year of life, as abnormal patterns of movement tend to be activated by voluntary motor activities such as reaching, crawling, and walking. Postural stability and gait are often greatly impaired. Large scale and bizarre dystonic patterns of movement may be observed. Speech impairment may be prominent in extrapyramidal (EP) CP, probably due to the complexity of demands that speech makes on the pyramidal, extrapyramidal and cerebellar motor systems, as well as cortical speech areas. Attempted speech may have a quality of strangulation, explosive moments, and great variability in pitch and speech meter. Laughter or crying may activate complex vocal dysfunction.

The various motor abnormalities of EP CP vary in intensity over time, tending to be more prominent with stress, fatigue, anxiety, frustration, embarrassment, or intercurrent illness. Attempts of affected individuals to restrain extraneous motor activation often worsen EP abnormalities. Fine motor function and self-care skills may be difficult or impossible to perform. The EP CP movement abnormalities disappear with sleep.

Examination may disclose variable tone ranging from rigidity of the “lead pipe” variety to hypotonia as well as clonus and hyperactive muscle stretch reflexes. Associated abnormalities may include epilepsy, learning disorders, or mental retardation. Milder forms of EP CP may manifest modest degrees of choreoathetosis or effort-induced dystonia. In its severest form, EP CP may cause exceeding impairment of movement, posture, and tone. Forceful head extension (retrocollis) in association with bizarre twisted posturing of the trunk may occur. Predominantly choreoathetotic or dystonic-dyskinetic CP is the characteristic result of kernicterus with injury to the pallidum and subthalamic nucleus and a characteristic pathology, termed status marmoratus. Hearing impairment and ataxia are common concomitants.

Predominantly dystonic CP most commonly occurs as a consequence of asphyxia with injury to the thalamus and putamen. Some individuals will have a mixture of manifestations and more widespread abnormalities of brain may be found, including injuries to cerebral and cerebellar gray or white matter or brainstem.3,5,8 It is particularly important to carefully exclude genetically determined conditions such as metabolic disturbances when evaluating children thought to have EP CP.30

Diminished or absent muscle stretch reflexes, marked leg weakness, and arms more hypotonic than weak and displaying relatively normal coordination characterize the uncommon condition called hypotonic (Hyp) cerebral palsy (CP). This syndrome has also been termed central hypotonia, whereas infants are described as floppy. The Förster sign on examination is characteristic: evocation of hip and leg flexion by holding the infant in vertical suspension with the examiner’s hands under the armpits. Head lag is prominent when the infant is pulled from recumbency to a seated position. Sometimes this condition precedes the onset of findings of extrapyramidal (EP) CP or (rarely) double hemiparetic (DHP) CP. One anatomically specific entity that may be distinguished is that of axioproximal weakness resulting from parasagittal brain infarction, an entity that may result from marked perinatal hypotension, such as may result from placental abruption or uterine rupture. Perinatal brain imaging usually discloses the “watershed infarction” pattern, sometimes with associated hemorrhage into the ischemic parasagittal tissues. In more severe cases, brainstem hemorrhagic infarction may occur, producing cranial nerve abnormalities.3,5 Maternofetal hyperthermia during the 21st to 28th day of gestation has been associated with the development of neural tube defects and infantile manifestation of Hyp CP.

Where Hyp CP is considered, care must be taken to exclude lower motor neuron diseases (diseases involving muscular, nerve, or anterior horn cells), as well as metabolic, degenerative, or other genetic conditions. Down syndrome is among the more common causes of infantile hypotonia. Other important considerations are such syndromes as Angelman, Coffin-Lowry, Miller-Dieker, Prader-Willi, or Zellweger. Each of these has characteristic findings on physical examination. Speculation as to the cause and anatomic locus of hypotonic CP has not produced any widely accepted conclusions. Very gradual improvement to normal strength may be observed, possibly associated with a lesser degree of residual hypotonia. In other instances, the abnormalities may be quite persistent. In such cases severe developmental abnormalities of the brain may be found, in which case the diagnosis should be changed to reflect the specific type of malformation.

Although it is commonly associated with signs of other forms of CP, such as diplegic (DP) CP, ataxic (Atx) CP is diagnosed where the evidence of cerebellar system dysfunction is predominant. Ataxia usually becomes apparent only near the end of the first year of life, with hypotonia, axial and appendicular ataxia, and nystagmus. Gross and fine motor skill development may be markedly delayed and slow gait development may be accompanied by frustrating persistence of wide base and frequent falls. Romberg test positivity also persists for a long interval in early childhood. Ataxic CP is a diagnosis by exclusion. Important differential considerations include Angelman syndrome and ataxia-telangiectasia. Where this syndrome is associated with mental retardation, variation in severity, or progression, more likely diagnoses are various heritable developmental, degenerative and metabolic conditions. Brain imaging discloses abnormalities of forebrain in about half the cases of ATx CP, while cerebellar abnormalities are less common. As noted above, ATx CP findings may be admixed with those of DP CP in some toddlers.30

The spasticity of double hemiparetic/quadriparetic (QP) cerebral palsy (CP) and the findings of extrapyramidal (EP) CP may overlap in some patients often with one or the other set of manifestations predominating. The most important examples of syndromes with overlapping features have been noted above. The classification features that predominate usually permit appropriate classification in the system noted above. Overlapping features that are less prominent, taken together with history, may have an important influence on diagnostic and therapeutic considerations as well as formulation of prognosis.

The most important neuropathologic correlates of various types of cerebral palsy (CP) have been noted above. To these observations it should be added that roughly one-third of children diagnosed with cerebral palsy are found to have some disorder of cortical migration. It is likely that additional careful studies will demonstrate that perhaps a majority of children with CP have underlying genetically determined developmental disorders.

The diagnosis of cerebral palsy (CP) is made in children with static central nervous system-mediated motor deficits for whom a more specific diagnosis cannot be made. It is often necessary to consider, and where possible to alleviate, maternal guilt concerning the role that her activities during pregnancy may have played as causes of cerebral palsy. Initial physician responsibilities include assuring that an appropriate range of diagnostic tests has been performed. Among these, imaging studies may be the most important tests with regard to proper classification, within the context of history and examination.2

The history and examination may suggest other appropriate tests, as is indicated in the preceding discussion. Genetic testing should be undertaken in order to provide appropriate counseling concerning risk of recurrence in subsequent pregnancies. The extent of such testing may best be defined by genetic consultation. Electroencephalograms (EEGs) are commonly helpful in evaluation of individuals with CP whose clinical evolution suggests that epilepsy may have developed, as it does in approximately one-third of individuals with CP. Other forms of testing may be required to characterize and treat as needed, problems with learning, language, coordination, mood, behavior, as well as vision, hearing, and other sensory functions.

Following diagnosis it is important to alleviate potential maternal guilt regarding potential etiologies resulting from pregnancy related events and to aid the family in adjustment to caring for a child with a chronic condition (see Chapter 123).

Issues of care including optimizing functionality and mobility, and care coordination are discussed in Chapter 124. Physical and occupational therapy should be provided on a consistent basis, with education and assistance for family members so that they can become active participants in the ongoing therapy. Variously modified recreational therapies involving activities such as sports and dancing may prove very helpful in the treatment of CP. Such activities entail enlisting the positive attitudes of patients and their families in a setting that provides fun and encouragement. The positive attitude and determination of the individual with CP is even more important than particular therapeutic approaches.

Attention should be paid to posture and seating, particularly when assistive devices are required, such as wheelchairs or standers. Adjuvant devices such as splinting, either diurnal or nocturnal, may be required in certain instances. If spasticity cannot be treated by more conservative means, other interventions may be brought to bear. The use of botulinum toxin injected into selected muscle groups has demonstrable efficacy for relieving spasticity so that physical therapy can be more successful. Other procedures, such as phenol injections, can be used in a similar fashion. The relief from these procedures is transient, but beneficial in certain instances. They should be administered by individuals well experienced with their use, particularly in light of the tendency for antibodies to botulinum to develop over time, thus limiting its efficacy.

In some individuals, continuous administration of intrathecal baclofen using an implanted pump can provide relief from spasticity. This can allow a precise titration so that a child can be left with sufficient muscle tone for ambulation but with reduced spasticity to avoid contractures. In other individuals, selective severing of the afferent dorsal rootlets in the lumbosacral region (usually L2 to S2) through a dorsal rhizotomy can produce relief, particularly when the spasticity involves legs more than it does arms. In both instances, careful selection of patients by a center well versed in the techniques is essential for good outcomes.

Attention may be directed to correcting problems with speech and drooling, and with tracheopharyngeal, pulmonary, gastrointestinal, and urinary function. These are problems that are important for the daily living, comfort, and dignity of individuals with CP. As many as half of individuals with CP have problems with attention, learning, or cognition that may require treatment or compensatory strategies. Conversely, it is important to recognize that many children with even severe motor impairment due to extrapyramidal (EP) or diplegic (DP) CP may have little if any intellectual impairment. Behavioral, mood, and sleep disorders may arise in individuals with CP, each requiring careful consideration and the provision of strategies for amelioration of the quality of life of such individuals. Additional concerns variously include dental and bone health, as well as sexual aspects of development as individuals with CP arrive at that stage of personal development. Careful collaboration between specialists, including physical and occupational therapists, orthotists, orthopedic surgeons, otolaryngologists, gastroenterologists, physiatrists, neurologists, neurosurgeons, and others, is often crucial for the achievement of the best possible outcomes.

With the diagnosis of CP, the treating physician should provide a prognostic estimation couched within appropriate limits based on adequate understanding of the breadth of possibilities for the specific CP syndrome. This estimation should be revised as the child grows and develops. It is important to recognize that gradual, if sometimes modest, improvements are observed in most children with CP, a process that may, even in individuals with severe CP, extend over decades. Some persons may not achieve unassisted ambulation until the third decade of life—a landmark no less important for the time it has taken to achieve. Those with milder CP may have considerable improvement within the first decade of life and function with near normality, although in such instances subtle motor manifestations (including fatigability) or signs (reflex changes, forearm clasp-knife response, clonus) may prove permanent.

Parental wishes concerning limits of treatment of acute life-threatening complications experienced by children with severe irremediable degrees of neurologic abnormality should be ascertained and, if appropriate, revisited as the child’s clinical course is followed. With the child’s growth and development, discussions should entail revisitation with various support and educational services appropriate to the needs of the individual with CP. Follow-up visits should, at the seeming conclusion of the visit, include repeatedly asking what else may arise. Often enough it is only after several such repetitions that families will confide the development of stress between siblings or parents or raise the question concerning whether they should have other children. It remains mysterious why such important questions have not been asked earlier in the visit. Considering and trying to answer such questions can be among the most important follow-up services. In some instances, it is necessary to provide informed discussion of alternative therapies for which there is as yet no objective evidence of efficacy, such as hyperbaric oxygen treatments or stem cell therapy.

In caring for persons of all ages with CP it is important to celebrate their individuality and remain supportive of the families caring for them. The psychological burdens of the disorder can be great for families and children alike. Appropriate psychological support, and vigilance for its implementation, is often needed. It is improper in most instances to claim to fully understand what parents are going through. This is particularly true in instances where the needs of a child are so large that institutionalization is the appropriate care choice; this can be a very difficult decision for family and child. Advocacy for access to appropriate education is part of the role of the clinician caring for a child with cerebral palsy. Federal and state laws in the United States guarantee a child a free and appropriate public education, but many factors can conspire against this. The clinician’s role of advocacy can be very useful for families.

Life expectancy for persons with CP varies in relation to the type of CP and severity of motor deficit as well as certain associated nonmotor deficits.25 Premature death, which may occur within the first 5 years of life, tends to be confined to individuals with double hemiparetic/quadriparetic CP severe enough to prevent independent rolling, and especially those infants requiring ventilatory support. Gastrointestinal reflux or epilepsy may also reduce life expectancy. Death from these various causes may result from aspiration pneumonia, bedsores, inanition, or status epilepticus. It is important to emphasize that modern approaches to care of individuals with CP has reduced the risk for premature death and that most individuals with CP, including severe forms, survive into adulthood.25 Although parents must be prepared for the possibility of serious complications in individuals with CP, it is a disservice to inappropriately suggest that a particular child “will not live long.”

Infections of the central nervous system (CNS) are less frequent than infections of other organ systems, because the brain is protected by both the anatomic barrier of the bony skull and blood-brain barrier. Nevertheless, CNS infections remain a significant cause of morbidity and mortality in children. Classic signs and symptoms of CNS infections are often not present or more subtle in young children, thereby making accurate diagnosis a challenge for the general pediatrician (Table 555-1). The outcome of CNS infection predominantly depends on the site of infection and etiologic organism in addition to host immune status. For full description of bacterial and viral CNS infections, see Chapters 231 and 232. In this chapter, we focus on the neurologic presentation of CNS infections and discuss the unique CNS involvement of purulent CNS infections, latent viral infections, and prion diseases.

Meningitis/Meningoencephalitis

The most common presentation of meningitis includes nonspecific signs and symptoms such as headache and nuchal rigidity. Meningismus refers to a condition in which the neck and back muscles tense as a reflex to avoid painful extension of the inflamed meninges. The physical findings of Kernig sign (passive extension of the knee from flexed thigh position elicits pain in the back) and Brudzinski sign (passive flexion of the neck elicits spontaneous flexion the lower extremities) are thought to reflect both the inflammation of the meninges and increased intracranial pressure. Nuchal rigidity is rare in neonates and uncommon in children ages 12 to 18 months. Other symptoms of meningitis vary depending on the etiology and location of the infection. The associated symptoms of fever, vomiting, lethargy, irritability, photophobia, anorexia, and dehydration all support the diagnosis.1 In neonates, a full fontanel may be present in addition to failure to thrive, irritability, apnea, seizures, opisthotonus, poor feeding, temperature instability, jaundice, and grey appearance.2

The anatomic boundaries between the meninges and brain parenchyma are indistinct. Many patients experience concurrent infections of the meninges and parenchyma, known as meningoencephalitis, often accompanied by signs of headache, generalized seizures, and mental status changes (delirium, agitation, somnolence, lethargy). Within the brain parenchyma, the inflammatory response is characterized by neutrophilic infiltrations and increased vascular permeability via alteration of the blood-brain barrier. Focal neurologic symptoms/signs may also be present including unilateral headache, paresis, cranial nerve palsy, or partial seizures. These findings may suggest a more localized involvement of brain parenchyma, or even focal infection, such as those caused by abscess or tuberculoma. Slowed blood flow secondary to infection within the parenchyma or meninges can result in acute vascular events such as venous infarction that then are also likely to produce more localizable neurologic signs. Patients who experience severely depressed consciousness, coma, vomiting, bulging fontanel, diastasis of sutures, or third or sixth cranial nerve palsy may have concurrent increased intracranial pressure secondary to inflammation from infection. These signs may also result from subdural effusions which develops in 10% to 30% cases of meningitis, particularly in infants.3 Progression to decorticate/decerebrate posturing; papilledema; hyperventilation; and the triad of hypertension, bradycardia, and apnea suggests the development of dangerously high intracranial pressure and impending herniation. It is imperative to start antibiotic treatment first and then to consider neuroimaging if focal signs/symptoms and/or suspicion of increased intracranial pressure are present.

Meningitis is associated with seizure in up to 23% of children.4 In the younger child, it may be difficult to distinguish between a classic febrile seizure and a symptomatic seizure associated with fever resulting from underlying meningitis/encephalitis. In one study, bacterial meningitis was discovered in up to 18% of children who presented with status epilepticus associated with fever.5 Similarly, complex febrile seizures are more frequently associated with bacterial meningitis in ages 1 month to 6 years.6 In general, febrile seizures typically occur within 24 hours of onset of fever and the seizure tends to be a generalized tonic-clonic event though any type of seizure is possible. Meningitis should be suspected if seizures occur 3 or more days after the onset of fever. Meningeal signs may be absent in children younger than 18 months of age who present with fever and seizure and there should be a low threshold to perform cerebrospinal fluid analysis. The American Academy of Pediatrics strongly urges physicians to consider lumbar puncture in infant less than 12 months who present with febrile seizure.7 Careful attention should be made to changes in serum glucose, calcium and sodium (secondary to syndrome of inappropriate antidiuretic hormone [SIADH]) concentrations as seizure precipitants. Lumbar puncture results may also help to distinguish between viral, bacterial, parasitic, and fungal processes so that therapy can be tailored appropriately. Table 555-2 shows a comparison of cerebrospinal fluid (CSF) profiles associated with various CNS infectious agents. Specific agents causing bacterial and viral meningitis are listed in Tables 231-1 and 232-1.

Cerebellitis/Brainstem Encephalitis

Localized infections of the cerebellum can produce an acute cerebellar ataxia. Acute onset of gait difficulties, incoordination and nystagmus, slurred speech, and vomiting suggests either infectious or postinfectious cerebellitis. Fever is noted in nearly 75% of cases and latency of illness to onset of ataxia averages 9 days.8 The differential diagnosis of fever with cerebellar signs includes cerebellar abscess and acute labrynthitis. Rhomboencephalitis or brainstem encephalitis results from infection of the brainstem, specifically the pons and medulla. Symptoms/signs include meningismus, fever, and headache in addition to cerebellar dysfunction, hemi/quadriparesis, cranial nerve abnormalities (facial palsy, diplopia, dysphagia, dysautonomia), and opsoclonus. Cerebrospinal fluid (CSF) pleocytosis with increased protein and decreased glucose concentrations, and magnetic resonance imaging (MRI) that demonstrates increased signal in the pons/medulla, suggest the underlying diagnosis. In the pediatric population, Listeria,9 West Nile virus,10 enterovirus 71,11 and HHV612 infections have all been reported as etiologic agents of rhomboencephalitis.

Myelitis

Infection of the spinal cord or infectious myelitis can also be categorized into focal and diffuse pathology. Certain viruses, such as poliovirus, Epstein-Barr virus, enterovirus, echovirus, and coxsackie virus exhibit tropism for the anterior horn cell.13 Infection of anterior horn cells produces asymmetric motor weakness with or without fever, encephalopathy, and nausea/vomiting. Headache and mental status changes suggest a more widespread meningoencephalitis. Weakness that extends to the face and bulbar nuclei can result in autonomic, respiratory, and circulatory compromise. If the infection is limited to the anterior horn cell, sensory examination may remain normal. Acute transverse myelitis (ATM) (see Chapter 556) is defined as inflammation of gray and white matter in one or more adjacent spinal cord segments. Acute transverse myelitis is thought to result either from direct infection or postinfectious immune mediated processes, leading to diffuse involvement in the spinal cord and subsequent sensory and motor dysfunction.14 Early signs of spinal cord dysfunction include paresthesias, back pain in segmental distribution, bilateral weakness, bowel/bladder dysfunction, and sensory level with dysesthesia or hyperalgesia. Autonomic dysfunction may or may not be present. Symptoms typically develop over 4 hours to 21 days ultimately with progression to flaccid paralysis and then spasticity over weeks. In the setting of ATM, magnetic resonance imaging (MRI) of the spine typically demonstrates T2 hyperintense lesions that extend more than 2 vertebral body lengths, often with cord expansion and variable contrast enhancement.15 Cerebrospinal fluid analysis demonstrates increased protein content, suggestive of inflammation. The constellation of symptoms including fever, back pain, point tenderness of the spinous processes, motor weakness, and/or sphincter compromise may suggest spinal epidural abscess (EDA). There are no clear-cut clinical diagnostic criteria for EDA, and signs and symptoms commonly overlap with ATM. Immediate MRI with and without gadolinium and intravenous (IV) antibiotics are indicated if concern for epidural abscess exists.

Neurologic signs and symptoms, laboratory investigations and neuroimaging studies can all help facilitate the localization of disease processes and provide guidance for management. After history and physical examination are complete, the decision to perform lumbar puncture (LP) or neuroimaging should be made. A concern is that if intracranial pressure (ICP) is elevated LP may precipitate herniation of the hindbrain through the foramen. Raised ICP is common in children with uncomplicated acute bacterial meningitis. Careful measurement of opening pressure with legs extended can help identify elevated ICP. Treatment with osmotic agents such as mannitol and hyperventilation help to prevent herniation and avoid a potentially fatal outcome.16 The use of a small-bore needle (21- or 22-gauge) is recommended whenever there is concern about increased ICP to minimize the cerebrospinal fluid (CSF) leak from the LP site. When the opening pressure (OP) is very high, just enough fluid (usually 2 to 4 mL) should be removed to permit a careful examination.17 In one study, 33 of 35 infants and children with pyogenic meningitis had a significant elevation in CSF opening pressure at the time of evaluation.18 The vast majority of children presenting with suspected bacterial meningitis, however, have no clinical evidence of herniation; therefore routine computerized tomography (CT) scan of the brain is not indicated.19 A diagnostic LP should be done expeditiously and appropriate antibiotic therapy should be promptly initiated.

A computerized tomography (CT) scan of the brain should be considered prior to lumbar puncture if patient presents with symptoms or signs of ICP such as depressed mental status, posturing, papilledema, increase in blood pressure with slow pulse rate, or focal neurologic symptoms or signs. As discussed below, signs of focality on neurologic examination may suggest intracranial purulent infection. High suspicion and low threshold for neuroimaging should be held in certain patients who are at risk for brain abscess: immunocompromised patients who have congenital heart disease or history of chronic otitis or sinus infection. Lumbar puncture should also be deferred and immediate neuroimaging performed in patients suspected of having focal purulent spinal infections. In this case, LP introduces the risk of disseminating microorganism into the CSF or causing permanent neurologic sequelae.

Risk of herniation with lumbar puncture still exists even with normal head CT, and there is considerable variation in normal ventricular and cisternal size, making interpretation of a single scan unreliable.20 Cerebral edemamay produce CT abnormalities including slit-like lateral and thirdventricles, generalized low attenuation of the white matter, andobliteration of the basilar and suprachiasmatic cisterns.21 If concern for herniation exists based on clinical judgment, the decision to perform an LP may need to be deferred. When the child’s condition has stabilized, the need for CSF evaluation can be reconsidered.

Cerebrospinal Fluid (CSF) Interpretation

Evaluation of cerebrospinal fluid (CSF) can help determine the diagnosis of bacterial or viral meningitis or encephalitis (Table 555-2). Although CSF is considered an acellular space, 5 white blood cell (WBC) count and 5 red blood cell (RBC) count per µL are considered normal when CSF is sampled by lumbar puncture (LP); newborns, in contrast, may have up to 20 WBC/μL in the CSF.22 Pleocytosis is the rule in bacterial meningitis with CSF WBC counts in the range of 100 to 10,000/μL. Early in the disease, WBC in CSF may be normal. Polymorphonuclear cells predominate and usually account for more than 90% of the total. Very high WBC counts (> 50,000/μL) raise the possibility of intracranial abscess. CSF glucose is usually less than 50% of simultaneous serum glucose concentration, but low CSF glucose is also found in tuberculosis, fungal meningitis, subarachnoid hemorrhage, and carcinomatous meningitis. CSF protein concentration is usually elevated to 100 to 500 mg/dL in bacterial meningitis. The alteration in protein concentration reflects disruption of blood-brain barrier but is not in itself indicative of bacterial meningitis. Protein concentrations may be significantly elevated in patients with meningitis caused by Mycobacterium tuberculosis. Gram stain is positive in more than 90% of untreated meningitis and culture positive in 70% to 90% of patients with untreated meningitis.

Recently, many studies have developed scoring systems to help clinicians predict the presence of bacterial meningitis. The Bacterial Meningitis Score is a system validated in a multicenter retrospective cohort study of 2903 children (ages 29 days to 19 years) with CSF pleocytosis.23 Five variables (one point each) were used: positive Gram stain, CSF WBC greater than 1000 cells/μL, CSF protein greater than 80 mg/dL, peripheral blood absolute neutrophil count greater than 10,000 cells/μL, and history of seizure before presentation. In the study, the absence of all features had negative predictive value of 99.9%. A score of 1 or more identified all children with bacterial meningitis older than 2 months.

The range of neurologic sequelae from central nervous system (CNS) infection largely depends on the etiologic agent, and duration and location of infection. CNS infections also vary in severity. Organisms with tropism to the brain can take years to demonstrate clinical disease, as with infections caused by transformed prions and slow viruses, or may produce rapid inflammation and neuronal destruction, as in some cases of meningococcal bacterial or herpes simplex virus (HSV) meningitis.

The neurologic complications after bacterial meningitis include bilateral severe or profound deafness, mental retardation, seizures, and spasticity and/or paresis.24 By contrast, most children with viral meningitis recover spontaneously, though persistent fatigue, sleep disturbances, behavior and concentration difficulties, and incoordination have been noted.25 Diseases attributed to chronic latent viruses and prion diseases are considered neurodegenerative diseases with uniformly poor outcome. Focal purulent collections in the brain and spine have shown dramatic improvement in mortality and reduction in neurologic sequelae as a result of advances in neuromaging and improved medical and neurosurgical techniques. Future investigations into the role of selective immunomodulation and neuroprotective strategies may lead to significant advances in management and outcome of CNS infections.

Table 555-1 briefly reviews the clinical presentation and management of specific CNS infections; many of the bacterial and viral infections are discussed in Section 17. This chapter focus on CNS abscesses, chronic latent infections and prion diseases.

A brain or spinal abscess is a focal, intraparenchymal infection that begins as a localized cerebritis and becomes encapsulated.26 Brain and spinal abscesses are relatively uncommon in pediatric patients, but are potentially neurologically devastating and life threatening. In children, the most common sources of infection are related to underlying cyanotic congenital heart disease, meningitis, chronic otitis media, mastoiditis, sinusitis, cellulitis of scalp, face, orbit, dental infection, penetrating head injury, immunodeficient states, and intracranial foreign bodies. Early diagnosis and treatment of brain abscess can be life saving. The diagnosis and treatment of both spinal and brain abscesses are discussed in detail in Chapter 231.

Epidemiology

Overall, it is estimated that 25% of brain abscesses occur in children, mostly in the 4 to 7 year age range.27 Rates of abscesses have not changed in the past two decades.28 Brain abscess is rare in children less than 2 years of age, but the number of neonates with brain abscess has increased in the last 20 years with a slight male predominance.28 Worldwide, the most common origin of microbial infection in children is direct or indirect cranial infection arising from the middle ear, paranasal sinuses, or teeth.27 At tertiary medical centers, congenital heart disease has become one of the most significant sources of brain abscesses in children.28 This suggests that increased vaccination and increased efficacy of antibiotics for treatment of middle ear and sinus infections have changed the epidemiology of brain abscesses in the United States. The number of brain abscesses occurring in immunocompromised children has increased, in part reflecting improved medical care and increased survival in these patients, in whom infection with any type of microorganism is possible and fungal infection is common.

Although the mortality remains high, improved imaging techniques, microbiologic isolation technologies, and advances in medical and surgical treatments have permitted earlier diagnosis of cerebral abscesses, which has translated into decreased mortality and increased survival.28-30

Among streptococci species, S milleri, S pyogenes group A or B, S pneumoniae, and S faecalis have been shown to cause infection with a slight predominance of S milleri, due to the proteolytic enzymes that predispose to necrosis of tissue and abscess formation.31 Streptococci reside in the oral cavity, appendix, and female genital tract and may be associated with otopharyngeal infection, cardiac conditions, and neurosurgical and medical procedures. Staphylococcus aureus is most commonly isolated in patients with cranial trauma, infective endocarditis, or status postneurosurgical procedure. S aureus abscesses resulting from penetrating injuries tend to be of singular etiology, whereas those caused by septic emboli, congenital heart disease, or meningitis can be associated with multiple organisms. Enteric gram-negative bacilli (Proteus, Pseudomonas, E coli, Klebsiella) can be found in patients with otic infection, septicemia, neurosurgical instrumentation, and immunocompromised status. In some cases, underlying meningitis is associated with high rates of abscess formation with specific pathogens such as Citrobacter, Proteus species Serratia marcescens or Enterobacter species.32,33Proteus sp. and Citrobacter sp. are most common in neonates.34Actinomycosis brain abscess typically result from hematologic spread due to primary infection of the lung, abdomen or pelvis.35Nocardial infection is most often isolated in patients with disorders of cell-mediated immunity or on corticosteroid therapy, organ transplant recipients, patients with HIV infection or neoplasm, but it has also been reported in patients with no apparent underlying condition.26 Mycobacterium tuberculosis and nontuberculous mycobacterium also produce focal infection; several cases have been reported in patients with HIV.36 The incidence of fungal brain abscess has increased with administration of immunosuppressive therapy, broad spectrum antibiotics and corticosteroid treatment. Candida and Asperigillus are the most common cause of fungal abscesses in immunocompromised patients. In one review of Asperigillus sp. brain abscesses, the predominant underlying condition in infants was prematurity and in children, leukemia.37Toxoplasma gondii infection can occur in patients who live in endemic areas as well as those with late stage HIV infection.

Pathogenesis

Organisms can access the brain to form abscess by direct invasion or hematogenous spread. In a review of 41 cases of brain abscess from an otogenic source, 54% were in the temporal lobe, 44% in the cerebellum, and 2% in both locations.38 Paranasal sinusitis is most often associated with frontal lobe abscess, but this site may also be accessed by contiguous dental infections and orbital cellulitis. Abscesses resulting from hematogenous dissemination, most commonly with cyanotic congenital heart disease or pulmonary arteriovenous malformation, can be multiple and multiloculated, and are often located at the gray-white border and middle cerebral artery distribution, and can be associated with higher rates of mortality.39,40The intracardiac or intrapulmonary right to left shunt in these cardiac defects bypass the effective phagocytic filtration action within the lungs and permits direct entry of organisms into the cerebral circulation.41 Brain abscess is less common in patients with infective endocarditis than in those with congenital heart disease.42 Brain abscess can result from chronic pulmonary disease, such as cystic fibrosis and from pyogenic lung diseases. Trauma is a third mechanism responsible for brain abscess, secondary to open cranial fracture with dural breach, foreign body, or neurosurgery. Brain abscesses occur infrequently with ventriculoperitoneal shunts.43 Foreign bodies such as bullet wounds to the brain, pencil tip lodged in the eye, and lawn darts have been reported to cause brain abscess.44,45 In approximately 20% of cases, the underlying etiology cannot be determined.

Pathogens can be identified in up to 86% of abscesses by aspiration, resection, or biopsy.28 Many abscesses contain multiple organisms, suggesting the need for initial broad-spectrum antibiotic coverage. The predominant organisms causing brain abscess in children are aerobic and anaerobic streptococci (60–70% cases), gram-negative anaerobic bacilli (20–40%), Enterobacteriaceae (20–30%), Staph aureus (10–15%), and fungi (1–5%).27

Clinical Manifestations

Less than 50% of patients with brain abscess will present with the classic triad of fever, headache, and focal neurologic symptoms.40 Clinical symptoms also include subacute fever, headache, vomiting, confusion, depressed consciousness, seizures, papilledema, and focal neurologic signs with or without nuchal rigidity. As an abscess grows or produces obstruction of cerebrospinal fluid (CSF) flow, intracranial pressure will increase and the potential for herniation exists. Signs of increased intracranial pressure include headache, vomiting, mental status changes, papilledema, and third and sixth cranial nerve palsy. Rupture of the abscess capsule into the ventricular system can lead to acute neurologic decompensation and symptoms of purulent meningitis, associated with a high mortality (up to 80% in some series).46 In neonates, brain abscess can present with irritability, bulging fontanel, and rapid increase in head circumference. However, abscesses may be more indolent, with no clear neurologic signs or symptoms.

Diagnosis

Brain abscess development can be considered in 4 stages: (1) early cerebritis (1–4 days), (2) late cerebritis (4–10 days), (3) early capsule formation (11–14 days), and (4) late capsule formation (> 14 days).47 Imaging features of brain abscess depend on the stage at the time of imaging and on the etiology of infection, but may provide prompt confirmation of diagnosis and determination of the location and number of abscesses. In early phases, noncontrast head computerized tomography (CT) may show low attenuation abnormality with mass effect and, in later phase, a complete peripheral ring can be seen.39 Magnetic resonance imaging (MRI) with and without gadolinium is the imaging modality of choice, allowing for earlier detection of cerebritis (the early stage prior to abscess formation), cerebral edema, spread of inflammation into the ventricles, and the presence of subarachnoid and satellite lesions.39 In the early cerebritis phase, MRI demonstrates a low T1 signal and high T2 signal with patchy enhancement. Later, the low T1 signal will become more demarcated with high T2 signal both in the cavity and surrounding parenchyma. Abscesses are visualized as ring-enhancing lesions on both CT and MR (eFig. 555.1), although this sign is not specific. Diffusion weighted MR imaging and MR spectroscopy can be helpful in distinguishing brain abscess from tumor and potentially differentiate bacterial from fungal etiology.48 Neoplastic lesions with high cellular turnover typically demonstrate restricted diffusion, while cerebral infections and abscesses demonstrate increased diffusion.

Laboratory investigation includes complete blood count (CBC) and blood cultures. Once the diagnosis has been established, additional studies may be indicated in order to identify predisposing factors and source of infection, including detailed examination of the teeth, ears, oral and nasopharynx, sinuses, scalp, and chest. If sinus infection is suspected, imaging should specifically include these areas. If endocarditis or heart disease is suspected, blood cultures and echocardiogram are indicated. Lumbar puncture should be approached extremely cautiously in any patient suspected of brain abscess, because of the risk of herniation, secondary to the underlying space-occupying lesion and associated increased intracranial pressure. Ultimately, stereotactic biopsy of the abscess site will produce the greatest yield in terms of identifying causative organism.

Specimen obtained from this aspirate should be sent for Gram stain and aerobic, anerobic, mycobacterial, and fungal culture. Special stains including acid-fast stain for mycobacterium, modified acid-fast stain for Nocardia, and fungal stains should also be considered. Serology for anti-toxoplasma toxoplasma immunoglobulin G (IgG) in blood and anticysticercal antibodies on CSF specimens can aid in diagnosis of Toxoplasma gondii or neurocysticercosis infection. Electroencephalography typically demonstrates focal slowing in the area of abscess.

Treatment

Empirical therapy for cerebral abcess typically consists of parental vancomycin, metronidazole, and ceftriaxone for 4 to 8 weeks, although duration of treatment should be approached on a case-by-case basis. In immunocompromised patients, antifungal agents such as amphoteracin B and/or voriconazole should be considered. In neonates, in whom Citrobacter and Listeria have been known to produce infection, third-generation cephalosporin and aminoglycoside should be considered. Duration of therapy is always guided by clinical course and response based on serial CT/MRI scans.

Neurosurgical consultation should be requested as soon as the diagnosis of brain abscess is made, although surgical intervention in treatment of abscess is controversial. Antimicrobials alone may be used to treat cerebritis, small solitary abscesses (< 3 cm in diameter), and patients who are neurologically intact and have no signs of increased intracranial pressure.32 Stereotactic needle aspiration can hasten resolution of disease by permitting therapeutic drainage and providing diagnostic specimens for culture and special stains. In the Children’s Hospital Boston 1981 to 2000 series, second (13/54), third (6/54), and fourth (1/54) surgical interventions were required because of new neurologic findings or continued abscess growth despite proper antibiotic therapy.28 Surgical excision is a more radical approach and may be indicated if there are signs of depressed sensorium, increased intracranial pressure, progressive growth of the lesion on neuroimaging, or lack of clinical improvement with aspiration and antibiotic therapy.49 Intracavitory antibiotic administration may be of value if abscesses are poorly responsive to parenteral antibiotics. It is necessary to remove by surgery, foreign bodies, such as shunt tubing or a bullet to prevent persistent infection or dissemination. Associated contiguous infections such as mastoiditis, sinusitis or periorbital abscess may also require surgical drainage. Corticosteroid therapy should be initiated in patients with significant edema and associated mass effect. Steroids should, however, be discontinued as soon as clinically possible because their use leads to slowing of capsule formation, increased risk of rupture of abscess into a ventricle, and decreased penetrance of antibiotics.50 The use of anticonvulsants should be strongly considered for seizure prophylaxis and will likely need to be continued for months after resolution of abscess.

Outcome

A cerebral abscess is a destructive lesion and neurologic sequelae are common. Depending on the location of the abscess, developmental delays, learning difficulties, epilepsy, hemiparesis, visual field deficits, and hydrocephalus may result.28,30 In the Children’s Hospital Boston series from 1981 to 2000, only 7 of 24 patients returned to their premorbid baseline.28 Improved imaging techniques, neurosurgical, and medical management have led to reduction in mortality rate to about 10% to 30%. A subset of patients are at risk of late morbidity, including children less than 1 year old, those with significant surgical-related neurodeficits or postoperative hemorrhage, and those in whom there is a delay of initial diagnosis.40

Subdural empyema (SDE) refers to a collection of infected cerebrospinal fluid (CSF) or pus between the dura and arachnoid spaces and accounts for 15% to 20% of all localized intracranial infections.51 Routine immunization for Haemophilus influenza has decreased the overall incidence because SDE was a common complication of H influenza meningitis.52 Now, the most common predisposing features are otorhinologic infections, especially paranasal sinus infections in children. Pathogens spread to the subdural space via valveless emissary veins in association with thrombophlebitis from infection of sinuses, mastoid, or middle ear or extension of osteomyelitis of the skull.53 Once infection reaches subdural space, it can easily spread over the convexities of the brain, extending to both hemispheres. Mastoiditis, untreated middle ear infection, skull trauma, neurosurgery, instrumentation of the ears or nose, and infection of preexisting subdural hematoma are known risk factors. In infants, SDE can result from poorly treated meningitis with infected subdural effusion, typically with the same hasorganism (Fig. 555-1).54 The causative agents of SDE represent those found in sinus and otic infections; aerobic and anaerobic streptococci are isolated in 44% to 60% of cases.55,56 Postoperative and posttraumatic infections are often due to staphylococci and gram negative aerobic bacilli.

Intracranial subdural empyema (SDE) can present with fever, headache, vomiting, altered mental status, and seizures. Meningismus may be present. Purulent material can spread widely in the subdural space causing focal or diffuse hemispheric signs. An enlarging head with spreading sutures in an infant who has or has had meningitis is probably caused by SDE or postmeningitic hydrocephalus. Diagnosis of SDE can be made by ultrasonography in infants. On computed tomography (CT) and magnetic resonance imaging (MRI), SDE may appear as a crescentic or elliptical area of hypodensity beneath the cranial vault or adjacent to the falx cerebri with or without loculations (Fig. 555-1). Subdural empyemas do not cross the midline, which distinguishes them from epidural abscess.53 Magnetic resonance imaging is the study of choice because of the ability to identify small subdural fluid collections, to delineate empyema at the base of the brain along the falx cerebri and posterior fossa, and to provide better anatomic delineation of infection.57 Lumbar puncture is contraindicated if SDE is suspected because of concern of increased intracranial pressure (ICP) and cerebral herniation; CSF gram stain and culture will be negative unless the course is complicated by bacterial meningitis. 58

Subdural empyema (SDE) is a medical emergency and may require urgent medical, as well as neurosurgical, treatment. Choice of antibiotic should be tailored to the suspected route of infection. Cultures (aerobic and anaerobic) of purulent material are needed to guide specific antimicrobial agents and surgical decompression is useful for controlling intracranial pressure. Vancomycin is used if S aureus is suspected and can be changed to nafcillin (an agent that targets streptococci as well) once the organism is proven to be methicillin susceptible. Metronidazole is suggested if anaerobic infection is suspected. For infection of suspected gram-negative bacilli, empirical treatment with cefipime, ceftazidime, or meropenim is appropriate. There are no firm data regarding course of treatment, but a 3 to 4 week course of parental antibiotics is generally adopted.51 Neurosurgical evacuation of purulent material via burr hole or craniotomy diminishes mass effect, allows better antibiotic penetration, and permits identification of the causative organism. In infants, subdural taps through an open anterior fontanel can be considered. Once the aspirate reveals an organism, antibiotic therapy can be tailored appropriately. Antibiotic treatment alone has been used successfully in patients with minimal or no impairment of consciousness, no major neurologic deficit, limited extension of empyema without midline shift, and early improvement with antibiotics.51,59 All patients should be monitored with frequent imaging to document resolution of empyema. A course of oral antibiotics may also be considered after parental antibiotics are stopped. In the modern era, mortality rates of patients with cranial SDE are reported 0% to 12%.51,60 Despite improved survival rates compared to the pre-antibiotic era, 16% to 50% of surviving patients experience permanent neurologic deficits including motor weakness, seizures, and/or cognitive deficits.61

Spinal Subdural Empyema

Spinal subdural empyema is rare and is thought to occur secondary to spread of infection from a distant site. Spinal empyema can present as radicular pain at multiple levels and with cord compression. The most frequent microbial isolates are Staphylococcus aureus and streptococci, coagulase negative staphylococci; gram negative bacilli are less frequent.51 Cases of spinal subdural empyema have been reported from hematogenous spread from skin lesions, systemic sepsis, direct spread from spinal osteomyelitis, complications of discography, and cervical acupuncture.62 Magnetic resonance imaging (MRI) is the diagnostic procedure of choice because it better defines the extent of the lesion compared to computerized tomography (CT).57 Laminectomy, in addition to parenteral antibiotics, may be necessary to drain the infection.

Epidural abscess (EDA) is a suppurative infection in the space between the cranium or vertebral column and dura. In contrast to infection in the subdural space, empyema in the epidural space will slowly progress because dura adheres tightly to the bone. As a result, the presentation of epidural empyema is more insidious and indolent than subdural infection. Symptoms may be present for weeks to months before diagnosis. Cranial EDA usually presents with localized tenderness and headache, but patients may otherwise feel well.53 If infection crosses to the cranial dura via emissary veins, signs and symptoms of subdural empyema will result. Infection can spread to overlying bone and cause osteomyelitis of the skull. A cranial EDA near the petrous bone can result in Gradenigo’s syndrome, characterized by involvement of cranial nerves V and VI with unilateral facial pain and weakness of the lateral rectus muscle. Cranial epidural abscesses may result from complications of head trauma, neurosurgical intervention, or spread of infection from contiguous structures such as nasal sinuses and middle ear. Cranial epidural abscess has been reported with fetal scalp monitoring and scalp venous catheter placement.63,64 The preferred imaging modality is MRI with gadolinium which will show characteristic finding of lenticular collection of fluid between bone and cerebral hemisphere with variable appearance and enhancement.39 Given the similar pathophysiology to subdural infection, management of cranial epidural abscess is identical to that of cranial subdural empyema discussed above. However, craniotomy or craniectomy may be necessary in treating epidural abscesses, as simple aspiration of purulent material through scalp or burr hole placement is rarely adequate.49,65

Spinal EDA is a rare condition in children and usually results from hematogenous dissemination from foci elsewhere in body, from bacteremia or by extension of vertebral osteomyelitis.66 In adults, spinal SDA is associated with intravenous (IV) drug use, immunosuppression and recent spinal surgery.67 Spinal abscesses have been reported in children with leukemia and sickle cell disease but, overall, children are less likely to have underlying disease compared to adults. Spinal EDA is a rare complication of lumbar puncture.68 The predominant pathogen in spinal SDA is S aureus and methicillin-resistant S aureus (MRSA) infection is becoming more frequent.69 Other causes include aerobic and anaerobic streptococci, aerobic gram negative bacilli, Nocardia species, M tuberculosis, and fungi. The majority of children with spinal SDA presented with fever and back pain and had trouble walking. Nerve-root pain with radiculopathy; paresthesias; spinal cord dysfunction with motor, sensory, and sphincter dysfunction; and complete paralysis may also be noted. Emergency magnetic resonance imaging (MRI) with gadolinium is needed for diagnosis and lumbar puncture (LP) should be deferred. Blood cultures, elevated white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) are also useful diagnostic tests. The standard management of spinal SDA is antibiotic therapy and surgical drainage. Empirical therapy may include vancomycin plus coverage for gram-negative bacilli (cefipime, ceftazidime, meropenem) especially if there is history of IV drug use or recent spinal procedure. Antibiotic treatment is generally provided for 6 to 8 weeks and duration of therapy is dictated by the clinical picture, normalization of ESR, CRP, and WBC, as well as radiographic improvement. Patients with neurologic dysfunction and spinal SDA may need emergency laminectomy with decompression and drainage or CT guided aspiration to minimize permanent sequelae.69 The main determinant of outcome for patient is neurologic status at the time of diagnosis. Neurologic sequelae in children with spinal SDA occurred in 18% in one study, with primarily motor weakness noted on follow-up examination69; death is unusual.

Chronic latent viral infections are thought to result in several slowly progressing diseases of the human central nervous system such as subacute sclerosing panencephalitis, progressive rubella panencephalitis, and progressive multifocal leukoencephalopathy. Chronic latent viruses typically have a long incubation time of months to years, which results in the slow progression of disease and protracted onset and recognition of symptoms. Although extremely rare, these diseases may result in neurologic devastation and even death. The latent viral infections are distinguished from “slow infections” or spongiform encephalopathies, which result from infection with unconventional transmissible agents, now called prions.

Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a progressive, neurodegenerative disease primarily of childhood and early adolescence caused by persistent measles virus infection of the brain. SSPE was initially recognized in the early 1930s by Dawson, a pathologist from Tennessee who described a progressive encephalitis and movement disorder in children, with accompanying neuropathologic changes of abundant cellular inclusion bodies, predominantly in the gray matter.70 Van Bogaert drew further attention to the disease in 1945 when he demonstrated involvement of white matter and gray matter with concomitant demyelination and glial proliferation in the white matter. He suggested the term “subacute sclerosing leukoencephalitis” to define this disease process. Attempts to culture a latent virus from brain tissue of such patients was unsuccessful until Bouteille used electron microscopy in 1965 and was able to identify viral structures resembling measles virus, in the brain. Measles virus was ultimately cultured from the brain of patients in 1969 by Chen and colleagues and thought to be an altered or a more persistent form of wild-type measles virus.71 SSPE affects children worldwide, with a reported annual incidence of 0.2 to 40 cases per million. Global initiatives for immunization against measles have produced a greater than 90% reduction in the incidence of SSPE from 1960 to 1975.72 In the United States, it was estimated that the average risk of developing SSPE was 8.5 cases per 1 million cases of measles in 1960 to 1974. By the late 1980s, the number of cases decreased from 1 to 2 cases per year, which correlated with a time when incidence of measles was low. Decreasing vaccination rates in the United States between 1989 and 1991 resulted in resurgence of measles during this time, with 55,622 measles cases reported. Subsequent identification of 22 cases of SSPE per 100,000 reported cases of measles was reported between 1992 and 2003, corresponding to the wild-type measles virus genotype associated with the outbreak (genotype D3), and supporting the hypothesis that vaccination against measles is preventative against SSPE.73 In the most recent report of USA/World SSPE Registry, the age range of neurologic onset of SSPE symptoms varied between ages 3 and 24 years, with average age of onset of age 10 years, and a male:female ratio of 4:1.74 In the United States, a unique racial distribution emerged with patients of Hispanic origin being more commonly affected.

The incubation period for SSPE is typically 7 to 13 years after primary measles infection, but may be shorter in children with earlier age at infection; 50% of reported US cases occurred in patients with primary infection prior to age 2 and 75% were in children infected before age 4 years. Symptomatically, SSPE is a triphasic disease.75 The initial phase is manifested by subtle changes in behavior at home and school, with temper outbursts and irritability, cognitive decline and attention problems, and sleep disturbance. In the second clinical stage, massive myoclonus of the extremities, trunk, and head occurs, which is thought to reflect an inflammatory process in the basal ganglia. Generalized or focal seizures are also common. Approximately 50% of patients with SSPE have chorioretinitis and visual impairment. In the third stage, involuntary movements disappear as the primitive motor structures of the basal ganglia are destroyed. Extrapyramidal signs such as choreoathetosis, immobility, masked facies, dystonia, pill rolling tremor, and lead pipe rigidity then develop, followed by dementia, stupor, and coma. Loss of brainstem nuclei that support breathing, heart rate, and blood pressure inevitably leads to death.

The diagnosis of SSPE can be established with the presence of 3 of the 5 clinical criteria: (1) clinical course suggestive of SSPE with typical signs like myoclonus in addition to one of the other criteria; (2) electroencephalogram (EEG) showing periodic, stereotyped, high-voltage discharges; (3) elevated cerebrospinal fluid (CSF) gammaglobulin or oligoclonal band pattern; (4) elevated serum measles titer on enzyme-linked immunosorbent assay (ELISA) testing (⩽ 1:256) and/or CSF (⩽ 1:4); or (5) brain biopsy suggestive of panencephalitis.76 Brain biopsy is therefore not routinely needed to establish the diagnosis of SSPE. A simple and sensitive method for detecting measles virus DNA by PCR has been developed for CSF analysis, but is not routinely used in clinical practice.77 There are reports of neuroimaging changes in patients with SSPE, magnetic resonanc imaging (MRI) demonstrates T2 prolongation, subcortical and periventricular white matter, and subsequent cortical atrophy.78 No curative therapy is currently available for SSPE, although the antiviral agent, isoprinosine and riboviron, and interferon α, which augments the immune response and suppresses viral replication, have all shown modest benefit. Treatment is mostly supportive. Death occurs 1 to 3 years from onset of infection, although there are reports of prolonged spontaneous remission.79

Progressive Rubella Panencephalitis

Progressive rubella panencephalitis (PRP) is an extremely rare neurodegenerative condition that can follow either congenital or postnatal rubella virus infection. PRP was first recognized in 1975 when progressive neurologic illness of late onset in children with congenital rubella infection was reported.80 Case reports of patient with PRP-like symptoms were later reported in children with acquired rubella (German measles) in childhood.81 There have been no reported cases in the literature in the past 30 years. The disease has affected children ages 8 to 19 years after primary rubella infection causing neurologic deterioration superimposed on existing deficits. The clinical syndrome mimics subacute sclerosing panencephalitis (SSPE), with decline in behavior and cognition resulting in dementia, clumsiness, and seizures (usually multifocal myoclonic type). Ataxia of gait, spasticity, dysarthria, dysphagia, and mutism may also ensue. Fundoscopic examination may demonstrate optic nerve atrophy. Diagnosis is based on elevated IgG concentrations and rubella antibody titers in the cerebrospinal fluid (CSF). In general, CSF analysis demonstrates a mild lymphocytosis with elevated protein. Radiologic studies later demonstrate severe cerebellar atrophy. Pathology consists of diffuse progressive subacute panencephalitis mainly affecting white matter. Neuronal loss, gliosis and severe demyelination, with focal cerebellar abnormalities are also noted.82 Rubella virus was isolated from the brain of a 12-year-old patient with PRP and history of congenital rubella infection suggesting a slow infectious pathogenesis in addition to postinflammatory changes.83 Treatment is supportive care and death occurs 2 to 5 years from symptom onset.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a rare and fatal John Cunningham (JC) virus infection affecting primarily the oligodendrocytes and leading to multifocal demyelination. This disease is caused by the JC virus, named after the initials of the patient in whom the virus was first isolated. JC virus is a polyomavirus and member of the Papovaviridae family, which comprises small, nonenveloped viruses with circular, double-stranded DNA genome. JC virus is ubiquitous and thought to be acquired in childhood with seroprevalence reaching 51% positivity among children 9 to 11 years of age and 60% to 80% in adulthood.84 It lies dormant until a person becomes immunocompromised, permitting active replication. Although the virus has been isolated from human urine, blood, and lymphocytes, there has been no reported involvement of extraneural organs.

Prior to the era of HIV/AIDS, PML was primarily seen in older adults with hematologic cancers or chronic immunosuppressive treatments. In the past 20 years, three-quarters of cases of PML have been in patients with AIDS and approximately 1% to 4% of patients with HIV infection will develop PML.85 Other important conditions associated with PML include chronic neoplastic disease (chronic lymphocytic leukemia, Hodgkin disease, lymphosarcoma, myeloproliferative disease), and, less commonly, nonneoplastic granulomatosis (tuberculosis, sarcoidosis). Patients receiving immunosuppressive treatments for renal cell disease, Crohn disease, and multiple sclerosis (MS) are also at risk. Most recently, cases were reported in patients receiving immunosuppressive therapy with natalizumab, a humanized monoclonal antibody designed to reduce migration of leukocytes from peripheral blood into tissue. Most recently, cases were reported in patients receiving immunosuppressive therapy with natalizumab, a humanized monoclonal antibody designed to reduce migration of leukocytes from peripheral blood into tissue. The medication was approved by the Food and Drug Administration (FDA) in 2004 for remitting relapsing multiple sclerosis. The manufacture voluntarily withdrew the medication after 2 patients with MS developed PML during early clinical trials. In a follow-up study involving 3116 patients with MS on natalizumab, the risk of PML was found to be less than 0.1%, which led to its reapproval by the FDA in 2006.86 PML is extremely rare among children; the majority of case reports are among children with AIDS.87

Clinical symptoms include personality changes, cognitive impairment, and hemiparesis, which evolve over days to weeks. Symptoms can progress to quadriparesis, visual changes, cranial nerve defects, cortical blindness, aphasia, ataxia, dysarthria, dementia, seizures, confusional state, and coma.88 Death occurs 3 to 6 months after the onset of neurologic symptoms and may be even more aggressive in AIDS patients untreated with highly active antiretroviral therapy.

The definitive diagnosis of PML is made by stereotactic brain biopsy. Pathologic features include areas of demyelination, accompanied by “ground glass” appearance of oligodendroglial nuclei, and bizarre astrocytes.89 Viral isolation of JC virus is hampered by slow growth of the virus in vitro and may require weeks to months. Electron microscopy reveals crystalline/filamentous arrays of polyomavirus particles in oligodendrocyte nuclei. Detection and amplification of JC virus DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) provides a noninvasive test for PML, with a reported sensitivities range from 60% to 100%, reflective of patient population, clinical definition of PML, and PCR methodology.90 False negatives exist; therefore, clinical symptoms and signs must also be present to support the diagnosis of PML. Cerebrospinal fluid (CSF) may show mononuclear pleocytosis and mild increase in protein content. Demyelination occurs predominantly in the cerebral hemispheres and subcortical regions but lesions in cerebellum, brain stem, and spinal cord have been reported. Lesions vary in size, ranging from microscopic areas of demyelination to massive multifocal plaques. Magnetic resonance imaging (MRI) is the more sensitive choice of neuroimaging and demonstrates patchy or confluent hyperintense lesions on T2-weighted and proton density images in the affected regions; overall, 5% to 10% of the lesions demonstrate contrast enhancement (Fig. 555-2).91 Electroencephalogram (EEG) may be normal or may demonstrate focal slowing.

Treatment for PML in patients without HIV is primarily supportive. There have been several reports of slowed disease progression with cytarabine, arabinoside, cidofovir, mirtazapine, interferon, idoxuridine, interleukin-2, and topotecan, but these failed to be reproduced in larger clinical trials of patients with PML with and without AIDS. In patients with AIDS, the use of protease inhibitors in addition to antiretroviral therapy has been shown to slow the progression of PML. The estimated overall survival at 6 months after diagnosis of PML for persons with AIDS who received antiretroviral therapy (ART) with a protease inhibitor was 68% compared to 10% for those who did not receive ART and protease inhibitors.92 However, a subset of patients has experienced rapid neurologic deterioration after starting ART therapy presumably resulting from immune reconstitution inflammatory syndrome. In these cases, steroids should be cautiously considered.93

Transmissible spongiform encephalopathies (TSE), or prion diseases, represent a group of clinical syndromes characterized by slow progression of neurodegenerative disease affecting humans and animals. At least 5 diseases of prion etiology are recognized in humans: Kuru; Creutzfeldt-Jakob disease (CJD) with its variants including sporadic (sCJD), familial (fCJD), iatrogenic (iCJD), and new variant (nvCJD); Gertmann-Straussler Scheinker syndrome; fatal familial insomnia; and sporadic familial insomnia. In the pediatric population, kuru and more recently nvCJD cases have been reported. Transmissible spongiform encephalopathies (TSEs) share many similar characteristics (see Table 555-3 for comparison).

Until the late 20th century, TSE was a disease of domestic livestock. Veterinarians coined the term “slow virus disease” because the disease was noted to be transmissible and characterized by a prolonged incubation period lasting years before clinical deterioration began. In the 1950s, kuru was reported as a progressive cerebellar ataxia and dementia associated with ritualistic cannibalism in the Fore tribe in Papua, New Guinea. In 1959, a veterinary pathologist, William Hadlow, observed a striking similarity between spongiform changes seen in patients with kuru and brains of sheep with scrapie. In the 1980s, researchers noted TSE agents were resistant to inactivation from agents that would normally kill most viruses (heat, ionizing radiation, alcohol, formalin, nucleases) and partly resistant to proteases. Prusiner postulated that the TSE agents may in fact be a self-replicating protein and coined the word prion for proteinacious infectious agent, to describe the transformation of the normal host protein (PrPc) to the pathogenic isoform (PrPsc) that could transmit disease in absence of nucleic acid. The transformation into PrPsc induces more of the normal PrPc to form PrPsc posttranslationally; hence, a chain reaction is set in motion with the exponential formation of the insoluble prion protein. This hypothesis was a paradigm shift in biology and Prusiner was awarded the Nobel Prize in 1997 for his work. Transmissible spongiform encephalopathy (TSE) became much discussed in the 1980s and 1990s with the appearance of bovine spongiform encephalopathy (BSE) or “mad cow disease.” In Britain alone, the country most affected by BSE, approximately 183,000 infected cows have been reported to date but infected cows have been reported worldwide.95 It is very likely that the disease was transmitted to humans from infected beef products resulting in 147 people (from 1995–2004) with new variant Creutzfeldt Jakob disease worldwide.96 In the United States, chronic wasting disease (CWD) has been reported in several states among cervids, including mule deer, white-tailed deer, elk, and moose. The Centers for Disease Control (CDC) currently has not stated that eating these meats is a risk factor for CJD. To minimize their risk of exposure to CWD, the CDC recommends that hunters should consult with their state wildlife agencies to identify areas where CWD occurs. Persons involved in field-dressing carcasses should wear gloves, bone out the meat from the animal, and minimize handling of the brain and spinal cord tissues.

TSEs are all transmissible to humans by inoculation of tissues from affected patients. Incubation periods range from several months to decades and illness lasts month to years with invariable progression to death. There is no host response and all TSEs share a noninflammatory pathologic response to prion protein. Histopathologic changes are confined to the CNS with spongiform degeneration. Typical pathologic features include vacuolization, neuronal loss, and glial proliferation, mostly in cerebral cortex or cerebellum. Amyloid plaques are found in all patients with GSS and kuru and 10% to 15% of patients with sCJD.94 The clinical course includes features of dementia, incoordination, visual abnormalities, involuntary movements, and terminal akinetic mutism.

Kuru

Kuru is progressive neurodegenerative disease with predominant cerebellar features that first demonstrated the transmissibility of human TSE. Gajdusek, an American physician and researcher, and coworkers defined the natural history of the disease only seen in the Fore tribe in Papua, New Guinea. The disease predominantly affected women and children of both sexes but only 2% of cases were adult men. Kuru (a Fore word for “trembling”) reached epidemic proportions among the Fore tribe in the 1950s, with nearly 1% of the population affected and was a significant cause of death.97 The disease was thought to be acquired through the preparation and ingestion of brains of dead relatives for ritualistic cannibalism. Clinical presentation begins with ataxia and progressive tremor of the trunk, extremities and head, and is then followed by choreiform movements months later. Intelligence is largely preserved though mood disturbances are reported. In most children, the disease is fatal 6 to 9 months from onset. Laboratory studies and CSF analysis are unremarkable. Gajdusek reported pathologic changes on microscopy including widespread neuronal degeneration, marked in the cerebellum, proliferation of astroglia and microglia, and minimal demyelination. Amyloid plaques secondary to accumulation of PrPsc product are also reported. The disease was transmissible to a chimpanzee after incubation 18 to 30 months in one of Gajdusek’s classic experiments. Incubation period may be lengthy, with up to several decades from time of inoculation.98 The gene PRNP, which codes PrPc and is located on chromosome 20, has a polymorphic (methionine/valine) codon 129 that influences features of TSE. Studies on kuru indicated that individuals homozygous for Met at PRNP codon 129 were preferentially affected with kuru.99 In contrast, PRNP analysis of the eleven patients with kuru with prolonged incubation times show heterozygosity at polymorphic codon 129.100

Creutzfeldt Jakob Disease

Creutzfeldt Jakob disease (CJD) has been recognized since the 1920s and is the most common human spongiform encephalopathy. Sporadic CJD (sCJD) comprises nearly 85% of CJD cases, at an annual rate of approximately 1 to 2 cases per million worldwide, with up to 100-fold higher rates reported in Slovakia and among Libyan-born Israelis, who have a high incidence of a mutation of the PRNP gene. The risk of CJD increases with age and in persons over age 50 years, for whom the annual rate is approximately 3.4 cases per million. Recently, the United States has reported fewer than 300 cases of CJD per year. Sporadic CJD is characterized by dementia, myoclonus, or, less commonly, other abnormal movements such as chorea, dystonia, cerebellar ataxia, and pyramidal and extrapyramidal tract signs.101 Late in the clinical course, patients experience akinetic mutism. Average survival is 1 year after onset of neurologic findings. Most laboratory studies are of little value in the diagnosis of CJD. Cerebrospinal fluid (CSF) analysis is often normal, but may reveal slight increase in protein levels. The 14-3-3 protein is a normal protein, not usually found in the CSF and its presence in the CSF may suggest CJD.102 The 14-3-3 protein has also been found in other neurologic diseases such as meningoencephalitis or stroke. The EEG shows generalized slowing early in the course and then progresses to periodic burst of biphasic or triphasic sharp wave complexes. Paroxysmal discharges may be precipitated by loud noises. Many patients have typical periodic suppression-burst complexes and high-voltage slow activity at some point on their EEG. At later stages of disease, CT reveals generalized atrophy and ventriculomegaly and MRI can reveal hyperintense signals in the basal ganglia on fluid attenuation inversion recovery (FLAIR) sequences. Brain biopsy for microscopic examination of brain tissue may be diagnostic but can only be recommended if a treatable disease is in the differential diagnosis, given risks to patients and transmissibility of disease. The demonstration of protease-resistant PrP proteins in brain extracts has been useful to confirm histopathologic diagnosis. Biopsy specimens of pharyngeal tonsil that show marked accumulation of PrP-res have also been valuable in diagnosis of CJD.103 No treatment has been proved to be effective.

Iatrogenic CJD (iCJD) presents similarly to sCJD, often with a shorter incubation period, ranging from 15 months to more than 20 years. There are links between iCJD and various medical and surgical interventions, including treatment with human pituitary growth and gonadotropin hormones derived from cadavers (hGH has been withdrawn from most countries since 1985), brain surgery with contaminated instruments and electrocorticographic electrodes, transplantation of infected corneas, and dura mater allografts. Epidemiologic studies have not suggested exposure to human blood or blood products as a cause of iCJD in humans, but low titers of TSE agents have been found in blood of experimentally infected animals.104 Secretions and excretions have not demonstrated transmissitivity. Only standard universal precautions are indicated in the management of patients with iCJD. The risk of transmission to family members and health care providers is low; however, caution should be used in obtaining CSF and handling tissues at autopsy. Decontamination of instruments is recommended by soaking them in at least a 1N sodium hydroxide solution for 1 hour or more and then autoclaving them to 134°C for at least 1 hour. Iatrogenic CJD (iCJD) and, more rarely, sCJD have affected children and young adults.

New variant CJD (nvCJD) is a distinct clinical-pathologic entity, which is widely accepted to result from the same agent responsible for bovine spongiform encephalopathy (BSE). Even though the temporal and geographic distribution of nvCJD supports causal relationship to BSE, the origin of nvCJD cannot be fully explained. Research showing that an isotype of PrP deposited in the brain in nvCJD is similar to experimental transmitted BSE. Also laboratory transmission studies of wild type human transgenic and bovine transgenic mice demonstrates that transmission characteristics of nvCJD and distribution of neuropathologic changes are distinct from sCJD.105 Since 1996, there have been 150 reports of nvCJD with striking prevalence in Britain. Several features of nvCJD distinguish it from sCJD, including younger age at diagnosis and longer duration of illness (13 months vs 4.5 months in sCJD).101 Neuropathology demonstrates specific florid or “daisy” plaques in 100% of the nvCJD cases. Psychiatric symptoms including depression and memory problems are common at disease onset. One third of patients develop persistent and often painful sensory symptoms or dysesthesias. After about 6 months, frank neurologic signs such as ataxia and involuntary movements (dystonia, myoclonus, chorea) occur in all cases with later development of akinetic mutism. Risk factors for nvCJD include young age, methionine homozygosity at codon 129 on the prion protein gene (PRNP), and residence in the UK. The reason for the young age of distribution of cases is not known but may be due to increased age-related exposure to BSE or increased susceptibility given young age. Patients with nvCJD lack the “typical” periodic electroencephalogram seen in sporadic CJD. Magnetic resonance imaging of the brain reveals increased signal intensity in the posterior thalamus in the majority of cases. Unlike the more classic forms of the disease, there is suggestion of increased infectivity outside the central nervous system. Four cases of transmitted infections of nvCJD have been reported, all in elderly patients who received transfusions of nonleukocyte reduced red cells from young patients who did not shows signs of nvCJD until years later.106 This raises concerns for the potential transmission of prion proteins via surgical procedures from individuals in the asymptomatic stage of the disease.

Other Prion Diseases

Familial forms of prion disease exist in Gertmann-Straussler Scheinker syndrome (GSS); fatal familial insomnia (FFI) and sporadic familial insomnia (SFI). Gertmann-Straussler Scheinker syndrome (GSS) is a rare, slowly progressive, autosomal dominant disease characterized by adult onset of memory loss, dementia, ataxia, and pathologic deposition of amyloidlike plaques in the brain. Cognitive decline begins in the thirties and forties, and the average disease duration is 7 years. Gertmann-Straussler Scheinker syndrome can be distinguished from CJD by earlier age at onset, longer disease duration, and prominent cerebellar ataxia.107 FFI is an autosomal dominant prion disease in which asparagine is substituted for aspartic acid at the 178 codon of the PrNP gene. The chief clinical features of FFI include a progressive insomnia, waking “sleep,” hallucinations, autonomic disturbances suggestive of sympathetic overdrive (tachycardia, hypertension, hyperhidrosis, hyperthermia), a rise in circulating catecholamine levels, cognitive changes (such as attentional disturbance and short-term memory deficits without a loss in general intelligence), motor system deficits (ataxia), and endocrine manifestations.108 Later cognitive changes involve a confusional state resembling dementia and, ultimately, death occurs. Mean age at onset is approximately 50 years, with most cases occurring between age 20 and 61 years. Rare SFI cases occur without PRNP mutation but have features similar to FFI. One case of fatal familial insomnia was reported in a 13-year-old child.109

The central role of the immune system in several pediatric central nervous system (CNS) disorders has been increasingly appreciated in recent years. Although relatively rare as individual diseases, collectively they constitute a sizable proportion of pediatric neurology practice. The acute, severe symptoms associated with these disorders usually lead to inpatient hospitalization. Due to the broad differential diagnoses associated with these conditions, multiple other pediatric subspecialists, such as infectious disease and rheumatology physicians, are often asked to evaluate affected patients. Last, because of the potential long-term sequelae of both the monophasic and recurrent immune-mediated CNS disorders, all aspects of a patient’s medical and psychosocial care can be affected. Thus, these disorders have relevance to general pediatricians and pediatric subspecialists in both the inpatient and outpatient settings.

Demyelinating disorders comprise the largest subgroup within CNS immune-mediated disorders. Myelin is composed of a lipid bilayer of cholesterol, phospholipids, and glycolipids along with membrane-associated proteins, such as proteolipid protein and myelin basic protein.1,2 In the CNS, oligodendrocytes produce myelin, which surrounds axons with periodic interruptions at nodes of Ranvier. The main functions of myelin are to speed the conduction of action potentials along axons and to support the development and maintenance of axons.

Myelin can be injured by many different mechanisms, such as hypoxia, metabolic derangements, and toxic insults. The disorders discussed in this chapter are considered to have an autoimmune etiology, with loss of tolerance resulting in an aberrant, self-reactive inflammatory process directed against CNS myelin.

Demyelination leads to slowing or blockade of action potential propagation, with resulting symptoms referable to the affected CNS areas. Although remyelination can occur in the CNS, the thickness of the original myelin sheath is never reachieved.3 Demyelination can also lead to secondary axonal loss, which leads to permanent disability.4

First Attack of Demyelination

Definitions, Terminology, and Classification

In the past, variable terminology and lack of consistent definitions in the literature hampered our understanding of pediatric CNS demyelinating disorders. In April 2007, diagnostic definitions were proposed by the International Pediatric Multiple Sclerosis (MS) Study Group.5 Although they have not yet been prospectively validated, these definitions provide a very useful framework both for clinical and research purposes.

With a first presentation of a CNS demyelinating disorder, determining whether mental status changes are present or absent serves as the initial step in classification (Fig. 556-1). When present and accompanied by multifocal symptoms, the appropriate diagnosis is acute disseminated encephalomyelitis (ADEM), which can be confirmed with magnetic resonance imaging (MRI). When the patient’s mental status is normal, first-time acute demyelinating events are collectively referred to as clinically isolated syndromes (CIS). Clinically isolated syndromes can be subdivided based on whether the symptoms and signs are focal or multifocal. Common locations for focal CIS include the optic nerve (optic neuritis), spinal cord (transverse myelitis), brain stem, and cerebellum. If multiple CNS locations are involved simultaneously but the mental status is normal, the appropriate diagnosis is a polysymptomatic CIS.

A patient with a CIS may have evidence of demyelination on MRI in numerous CNS sites without accompanying clinical symptoms and signs. Although such an MRI finding is important for the patient’s prognosis for the development of MS, it does not alter the diagnosis, which is based on clinical findings. For example, a patient with optic neuritis, normal mental status, and multiple, asymptomatic brain and spine MRI lesions should be classified as having optic neuritis, not ADEM, and is at high risk to develop MS.

Demyelination of the spinal cord (myelitis) can be partial with mild, asymmetric motor and sensory symptoms, or complete with severe, symmetric motor, sensory, and autonomic symptoms. Partial myelitis is a type of CIS and carries a high risk for the development of MS, and the complete form poses little risk of recurrence in the pediatric population. The term acute transverse myelitis (ATM) should be reserved for the complete form. Definitions of ATM have varied significantly in the literature. In 2002, the Transverse Myelitis Consortium Working Group published useful diagnostic criteria.6

General Aspects of the Differential Diagnosis

Although the differential diagnosis varies somewhat based on the site of CNS demyelination, general principles can be applied to all of the disorders. There are many conditions that can mimic and be mimicked by pediatric CNS demyelinating disorders. In addition, as there are no absolutely definitive diagnostic tests for CNS demyelinating disorders, a broad differential diagnosis must be considered. A complete discussion of the entire differential diagnosis is beyond the scope of this chapter but it has recently been reviewed.7 In common practice, one will obtain laboratory tests including erythrocyte sedimentation rate, C reactive protein, serum Lyme titers, antinuclear antibody, and vitamin B12 level in all patients with CNS demyelinating disorders, with additional testing if necessary as guided by the history and examination. In general, the differential diagnosis and subsequent workup should be expanded in patients with younger onset, progressive decline in function, poor response to immunomodulation, and extra-CNS organ system involvement. The main disease categories that should be considered are infectious diseases, rheumatological disorders, metabolic disorders, and neoplastic conditions.

Regarding infectious diseases, microorganisms can directly infect the CNS (Fig. 556-2A) or can infect peripheral organs and secondarily trigger an autoimmune response. If there is any clinical concern for CNS infection in a patient with suspected CNS demyelination, cerebrospinal fluid (CSF) should be examined for common infections, such as enterovirus, and serious, treatable infections, such as herpes simplex virus, with polymerase chain reaction testing. Additional infectious disease testing can be tailored based on the season of the year and the patient’s geographic region, exposures, and immunocompetence, with strong consideration given to testing for Borrelia burgdoferi, Mycoplasma pneumoniae, and Epstein-Barr virus.

Many rheumatological disorders such as systemic lupus erythematosus (SLE) have been associated with CNS complications, which may be partially mediated by inflammatory demyelination (Fig. 556-2B). If there are organ systems other than the CNS affected, particularly the skin, joints, and kidneys, these disorders should be assessed with appropriate diagnostic testing. Primary and secondary CNS vasculitis can also mimic demyelination and should be considered, particularly when headaches are a prominent symptom, symptoms recur during steroid withdrawal, or MRI reveals significant cortical involvement (Fig. 556-2C).

Leukodystrophies are genetic and metabolic disorders that preferentially affect the white matter and therefore mimic CNS demyelination. In patients with a subacute to chronic course, progressive degeneration, and symmetric white matter involvement on MRI, metabolic testing should be considered, with specific tests based on the patient’s age, presentation, and MRI findings (Fig. 556-2D). These disorders are discussed in Chapter 576.

Neoplasms can be confused with demyelination, particularly when there is a large, focal inflammatory lesion (ie, tumefactive demyelination) (Fig. 556-2E). MRI of the entire neuroaxis to look for multifocal involvement and cytological examination of the CSF should be obtained in such circumstances. Rarely, biopsy of the lesion is needed to make a definitive diagnosis.

General Aspects of Acute Treatment

The treatment of pediatric CNS demyelinating disorders can be generally divided into acute and prophylactic phases. Acutely, attacks of demyelination are treated similarly, regardless of etiology (Fig. 556-3). High-dose intravenous (IV) corticosteroids are the first-line treatment. They likely act via multiple mechanisms in CNS demyelinating disorders, including apoptosis of autoreactive T cells, reduction in the production of proinflammatory cytokines, and decreased transmigration of immune cells across the blood-brain barrier.8

Within the adult MS population, high-dose intravenous corticosteroids have been shown to speed the rate of recovery in acute attacks of MS and optic neuritis, but do not significantly alter long-term disability or risk of recurrence.9,10 Although not formally tested in pediatric patients, high-dose IV corticosteroids are used for the initial treatment of acute attacks of demyelination. The most commonly used protocol consists of methylprednisolone 20 to 30 mg/kg/dose (maximum 1 gram) intravenously once a day for 3 to 5 days. During use of this steroid, pulse, vital signs, especially blood pressure, and glucose control should be monitored. Ulcer prophylaxis should be used. Common adverse side effects include insomnia and mood changes. Rare acute side effects include aseptic necrosis of the hip. Short courses of IV steroids are not associated with long-term adverse effects on adrenal function or bone mineralization. Although there are many potential side effects, this protocol is usually well-tolerated in the pediatric population.

The use of oral steroid tapers following intravenous treatment is controversial. Patients who have complete or nearly complete symptom resolution may not need tapers, but those with incomplete recovery may benefit from a 2- to 3-week taper. Due to the adverse effects of chronic corticosteroid use and the availability of other immunomodulatory agents, prolonged courses of oral steroids for the treatment of CNS demyelinating disorders is not recommended.

If significant functional disability remains after several days of observation following high-dose steroid treatment, additional options include intravenous immunoglobulin (IVIg) and plasma exchange. Based on case reports, IVIg 0.4 grams/kg for 5 days or 1 gram/kg for 2 days can be used as second-line treatment.11,12 The mechanism of action of IVIg is uncertain, but likely involves decreased production of autoantibodies.13 Based on case reports, IVIg 0.4 grams/kg for 5 days or 1 gram/kg for 2 days can be used as second-line treatment.11,12 The mechanism of action of IVIg is uncertain, but likely involves decreased production of autoantibodies.13 The most common side effect of IVIg is a nonspecific headache, which can be managed with slower infusion rates and nonsteroidal anti-inflammatory medications. Rare side effects include aseptic meningitis and thrombosis.

If IVIg is ineffective, plasma exchange administered every other day for a total of 5 exchanges can be considered. This regimen has been used successfully in 1 case series of 6 pediatric patients with ADEM who did not respond adequately to steroids and IVIg.14 The use of plasma exchange is also supported by a randomized trial in adult patients with steroid-refractory CNS demyelination and appears to be more effective when administered within the first 3 weeks of symptom onset.15,16 Plasma exchange may work via the removal of pathogenic autoantibodies from the circulation.17 Potential adverse effects of plasma exchange include the complications associated with a central venous line (if one is needed), such as pneumothorax and infection, as well as side effects of the treatment, such as hypotension and hypocalcemia.

It is unclear from the existing literature whether the improvements observed in some patients following IVIg and plasma exchange reflect delayed effects of the previously administered treatments or a combined effect of therapies. The potential benefits of IVIg and plasma exchange should be weighed against the potential adverse effects described above. The proposed algorithm (Fig. 556-3) has been useful in practice but requires further study.

Acute Disseminated Encephalomyelitis (ADEM)

Epidemiology

Acute disseminated encephalomyelitis (ADEM) is defined as an acute or subacute inflammatory demyelinating event affecting multifocal areas of the CNS with multiple accompanying symptoms, which must include encephalopathy.5 The incidence of ADEM is approximately 4 cases per 1 million persons under the age 20 per year.18 It is more common in children than adolescents and adults, with a mean age of onset between 5 and 8 years of age.

Pathophysiology

Although the pathophysiology of ADEM is likely autoimmune mediated, the precise mechanisms remain uncertain. Indirect evidence implicating the immune system includes the frequent association with a preceding viral infection or, less commonly, a vaccination, as well as the apparent effectiveness of immunomodulation. The former point suggests that molecular mimicry, whereby epitopes on microorganisms mimic those found in CNS myelin and thus provoke an autoimmune response, may play a role in the pathophysiology of ADEM. As most of the infections reported to act as triggers for ADEM are very common, additional host susceptibility factors must be present in patients with ADEM but are largely undefined.

Both B and T lymphocytes appear to play a role in ADEM. Regarding B cells, autoantibodies to myelin oligodendrocyte glycoprotein were found in 20% of patients with ADEM.20 Antimyelin autoreactive T cells have also been found in the serum of a small group of patients with ADEM.21 Additional work is needed to clarify the immune and genetic mechanisms of ADEM.

Although biopsies are rarely needed to establish the diagnosis of ADEM, those that are performed provide more direct evidence of the role of the immune system. Biopsy specimens typically show perivenous infiltrates of lymphocytes and macrophages with accompanying demyelination and relative axonal sparing (Fig. 556-4).

Both B and T lymphocytes appear to play a role in ADEM. Regarding B cells, autoantibodies to myelin oligodendrocyte glycoprotein were found in 20% of patients with ADEM.20 Antimyelin autoreactive T cells have also been found in the serum of a small group of patients with ADEM.21 Additional work is needed to clarify the immune and genetic mechanisms of ADEM.

Clinical Presentation

Children with ADEM present with a combination of nonspecific symptoms and signs suggestive of meningoencephalitis, as well as focal neurologic deficits. Approximately 70% of cases follow a viral illness or vaccination, usually occurring 7 to 14 days prior to the onset of neurological symptoms. The most common associated infection is a nonspecific upper respiratory tract infection. Pooled data from nine case series totaling 411 patients yield the following estimates for presenting symptoms and signs: motor (60%), fever (50%), headache (40%), vomiting (40%), ataxia (40%), cranial nerve deficits (40%), seizures (25%), and vision loss (15%).18,22-29 Thus, a typical clinical scenario is that of a previously healthy child who develops a nonspecific infection, fully recovers, and then develops acute encephalopathy and multifocal neurological symptoms and signs.

Differential Diagnosis

As suggested by these symptoms, the presentation of ADEM can be indistinguishable from meningoencephalitis. Thus, direct CNS infection should be ruled out with lumbar puncture and appropriate studies in all patients with suspected ADEM. Cerebrospinal fluid (CSF) analysis is abnormal in approximately 60% of patients with ADEM, with the most common findings being lymphocytic pleocytosis or elevated protein concentration, or both.18,22-29 Thus, basic CSF studies may not distinguish ADEM from encephalitis, and testing for specific causes of viral encephalitis should be performed. Additional testing should be guided by clues in the history, examination, or neuroimaging as described above.

Diagnostic Evaluation

All patients with acute disseminated encephalomyelitis (ADEM) should undergo contrast-enhanced MRI of the brain and spine. Although patients with ADEM may initially require computerized tomography (CT) of the head to rule out other emergent conditions, CT has a poor sensitivity of approximately 40% when compared to MRI in patients with ADEM.18,22-29 MRI typically shows bilateral, asymmetric, multifocal hyperintense lesions on T2 and fluid-attenuated inversion recovery (FLAIR) sequences. The lesions predominantly affect the cerebral white matter, more so in subcortical rather than periventricular regions. However, cortical, deep grey nuclei, brain stem, cerebellar, and spinal cord lesions are also seen (Fig. 556-5). Lesions tend to be large with ill-defined borders and lack contrast enhancement.

Treatment

The initial treatment of ADEM is similar to that used for all acute attacks of CNS demyelination (see above). In addition to immunomodulation, supportive care during the acute attack may include airway management in patients with depressed mental status, anticonvulsants in patients with seizures, and pain management. As ADEM is a terrifying event for patients and their families, psychosocial support should also be given. By definition, ADEM is a monophasic disorder and does not require chronic immunomodulation. However, patients with ADEM are at risk for long-term sequelae (see below) and therefore should be followed by a pediatric neurologist with treatment of cognitive deficits, physical handicaps, and epilepsy, as appropriate.

Prognosis

Approximately 80% of patients with ADEM make a full recovery.18,22-29 Most show significant improvement prior to hospital discharge, with the remainder of the recovery occurring gradually over several months. However, some patients are left with motor (10–15%), cognitive or behavioral (10%), epileptic (5–10%), or visual (5%) sequelae.18,22-29 Cognitive sequelae may be more common than previously appreciated, as suggested by 2 recent studies that demonstrated a high percentage of cognitive deficits with formal neuropsychological testing, particularly in patients with the onset of ADEM at less than 6 years of age.30,31 Thus, children with ADEM should be followed closely for declines in cognition or school performance following the acute illness.

Approximately 80% of patients with ADEM experience a single event without recurrences.18,22-29 Based on the expert opinion of the International Pediatric MS Study Group, symptoms occurring within 3 months of the initial onset of ADEM can be considered part of the initial event.5 Patients who have later relapses of neurological symptoms following ADEM comprise a controversial group.

The reemergence of the initial symptoms after 3 months has been designated recurrent ADEM. If the symptoms are different than the initial presentation, the term multiphasic ADEM can be used5 (Fig. 556-6). Both recurrent and multiphasic ADEM require that the relapses be accompanied by mental status changes. In 1 series of 84 patients with ADEM, 10% developed a second attack identical to the first attack and would be classified as having recurrent ADEM.26 None of these patients developed further attacks or met criteria for MS with follow-up ranging from 3 to 16 years. Multiphasic ADEM is less common than recurrent ADEM, occurring in less than 5% of patients overall.18,22-29 Given the relative rarity of recurrent and multiphasic ADEM, a broad differential diagnosis should be reconsidered before making these diagnoses. Patients with recurrent or multiphasic ADEM do not generally require chronic immunomodulation, but it could be considered for unusual patients with frequent or severe attacks. If mental status changes are not present during the second event following ADEM, it will most likely represent a CIS-type event (ie, optic neuritis). Whether or not such patients should be classified as having MS is very controversial. The International Pediatric MS Study Group took a conservative approach and required that 2 CIS-type events occur following ADEM prior to making a diagnosis of MS.5

The percentage of patients with an initial diagnosis of ADEM who later develop MS is uncertain. Estimates of this risk have ranged from 0%26 to as high as 18%32 in the existing literature, with a pooled average of approximately 10%.18,22-29 Although there are no highly predictive risk factors, optic nerve involvement with ADEM, family history of CNS demyelination, and MRI features suggestive of MS may increase the risk of developing MS following ADEM.32

Acute Transverse Myelitis

Epidemiology

Idiopathic, complete acute transverse myelitis (ATM) affects approximately 1.34 persons per million per year.33 In the pediatric age group, patients present at a mean age of 8 years with an equal gender ratio.34-40 Approximately 280 cases of ATM occur in pediatric patients in the United States per year.41,42

Pathophysiology

Although the pathophysiology of ATM is uncertain, the frequent association with preceding infections and accumulating immunological data support an inflammatory cause for the disorder.33,34,43,44 Approximately 50% of patients report a preceding infection, typically a nonspecific upper respiratory tract infection, with an intervening symptom-free interval of 5 to 11 days.33,34,39,41 Some cases of ATM are associated with recent vaccination.

Increased responses to myelin basic protein by peripheral blood lymphocytes have been demonstrated in the research setting in patients with ATM.45 In addition, the production of interleukin-6 by astrocytes appears to lead to nitric oxide–induced injury to spinal cord oligodendrocytes and axons in patients with idiopathic ATM.43

Clinical Presentation

Pooled data from 7 published case series (n = 205) of pediatric ATM patients reveal common symptoms.34-39,41 Patients with ATM universally report acute to subacute, bilateral leg weakness. Arm involvement occurs in about 40% of patients. Approximately 90% complain of bowel and bladder dysfunction and sensory symptoms, including parasthesias and numbness. A spinal cord sensory level is usually located in the thoracic region (80%) and less commonly in the cervical (10%) or lumbar (10%) area.33 Back pain and fever afflict nearly 50% of patients. These symptoms develop rapidly, peaking at an average of 2 to 5 days.34,41

Differential Diagnosis

Numerous disorders can affect the spinal cord and produce identical symptoms and signs that mimic idiopathic ATM. Such conditions must be ruled out through a combination of history, physical examination, neuroimaging, and laboratory evaluation.

In patients with acute, isolated spinal cord dysfunction, extramedullary compressive lesions, including spinal epidural abscesses,46 spinal epidural hematomas,47 and tumors,48 are neurosurgical emergencies that must be diagnosed rapidly for effective treatment. Intramedullary lesions that can mimic ATM include primary spinal cord tumors (most commonly astrocytomas and ependymomas),49-51 radiation injury,52 spinal cord infarction, and vascular malformations.53 Direct infections of the spinal cord, typically viral in etiology, can also occur. Acute transverse myelitis can also be secondary to a variety of systemic autoimmune disorders.

The initial clinical presentation of ATM can be similar to that of Guillain Barre syndrome. Both can present with back pain, paraparesis, and sensory abnormalities. However, the presence of a spinal cord sensory level and bowel and bladder involvement is highly suggestive of ATM.

Some patients may present with spinal cord dysfunction, as well as symptoms or signs referable to other parts of the CNS. The presence of mental status changes and cerebral white matter magnetic resonance imaging (MRI) abnormalities suggest ADEM as the correct diagnosis. Mild, asymmetric spinal cord symptoms, previous episodes of transient neurological symptoms attributable to locations other than the spinal cord, and subclinical brain MRI lesions point toward MS.54 Concurrent or preceding optic neuritis suggests neuromyelitis optica (NMO) as a possible diagnosis.55

Diagnostic Evaluation

Every patient with suspected ATM should undergo emergent gadolinium-enhanced MRI of the entire spine in order to confirm the diagnosis and rule out alternative diagnoses, particularly compressive lesions. All patients with ATM should also undergo gadolinium-enhanced MRI of the brain to assess for additional demyelinating lesions suggestive of ADEM or MS. Spinal MRI in ATM typically reveals T1 isointense and T2 hyperintense signal over several contiguous spinal cord segments34 and may involve the entire spine56 (Fig. 556-7). Spinal cord swelling with effacement of the surrounding cerebrospinal fluid spaces may be present in severe cases. Contrast enhancement is present in as many as 74% of patients.41 In some patients with very suggestive clinical features, the initial spine MRI may be normal, and it should be repeated several days later.34,35,37

Unless a specific contraindication exists, all patients with ATM should undergo lumbar puncture. Approximately 50% of pediatric patients with ATM have CSF pleocytosis, typically with a lymphocytic predominance.41 Elevated CSF protein levels, either in isolation or in conjunction with pleocytosis, are also detected in about 50% of patients.41 Glucose concentration is typically normal. A normal CSF profile does not rule out ATM, as it occurs in approximately 25% of patients. In addition to MRI and lumbar puncture (LP), further testing should be guided by clues in the history, examination, or neuroimaging as described above.

Treatment

The initial treatment of ATM is similar to that used for all acute attacks of CNS demyelination (see above). There have been no randomized, controlled trials in ATM to support this approach. However, case reports and series have suggested a beneficial effect of high-dose corticosteroids.36,57,58 In 1 series of 12 children with severe ATM compared to a historical control group of 17 patients, the use of high-dose intravenous methylprednisolone significantly increased the proportion of children walking independently at 1 month (66% compared to 18%) and with full recovery at 1 year (55% compared to 12%).36 For patients who do not improve adequately with intravenous steroids, intravenous immunoglobulins12 or plasmapharesis can be considered. Additional treatment includes pain management, urinary bladder catheterization, bowel regimens, peptic ulcer and deep venous thrombosis prophylaxis, physical therapy, and psychosocial support. Mechanical ventilation is required in approximately 5% of patients.

Prognosis

Although limited by variable definitions in the literature, the prognosis for pediatric patients with ATM is generally favorable.59 Paine and Byers’ recovery categories have been the most widely reported outcome scale.39 Based on this scale, approximately 80% of pediatric patients who receive high-dose IV steroids achieve full or good recovery, and 20% have a fair or poor outcome.36,57 Among patients not treated with high-dose IV steroids, 60% have a full or good recovery, and 40% have a fair or poor outcome.39 Higher rostral levels and number of overall spinal segments on spine MRI predicts worse outcome.41