Chapter 25: Neurologic & Muscular Disorders

HISTORY & EXAMINATION

History

Even in this era of increasingly sophisticated neurodiagnostic testing, the assessment and diagnosis of a child with a possible neurologic disorder still hinges on a detailed history and examination. The standard pediatric history and physical examination are presented in Chapter 9. In particular, determining the temporal progression of the neurologic signs and symptoms (acute vs chronic, progressive vs static, episodic vs continuous) can direct the evaluation. Episodic events, such as headaches or seizures, warrant emphasis on the symptoms preceding, during, and succeeding the event. Spells can also be videotaped, allowing the examiner to obtain first-hand observation of important details that can clarify the diagnosis. Both acute and chronic neurologic symptoms may be associated with other organ system involvement, such as joint pain, changes in appetite or bowel/bladder habits, or a preceding viral illness, which can provide additional clues to the diagnosis. Birth history should include assessment of fetal movement and whether the infant was breech or vertex. A thorough past medical history and family history can illuminate risk factors for certain neurologic disorders. Social history should include school performance, preferred activities, and travel history.

Neurologic Examination

A general physical examination is essential in any neurologic assessment. Growth parameters and head circumference should be charted (see Chapter 3). A developmental assessment, often with an appropriate screening tool, is fundamental for every neurologic evaluation of an infant or young child (see Chapter 3 for details of developmental landmarks and example screening tools). The specifics of the neurologic examination are determined by the age of the child and the ability to cooperate with the examination. Expected infant reflexes and other age-related examination findings are included in Chapter 2. The hallmark of neurologic diagnosis is localization—determining where within the nervous system the “lesion” is located. While not all childhood neurologic disorders are easily localized, the part of the nervous system involved—for example, central versus neuromuscular—can often guide further evaluation and diagnosis.

Table 25–1 outlines components of the neurologic examination—mental status, cranial nerves, motor (including tone, muscle bulk, and strength), reflexes, sensation, coordination, and gait. Much of the examination of the frightened or active child is, by necessity, observational, and the examiner must capitalize on moments of opportunity while maintaining a systematic approach to avoid overlooking a key component. Playing games engages a toddler or preschooler; activities such as throwing a ball, stacking blocks, hopping, jogging, counting, and drawing (circles, lines) can reduce anxiety and allow assessment of fine and gross motor coordination, balance, and handedness. In the older child, “casual” conversation can reveal both language and cognitive competence.

DIAGNOSTIC TESTING

Electroencephalography

Electroencephalography (EEG) is a noninvasive method for recording neuronal electrical activity in the brain. The background patterns of the EEG vary by both age (infant, toddler, or adolescent) and clinical state (awake, drowsy, or asleep). Intermittent activity, such as slowing of the background, often reflects disordered central nervous system (CNS) function. The EEG has its greatest clinical applicability in the evaluation of seizure disorders. An EEG may demonstrate “epileptiform activity,” that is, patterns that can indicate risk for seizures and epilepsy. At times, however, the findings on an EEG can be diagnostic, as in the hypsarrhythmia pattern seen in infantile spasms (West syndrome) or generalized 3-Hz spike-wave activity seen in childhood absence epilepsy. Synchronized video recording with EEG has increased the utility of EEG in assessing episodic disorders that may or may not represent seizures. EEG also can be very useful in the evaluation of altered mental status and in some encephalopathies.

The EEG is rarely diagnostic in isolation, but is rather only one part of the child’s clinical picture. Routine EEG, obtained in the outpatient setting, is usually brief (< 30 minutes). Therefore, events of interest are usually not recorded. If the child is unable to cooperate, it may be impossible to obtain a study, or the study may be uninterruptable due to artifact from movement, crying, etc. Medications used for sedation of an uncooperative child, especially barbiturates and benzodiazepines, may produce artifact or iatrogenic changes in the EEG, which can confuse interpretation and may decrease the likelihood of recording abnormalities such as epileptiform discharges. In addition, children without a history of epilepsy may, in fact, have an abnormal EEG. EEG findings such as those occasionally seen in migraine, learning disabilities, or behavior disorders are often nonspecific and do not reflect structural brain damage or dysfunction. When questions arise regarding the clinical significance of EEG findings, consultation with a pediatric neurologist is appropriate.

Due to more prolonged duration, ambulatory EEG obtained over 24–72 hours can be useful in capturing and assessing events to ascertain if they are due to epileptic seizures. Likewise, recording the EEG during nocturnal polysomnograms can help differentiate between nonepileptic sleep-related events from nocturnal epileptic seizures.

Prolonged or continuous inpatient EEG recordings are useful in the assessment of patients with altered mental status, suspected nonconvulsive status epilepticus, and drug-induced coma, as well as infants with hypoxic ischemic encephalopathy. The EEG is less commonly helpful in determining electrocerebral silence (brain death).

A continuous video-EEG recording, obtained in conjunction with inpatient admission to an epilepsy monitoring unit (EMU), allows assessment of the patient with medically intractable epilepsy. The children are admitted to a specialized inpatient unit for up to a week or more, sometimes with reduction or discontinuation of medication, increasing the likelihood of recording an event. Localization of the seizure focus by EEG recording during seizures can indicate candidacy of surgical resection or other surgical procedures for patients who have failed medical therapy. Correlating video with EEG has also proven useful in characterizing spells that may or may not be seizures.

Evoked Potentials

Visual-, auditory-, or somatosensory-evoked potentials (evoked responses) can be obtained by repetitive stimulation of the retina by light flashes, the cochlea by sounds, or a nerve by galvanic stimuli. These stimuli result in cortical responses recorded from the scalp surface. The presence or absence of evoked potential waves and their latencies from the time of the stimuli can be useful in some specific situations, such as the use of visual-evoked potentials (VEP) in patients with optic neuritis, multiple sclerosis (MS), or other demyelinating diseases, as well as somatosensory-evoked potentials (SSEP) in the monitoring of patients during spinal surgery for rapid identification of potentially reversible spinal cord injury. Similar techniques are used in other surgeries when there is risk of nerve injury such as craniofacial surgeries. However, evoked potentials are not routinely obtained for evaluation of neurologic disorders. One important exception is the use of brainstem auditory-evoked responses (BAER), which are now considered standard for screening hearing in neonates.

Lumbar Puncture

Spinal fluid is usually obtained by inserting a small-gauge needle (eg, No. 22) through the L3–L4 intervertebral space into the thecal sac while the patient is lying in a lateral recumbent position. Radiographic guidance and sedation may be necessary in some patients. After an opening pressure is measured, fluid is removed to examine for evidence of infection, inflammation, or metabolic disorders (Table 25–2). Special staining techniques can be used for mycobacterial and fungal infections, and further testing can be performed for specific viral agents, antibody titer determinations, cytopathologic studies, lactate and pyruvate concentrations, amino acid levels, and neurotransmitter analysis. Lumbar puncture is imperative when bacterial meningitis is suspected. Caution must be exercised, however, when signs of increased intracranial pressure (eg, papilledema) or focal neurologic signs are present that might indicate a substantial risk of precipitating tentorial or tonsillar herniation.

Genetic/Metabolic Testing

The diagnostic yield of genetic and metabolic evaluation of children with global developmental delay or intellectual disability (GDD/ID) depends on the specific testing done. Chromosomal microarray testing is diagnostic in almost 8% of children with GDD/ID and in other appropriate clinical situations; tests for metabolic disorders have a yield of up to 5%. Thus, focused assessments for genetic disorders should be part of the evaluation of the child with GDD/ID.

Electromyography & Nerve Conduction Velocity Testing

Electromyography (EMG) and nerve conduction velocity testing (NCV) are used for assessment of multiple neuromuscular disorders, including spinal muscular atrophy, Guillain-Barre syndrome, defects in neuromuscular transmission such as myasthenia gravis and infantile botulism, myopathies, acquired and hereditary neuropathies, leukodystrophies, and disorders associated with central as well as peripheral demyelination.

NCV is performed by introducing a small current into peripheral nerves and calculating the conduction velocity of the stimulus. EMG records spontaneous and volitional electrical activity of skeletal muscle tissue. It requires placement of needles into selected muscles. For more details, refer to section within this chapter entitled “Disorders of Childhood Affecting Muscles.”

PEDIATRIC NEURORADIOLOGIC PROCEDURES

Computed Tomography

CT scanning allows visualization of intracranial contents by obtaining a series of cross-sectional roentgenograms. Current scanning techniques allow rapid acquisition of data, often without sedation. CT scanning has high sensitivity (88%–96% of lesions larger than 1–2 cm can be seen), but low specificity (tumor, infection, or infarct may look the same). It is particularly useful for assessment of head trauma, allowing excellent visualization of intracranial blood. It allows visualization of the ventricular system to assess hydrocephalus. It is useful in determining the presence of intracranial calcifications such as those associated with intrauterine infections, tubers in patients with tuberous sclerosis complex, etc. Intravenous injection of iodized contrast media may be helpful in some situations but is not routinely used for the purposes of neuroimaging. CT angiography (CTA) is possible using contrast and specialized techniques to visualize vascular anatomy and can replace catheter angiography in evaluation of stroke. When ordering CT scan of the head as well as repeated CT scans, consider radiation exposure. A single CT scan of the head is approximately 2 millisieverts (mSv; typical chest x-ray PA view = 0.02 mSv), which equates to ~8 months of exposure to the naturally occurring radiation in the environment. The additional lifetime risk of malignancy is thought to be 1 brain tumor per 10,000 patients in the 10 years following CT exposure.

Magnetic Resonance Imaging

MRI provides high-resolution images of soft tissues by detecting the response (resonance) of hydrogen protons to electromagnetic radiation. The strength of MRI signals varies with the relationship of water to protein and lipid in tissue. MRI can provide information about the histological, physiological, and biochemical status of tissues, as well as gross anatomic features. Sedation usually is necessary for MRI scans in children who are unable to lie still for 45 minutes to avoid movement artifact.

MRI is used to assess a wide variety of neurologic disorders such as tumors, edema, ischemic and hemorrhagic lesions, vascular disorders, inflammation, demyelination, CNS infection, metabolic disorders, and degenerative processes. Because bone does not produce artifact in the images, the posterior fossa contents can be studied far better with MRI than with CT scans, allowing imaging of the brainstem, blood vessels, and cranial nerves. The lack of ionizing radiation exposure is an advantage over CT.

Magnetic resonance angiography (MRA) or venography (MRV) is used to visualize large extra- and intracranial blood vessels, though they are not as sensitive as conventional angiography. Perfusion-weighted imaging and diffusion-weighted imaging (DWI) (measuring random motion of water molecules) are used to evaluate brain ischemic penumbra and cytotoxic edema in acute stroke as well as toxic and metabolic brain disorders.

MR spectroscopy (MRS) assesses biochemical changes in CNS tissue, measuring signals of increased cellular activity and oxidative metabolism such as occur, for example, in brain tumors.

Newer functional MRI (fMRI), can localize various brain functions such as language and motor activity by assessing blood oxygenation changes in an area of interest during language or motor tasks. The axonal tracts of neurologic pathways, such as the optic radiations or motor system, can be identified using diffusion tensor imaging (DTI). These techniques generally require a team involving a neuropsychologist and radiologist to derive specific paradigms for testing and evaluation of imaging, as well as a cooperative patient.

Positron Emission Tomography

Positron emission tomography (PET) uses radiolabeled substrates such as intravenously administered fluorodeoxyglucose to measure the metabolic rate at given sites within the brain, producing three-dimensional reconstructions for localization of CNS function. These scans may be co-registered with a traditional CT scan or MRI, allowing more precise localization of functional processes, particularly for example in preoperative evaluation for epilepsy surgery. PET is most often performed in the interictal state. The information from PET scans complement EEG, single-photon emission computerized tomography (SPECT), and MRI findings to aid in defining the epileptogenic zone (“focus”) of a patient’s seizures. PET co-registered with CT scans or MRI scans is particularly useful for assessing systemic tumors, as well as general assessment of the CNS.

Single-Photon Emission Computerized Tomography (SPECT Scans)

SPECT scans image cerebral blood flow using a radioactive tracer (typically technetium-99m) to produce multiple cuts similar to those obtained in CT scans. This allows virtual three-dimensional visualization of vascular blood flow. It is useful in assessment of patients for epilepsy surgery, aiding in identification of increased blood flow in a seizure focus during a seizure. In children with brain tumors, SPECT can help differentiate tumor recurrence from post-treatment changes, assessing the response to treatment, directing biopsy, and planning therapy. Regional cerebral blood flow can be assessed in children with strokes due to vascular stenosis and moyamoya syndrome.

Ultrasonography

Ultrasonography (US) allows assessment of brain structures quickly with easily portable equipment, without ionizing radiation, and at about one-fourth the cost of CT scanning. Sedation is usually not necessary, and the procedure can be repeated as often as needed without risk to the patient. The thin skull and the open anterior fontanel in neonates facilitate imaging of the brain to screen and follow neonates at risk for intracranial hemorrhage and detect hydrocephalus, periventricular ischemic lesions, major brain and spine malformations, and calcifications. Once the fontanels start to close, this modality is no longer useful due to inability of ultrasound waves to penetrate bone.

Cerebral Angiography

Arteriography remains useful in the diagnosis of cerebrovascular disorders, particularly ischemic and hemorrhagic stroke, as well as potentially operable vascular malformations. In some brain tumors, arteriography may be used to define the nature of tumors and for surgical planning. Since cerebral angiography uses traditional x-ray to produce images, there is significant exposure to ionizing radiation.

Myelography

Radiographic examination of the spine may be indicated in some cases of spinal cord tumors, myelitis, or various forms of spinal dysraphism, and in the rare instance of herniated disks in children, although MRI has largely replaced sonography, CT, and myelography for such purposes.

ALTERED STATES OF CONSCIOUSNESS (COMA)

Consciousness encompasses both the patient’s level of wakefulness and the patient’s ability to interact with the environment. The neurologic substrate for consciousness is the ascending reticular activating system (RAS) comprised of the reticular formation in the brainstem, thalamic intralaminar nuclei, and portions of the hypothalamus. Dysfunction of the cerebral cortex, especially bilateral lesions, can also cause coma.

Clinical Findings

A. Symptoms and Signs

Many terms, including obtundation, lethargy, somnolence, stupor, and coma, are used to describe the continuum from fully alert and aware, to complete unresponsiveness. Physicians can use a scale, such as the commonly used Glasgow Coma Scale summarized in Table 12–4, but they should also provide qualitative descriptions such as, “opens eyes with painful stimulus, but does not respond to voice.” These descriptions help subsequent observers quantify unconsciousness and evaluate changes in the patient’s condition. Coma is defined by the complete absence of wakefulness and interaction with the environment for at least 1 hour. When coma persists, evaluation for the presence of sleep-wake cycles or absence of all brain function can further delineate the severity of the disorder of consciousness (Table 25–3).

• Persistent or permanent vegetative state (PVS) denotes a chronic condition (persistent if > 4 weeks; permanent if > 3–12 months, depending on etiology) in which sleep-wake cycles are preserved, but the patient has no awareness of self or the environment. PVS is sometimes referred to as “wakefulness without awareness.”

• Minimally conscious state (MCS) denotes patients who demonstrate sleep-wake cycles and some residual degree of interaction with the environment. For instance, these patients occasionally may have purposeful movements. Thus, MCS involves “partial preservation of consciousness.”

• Brain death (death by neurologic criteria) refers to patients in coma who have cessation of all brain function, including cortical activity, brainstem reflexes, and spontaneous respirations.

B. Laboratory and Imaging Diagnostics

Medical causes account for 90% of cases of coma in children; structural causes comprise the remaining 10% (Table 25–4). If the cause of the coma is not obvious, emergency laboratory tests must be obtained, such as blood glucose, complete blood count, urine studies (obtained by catheterization if necessary), pH and electrolytes (including bicarbonate), serum urea nitrogen, liver function tests, and ammonia. Urine, blood, and even gastric contents can be sent for toxin screens if the underlying cause is not obvious. Infection is a common cause (30%), and blood cultures and lumbar puncture often are necessary. However, papilledema or focal neurologic deficits are relative contraindications to lumbar puncture prior to imaging. In obscure cases of coma, additional testing might include oxygen and carbon dioxide partial pressures, serum and urine osmolality, porphyrins, lead, amino acids, and urine organic acids.

If severe head trauma, intracranial hemorrhage, or increased intracranial pressure is suspected, an emergency CT scan or MRI is necessary. CT is typically faster and superior to MRI for detecting small hemorrhages, but MRI is more sensitive in detecting stroke and anoxic brain injury. Abbreviated MRI protocols are also increasingly being used to rule out hemorrhage and hydrocephalus, sparing the patient from unnecessary ionizing radiation exposure from a CT. Bone windows on CT or skull radiographs may demonstrate skull fractures better. The absence of skull fracture does not rule out coma caused by closed head trauma, such as from abusive head trauma. Treatment of head injury associated with coma is discussed in detail in Chapter 12.

EEG can sometimes aid in diagnosing the cause of coma, such as with nonconvulsive status epilepticus, a specific abnormality (such as periodic lateralized epileptiform discharges seen with herpes encephalitis), or focal slowing (such as with stroke or cerebritis). The EEG also may correlate with the stage of coma and add prognostic information.

Differential Diagnosis

Conditions mistaken for coma:

• Locked-in syndrome describes patients who are conscious (awake and aware) but cannot demonstrate interactiveness with their environment due to a massive loss of motor function, typically due to a lesion in the pons. Vertical eye movements may be preserved.

• Akinetic-mutism denotes a patient who is awake and aware, but does not speak, initiate movements, or follow commands, typically due to lesions of the frontal lobes.

• Catatonia refers to patients with abnormal alertness and awareness (though typically not completely absent) secondary to psychiatric illness. Patients often retain the ability to maintain trunk and limb postures.

Treatment

As with any emergency, the clinician must first stabilize the comatose child using the ABCs of resuscitation. Signs of intracranial pressure and impending brain herniation are another priority of the initial assessment. Bradycardia, high blood pressure, and irregular breathing (Cushing’s Triad) or third nerve palsy (with the eye deviated down and out), and a “blown” pupil (unilateral pupillary dilation) indicate prompt neurosurgical consultation and head CT. Initial treatment of impending herniation includes elevating the head of the bed to 15–30 degrees and providing moderate hyperventilation. The use of mannitol, hypertonic saline, pharmacologic coma, hypothermia, and drainage of cerebrospinal fluid (CSF) are more heroic measures covered in detail in Chapter 14.

Prognosis

About 50% of children with nontraumatic causes of coma have a good outcome. Outcome can be successfully predicted at an early stage in approximately two-thirds of patients by assessing coma severity, extraocular movements, pupillary reactions, motor patterns, blood pressure, temperature, and seizure type. In patients with severe head trauma, a Glasgow Coma Scale ≤ 5, hypothermia, hyperglycemia, and coagulation disorders are factors associated with an increased risk of mortality. Other characteristics such as the need for assisted respiration, the presence of increased intracranial pressure, and the duration of coma are not significantly predictive.

SEIZURES & EPILEPSY

A seizure is a sudden, transient disturbance of brain function, manifested by involuntary motor, sensory, autonomic, or psychic phenomena, alone or in any combination, often accompanied by alteration or loss of consciousness. Seizures can be caused by any factor that disturbs brain function. They may occur after a metabolic, traumatic, anoxic, or infectious insult to the brain (classified as symptomatic seizures), or spontaneously without prior known CNS insult. Genetic mutations are increasingly identified in many patients without prior known cause of seizures.

Epilepsy is defined as two seizures that are separated by at least 24 hours, a single seizure associated with a greater than 60% risk of recurrence or the diagnosis of an epilepsy syndrome. During childhood, the incidence is highest in the newborn period. Prevalence flattens out after age 10–15 years. The chance of having a second seizure after an initial unprovoked episode in a child is about 50%. The risk of recurrence after a second unprovoked seizure is 85%. Sixty-five to seventy percent of children with epilepsy will achieve seizure remission with appropriate medication.

Classification

The International League Against Epilepsy (ILAE) has established classifications of seizures and epilepsy syndromes. Seizures are classified as either focal, previously called partial (with suspected seizure onset that can be localized to one part of the brain), generalized (likely involving the whole brain or a network of the brain), or “unknown” if it is not clear if they are focal or generalized.

There are several types of generalized seizures that are recognized with the new classification: generalized tonic-clonic, absence (typical, atypical, and with special features), myoclonic, myoclonic atonic, tonic, clonic, and atonic seizures. New nomenclature is suggested for focal seizures that is based on the presentation of the seizure. The description of the seizure is most beneficial with suggested terms such as “without alteration of awareness,” “hyperkinetic,” “emotional,” or “autonomic” seizure. Such descriptions allow better classification of seizures.

Epilepsy syndromes are defined by the nature of the seizures typically present, age of onset, EEG findings, and other clinical factors. New terminology has been developed for epilepsy syndromes to reflect our growing understanding of underlying etiology. The newest classification allows for classification based on the information that is available at the time of the seizure, with a hierarchical approach whereby patients can be classified by types of seizures, epilepsy type (focal, generalized, combined or unknown), or a specific epilepsy syndrome. In parallel, patients may have an etiologic diagnosis (structural, genetic, infectious, etc.) and may have comorbid diagnoses (ADHD, depression, anxiety, etc.). Tools to aid in the classification of seizures and epilepsy syndromes can be found at the International League Against Epilepsy website https://www.ilae.org/education/diagnostic-manual.

1. Seizures & Epilepsy in Childhood

Characterizing the seizure and subsequent epilepsy syndrome is necessary for accurate diagnosis, which will determine the nature of further evaluation and treatment. This also assists with prognostication (Table 25–5) and research of specific syndromes.

Clinical Findings

A. Symptoms and Signs

Seizures are stereotyped paroxysmal clinical events; the key to diagnosis is usually in the history. Not all paroxysmal events are epileptic. A detailed description of seizure onset is important in determining if an event is a seizure and if there is localized onset (focal seizure). Events prior to, during, and after the seizure need to be ascertained. Although observers often initially recall little except generalized convulsive activity because of its dramatic appearance, careful detailed questions can lead to a better description of the event and situation in which it occurred. An aura may precede the clinically apparent seizure and indicates focal onset. The patient may describe a feeling of fear, numbness or tingling in the fingers, or bright lights in one visual field. The specific symptoms may help define the location of seizure onset (eg, déjà vu suggests temporal lobe onset). Often, the child does not recall or cannot define the aura, though the family may note alterations in behavior at the onset. Videotapes of events have been extremely useful.

Postictal states can be helpful in diagnosis. After many focal seizures and most generalized convulsive seizures, postictal sleep typically occurs. However, postictal changes are not seen after generalized absence seizures. It also helps to determine if there were loss of speech after the seizure (suggesting left hemisphere involvement) or if the patient were able to respond and speak in short order. The parent may report lateralized motor activity (eg, the child’s eyes may deviate to one side or the child may experience dystonic posturing of a limb). Motor activity without impaired awareness supports the diagnosis of focal seizures as do impaired awareness and automatisms previously defined as a “complex partial seizure.”

In contrast, generalized seizures usually manifest with acute loss of consciousness, usually with generalized motor activity. Tonic posturing, tonic-clonic activity, or myoclonus (spasms) may occur. In children with generalized absence seizures, behavioral arrest may be associated with automatisms such as blinking, chewing, or hand movements, making it difficult to differentiate between absence seizures and focal seizures.

Frequently, the child presenting with a presumed first seizure has experienced unrecognized seizures before the event that brings the child to medical attention. Focal, myoclonic, and absence seizures, in particular, may not be recognized except in retrospect. Thus, careful questioning regarding prior events is important in the child being evaluated for new onset of seizures. Events that are perceived as seizures but are not epileptic, such as syncopal events, can also be determined by careful questioning.

B. Diagnostic Evaluation

Many factors determine the extent and urgency of the diagnostic evaluation, such as the child’s age, the severity and type of seizure, whether the child is ill or injured, and the clinician’s suspicion about the underlying cause. Seizures in early infancy often have an underlying cause that is structural, genetic, or metabolic and will guide prognosis and management. Therefore, the younger the child, the more extensive must be the diagnostic assessment.

It is generally accepted that every child with new onset of unprovoked seizures should be evaluated with an EEG and MRI, although this need not be done emergently. An EEG is very unlikely to yield clinically useful information in the child with a febrile seizure. Other diagnostic studies should be used selectively.

Metabolic abnormalities are seldom found in the well child with seizures. Unless there is a high clinical suspicion of serious medical conditions (eg, uremia, hyponatremia, hypocalcemia, etc), “routine” laboratory tests rarely yield clinically significant information. Special studies may be necessary in circumstances that suggest an acute systemic etiology for a seizure, for example, in the presence of apparent renal failure, sepsis, or substance abuse. Emergent imaging of the brain is usually not necessary in the absence evidence of trauma or of acute abnormalities on examination.

C. Electroencephalography

The limitations of EEG even with epilepsy, for which it is most useful, are considerable. A routine EEG captures electrical activity during a very short period, usually 20–30 minutes. Thus, it is useful primarily for defining interictal activity (except for the fortuitous recording of a clinical seizure or in situations when seizures are easily provoked such as childhood absence epilepsy). A seizure is a clinical phenomenon; an EEG showing epileptiform activity may confirm and clarify the clinical diagnosis (for instance, defining an epilepsy syndrome), but it is only occasionally diagnostic (see EEG under diagnostic section earlier in chapter).

Differential Diagnosis

It is extremely important to be accurate in the diagnosis of epilepsy and not to make the diagnosis without ample proof. To the layperson, epilepsy often has connotations of brain damage and limitation of activity. A person so diagnosed may be excluded from certain occupations in later life. It is often very difficult to change an inaccurate diagnosis of many years’ standing.

Misinterpretation of behaviors in children is the most common reason for misdiagnosis. Psychogenic nonepileptic events are much less common in children than in adults but must be considered even in the young or cognitively impaired child. The most commonly misinterpreted behaviors are inattention in school-aged children with attention disorders, stereotypies in children with autistic spectrum disorder, sleep-related movements, habit movements such as head-banging and so-called infantile masturbation (sometimes referred to as gratification movements), and gastroesophageal reflux in very young (often impaired) infants. Some of the common nonepileptic events that mimic seizure disorder are listed in Table 25–6.

Complications & Sequelae

A. Psychosocial Impact

Emotional disturbances, especially depression but also anxiety, anger, and feelings of guilt and inadequacy, often occur in the patient as well as the parents of a child with epilepsy. Actual or perceived stigmas as well as issues regarding “disclosure” are common. There is an increased risk of suicide in people with epilepsy. Schools often limit activities of children with epilepsy inappropriately and stigmatize children by these limitations.

Epilepsy with onset in childhood has an impact on adult function. Adults with early onset of epilepsy, even when well controlled, are less likely to complete high school, have less adequate employment, and are less likely to marry. Persistent epilepsy results in significant dependence; even when epilepsy is successfully treated, patients with long-standing epilepsy often do not become independent due to driving restrictions and safety concerns.

B. Cognitive Delay

Children living with epilepsy, particularly with untreated or poorly controlled seizures, can develop reduced cognition and memory. Clearly, epileptic encephalopathy (ie, epileptic activity or frequent seizures are contributing to worse neurocognitive function) does occur, particularly in young children with epilepsies such as infantile spasms (West syndrome), Dravet syndrome, and Lennox-Gastaut syndrome. The impact of persistent partial seizures on development is less clear, although persistent temporal lobe seizures in adults are associated with cognitive dysfunction. It is not likely that interictal epileptiform activity contributes to cognitive impairment in older children, although increased epileptiform burden has been demonstrated to cause mild cognitive problems in some disorders previously thought to be benign, such as benign epilepsy with central temporal spikes (BECTS). Continuous epileptiform activity in sleep is associated with Landau-Kleffner syndrome (acquired epileptic aphasia) and the syndrome of electroencephalographic status epilepticus in sleep (ESES), both of which are associated with cognitive decline.

“Pseudodementia” may occur in children with poorly controlled epilepsy because their seizures interfere with their learning. Depression is a common cause of impaired cognitive function in children with epilepsy. Anticonvulsants are less likely to cause such interference at usual therapeutic doses, although phenobarbital, topiramate, and zonisamide may produce cognitive impairment, which is reversible on discontinuing the medication. Psychosis also can occur after seizures or as a side effect of medications.

C. Injury and Death

Children with epilepsy are at far greater risk of injuries than the general pediatric population. Physical injuries, especially lacerations of the forehead and chin, are frequent in atonic (previously called astatic) seizures (so-called drop attacks), necessitating protective headgear. In all other seizure disorders in childhood, injuries as a direct result of a seizure are not as common, although drowning, injuries related to working in kitchens, and falls from heights remain potential risks for all children with active epilepsy. It is therefore extremely important to stress “seizure precautions,” in particular water safety. Showers are recommended over bathing as they decrease the likelihood of drowning. Ultimately, patients with epilepsy should not participate in activities that could result in serious injury in the case of sudden loss of consciousness, without taking precautions to address that possibility. However, for most activities simple accommodations allow individuals with epilepsy to lead very normal lives.

The greatest fear of a parent of a child with new-onset of epilepsy is the possibility of death or brain injury. There is an increased risk of premature death in children with epilepsy, especially those who have not achieved seizure control. Most of the mortality in children with epilepsy is related to the underlying neurologic disorder, not the seizures. Sudden unexpected death with epilepsy (SUDEP) is a rare event in children. Although children with epilepsy have an increased risk of death, SUDEP occurs in only 1–2:10,000 patient-years. The greatest risk for SUDEP is in children with medically uncontrolled epilepsy. The etiology of SUDEP is not yet known and there is no current proven strategy to prevent SUDEP other than seizure control. Identifying life-threatening disorders (eg, identifying patients with cardiac arrhythmias, especially prolonged QT syndrome) as the cause of misdiagnosed epilepsy is clearly of utmost importance. While SUDEP is rare, increased mortality in children with epilepsy should be mentioned when counseling families.

Treatment

The ideal treatment of acute seizures is the correction of specific causes. However, even when a biochemical disorder, a tumor, meningitis, or another specific cause is being treated, anti-seizure drugs are often still required.

A. First Aid

Caregivers should be instructed to protect the patient against self-injury. Turning the child to the side is useful for preventing aspiration. Placing any objects in the mouth of a convulsing patient or trying to restrain tonic-clonic movements may cause worse injuries than a bitten tongue or bruised limb and could potentially become a choking hazard. Parents are often concerned that cyanosis will occur during generalized convulsive seizures, but it is rare for clinically significant hypoxia to occur. Mouth-to-mouth resuscitation is rarely necessary and is unlikely to be effective.

For prolonged seizures (those lasting over 5 minutes), acute home treatment with benzodiazepines such as rectal diazepam gel (Diastat) or intranasal midazolam may be administered to prevent the development of status epilepticus and has proven to be safe even when administered by nonmedical professionals, including teachers and day care providers, when appropriately instructed.

B. Antiepileptic Drug (AED) Therapy

1. Drug selection

Several issues should be considered when choosing an anti-seizure medication including effectiveness, side effects (good or bad), risk, and what other medications the patient is already taking. Some medications are good for focal seizures but can make generalized seizures worse (eg, oxcarbazepine and carbamazepine), while other medications are good for most seizure types and are relatively safe (levetiracetam). Many medications may be effective for most seizure types but are thought to be particularly good for certain seizures (clobazam for myoclonic seizures). It is worth noting that most of this “knowledge” is based on experience and expert opinion rather than comparative effectiveness or randomized control trials. In some cases, side effects can help guide treatment; for example, topiramate tends to suppress appetite whereas valproic acid often precipitates weight gain. When weighing risks, side effects, and potential effectiveness, one must consider the impact on the patient and their family’s life.

2. Treatment strategy

The goal of anti-seizure treatment is “no seizures and no side effects.” The child with a single seizure has a 50% chance of seizure recurrence. Thus, it is usually not necessary to initiate therapy until the diagnosis of epilepsy is established, that is, there is a second seizure. The seizure type and epilepsy syndrome as well as potential side effects will determine which drug to initiate as discussed earlier. If monotherapy fails, a second, and when necessary a third medication may be required to help reduce seizure frequency. Care must be taken when using multiple anti-seizure medications, as this increases the chance of side effects and often does not substantially improve seizure control. There is some evidence that anti-seizure medications with different mechanisms of action may improve their combined tolerability and effectiveness.

3. Long-term management and discontinuation of treatment

Therapy should be continued until the patient is free of seizures for at least 1–2 years. In about 75% of patients, seizures will not recur following discontinuation of medication after 2 years of remission. Variables such as younger age at onset, normal EEG, undetermined etiology, and ease of controlling seizures carry a favorable prognosis, whereas identified etiology, later onset, continued epileptiform EEG, difficulty in establishing initial control of the seizures, polytherapy, generalized tonic-clonic or myoclonic seizures, as well as an abnormal neurologic examination are associated with a higher risk of recurrence. Most AEDs (with the exception of barbiturates and benzodiazepines) can be withdrawn over 6–8 weeks. There does not appear to be an advantage to slower withdrawal.

Recurrent seizures affect up to 25% of children who attempt withdrawal from medications. Recurrence of seizures is most likely within 6–12 months of discontinuing medications. Therefore, seizure safety precautions will need to be reinstituted, including driving restriction. If seizures recur during or after withdrawal, AED therapy should be reinstituted and maintained for at least another 1–2 years. The majority of children will again achieve remission of their seizures.

C. Alternative Treatments

1. Adrenocorticotropic hormone (ACTH) and corticosteroids

Treatment with ACTH or oral corticosteroids is the standard of care for infantile spasms. Duration of therapy is guided by cessation of clinical seizures and normalization of the EEG. Vigabatrin is an alternative treatment that is also considered standard of care for infantile spasms and has been shown to be superior for infantile spasms resulting from tuberous sclerosis. All other treatments for infantile spasms have a lower likelihood of being effective.

Precautions: It is important to guard against infections, provide GI prophylaxis, and follow for possible hypertension, and discuss the cushingoid appearance and its disappearance. Oral corticosteroids should not be withdrawn suddenly. Side effects in some series occur in up to 40% of patients. In some regions of the country, prophylaxis against Pneumocystis infection may be required. Careful and frequent follow-up is necessary. Visiting nurse services and partnering with a medical home can be very helpful in surveillance such as monitoring blood pressure, weight, and potential adverse effects.

2. Ketogenic diet

Fasting has been described to stop seizures for centuries and a diet high in fat and low in protein and carbohydrates will result in ketosis and simulate a fasting state. Such a diet has been observed to decrease and even control seizures in some children. This diet should be monitored very carefully (by a clinical team familiar with the ketogenic diet) to ensure sufficient nutrients, including vitamins and minerals, to maintain overall health. Recent reports suggest potential efficacy with a modified Atkins diet or a low-glycemic index diet in older and higher functioning children who will not accept the ketogenic diet.

The mechanism for the anticonvulsant action of the ketogenic diet is not understood. The ketogenic diet requires close adherence and full cooperation of all family members. However, when seizure control is achieved by this method, acceptance of the diet is usually excellent. Families must be cautioned that abrupt withdrawal (accidental or purposeful) of the diet can precipitate seizures and even status epilepticus. Increased use of the ketogenic diet and family support groups have increased the number of palatable recipes for patients and families on the ketogenic diet.

As with all therapies, potential adverse effects can occur with the ketogenic diet. These include acidosis and hypoglycemia, particularly on initiation of the diet. The child should be admitted to a center well versed in managing ketogenic diet to start this treatment. Close follow-up will help prefent risk for renal stones, pancreatitis, and acidosis. In addition, vitamin and minerals need to be followed carefully to avoid deficiencies, especially carnitine, iron, and vitamin D.

3. Vagus nerve stimulator (VNS)

The VNS is a pacemaker-like device that is implanted below the clavicle and attached to the left vagus nerve. A cycle of electrical stimulation of the nerve is established, which has an antiepileptic effect, reducing seizures by at least 50% in over half the children treated. In addition, an emergency mode that is activated by swiping a magnet (of abrupt tachycardia on newer models) may interrupt a seizure. With current technology, the battery in the stimulator may last 7 or more years in many patients.

D. Surgery

An evaluation for epilepsy surgery is indicated for all children with medically intractable partial epilepsy (generally defined as failure of two anti-seizure medications at effective doses). The evaluation and surgery should be performed at a center with expertise in epilepsy surgery and which has a dedicated neurosurgeon, epileptologists and neuropsychologists with experience in epilepsy surgery.

The first surgery for treatment of epilepsy took place over 100 years ago, and surgery is now established as an appropriate treatment option for adults and children with epilepsy refractory to medical treatment. Evaluation for possible surgical treatment should begin as soon as it is apparent that a child with focal onset seizures is not responding to standard therapy. Medication resistant (“refractory”) epilepsy is usually defined as failure of two or three anti-epileptic drugs alone or as combination therapy to control seizures. Advances in technology allow for definition and removal of the epileptogenic focus even in young infants. Many centers now have access to variety of resources for identifying the region of seizure onset. Ultimately, the chance of seizure freedom can range from 50% to 95% depending on the clinical circumstance. Some children with more generalized seizures may qualify for other types of surgery, such as corpus callosotomy, that aim to reduce seizure burden.

E. General Management of the Child with Epilepsy

1. Education

The initial diagnosis of epilepsy is often devastating for families. The patient and parents must be helped to understand the nature of epilepsy and its management, including etiology, prognosis, safety issues, and treatment options.

Excellent educational materials are available for families of a child with epilepsy, both in print and online. An excellent website is http://www.epilepsy.com. Materials on epilepsy—including pamphlets, monographs, films, and videotapes suitable for children and teenagers, parents, teachers, and medical professionals—may be purchased through the Epilepsy Foundation: 8301 Professional Place, Landover, MD 20785; (800) 332–1000. The foundation’s local chapter and other community organizations are able to provide guidance and other services. Support groups exist in many regions for older children and adolescents and for their parents and others concerned.

2. Privileges and precautions in daily life

“No seizures and no side effects” is a motto established by the Epilepsy Foundation. The child should be encouraged to live as normal a life as possible. Children should engage in physical activities appropriate to their age and social group. After seizure control is established, swimming is generally permissible with a buddy system or adequate lifeguard coverage. Scuba diving and high climbing without safety harness is generally not allowed. There are no absolute contraindications to any other sports, although some physicians recommend against contact sports. Physical training and sports are usually to be welcomed rather than restricted. There is some literature that suggests that exercise decreases overall seizure burden and may also be helpful to maintain good bone health.

Depression, anxiety, and attentional difficulties are common comorbidities of epilepsy, particularly in adolescents, and need to be treated as they can be as (or more) debilitating as the seizures. Sleep deprivation and alcohol should be avoided as they can be triggers for seizures for patients with epilepsy. Prompt attention should be given to intercurrent illnesses that can also trigger seizures.

Although every effort should be made to control seizures, treatment must not interfere with a child’s ability to function normally. A child may do better having an occasional mild seizure than being so heavily sedated that function at home, in school, or at play is impaired. Therapy and medication adjustment often require much art and fortitude on the physician’s part.

3. Driving

Driving becomes important to most young people at age 15 or 16 years. Restrictions for persons with epilepsy and other disturbances of consciousness vary from state to state. In most states, a learner’s permit or driver’s license will be issued to an individual with epilepsy if he or she has been under a physician’s care and free of seizures for at least 6–12 months provided that the treatment or basic neurologic problems do not interfere with the ability to drive. A guide to this and other legal matters pertaining to persons with epilepsy is published by the Epilepsy Foundation, and its legal department may be able to provide additional information.

4. Pregnancy

Contraception (especially interaction of oral contraceptive with some AEDs), childbearing, potential teratogenicity of AEDs, and the management of pregnancy should be discussed as soon as appropriate with the adolescent young woman with epilepsy. Daily use of vitamin preparations and high-dose folic acid can be protective against neural tube defects. For the pregnant teenager with epilepsy, management by an obstetrician conversant with the use of AEDs in pregnancy is appropriate. The patient should be cautioned against discontinuing her medications during pregnancy. The possibility of teratogenic effects of AEDs, such as facial clefts (two to three times increased risk), must be weighed against the risks from seizures. All AEDs appear to have some risk for teratogenicity, although valproate carries a particularly high risk for spinal dysraphism as well as being associated with cognitive issues in children exposed to valproate in utero. Dosing may need to be adjusted frequently during pregnancy as blood volume expands. Frequent AED blood levels may be helpful in making these adjustments.

5. School intervention and seizure response plans

Schools are required by federal law to work with parents to establish a seizure action plan for their child with epilepsy. A template for such a plan is available on the Epilepsy Foundation website at https://www.epilepsy.com/sites/core/files/atoms/files/130SRP_MySeizureResponsePlan-fillable.pdf. These plans usually require the approval of the child’s physician. Schools are sometimes hesitant to administer rescue medications. Often, information from the physician, especially that obtained from the Epilepsy Foundation website, will relieve anxieties. School authorities should be encouraged to avoid needless restrictions and to address the emotional and educational needs of all children with disabilities, including epilepsy. The local affiliates of the Epilepsy Foundation can often provide support and education for both families and schools.

2. Status Epilepticus

Status epilepticus is usually defined as a clinical or electrical seizure lasting at least 15 minutes, or a series of seizures without complete recovery over a 30-minute period. Importantly, this time cut-off keeps getting shorter as more evidence accrues that even relatively short seizures may be harmful to the brain. After 30 minutes of seizure activity, hypoxia and acidosis occur, with depletion of energy stores, cerebral edema, and structural damage. Eventually, high fever, hypotension, respiratory depression, and even death may occur. Status epilepticus is a medical emergency. Aggressive treatment of prolonged seizures may prevent development of status epilepticus. It is generally recommended that treatment with benzodiazepines at home for prolonged seizures be initiated 5 minutes after onset of a seizure. There are currently several forms of benzodiazepines that can be administered safely at home, including rectal valium, intranasal midazolam, sublingual lorazepam, and intramuscular diazepam.

Status epilepticus is classified as (1) convulsive (the common generalized tonic-clonic type) or (2) nonconvulsive (characterized by altered mental status or behavior with subtle or absent motor components). Absence status, or spike-wave stupor, and focal status epilepticus are examples of the nonconvulsive type. An EEG may be necessary to aid in diagnosing nonconvulsive status because patients sometimes appear merely stuporous and lack typical convulsive movements. Status epilepticus that has not responded to two medications is considered refractory status epilepticus and often requires care in an intensive care unit.

Treatment

For treatment options, see Table 25–7.

3. Febrile Seizures

Clinical Findings

A. Symptoms and Signs

Criteria for febrile seizures are (1) age 3 months to 6 years (most occur between ages 6 and 18 months), (2) fever of greater than 38.8°C, and (3) non-CNS infection. More than 90% of febrile seizures are generalized, last less than 5 minutes, and occur early in the illness causing the fever. Often the fever is not noted until after the seizure occurs. Febrile seizures occur in 2%–3% of children. Acute respiratory illnesses are most commonly associated with febrile seizures. Gastroenteritis, especially when caused by Shigella or Campylobacter, and urinary tract infections are less common causes. Roseola infantum is a rare but classic cause. One study implicated viral causes in 86% of cases. HHV-6 and HHV-7 are common causes for febrile status epilepticus, both accounting for one-third of cases. Febrile seizures rarely (1%–3%) evolve to recurrent unprovoked seizures (epilepsy) in later childhood and adult life (risk is increased two- to fivefold compared with children who do not have febrile seizures). The chance of later epilepsy is higher if the febrile seizures have complex features, such as duration longer than 15 minutes, more than one seizure in the same day, or focal features. Other predictive factors are an abnormal neurologic status preceding the seizures (eg, cerebral palsy or mental retardation), early onset of febrile seizure (before age 1 year), and a family history of epilepsy. Even with adverse factors, the risk of epilepsy after febrile seizures is still only in the range of 15%–20%, although it is increased if more than one risk factor is present. Recurrent febrile seizures occur in 30%–50% of cases. Therefore, families should be prepared to expect more seizures. In general, recurrence of febrile seizures does not worsen the long-term outlook.

B. Diagnostic Evaluation

The child with a febrile seizure must be evaluated for the source of the fever, in particular to exclude CNS infection. Routine studies such as serum electrolytes, glucose, calcium, skull radiographs, or brain imaging studies are seldom helpful unless warranted based on clinical history or suspicion of abuse. History and the examination should guide the work-up and any treatment amenable underlying infection should be addressed. Meningitis and encephalitis must be considered. Signs of meningitis (eg, bulging fontanelle, stiff neck, stupor, and irritability) may be absent, especially in a child younger than age 18 months.

C. Lumbar Puncture

After controlling the fever and stopping an ongoing seizure, the physician must decide whether to do a lumbar puncture. The fact that the child has had a previous febrile seizure does not rule out meningitis as the cause of the current episode. It is very important, especially in younger children, to exclude CNS infection as a source; these children are not classified as having a febrile seizure. A recent study demonstrated that 96% of children with febrile status epilepticus who received an LP had less than three WBC in the CSF. Therefore, seizure should not be an acceptable explanation for elevated cells in the CSF. Although the yield is low, a lumbar puncture should probably be considered done if the child is younger than age 18 months, and has been pretreated with antibiotics or is under-immunized. Certainly any child with meningeal signs fever and seizure should have an examination of their CSF. Occasionally observation in the emergency department for several hours obviates the need for a lumbar puncture, but in general one should have a low threshold for performing this potentially life-saving test.

D. EEG

EEG is rarely useful. An EEG may be considered if the febrile seizure is complicated, focal, or otherwise unusual, but has little predictive value. In uncomplicated febrile seizures, the EEG is usually normal. If performed, the EEG should be done at least a week after the illness to avoid transient changes due to fever or the seizure itself. In older children, 3-Hz spike-wave discharges, suggestive of a genetic propensity to epilepsy, may occur. In the young infant, EEG findings seldom aid in assessing the chance of recurrence of febrile seizures or in long-term prognosis. Thus, EEG is not recommended for the child with simple febrile seizures.

Treatment

Prophylactic anticonvulsants are not recommended after a febrile seizure. Only phenobarbital and valproic acid have demonstrated efficacy in preventing febrile seizures; phenytoin and carbamazepine have been shown to be ineffective. Newer antiepileptic drugs have not been studied. Diazepam started at the first onset of fever for the duration of the febrile illness (0.5 mg/kg two or three times per day orally or rectally) may be effective but will sedate a child and possibly complicate the evaluation for a source of the fever. Prophylactic diazepam is also limited by the fact that a seizure is often the first evidence of fever associated with an acute illness. Diastat (rectal diazepam gel) can be used to prevent febrile status epilepticus in the child with a prolonged febrile seizure (one lasting over 5 minutes), often the greatest concern.

Measures to control fever such as sponging or tepid baths, antipyretics, and the administration of antibiotics for proven bacterial illness are reasonable but unproven to prevent recurrent febrile seizures.

Prognosis

Simple febrile seizures do not have any long-term adverse consequences. As noted earlier, there is only a small increase in the risk of developing epilepsy. Cognitive function is not significantly different from that of siblings without febrile seizures.

SLEEP DISORDERS

Sleep disorders can originate from abnormalities within the respiratory system, the neurologic system and the coordination (or lack thereof) between these two systems. In order to understand abnormal sleep, one must understand normal sleep, which changes as the child develops. Sleep and its development are reviewed in Chapter 3. Chapter 3 also discusses behavioral considerations in the treatment of sleep disorders. Respiratory abnormalities that are associated with sleep such as obstructive sleep apnea are described in Chapter 19. This discussion focuses on neurologic features of several sleep disorders affecting children.

1. Narcolepsy

Narcolepsy, a primary disorder of sleep, is characterized by chronic, inappropriate daytime sleep that occurs regardless of activity or surroundings and is not relieved by increased sleep at night. One half of individuals affected by narcolepsy experience their initial symptoms in childhood. Of children with narcolepsy, 4% are under age 5, 18% are younger than age 10, and 60% are between puberty and their late teens.

Additional symptoms are cataplexy, hypnagogic and/or hypnopompic hallucinations (visual or auditory), and sleep paralysis. Cataplexy is a transient partial or total loss of muscle tone, often triggered by laughter, or other heightened emotional states. Consciousness is preserved during these spells, which can last several minutes in duration. Most patients with narcolepsy will develop cataplexy (60%–90%). Hypnagogic hallucinations are intense visual or auditory hallucinations noted while falling asleep, whereas hypnopompic hallucinations occur while waking from sleep. Sleep paralysis is a brief loss of voluntary muscle control typically occurring at sleep-wake transitions and lasting for minutes.

Abnormally short latency between sleep onset and transition into rapid eye movement (REM) sleep occurs in subjects with narcolepsy. The first cycle of REM sleep usually occurs after 80–100 minutes in normal children. Nocturnal polysomnography and Multiple Sleep Latency Testing (MSLT) can demonstrate abnormal REM latency and are used to diagnose narcolepsy. Human leukocyte antigen (HLA) subtypes DQB1*0602 and DRB1*1501 are associated with narcolepsy, as well as absence of a hypothalamic neuropeptide, hypocretin, which can be measured in CSF. Sleep hygiene and behavior modification are used to treat patients with narcolepsy. In general, medications used for the treatment of narcolepsy in children are off label. CNS stimulants such as amphetamine mixtures are typically used to treat excessive daytime sleepiness. Modafinil and sodium oxybate are an effective treatment in adults; controlled studies in children are lacking. Cataplexy responds to fluoxetine, clomipramine, or sodium oxybate.

2. Benign Neonatal Sleep Myoclonus

Benign neonatal sleep myoclonus is characterized by myoclonic jerks, usually bilateral and synchronous, which occur only during sleep and stop abruptly when the infant is aroused. It is a benign condition that is frequently confused with epileptic seizures. Onset is typically in the first 2 weeks of life and resolves spontaneously in the first months of life, although these may occur as late as 10 months. Clusters of jerks may last from a few seconds up to 20 minutes.

3. Nocturnal Frontal Lobe Epilepsy

Nocturnal frontal lobe epilepsy (NFLE) is characterized by paroxysmal arousals from NREM sleep with hypermotor seizures characterized by bizarre stereotyped hyperkinetic of dystonic motor movements lasting up to 5 minutes. NFLE is a heterogeneous disorder which includes both sporadic and familial forms. Lack of definitive epileptiform abnormalities on EEG recordings may lead to misdiagnoses of a parasomnia, such as night terrors or somnambulism.

4. Parasomnias

Parasomnias are abnormal behavioral or physiologic events that occur in association with various sleep stages or the transition between sleeping and waking. The parasomnias of childhood are divided into those occurring in non-REM sleep (NREM) and REM sleep. The NREM parasomnias consist of partial arousals, disorientation, and motor disturbances and include sleep-walking (somnambulism), sleep talking, confusional arousals, and night terrors, among others. These are discussed in more detail in Chapter 3. The REM sleep parasomnias include nightmares, hypnagogic and hypnopompic hallucinations (as can occur in narcolepsy), and REM sleep behavior disorder, which is characterized by physical and sometimes violent movements during the dream state, and is primarily seen in adulthood. These typically occur during the second half of sleep, when REM comprises a larger part of the sleep cycle.

5. Restless Legs Syndrome

Restless legs syndrome refers to a feeling of needing to move the legs (dysesthesia) that often starts when resting at night. Movement of the legs temporarily relieves the symptoms, though this can interfere with the ability to fall asleep. This disorder can be familial; therefore, a detailed family history may be helpful. Occasionally, anemia (low ferritin) has been noted in adults and children with the disorder; in these cases, improvement has occurred with ferrous sulfate treatment. These are discussed in more detail in Chapter 3.

HEADACHES

Headaches are common in children and adolescents and health providers need to recognize and differentiate the common from the more serious causes of headaches. Approximately 45% of children experience at least one debilitating headache, and up to 28% of adolescents have migraines. First, the clinician must determine if the headache is primary or secondary. Symptoms and signs are the center of evaluation; however, red flags (Table 25–8) may prompt further workup and evaluation. Correct diagnosis of headache disorders will guide treatment and management.

Clinical Findings

A. Symptoms and Signs

Based on the 2013 International Classification of Headache Disorders, 3rd Edition (beta version) (ICHD-III beta), primary headaches are divided into three major categories: migraine, tension-type, and trigeminal autonomic cephalalgias. Clinical features of migraine without aura and tension-type headache are compared in Table 25–9. Individuals with greater than 15 headaches (migraine or tension-type) per month are considered chronic, and medication overuse must be excluded. Triggers of head pain can include stress, sleep deprivation, dehydration, skipped meals, caffeine, and possibly specific foods (eg, monosodium glutamate or nitrites). Trigeminal autonomic cephalalgias (or sub-category, cluster headache) are rare in children. They present as recurrent, unilateral severe headaches with autonomic dysfunction (watery eye, congestion, facial sweating, miosis, ptosis).

According to the ICHD-III beta, migraines include childhood periodic syndromes such as cyclic vomiting, abdominal migraine, and benign paroxysmal vertigo of childhood. History of these periodic syndromes may be discovered in children and adolescents with migraines. Infantile colic may also be a precursor or early manifestation of migraine.

B. Laboratory Findings

Routine laboratory testing has not been found to be helpful, though the evidence is limited. History and examination may prompt screening for general medical conditions as indicated.

C. Imaging Studies

Routine neuroimaging is not indicated for children presenting with recurrent headaches and a normal neurologic examination. Red flags as noted in Table 25–8 should at least prompt consideration of imaging. The type of imaging (CT vs MRI) depends on the urgency of evaluation (ie, acute onset severe headache vs worsening headache over 1–2 weeks). See the discussion on pediatric neuroradiologic procedures for discussion on benefits of different imaging modalities.

Differential Diagnosis

Secondary causes of headache include broad categories such as head trauma, infection, vascular, intracranial pressure changes, structural, metabolic, toxic, medication, illicit drug related, and hematologic (Table 25–10). Headaches associated with head trauma are those that start within 2 weeks of closed head injury. They can have either features of migraines or tension-type headaches. Neck pain and headache after head trauma warrant evaluation for a dissection, especially if examination is suggestive for a connective tissue disorder such as Marfans. Headaches that worsen with lying down or vomiting without nausea are concerning for increased intracranial hypertension such as IIH, sinus venous clot producing increased CSF pressure, hydrocephalus, or mass. It is worth noting that, in studies evaluating the utility of imaging in pediatric headache, up to 98% of patients with intracranial process requiring surgical intervention had an abnormal neurologic examination. Headaches that worsen with standing and improve with lying down are suggestive of low-pressure headaches caused by a tear in the dura from a preceding LP or spontaneous leak.

Medication and illicit drug ingestion and withdrawal are both culprits to secondary headaches. Steroids, vitamin A toxicity, oral contraceptives, and tetracycline are all associated with IIH. Medications that are commonly associated with medication overuse headache include aspirin, acetaminophen, NSAIDs, triptans, and combination analgesics such as acetaminophen, butalbital, and caffeine. Other toxins such as lead, carbon monoxide, or organic solvent poisoning cannot be overlooked.

Infections both of the CNS or systemically are associated with new onset headaches. Additionally, common systemic or other focal infections may cause headaches such as viral upper respiratory infections, strep pharyngitis (especially in younger children), rhinosinusitis (sinus headache), influenza, and Lyme disease. Migraines are frequently misdiagnosed as sinus headaches and physicians should carefully obtain history of pain in the face, ears, or teeth and evaluate for signs of rhinosinusitis on either physical examination or imaging.

Any cause of hypoxia (eg, cardiac, respiratory, altitude, anemia) may cause a bifrontal throbbing headache that may be worsened with exertion, straining, or laying down. Hypercapnia causes a nonspecific headache and may be secondary to sleep apnea or other underlying metabolic or respiratory disorder.

Although eye strain and temporal mandibular joint dysfunction are rare causes of recurrent headaches, they can be simply treated; therefore, when suspected, evaluation by ophthalmology or dentistry, respectively, is indicated. Examination in temporomandibular joint dysfunction can include local pain, deviation of the mandible, jaw clicking, and limitations of chewing motion.

A thorough history and physical examination helps diagnose most of these conditions.

Complications

Migraines and tension-type headaches are episodic headache disorders but may transform into chronic headaches when a child has more than 15 headache days per month for three or more months. Risk factors for chronicity include psychological comorbidity, obesity, and excessive medication.

Depression and anxiety are both comorbid with headaches and are associated with increased headache burden and disability, such as school absenteeism and poor school performance. Equally, childhood psychiatric disorders also have increased rates of primary headaches. Maintaining school attendance in children with headaches is a key factor in limiting chronicity and further disability from headaches.

Treatment

Treatment is divided into two categories: acute/abortive and preventative. Management of headaches should emphasize the necessity for early and adequate treatment during a headache, in addition to self-management skills to reduce frequency and disability such as life-style modification and headache diaries. Pharmacologic preventative treatment can be considered if frequency or disability is significant.

A. Acute/Abortive Treatment

Acute treatment for pediatric migraine includes use of simple analgesics and migraine-specific medications. Any medication used to abort a headache (abortive medication) should be given as early as possible after the onset of headache. Simple analgesics include acetaminophen (15 mg/kg; max dose 650 mg) and ibuprofen (10 mg/kg; max dose 800 mg), often used as first-line therapy. The United States FDA has approved almotriptan (ages 12–17) and rizatriptan (ages 6–17). Studies have shown significant benefit for pediatric migraine using rizatriptan oral (5 mg for 20–39 kg, 10 mg for > 40 kg), almotriptan oral (6.25 or 12.5 mg), zolmitriptan nasal (5 mg > 12 y), and sumatriptan nasal (10 mg for < 40kg, 20 mg for > 40 kg). Occasionally home treatment fails and patients may need IV medications either in an emergency department or infusion center. When a patient fails emergency room treatments, IV dihydroergotamine can be effective with nausea as the most common side effect. All medications used for abortive treatment should be used cautiously to avoid medication overuse headache. Simple analgesics should be limited to 2–3 times per week and migraine-specific medications to less than 1–2 times per week. During a headache biobehavioral techniques include rest, relaxation, and cold/hot packs. Providing the child with a cool dark room in which to rest may provide added benefit.

B. Prevention

Any child with headaches should have biobehavioral management as a center point to treatment. This includes sleep hygiene (such as bedtime routine, adequate duration, and good quality of sleep), improved fluid intake, elimination of caffeine, regular nutritional meals, regular exercise and stretching, and stress management. Preventative treatment can be considered in individuals with headache frequency of one or more per week. Treatments should be chosen by optimizing wanted side-effects and minimizing unwanted side effects (eg, using topiramate in an obese child given its side-effect of weight loss).

Treatments are categorized into antiepileptic (eg, topiramate, valproic acid, levetiracetam), antihypertensive (eg, β-blockers, calcium channel blockers), antidepressants (eg, amitriptyline), antihistamine/antiserotonergic (eg, cyproheptadine), and nutraceuticals. Only small randomized double-blinded or open-label studies have tested these agents. The only FDA-approved migraine preventive medication in pediatric populations is topiramate for migraines in adolescents 12–17 years old.

Topiramate, amitriptyline, and cyproheptadine are the most commonly prescribed medications for pediatric headache. If topiramate is started slowly and at low doses, cognitive side effects can be avoided. Peripheral tingling is uncommon and when present usually can be tolerated by most children. Decreased appetite and weight loss should be monitored at routine appointments. Amitriptyline is usually dosed at nighttime given its side effect of sedation, in addition to other common side effects including constipation, dry mouth, and prolonged QT (typically at higher doses). Cyproheptadine is a good medication to use in younger children given its small side-effect profile of primary increased appetite and sedation. Divalproex sodium has not shown efficacy and side effects including weight gain, tremor, hair loss, and teratogenicity warrant caution in adolescent female patients.

Cognitive behavioral therapy is efficacious in significantly decreasing migraine frequency and disability in youth. Coenzyme q10 and magnesium oxide have shown some efficacy in childhood migraine. They may be a useful option for children with low frequency headache, low disability, or individuals who favor nonpharmaceutical options.

Prognosis

From the few studies regarding long-term prognosis in adolescents presenting with migraines, approximately 25%–40% of adolescents will have remission of migraine symptoms, 40%–50% have persistence, and 20%–25% convert to tension-type headache. Of those with TTH, 20% convert to migraine. Headache severity at diagnosis is thought to be predictive of headache outcome in the long term.

PSEUDOTUMOR CEREBRI (IDIOPATHIC INTRACRANIAL HYPERTENSION)

Pathogenesis

The pathogenesis of idiopathic intracranial hypertension (IIH) is essentially unknown. Multiple risk factors have been identified, but obesity is the most common. Interestingly, multiple medications have been associated with IIH, including tetracycline, steroids, and retinol.

Clinical Findings

Presenting features include new or chronic positional headache, vomiting, pulsatile tinnitus, papilledema, and diplopia. Later findings may include visual loss and optic atrophy. Visual symptoms are commonly secondary to transient visual obscurations (TVOs), which are transient (< 1 minute) and reversible alterations of vision in these patients. This must be distinguished from visual field anomalies, which can be permanent. IIH is characterized by increased intracranial pressure as documented by a lumbar puncture performed in the lateral decubitus position in the absence of an identifiable intracranial mass, infection, metabolic derangement, or hydrocephalus.

Differential Diagnosis

The cause of IIH is usually unknown, but it has been described in association with a variety of inflammatory, metabolic, toxic, and connective tissue disorders (Table 25–11). Assessing for alternative causes of increased intracranial pressure is essential to the diagnosis. MRI (or urgent CT for critically ill patients) may reveal hydrocephalus, tumor, or abscess. MRV may demonstrate a cerebral sinovenous thrombosis (CSVT), requiring hematological evaluation and consideration of anticoagulation. As noted in Table 25–11, medications, endocrinologic disturbances, and rheumatologic anomalies may all predispose patients to IIH. Lumbar puncture is essential to the diagnosis, as it confirms the presence of increased pressure (above 180–250 mm H₂O depending on technique and anesthetic used), but also assesses for white blood cell count, glucose, and protein (looking for an infectious mimicker, such as chronic meningitis). In some inflammatory and connective tissue diseases, the CSF protein concentration may also be increased.

Complications

Vision loss is the main complication of IIH, as chronic papilledema may lead to permanent optic nerve damage. Vision loss usually occurs in the blind spot and/or nasal aspects of the visual field prior to affecting central vision. Headache, TVOs, cranial nerve VI palsy, and malaise are usually reversible.

Treatment

Treatment of IIH is aimed at correcting the identifiable predisposing condition and preventing vision loss. Sequential ophthalmologic evaluation to assess optic nerve swelling and visual fields is important. Obese patients will benefit significantly from weight loss. Some patients may benefit from the use of acetazolamide or topiramate to decrease the volume and pressure of CSF within the CNS. If a program of medical management and ophthalmologic surveillance fail, lumboperitoneal shunt, ventriculoperitoneal shunt, or optic nerve fenestration may be necessary to prevent irreparable visual loss and damage to the optic nerves. Dural venous stenting has limited data in adults with no randomized studies in either adults or children.

Prognosis

With appropriate workup and treatment, most patients recover from IIH without long-term sequela including visual outcome. Reoccurrence risk is greatest within 18 months.

CEREBROVASCULAR DISEASE

Pediatric arterial ischemic stroke is subdivided into two categories: perinatal arterial ischemic stroke (perinatal AIS) and childhood arterial ischemic stroke (childhood AIS). Generally, perinatal AIS is defined as arterial ischemia occurring in a patient younger than age 28 days and older than 28 weeks gestation. Childhood AIS is any ischemic stroke occurring in a patient between 28 days and 18 years old.

1. Childhood Arterial Ischemic Stroke

Childhood AIS is emerging as a serious and increasingly recognized disorder, affecting 1.6 per 100,000 children per year. There are numerous adverse outcomes, which include death in 10%, neurologic deficits or seizures in 70%–75%, and recurrent ischemic stroke in up to 20%. It is essential to recognize that childhood AIS represents a neurologic emergency, for which prompt diagnosis can affect treatment considerations and outcome. Unfortunately, most pediatric AIS is not recognized until > 24 hours after onset; and treatment considerations matter most in the first few hours after stroke onset. When possible, all children who present with ischemic stroke should be transferred to a tertiary care center that specializes in pediatric stroke management. The evaluation should include a thorough history of prior illnesses, especially those associated with varicella (even in the prior 1–2 years) preceding viral infection, minor head or neck trauma, and familial clotting tendencies. A systematic search for evidence of cardiac, vascular, hematologic, or intracranial disorders should be undertaken (Table 25–12). Although many ischemic strokes are not associated with a single underlying systemic disorder, congenital heart disease is the most common predisposing condition, followed by hematologic and neoplastic disorders. In many instances the origin is multifactorial, necessitating a thorough investigation even when the cause may seem obvious. Arteriopathy is seen in as many as 80% of “idiopathic” patients, and likely confers an increased recurrence risk.

Clinical Findings

A. Symptoms and Signs

Manifestations of arterial ischemic stroke in childhood vary according to the vascular distribution to the brain structure that is involved. Because many conditions leading to childhood ischemic stroke result in emboli, multifocal neurologic involvement is common. Children may present with acute hemiplegia similarly to ischemic stroke in adults. Unilateral weakness, sensory disturbance, dysarthria, and/or dysphagia may develop over a period of minutes, but at times progressive worsening of symptoms may evolve over several hours. Bilateral hemispheric involvement may lead to a depressed level of consciousness. The patient may also demonstrate disturbances of mood and behavior and experience focal or multifocal seizures. Physical examination of the patient is aimed not only at identifying the specific deficits related to impaired cerebral blood flow, but also at seeking evidence for any predisposing disorder. Retinal hemorrhages, splinter hemorrhages in the nail beds, cardiac murmurs, rash, fever, neurocutaneous stigmata, and signs of trauma are especially important findings.

B. Laboratory Findings and Ancillary Testing

In the acute phase, certain investigations should be carried out emergently with consideration of treatment options. This should include complete blood count, complete metabolic panel, serum or urine pregnancy test, disseminated intravascular coagulation (DIC) panel, fibrin split products, erythrocyte sedimentation rate, C-reactive protein, prothrombin time/partial thromboplastin time, anti-factor Xa activity, chest radiography, ECG, urine toxicology, and imaging (see the following section). Subsequent studies can be carried out systemically, with particular attention to disorders involving the heart, blood vessels, platelets, red cells, hemoglobin, and coagulation proteins. Twenty to fifty percent of pediatric ischemic stroke patients will have a prothrombotic state. Additional laboratory tests for systemic disorders such as vasculitis, mitochondrial disorders, and metabolic disorders are sometimes indicated.

Examination of CSF is indicated in patients with fever, nuchal rigidity, or altered mental status when the diagnosis of intracranial infection requires exclusion. Lumbar puncture may be deferred until a neuroimaging scan (excluding brain abscess or a space-occupying lesion that might contraindicate lumbar puncture) has been obtained. In the absence of infection, rheumatologic disease or intracranial subarachnoid hemorrhage, CSF examination is rarely helpful in defining the cause of the cerebrovascular disorder.

EEG may help in patients with severely depressed consciousness. ECG and echocardiography are useful both in the diagnostic approach to the patient and in ongoing monitoring and management, particularly when hypotension or cardiac arrhythmias complicate the clinical course or when the stroke is thought to be embolic in nature.

C. Imaging

CT and MRI scans of the brain are helpful in defining the extent of cerebral involvement with ischemia or hemorrhage. CT scans may be normal within the first 12–24 hours of an ischemic stroke and are more useful to exclude intracranial hemorrhage. This information may be helpful in the early stages of management and in the decision to treat with anticoagulants. Given the high incidence of ischemic stroke mimickers in the pediatric population (migraine with aura, Todd’s paralysis, encephalitis, etc.), urgent MRI with diffusion-weighted imaging (DWI) is increasingly used in pediatric stroke centers.

Vascular imaging of the head and neck is an important part of pediatric ischemic stroke management and may include CTA, MRA, or conventional angiography. In studies in which both MRA and cerebral angiography have been used, up to 80% of patients with idiopathic childhood-onset arterial ischemic stroke have demonstrated a vascular abnormality. Vascular imaging is helpful in diagnosing disorders such as transient cerebral arteriopathy, arteriopathy associated with sickle cell disease, moyamoya disease, arterial dissection, aneurysm, fibromuscular dysplasia, and vasculitis. Studies have demonstrated that patients with vascular abnormalities on MRA or conventional angiography have a much greater recurrence risk than patients with normal vessels. When vessel imaging is performed, all major vessels should be studied from the aortic arch. With evidence of fibromuscular dysplasia in the intracranial or extracranial vessels, renal arteriography is indicated.

Differential Diagnosis

Patients with an acute onset of neurologic deficits must be evaluated for other disorders that can cause focal neurologic deficits. Hypoglycemia, prolonged focal seizures, a prolonged postictal paresis (Todd’s paralysis), acute disseminated encephalomyelitis (ADEM), meningitis, hemorrhagic stroke, encephalitis, hemiplegic migraine, ingestion, and brain abscess should all be considered. Migraine with focal neurologic deficits may be difficult to differentiate initially from ischemic stroke. Occasionally, the onset of a neurodegenerative disorder (eg, adrenoleukodystrophy or mitochondrial disorder) may begin with the abrupt onset of seizures and focal neurologic deficits. The possibility of drug abuse and other toxic exposures must be investigated diligently in any patient with acute mental status changes.

Treatment

The initial management of ischemic stroke in a child is aimed at providing support for pulmonary, cardiovascular, and renal function. Patients should be administered oxygen and are usually monitored in an intensive care setting. Typically, maintenance fluids without glucose are indicated to augment vascular volume. Pyrexia should be treated aggressively. Specific treatment of ischemic stroke, including blood pressure management, fluid management, and anticoagulation measures, depends partly on the underlying pathogenesis. Meningitis and other infections should be treated. Sickle cell patients require hematologists to perform urgent exchange transfusion and most patients will require chronic transfusions after hospital discharge. Moyamoya is usually treated with surgical revascularization, while patients with vasculitis are often given anti-inflammatory therapy, such as steroids.

In most idiopathic cases of childhood ischemic stroke, anticoagulation or aspirin therapy is indicated. The Royal College of Physicians Pediatric Ischemic Stroke Working Group recommends aspirin, 5 mg/kg daily, as soon as the diagnosis is made. Aspirin use appears safe but the American Heart Association (AHA) recommends yearly flu-shots and close monitoring for Reye syndrome in pediatric patients. Other groups, such as the American College of Chest Physicians, recommend initial treatment with anticoagulants, such as low-molecular-weight heparin or unfractionated heparin, for 5–7 days (while excluding cardiac sources and dissection) and then switching to aspirin (3–5 mg/days). Recent AHA guidelines support both of these approaches. In some situations, such as arterial dissection or cardioembolic events, heparinization is usually considered. In adults with cerebrovascular thrombosis, thrombolytic agents (tissue plasminogen activator) used systemically or delivered directly to a vascular thrombotic lesion using interventional radiologic techniques has been shown to improve outcome in the appropriate patients. Although case reports exist, studies in children have not been completed. AHA guidelines recommend against the thrombolysis, outside of a clinical trial for children, while equivocating in the case of adolescents. Given the time lag to diagnosis and the lack of evidence in children, tissue plasminogen activator is currently used in less than 2% of US children with ischemic stroke. The use of tissue plasminogen activator (tPA) should be limited to practitioners who are familiar with cerebrovascular disease in children.

Long-term management requires intensive rehabilitation efforts and therapy aimed at improving the child’s language, educational, and psychological performance. Length of treatment with antithrombotic agents, such as low-molecular-weight heparin and aspirin, is still being studied and depends on the etiology. Constraint therapy may be particularly helpful in cases of hemiparesis.

Prognosis

The outcome of ischemic stroke in infants and children is variable. Roughly one-third may have minimal or no deficits, one-third are moderately affected, and one-third are severely affected. Underlying predisposing conditions and the vascular territory involved all play a role in dictating the outcome for an individual patient. When the ischemic stroke involves extremely large portions of one hemisphere or large portions of both hemispheres and cerebral edema develops, the patient’s level of consciousness may deteriorate rapidly, and death may occur within the first few days. In contrast, some patients may achieve almost complete recovery of neurologic function within several days if the cerebral territory is small. Seizures, either focal or generalized, may occur in 30%–50% of patients at some point in the course of their cerebrovascular disorder. Recurrence is up to 14%, and is more prominent in some conditions, such as protein C deficiency, lipoprotein (a) abnormalities, and arteriopathies. Chronic problems with learning, behavior, and activity are common. Long-term follow-up with a pediatric neurologist is indicated and if possible a multidisciplinary ischemic stroke team.

2. Perinatal Arterial Ischemic Stroke

Perinatal arterial ischemic stroke is more common than childhood ischemic stroke, affecting 1:3500 children. Perinatal ischemic stroke has two distinct presentations: acute and delayed. Most patients with an acute presentation develop neonatal seizures during the first week of life, usually in association with a perinatal event. The seizures in acute perinatal ischemic stroke are often focal motor seizures of the contralateral arm and/or leg. The presentation is stereotypical because of the predilection of the ischemic stroke to occur in the middle cerebral artery. The presence of diffusion-weighted abnormalities on an MRI scan confirms an acute perinatal ischemic stroke during the first week of life. Other patients present with delayed symptoms, typically with an evolving hemiparesis at an average of 4–8 months. These patients are termed “presumed perinatal arterial ischemic stroke.”

Acute treatment of a perinatal ischemic stroke is usually limited to neonates with seizures. Unless an embolic source is identified, aspirin and anticoagulation are almost never prescribed. Management is based on supportive care, identification of comorbid conditions, and treatment of seizures. In acute perinatal ischemic stroke, treatable causes such as infection, cardiac embolus, metabolic derangement, and inherited thrombophilia must be ruled out. In appropriate cases, echocardiography, thrombophilia evaluation, and lumbar puncture are indicated. Supportive management focuses on general measures, such as normalizing glucose levels, monitoring blood pressure, and optimizing oxygenation.

Long-term management of perinatal ischemic stroke usually starts with identifying risk factors, which might include coagulation disorders, cardiac disease, drugs, and dehydration. Although prothrombotic abnormalities with the best evidence of association are factor V Leiden, protein C deficiency, and high lipoprotein (a), many practitioners perform an extensive hematologic workup. Maternal risk factors such as infertility, antiphospholipid antibodies, placental infection, premature rupture of membranes, and cocaine exposure are all independently associated with perinatal ischemic stroke.

The prognosis for children who sustain perinatal ischemic strokes has been considered better than for children or adults with ischemic strokes, presumably because of the plasticity of the neonatal brain. The range of cognitive and motor outcomes after perinatal stroke is broad. Twenty to forty percent of patients who experience perinatal ischemic strokes are neurologically normal. Motor impairment affects about 40%–60% of patients and is predominantly hemiplegic cerebral palsy. In acute presentations, MRI can be predictive of motor impairment, as descending corticospinal tract diffusion-weighted MRI signal is associated with a higher incidence of hemiplegia. Language delays, behavioral abnormalities, and cognitive deficits are seen in up to 55% of infants who experience perinatal ischemic strokes. Patients are also at an increased risk for seizures. Ischemic stroke recurs in 3% of neonates and is usually associated with a prothrombotic abnormality or an underlying illness, such as cardiac malformation or infection. Given the low incidence of recurrence, long-term management is largely rehabilitative, including constraint therapies.

CONGENITAL MALFORMATIONS OF THE NERVOUS SYSTEM

Malformations of the nervous system occur in 3% of living neonates and are present in 40% of infants who die in the first year of life. Structural malformation of the CNS may result from a variety of causes, including infectious, toxic, genetic, metabolic, and vascular insults. The specific type of malformation that results from such insults depends more on the gestational period during which the insult occurs than on the specific cause. The period of induction, days 0–28 of gestation, is the period during which the neural plate appears and the neural tube forms and closes. Insults during this phase can result in a major absence of neural structures, such as anencephaly, or in a defect of neural tube closure, such as spina bifida, meningomyelocele, or encephalocele. Cellular proliferation and migration characterize neural development that occurs from 12–20 weeks gestation. During this period, lissencephaly, pachygyria, agyria, and agenesis of the corpus callosum (ACC) may arise depending on the type of developmental disruption.

1. Abnormalities of Neural Tube Closure

Defects of neural tube closure constitute some of the most common congenital malformations affecting the nervous system, occurring in 1:1000 live births prior to the introduction of folate supplementation (which decreased incidence by 50%–75%). Up to 6% of fetuses with isolated spinal cord defects have an associated chromosomal abnormality (typically Trisomy 13 or 18), which should be screened for upon identification of the defect. Spina bifida with associated myelomeningocele or meningocele is commonly found in the lumbar region. Depending on the extent and severity of the involvement of the spinal cord and peripheral nerves, lower extremity weakness, bowel and bladder dysfunction, and hip dislocation may be present. Delivery via cesarean section followed by early surgical closure of meningoceles and meningomyeloceles is usually indicated. Additional treatment is necessary to manage chronic abnormalities of the urinary tract, orthopedic abnormalities such as kyphosis and scoliosis, and paresis of the lower extremities. Hydrocephalus is very common and usually requires ventriculoperitoneal shunting. For selected patients, pre-natal repair has been shown to reduce the need for VP shunt at one year and result in improved motor function at 30 months of age, though pregnancy and delivery-related complications were higher. This is a promising option for patients who meet the surgical criteria.

Diagnosis & Prevention

In general, the diagnosis of neural tube defects is obvious at the time of birth. The diagnosis may be strongly suspected prenatally on the basis of ultrasonographic findings and the presence of elevated α-fetoprotein and acetylcholinesterase in the amniotic fluid. All women of childbearing age should take prophylactic folate, which can prevent these defects and decrease the risk of recurrence by 70%.

2. Disorders of Cortical Development

Malformations of cortical development are known causes of a wide spectrum of developmental and cognitive disabilities as well as epilepsy. They are a diverse group of disorders characterized by disruption of the cortex primarily identified on MRI. Although MCD was historically classified based on stages of brain development disrupted, the field of neurogenetics has revealed over a hundred genetic mutations leading to a wide variety of overlapping structural phenotypes.

Pathogenesis

MCD can occur when one of the three primary stages of cortical development are disrupted: (1) neuronal proliferation, (2) neuronal migration, or (3) post-migrational development. The genes associated with MCD include cell-cycle regulation, angiogenesis, protein synthesis, apoptosis, cell-fate specification, cytoskeletal structure and function, neuronal migration and basement-membrane function, and inborn errors of metabolism.

Clinical Findings

Clinical presentation is variable and can be divided into those children who present early with severe neurodevelopmental deficits and diffuse MCD, and those children who present later in childhood with focal seizures or more mild developmental and intellectual disabilities and are found to have focal or multi-focal MCD.

Diffuse MCD is typically associated with a variety of signs including seizures, global developmental delay, feeding, hearing, and vision impairments, poor sleep, abnormal head size, hydrocephalus, behavior problems, autonomic dysregulation, and movement disorders. Typically, there is a higher risk for shortened lifespan in these children.

Focal MCD can be associated with normal development or mild developmental delays. Focal seizures are a common presentation. Neurodevelopmental disabilities may include mild learning disabilities and behavioral concerns (including ADHD). Sometimes, focal MCD is found incidentally when neuroimaging is done for other reasons.

Differential Diagnosis

A. Megalencephaly

Megalencephaly is an example of neuronal proliferation dysfunction and results in a brain size that is greater than three standard deviations above the mean. On MRI megalencephaly can be associated with normal cortical development, polymicrogyria, and hemimegalencephaly. Associated neurologic outcomes can include normal development, developmental delay, intellectual disability, and seizures. There are several genes and syndromes associated including Neurofibromatosis 1.

B. Lissencephaly and Subcortical Band Heterotopia

Lissencephaly is an example of abnormal migration and increased apoptosis. This severe malformation of the brain is characterized by a smooth cortical surface with minimal sulcal and gyral development. Lissencephalic brains have a primitive cortex with less than the normal six-layered cortical mantle. The pattern of pachygyria (thick gyri) and agyria (absence of gyri) may vary in an anterior to posterior gradient and help guide genetic diagnosis. Patients with lissencephaly usually have severe neurodevelopmental delay, microcephaly, and seizures (including infantile spasms), although there is significant phenotypic heterogeneity. These disorders are autosomal recessive and X-linked. LIS1 mutations on chromosome 17 are sometimes associated with dysmorphic features (Miller-Dieker syndrome). Mutations in the RELN gene, results in a lissencephaly with severe hippocampal and cerebellar hypoplasia. X-linked syndromes involving mutations in DCX and ARX (associated with ambiguous genitalia) affect males with lissencephaly and females with band heterotopias or ACC.

Lissencephaly with hydrocephalus, cerebellar malformations, or muscular dystrophy may occur in Walker-Warburg syndrome (POMT1 mutations and others), Fukuyama muscular dystrophy (FKTN mutation), and muscle-eye-brain disease (POMGnT1 mutation). It is particularly important to identify these syndromes not only because clinical tests are available, but also because of their genetic implications. Lissencephaly may be a component of Zellweger syndrome, a peroxisomal disorder with elevated concentrations of very-long-chain fatty acids in the serum. No specific treatment for lissencephaly is available.

C. Polymicrogyria with or Without Schizencephaly

Polymicrogyria is a post-migrational disorder characterized by an overfolded and malformed cortex that can be associated with schizencephaly, diffuse, or focal, such as bilateral perisylvian polymicrogyria (the classic form). Patients with bilateral perisylvian polymicrogyria may have bulbar dysfunction, variable cognitive deficits, developmental delay, and epilepsy. Etiologies of polymicrogyria vary including genetic mutations, infectious, and vascular causes.

Treatment

Treatment of MCD center on early child development intervention and focused symptomatic treatment (eg, attention deficit, hearing impairment, physical therapy for gait abnormalities).

3. Disorders of Cerebellum Development

A. Arnold-Chiari Malformations

Arnold-Chiari malformation type I consists of elongation and displacement of the caudal end of the brainstem into the spinal canal with protrusion of the cerebellar tonsils through the foramen magnum. In association with this hindbrain malformation, minor to moderate abnormalities of the base of the skull can occur, including basilar impression (platybasia) and small foramen magnum. Arnold-Chiari malformation type I typically remains asymptomatic for years, but in older children and young adults it may cause progressive cerebellar signs (vertigo, ataxia), paresis of the lower cranial nerves or neck/posterior head pain exacerbated by straining; rarely may it present with apnea or disordered breathing. Posterior cervical laminectomy may be necessary to provide relief from symptoms.

Arnold-Chiari malformation type II consists of the malformations found in Arnold-Chiari type I plus an associated myelomeningocele. Hydrocephalus develops in approximately 90% of children with Arnold-Chiari malformation type II. These patients may also have, hydromyelia, syringomyelia, and cortical dysplasias. The clinical manifestations of Arnold-Chiari malformation type II are most commonly caused by the associated hydrocephalus and meningomyelocele. In addition, dysfunction of the lower cranial nerves may be present. Up to 25% of patients may have epilepsy, likely secondary to the cortical dysplasias. Higher lesions of the thoracic or upper lumbar cord are associated with mild intellectual disability in about half of patients, while over 85% of patients with lower level lesions have normal intelligence quotients (IQs).

Arnold-Chiari malformation type III is characterized by herniation of the cerebellum through the foramen magnum with associated cervical spinal cord defect. Hydrocephalus is extremely common with this malformation.

B. Dandy-Walker Syndrome

Despite being described over a century ago, the exact definition of the Dandy-Walker syndrome is still debated. Classically, it is characterized by aplasia of the vermis, cystic enlargement of the fourth ventricle, and rostral displacement of the tentorium. Although hydrocephalus is usually not present congenitally, it develops within the first few months of life. Ninety percent of patients who develop hydrocephalus do so by age 1 year.

On physical examination, a rounded protuberance or exaggeration of the cranial occiput often exists. In the absence of hydrocephalus and increased intracranial pressure, few physical findings may be present to suggest neurologic dysfunction. An ataxic syndrome occurs in fewer than 20% of patients and is usually late in appearing. Many long-term neurologic deficits result directly from hydrocephalus. CT or MRI scanning of the head confirms diagnosis of Dandy-Walker syndrome. Treatment is directed at the management of hydrocephalus.

4. Agenesis of the Corpus Callosum

Agenesis of the corpus callosum (ACC), once thought to be a rare cerebral malformation, is more frequently diagnosed with modern neuroimaging techniques, occurring in 1:4000 births. There does not appear to be a single cause of this malformation. Rather, multiple single and muti-gene mutations have been associated. An underlying genetic cause can be found in up to 45% of cases. It has been found in X-linked conditions, such as ARX mutations (lissencephaly and ambiguous genetalie), recessive conditions such as Andermann syndrome (neuropathy and dementia), and polygenic conditions such as Aicardi syndrome (chorioretinal lacunae, infantile spasms, skeletal abnormalities). No specific clinical pictureis typical of ACC, although many patients have seizures, developmental delay, microcephaly, or eurobehavioral problems (autism, difficulties with social interactions). Interestingly, the malformation may be found coincidentally by neuroimaging studies in otherwise normal patients.

5. Hydrocephalus

Hydrocephalus is an increased volume of CSF with progressive ventricular dilation. In communicating hydrocephalus, CSF circulates through the ventricular system and into the subarachnoid space without obstruction. In noncommunicating hydrocephalus, an obstruction blocks the flow of CSF within the ventricular system or blocks the egress of CSF from the ventricular system into the subarachnoid space. A wide variety of disorders, such as hemorrhage, infection, tumors, and congenital malformations, may play a causal role in the development of hydrocephalus. Clinical features of hydrocephalus include macrocephaly, an excessive or rapidhead growth, irritability, bulging or full fontanelle, vomiting, loss of appetite, impaired upgaze (known as “sun setting” phenomenon), impaired extraocular movements, hypertonia of the lower extremities, and generalized hyperreflexia. Without treatment, optic atrophy may occur. In infants, papilledema may not be present, whereas older children with closed cranial sutures can eventually develop swelling of the optic disk. Hydrocephalus can be diagnosed on the basis of the clinical course, findings on physical examination, and CT or MRI scan.

Treatment of hydrocephalus is directed at providing an alternative outlet for CSF from the intracranial compartment. The most common method is ventriculoperitoneal shunting. Other treatment should be directed, if possible, at the underlying cause of the hydrocephalus.

ABNORMAL HEAD SIZE

Bone plates of the skull have almost no intrinsic capacity to enlarge or grow. Unlike long bones, they depend on extrinsic forces to stimulate new bone formation at the suture lines. Although gravity and traction on bone by muscle and scalp probably stimulate some growth, the single most important stimulus for head growth during infancy and childhood is brain growth. Therefore, accurate assessment of head growth is one of the most important aspects of the neurologic examination of young children. A head circumference that is two standard deviations above or below the mean for age requires investigation and explanation.

1. Craniosynostosis

Craniosynostosis, or premature closure of cranial sutures, is usually sporadic and idiopathic occurring in 1 in 2000 live births.

Clinical Findings

Both idiopathic and genetic etiologies occur in children with craniosynostosis. Syndromic children, that is, those with other physical anomalies, are more likely to have a genetic etiology. For example, Apert syndrome and Crouzon disease are associated with abnormalities of the digits, extremities, and heart, as well as craniosynostosis. An interdisciplinary approach is commonly required given the numerous other systems possibly involved including learning and development, oral health, visual and ocular abnormalities, hearing and middle ear abnormalities, and speech and language development. Craniosynostosis may be associated with an underlying metabolic disturbance such as hyperthyroidism and hypophosphatasia.

Differential Diagnosis

The most common form of craniosynostosis involves the sagittal suture and results in scaphocephaly, an elongation of the head in the anterior to posterior direction. Premature closure of the coronal sutures causes brachycephaly, an increase in cranial growth from left to right. Unless many or all cranial sutures close prematurely, intracranial volume will not be compromised, and the brain’s growth will not be impaired. Closure of only one or a few sutures will not cause impaired brain growth or neurologic dysfunction.

A common complaint is abnormal head shape secondary to positional plagiocephaly due to supine sleep position, not from occipital lambdoid suture craniosynostosis. Repositioning the head during naps (eg, with a rolled towel under one shoulder), and “tummy time” when awake are remedies. Rarely is a skull film or consultation necessary to rule out craniosynostosis. Most positional nonsynostotic plagiocephaly resolves by age 2 years.

Treatment

Management of craniosynostosis is directed at preserving normal skull shape and consists of excising the fused suture and applying material to the edge of the craniectomy to prevent reossification of the bone edges. The best cosmetic effect on the skull is achieved when surgery is performed during the first 6 months of life. Inter-disciplinary team approach to manage all systems affected is essential in providing the best neurologic and psychological outcomes.

2. Microcephaly

Microcephaly is defined as a head circumference more than two standard deviations below the mean for age and sex. More important than a single head circumference measurement is the rate or pattern of head growth over time. Head circumference measurements that progressively drop to lower percentiles with increasing age are indicative of a process or condition that has impaired the brain’s capacity to grow. Primary microcephaly is present at birth and secondary microcephaly develops postnatally. The causes of microcephaly are numerous. Some examples are listed in Table 25–13.

Clinical Findings

A. Symptoms and Signs

Head circumference should be monitored at every well-child check. However, microcephaly may be discovered when the child is examined because of delayed developmental milestones or neurologic problems, such as seizures or spasticity. There may be a marked backward slope of the forehead (as in familial microcephaly) with narrowing of the bitemporal diameter. The fontanelle may close earlier than expected, and sutures may be prominent. Abnormal dermatoglyphics (neurocutaneous marks) may be present when the injury occurred before 19 weeks’ gestation. Parents’ heads may need measurement to rule out a rare dominantly inherited familial microcephaly. Eye, cardiac, and bone abnormalities may also be clues to congenital infection.

B. Laboratory Findings

Laboratory findings vary with the cause. In the newborn, IgM antibody titers for toxoplasmosis, rubella, CMV, herpes simplex virus, and syphilis and urine culture for CMV may be assessed for sign of congenital infection. Genetic testing can be targeted based on history and physical examination. Genetic screening tests may be considered such as array comparative genomic hybridization (CGH) or karyotyping. Most metabolic disorders present either as congenital syndromic microcephaly (ie, dysmorphisms present on examination) or with postnatal microcephaly and global developmental delay. Nonsyndromic microcephaly presenting at birth may be due to maternal PKU (maternal serum with elevated phenylalanine), phosphoglycerate dehydrogenase deficiency (disorder of L-serine biosynthesis), or Amish lethal microcephaly (elevated urine alpha-ketoglutaric acid).

C. Imaging Studies

CT or MRI scans may aid in diagnosis and prognosis. These studies may demonstrate calcifications, malformations, or atrophic patterns that suggest specific congenital infections or genetic syndromes. Plain skull radiographs are of limited value. MRI is most helpful in definitive diagnosis, prognosis, and genetic counseling.

Differential Diagnosis

Common forms of craniosynostosis involving sagittal, coronal, and lambdoidal sutures are associated with abnormally shaped heads but do not cause microcephaly. Recognizing treatable causes of undergrowth of the brain such as hypopituitarism or hypothyroidism and severe protein-calorie undernutrition is critical so that therapy can be initiated as early as possible. Refer to Table 25–13 for examples of causes of microcephaly.

Treatment & Prognosis

Genetic counseling should be offered to the family of any infant with significant microcephaly. Many children with microcephaly are developmentally delayed. The notable exceptions are found in cases of hypopituitarism (rare) or familial autosomal dominant microcephaly. Individuals may need screening for vision and hearing abnormalities as well as supportive therapies for developmental delay.

3. Macrocephaly

A head circumference more than two standard deviations above the mean for age and sex denotes macrocephaly. Rapid head growth rate suggests increased intracranial pressure, most likely caused by hydrocephalus, extra-axial fluid collections, or neoplasms. Macrocephaly with normal head growth rate suggests familial macrocephaly or true megalencephaly, as might occur in neurofibromatosis. Other causes and examples of macrocephaly are listed in Table 25–14.

Differential Diagnosis

A. Catch-Up Growth

This can be seen when a neurologically intact preterm infant has rapid head enlargement in the first weeks of life. As the expected normal size is reached, head growth slows and then resumes a normal growth pattern.

B. Familial Macrocephaly

This condition may exist when another family member has an unusually large head with no signs or symptoms referable to such disorders as neurocutaneous dysplasias (especially neurofibromatosis) or cerebral gigantism (Sotos syndrome), or when there are no significant mental or neurologic abnormalities in the child.

C. Hydrocephalus

See section on Congenital Malformations of the Nervous System.

Other causes of macrocephaly are dependent on the etiology such as metabolic or genetic causes.

Clinical Findings

Clinical and laboratory findings vary with the underlying process. In neonates and young infants, ultrasound can be used to evaluate for subdural effusions, hydrocephalus, hydranencephaly, and cystic defects. A surgically or medically treatable condition must be ruled out. Thus, the first decision is whether and when to perform an imaging study.

A. Imaging Studies

An imaging study is necessary if signs or symptoms of increased intracranial pressure are present. If the fontanelle is open, cranial ultrasonography can assess ventricular size and diagnose or exclude hydrocephalus. CT or MRI scans are used to define any structural cause of macrocephaly and to identify an operable disorder. Even when the condition is untreatable (or does not require treatment), the information gained may permit more accurate diagnosis and prognosis, guide management and genetic counseling, and serve as a basis for comparison should future abnormal cranial growth or neurologic changes necessitate a repeat study.

NEUROCUTANEOUS DYSPLASIAS

Neurocutaneous dysplasias are diseases of the neuroectoderm and sometimes involve endoderm and mesoderm. Birthmarks and later appearing skin growths suggest a need to look for brain, spinal cord, and eye disease. Hamartomas (benign tumors that are histologically normal tissue growing abnormally rapidly or in aberrant sites) are common. The most common dysplasias are inherited autosomal dominantly. Benign and even malignant tumors may develop in these conditions.

1. Neurofibromatosis Type 1

Neurofibromatosis is a multisystem disorder with a prevalence of 1:3000. Fifty percent of cases are due to new mutations in the NF1 gene, which is located on chromosome 17q11.2 encoding neurofibromin. Forty percent of patients develop medical complications over their lifetime. Two or more positive criteria are diagnostic; others may appear over time. Children with six or more café au lait spots and no other positive criteria should be followed; 95% develop neurofibromatosis type 1.

Clinical Findings

A. Symptoms and Signs

The most common presenting symptoms are cognitive or psychomotor problems; 40% have learning disabilities, and 8% have intellectual disability. The history should focus on cutaneous abnormalities causing disfigurement, functional problems, or pain. Café au lait spots are seen in most affected children by age 1 year. The typical skin lesion is 10–30 mm, ovoid, and smooth-bordered. Discrete well-demarcated neurofibromas or lipomas can occur at any age. Plexiform neurofibromas are diffuse and can invade normal tissue. They are congenital and are frequently detected during periods of rapid growth. If the face or a limb is involved, there may be associated hypertrophy or overgrowth.

Clinicians should evaluate head circumference, blood pressure, vision, hearing, spine for scoliosis, and limbs for pseudarthroses. Strabismus or amblyopia dictates a search for optic glioma, a common tumor in neurofibromatosis. The eye examination should include checking for proptosis and iris Lisch nodules. The optic disk should be examined for atrophy or papilledema. Any progressive or new neurologic deficit calls for neuroimaging to rule out tumor of the spinal cord or CNS. Short stature and precocious puberty are occasional findings.

Parents should be examined in detail. Family history is important in identifying dominant gene manifestations.

B. Laboratory Findings

Laboratory tests are not likely to be of value in asymptomatic patients. Selected patients require brain MRI with special cuts through the optic nerves to rule out optic glioma. A common finding is hyperintense, non-mass lesions seen on T₂-weighted MRI images. These “unidentified bright objects” (“UBOs”) often disappear with time. Hypertension necessitates evaluation of renal arteries for dysplasia and stenosis. Cognitive and school achievement testing may be indicated. Scoliosis or limb abnormalities should be studied by appropriate imaging.

Differential Diagnosis

Patients with McCune-Albright syndrome often have larger café au lait spots with precocious puberty, polyostotic fibrous dysplasia, and hyperfunctioning endocrinopathies. One or two café au lait spots are often seen in normal children. A large solitary café au lait spot is usually innocent.

Complications

Seizures, deafness, short stature, early puberty, and hypertension occur in less than 25% of patients with neurofibromatosis. Optic gliomas occur in about 15%. Although the tumor may be apparent at an early age, it rarely causes functional problems and is usually nonprogressive. Patients have a slightly increased risk (5% life risk) for various malignancies. Other tumors may be benign but may cause significant morbidity and mortality because of their size and location in a vital or enclosed space, for example, plexiform neurofibromas. These “benign” infiltrating tumors can disfigure facially, impair spinal cord, renal, or pelvic-leg function, and are often difficult to treat. PET scans are helpful to detect malignant transformations (most commonly to sarcomas). Experimental trials of interferons and mTOR inhibitors (rapamycin=sirolimus) are ongoing at many centers. Strokes from NF-1 cerebral arteriopathy are rare but needs to be noted; arteriopathy of renal arteries can cause reversible hypertension in childhood.

Treatment

Genetic counseling and screening is important and the risk to siblings is 50%. The disease may be progressive, but with serious complications only occasionally seen. Patients sometimes worsen during puberty or pregnancy. Annual or semiannual visits are important in the early detection of school problems and bony or neurologic abnormalities.

The following parameters should be recorded at each annual visit:

1. Child’s development and progress at school

2. Visual symptoms, visual acuity, and funduscopy until age 7 years (to detect optic pathway glioma, glaucoma)

3. Head circumference (rapid increase might indicate tumor or hydrocephalus)

4. Height (to detect abnormal pubertal development)

5. Weight (to detect abnormal pubertal development)

6. Pubertal development (to detect delayed or precocious puberty due to pituitary or hypothalamic lesions)

7. Blood pressure (to detect renal artery stenosis or pheochromocytoma)

8. Cardiovascular examination (for congenital heart disease, especially pulmonary stenosis)

9. Evaluation of spine (for scoliosis and underlying plexiform neurofibromas)

10. Evaluation of the skin (for cutaneous, subcutaneous, and plexiform neurofibromas)

11. Examination of other systems, depending on specific symptoms

Multidisciplinary clinics at medical centers around the United States can be excellent resources. Prenatal diagnosis is likely on the horizon, but the variability of manifestations (trivial to severe) will make therapeutic abortion an unlikely option. Chromosomal linkage studies are under way (chromosome 17q11.2). Information for lay people and physicians is available from the National Neurofibromatosis Foundation (http://www.nf.org).

2. Neurofibromatosis Type 2

NF-2 is a dominantly inherited neoplasial syndrome manifested as bilateral vestibular schwannomas (VIII nerve tumors), which may appear in childhood (with loss of hearing, etc). Café au lait spots are not part of NF-2. In 50% of the patients, the mutation occurs de novo (neither parent carrying the faulty gene). Tumors of cranial nerve VIII (Schwannomas) virtually never occur in neurofibromatosis type 1 but are pathognomonic in neurofibromatosis type 2, a rare autosomal dominant disease. Café au lait spots are less common in neurofibromatosis type 2. Other tumors of the brain and spinal cord are common: meningiomas, other cranial nerve schwannomas, and ependymomas. Posterior lens cataracts are a third risk.

3. Tuberous Sclerosis

Tuberous sclerosis (TS) is a dominantly inherited disease. Almost all individuals have deletions on chromosome 9 (TSC1 gene) or 16 (TSC2 gene). The gene products hamartin and tuberin have tumor-suppressing effects, therefore TS patients are more susceptible to hamartomas in many organs and brain tubers and tumors. A triad of seizures, mental retardation, and adenoma sebaceum occurs in only 33% of patients. Parents formerly thought to not harbor the gene are now being diagnosed as asymptomatic carriers.

Clinical Findings

Tuberous sclerosis has a wide spectrum of disease: asymptomatic with only skin findings to severe infantile spasms and mental retardation. Seizures in early infancy correlate with later mental retardation.

A. Symptoms and Signs

1. Dermatologic features

Skin findings bring most patients to the physician’s attention (Tables 25–15 and 25–16). Ninety-six percent of patients have one or more hypomelanotic macules, facial angiofibromas, ungual fibromas, or shagreen (leathery orange peel) patches. Adenoma sebaceum (facial skin hamartomas) may first appear in early childhood, often on the cheek, chin, and dry sites of the skin where acne is not usually seen. Ash-leaf spots are off-white hypomelanotic macules often oval or “ash leaf” in shape and follow the dermatomes. A Wood lamp (ultraviolet light) shows the macules more clearly. The equivalent to an ash leaf spot in the scalp is poliosis (whitened hair patch). Subungual and periungual fibromas are more common in the toes. Café au lait spots are occasionally seen. Fibrous or raised plaques may resemble coalescent angiofibromas.

2. Neurologic features

Seizures are the most common and up to 20% of patients with infantile spasms have TS. Thus, any patient presenting with infantile spasms (and the parents as well) should be evaluated for this disorder. An imaging study of the CNS, such as a CT scan, may show calcified subependymal nodules; MRI may show dysmyelinating white matter lesions or cortical tubers. Virtually any kind of symptomatic seizure (eg, atypical absence, partial complex, and generalized tonic-clonic seizures) may occur. Mental retardation occurs in up to 50% of patients referred to tertiary care centers; the incidence is probably much lower in randomly selected patients. Patients with seizures are more prone to mental retardation or learning disabilities.

3. Renal lesions

Renal cysts or angiomyolipomas may be asymptomatic. Hematuria or obstruction of urine flow sometimes occurs; the latter requires operation. Ultrasonography of the kidneys should be done in any patient suspected of tuberous sclerosis, both to aid in diagnosis if lesions are found and to rule out renal obstructive disease.

4. Cardiopulmonary involvement

Rarely cystic lung disease may occur. Rhabdomyomas of the heart may be asymptomatic but can lead to outflow obstruction, conduction difficulties, and death. Chest radiographs and echocardiograms can detect these rare manifestations. Cardiac rhabdomyoma may be detected on prenatal ultrasound examination. Rhabdomyomas typically regress with age; thus, symptomatic presentations are typically in the perinatal period or infancy when rhabdomyomas are largest.

5. Eye involvement

Retinal hamartomas are often near the disk and usually asymptomatic.

6. Skeletal involvement

Cystic rarefactions can be found in the bones of the fingers or toes.

B. Imaging Studies and Special Tests

Plain radiographs may detect areas of thickening within the skull, spine, and pelvis, and cystic lesions in the hands and feet. Chest radiographs may show lung honeycombing. MR and CT imaging can show the virtually pathognomonic subependymal nodular calcifications, sometimes widened gyri or tubers, and brain tumors. Hypomyelinated lesions may be seen with MRI. EEG should be considered in any TS patient with new-onset spells concerning for seizures.

Treatment

Therapy is as indicated by underlying disease (eg, seizures and tumors of the brain, kidney, and heart). Skin lesions on the face may need dermabrasion or laser treatment. Genetic counseling emphasizes identification of the carrier. The risk of appearance in offspring if either parent is a carrier is 50%. The patient should be seen annually for counseling and reexamination in childhood. Identification of the chromosomes (9,16; TSC1 and TSC2 genes) may in the future make intrauterine diagnosis possible. Treatment of refractory epilepsy may lead to surgical extirpation of epileptiform tuber sites.

Recent research has suggested the “mammalian target of rapamycin” (mTOR) inhibitors (eg, rapamycin) may inhibit epilepsy in tuberous sclerosis, even shrink dysplasia/tubers, tumors, adenoma sebacea, and possibly improve learning.

4. Encephalofacial Angiomatosis (Sturge-Weber Disease)

Sturge-Weber disease is a sporadic neurovascular disease, which consists of a facial port wine nevus involving the upper part of the face (in the first division of cranial nerve V), a venous angioma of the meninges in the occipitoparietal regions, and choroidal angioma. The syndrome has been described without the facial nevus (rare, type III, exclusive leptomeningeal angioma).

Clinical Findings

A. Symptoms and Signs

In infancy, the eye may show congenital glaucoma, or buphthalmos, with a cloudy, enlarged cornea. In early stages, the facial nevus may be the only indication, with no findings in the brain even on radiologic studies. Focal seizures are common in infancy. Cognitive impairment, headache and migraines, and stroke-like signs are other neurologic manifestations. The characteristic cortical atrophy, calcifications of the cortex, and meningeal angiomatosis may appear with time, solidifying the diagnosis.

Physical examination may show hemiparesis on the side contralateral to the cerebral lesion. The facial nevus may be much more extensive than the first division of cranial nerve V; it can involve the lower face, mouth, lip, neck, and even torso. Hemiatrophy of the contralateral limbs may occur. Mental handicap may result from poorly controlled seizures. Late-appearing glaucoma and rarely CNS hemorrhage occur.

B. Imaging and Special Tests

Radiologic studies may show calcification of the cortex; CT scanning may show this much earlier than plain radiographic studies. MRI often shows underlying brain involvement.

The EEG often shows depression of voltage over the involved area in early stages; later, epileptiform abnormalities may be present focally.

Differential Diagnosis

The differential diagnosis includes (rare) PHACES syndrome: Posterior fossa malformation, segmental (facial) Hemangioma, Arterial abnormalities, Cardiac defects, Eye abnormalities, and Sternal (or ventral) defects; often, only portions of that list are present.

Management & Treatment

Early control of seizures is important to avoid consequent developmental setback. If seizures do not occur, normal development can be anticipated. Careful examination of the newborn, with ophthalmologic assessment to detect early glaucoma, is indicated. Rarely, surgical removal of the involved meninges and the involved portion of the brain may be indicated, even hemispherectomy.

5. Von Hippel-Lindau Disease (Retrocerebellar Angiomatosis)

Von Hippel-Lindau disease is a rare, dominantly inherited condition with retinal and cerebellar hemangioblastomas; cysts of the kidneys, pancreas, and epididymis; and sometimes renal cancers. The patient may present with ataxia, slurred speech, and nystagmus due to a hemangioblastoma of the cerebellum or with a medullary spinal cord cystic hemangioblastoma. Retinal detachment may occur from hemorrhage or exudate in the retinal vascular malformation. Rarely a pancreatic cyst or renal tumor may be the presenting symptom.

The diagnostic criteria for the disease are a retinal or cerebellar hemangioblastoma with or without a positive family history, intra-abdominal cyst, or renal cancer.

CENTRAL NERVOUS SYSTEM DEGENERATIVE DISORDERS OF INFANCY & CHILDHOOD

The CNS degenerative disorders of infancy and childhood are characterized by developmental arrest and loss, usually progressive but at variable rates, of cognitive, motor, and visual functioning (Tables 25–16). Seizures are common especially in those with gray matter involvement. Symptoms and signs vary with age at onset and primary sites of involvement.

These disorders are fortunately rare. An early clinical pattern of decline often follows normal early development. Referral for sophisticated biochemical testing is usually necessary before a definitive diagnosis can be made. Patients with metachromatic leukodystrophy, Krabbe disease, and adrenoleukodystrophy are candidates for bone marrow transplantation. Treatment of some lysosomal storage diseases, such as Gaucher disease, with enzyme replacement therapy (ERT) has shown promising results.

Ataxia can be divided into categories based on the chronicity of symptoms. Acute ataxia is a common reason for emergent neurologic consultation. Typically, the patient was previously healthy, without developmental delay or neurologic deficits, and then developed symptoms within 72 hours of presentation. The evaluation should include a detailed history of the antecedent events and current symptoms, as well as a comprehensive neurologic examination. In contrast, a patient with a subacute, episodic, or chronic ataxia often has developmental delay, other neurologic deficits, or other organ system involvement. In this section, a brief overview of the most common causes of ataxia, and the evaluation and the management of each, is provided.

ACUTE ATAXIAS OF CHILDHOOD

Pathogenesis

Causes of acute ataxia that require emergent evaluation include toxic ingestion, CNS infection, increased intracranial pressure due to mass lesion, trauma, and stroke. Therefore, a detailed history should assess for exposures, fever, altered mental status, irritability, persistent or recurrent headaches, developmental regression, blurry or double vision, nausea/vomiting, and other neurologic deficits.

Clinical Findings

A thorough examination should be performed, with attention to signs suggesting a serious central nervous system disorder. Changes in mental status may suggest an ingestion, CNS infection, acute disseminated encephalomyelitis, or opsoclonus-myoclonus syndrome (OMS). The presence of papilledema or cranial nerve palsy suggests an intracranial mass lesion or hydrocephalus. The evaluation of an acutely ataxic patient can be difficult as the patient may refuse to participate due to the discomfort of being ataxic or associated mental status changes. Therefore, distinguishing between weakness, sensory loss, and ataxia can be difficult, but it is essential to localizing the lesion and making the correct diagnosis. For example, asymmetry in the examination would be unusual for acute cerebellar ataxia. Ataxia from a sensory lesion worsens with closed eyes, whereas ataxia from a cerebellar lesion does not. Cerebellar lesions often have a characteristic pattern. A midline cerebellar lesion may present with dysarthria or truncal titubation. In contrast, a lesion of the cerebellar hemispheres may cause speech disturbances, dysmetria, tremor, or hypotonia, and the patient tends to fall toward the side of the lesion. A resting tremor, myoclonus, or opsoclonus suggests a lesion affecting the deep cerebellar nuclei.

Laboratory and Imaging Findings

Red flags in the history or examination should prompt timely and targeted testing. These include trauma, abrupt onset of signs/symptoms (over minutes), progressive or prolonged time course, headache, altered mental status, seizures or myoclonic jerks, and opsoclonus. A recent study found that for children older than 3 years who presented with more than 3 days of symptoms, brain imaging demonstrated clinically urgent intracranial pathology (such as brain tumor or ADEM) in 10%–20%. Younger children and children with no more than 3 days of symptoms warrant close observation but may not need urgent brain imaging. Lumbar puncture should be performed if an inflammatory, demyelinating, or infectious etiology is possible.

Differential Diagnosis

A. Acute Postinfectious Cerebellar Ataxia

Acute postinfectious cerebellar ataxia (APCA, also called acute cerebellar ataxia or ACA) causes approximately 40% of cases of acute ataxia and typically affects children aged 2–4 years. Clinical signs occur abruptly (over hours), evolve rapidly, and typically include unsteady gait, truncal swaying, dysmetria, tremor, or abnormal eye movements. Mental status is essentially normal, though some patients are mildly irritable. Sensation, strength, and reflex testing are normal. In 70% of patients, a prodromal illness, such as varicella, influenza, Epstein-Barr virus, or Scarlet fever, occurs within 3 weeks of onset. Diagnostic testing should include lumbar puncture and brain imaging. CSF opening pressure, protein, and glucose levels are typically normal, though a mild pleocytosis with lymphocytic predominance can be seen. Significant elevation in WBC or protein level suggests an alternative diagnosis, such as CNS infection or Guillain-Barre syndrome. Brain MRI is typically normal, but can show T2 hyperintensities in the cerebellum. Treatment for APCA is typically supportive. Intravenous immunoglobulin (IVIg) has been used in severe cases. Steroids are not effective. Physical therapy can be helpful. Most patients recover without sequelae within 8 months, though some may have neurologic sequelae.

B. Toxic Cerebellar Syndrome

Toxic ingestion accounts for one-third of cases of acute ataxia in children. Common substances include anticonvulsants, benzodiazepines, alcohol, marijuana, and cough syrup (dextromethorphan). Environmental agents, such as heavy metals (bismuth, mercury, and lead), can also cause ataxia. Mental status changes, nystagmus, pupillary changes, tremor, or other toxidromal symptoms may also occur. Urine toxicology screen may not detect specific medications or illicit substances. Imaging is typically normal. Therefore, a detailed history is required to guide testing for specific substances or make an empiric diagnosis. Treatment is guided by the ingested agent and requires toxicology consultation.

C. Intracranial Mass Lesions

Posterior fossa tumors (arising from the cerebellum or brainstem) comprise up to 60% of childhood brain tumors. Most patients experience gradual onset of progressive ataxia and clinical signs and symptoms of increased intracranial pressure, such as lethargy, headache, vomiting, or eye movement abnormalities. However, some children can present with a more rapid evolution of signs and symptoms, and even children with a large tumor and obstructive hydrocephalus can initially have only minor deficits. Therefore, any patient with a history of nocturnal headaches, nocturnal emesis, focal neurologic deficits, visual changes, or other signs concerning for mass lesion should have neuroimaging performed immediately.

D. Posterior Circulation Stroke (Ischemic or Hemorrhagic)

Though rare, stroke should be considered in the differential for acute ataxia, particularly if a history of neck trauma or family history of vascular or hematologic abnormalities is present. Due to the brainstem/cerebellar involvement of a posterior circulation stroke, the patient may also have significant vertigo, nausea/vomiting, nystagmus, cranial nerve palsies, hearing changes, hiccups, sensory loss, hemiparesis, or even quadriparesis. Cerebral venous sinus thrombosis should also be considered.

E. CNS Infections—Cerebellitis, Brainstem Encephalitis, and Meningitis

Some infectious agents, such as Listeria, varicella, and enterovirus 71, have a predilection for the brainstem and cerebellum, either via leptomeningeal involvement or direct invasion of the parenchyma. In some cases, postinfectious inflammation can be quite severe. Patients are typically quite ill and encephalopathic. Brain MRI may demonstrate cerebellar edema, which in some cases has required decompressive craniectomy.

F. Acute Demyelinating Encephalomyelitis

Ataxia can be a presenting symptom of acute demyelinating encephalomyelitis (ADEM), an immune-mediated, transient demyelinating disorder. ADEM often occurs after a viral infection or vaccination, most commonly in children aged 2–10 years. Unlike ACA, ADEM is typically associated with additional deficits, such as a dramatic change in mental status (encephalopathy), seizures, cranial nerve palsies, or extremity weakness. Refer to section “Noninfectious Inflammatory Disorders of the Central Nervous System.”

G. Sensory Ataxia

Pathology within the spinal cord, spinal nerve roots, or peripheral nerves can disrupt sensory input to the cerebellum, resulting in a sensory ataxia. Etiologies may include poliomyelitis-like infections, spinal cord demyelinating process (such as ADEM, transverse myelitis, MS, or neuromyelitis optica spectrum disorder), (typically due to vitamin B12 deficiency), Guillain-Barre syndrome (GBS; also called acute inflammatory demyelinating polyneuropathy, AIDP) or its variant, Miller-Fisher syndrome, or toxins. In addition to ataxia, patients typically have hypotonia or hypertonia, weakness, abnormal tendon reflexes, abnormal Romberg sign, loss of proprioception and vibratory sensation, or a high “steppage” gait. Autonomic instability or bowel/bladder dysfunction can also be notable. Diffuse or difficult to localize pain can be a predominate feature. Testing for suspected GBS should include a lumbar puncture to evaluate for elevated CSF protein with normal CSF white blood cell count, known as albuminocytologic dissociation, but early in the course, CSF can be normal in up to 50% of children. Antibodies against GQ1b may be positive in Miller-Fisher syndrome. Screening for toxins and vitamin deficiencies may be appropriate if the history is suggestive. Spine MRI may show enhancement of the nerve roots in GBS or infectious radiculoneuritis (such as Lyme disease). Posterior column lesions suggest demyelination, myelitis, or neurodegenerative changes. Nerve conduction studies and EMG may be helpful, though these are often normal during the acute period. GBS can be treated with either IVIg (2 g/kg divided over 3–5 days) or plasmapheresis, which have similar efficacies. Steroids have no benefit in GBS. Most patients with GBS will make a full recovery within 6–12 months. Treatment and outcome for myelopathy/myelitis will depend on etiology.

H. Paraneoplastic Syndromes

Acute ataxia can occasionally be seen in OMS, sometimes called opsoclonus-myoclonus-ataxia syndrome, a rare paraneoplastic/autoimmune disorder that primarily affects young children. Proposed diagnostic criteria for OMS (rapid, multidirectional conjugate abnormal eye movements) are myoclonus (nonepileptic jerks of the face, head, or extremities) and/or ataxia, behavioral changes and/or sleep disruption, and/or neuroblastoma. Cognitive dysfunction can also be seen. Many patients do not immediately meet diagnostic criteria, and a high index of suspicion is needed to ultimately make the diagnosis.

I. Migraine with brainstem Aura (Formerly Called “Basilar Migraine”)

Migraine with brainstem aura can be associated with ataxia. Most patients will have other neurologic signs and symptoms, such as vertigo, nausea, vomiting, cranial nerve dysfunction, and/or headache. Positive visual phenomenon (such as flashing lights or “zig-zag” lines) or a “marching” progression of symptoms (reflecting cortical spreading depression) can provide clues to the diagnosis of migraine. However, migraine with aura is a diagnosis of exclusion, and the initial presentation warrants a prompt workup for possible stroke.

J. Vestibular Pathology

Disturbances in the vestibular system can cause ataxia, often accompanied by dramatic vertigo, nausea/vomiting, eye movement abnormalities (such as skew deviation or nystagmus), or hearing changes. Causes can include labyrinthitis/vestibular neuritis or benign paroxysmal vertigo, as well as posterior circulation stroke or migraine with brainstem aura.

K. Functional Ataxia (Also Called Pseudoataxia or Conversion Disorder)

In functional ataxia, the patient appears to lurch and stagger when walking, the gait is not wide-based, and falls are rare. The findings on the neurologic examination are often inconsistent and incompatible with neuroanatomic localization, meeting DSM-V criteria for functional symptoms.

CHRONIC & EPISODIC ATAXIAS

Differential Diagnosis

1. Inborn Errors of Metabolism

Inborn errors of metabolism should be strongly considered for both intermittent and chronic ataxia. Metabolic disorders known to cause episodic or progressive ataxia include amino-acidopathies, urea cycle defects, primary lactic acidoses, leukodystrophies, lysosomal disorders, peroxisomal disorders, and disorders of glycosylation. Since some of these disorders are treatable, consider sending screening labs such as complete blood count with peripheral smear, compete metabolic panel, thyroid panel, serum organic acids, urine organic acids, lactate, and pyruvate. Depending on these results, additional testing may involve immunoglobulin panel, alpha-fetoprotein, ammonia, vitamin B12, MMA, homocysteine, biotinidase, phytanic acid, homocysteine, vitamin E, copper, ceruloplasmin, lipid panel, acylcarnitine profile, carnitine, or very long chain fatty acids. Ideally, testing is sent when the patient is symptomatic. Brain MRI may also demonstrate characteristic features in some metabolic disorders. For more details, refer to Chapter 36 on Inborn Errors of Metabolism.

2. Autosomal Dominant Hereditary Ataxias (Chronic and Episodic)

Most forms of spinocerebellar ataxia (SCA) and episodic ataxia are dominantly inherited, and many are due to channelopathies. Channelopathies are a broad category of disorders that result from altered function of ion channels and membrane excitability in neurons and other cells. Examples include episodic ataxia type 1 (EA1), which is due to a mutation in KCNA1, a potassium channel, and episodic ataxia type 2 (EA2) which is caused by a mutation in CACNA1A, a calcium channel. Interestingly, CACNA1A mutations can also cause spinocerebellar ataxia type 6 (SCA6), as well as hemiplegic migraine and epilepsy. Over 40 dominantly inherited spinocerebellar ataxias have been described, and the various forms often have distinctive features, such as downbeat nystagmus or palatal tremor.

3. Autosomal Recessive Hereditary Ataxias

The two most common autosomal recessive hereditary ataxias affecting children are Friedreich ataxia and ataxia-telangiectasia and are discussed below. In addition, rare but treatable autosomal recessive ataxias include ataxia with vitamin E deficiency, cerebrotendinous xanthomatosis, mitochondrial disorders, Refsum disease, and abetalipoproteinemia.

A. Friedreich Ataxia

Friedreich ataxia is the most common autosomal recessive ataxia. The classic presentation is a school-aged/adolescent with progressive clumsiness, sensory loss, and weakness that ultimately leads to loss of ambulation by young adulthood. Patients can develop orthopedic deformities, including scoliosis, as well as dysarthria, hypertrophic cardiomyopathy, and diabetes mellitus. Friedrich ataxia is caused by a triplet GAA expansion in the frataxin gene (FXN).

B. Ataxia-Telangiectasia

Ataxia-telangiectasia is a multisystem disorder arising from a defect in DNA repair and is the second most common autosomal recessive ataxia. Greater than 99% of individuals with classic ataxia-telangiectasia have mutations in the ATM gene. Patients typically present between 1 and 4 years of age with ataxia, oculomotor apraxia, recurrent infections (due to immunoglobulin deficiencies), and conjunctival telangiectasias. Choreoathetosis and sensorimotor neuropathy are also quite common. Serum alpha-fetoprotein is typically elevated but can be normal early in the course. Patients are at increased risk of malignancy.

MOVEMENT DISORDERS

Movement disorders (also called extrapyramidal disorders) are characterized by the presence in the waking state of excessive, unwanted movements: dyskinesias, athetosis, chorea, ballismus, tremors, rigidity, tics, and dystonias. The precise pathologic and anatomic localizations of these disorders are not understood. Motor pathways synapsing in the striatum (putamen and caudate nucleus), globus pallidus, red nucleus, substantia nigra, and the subthalamic nucleus are involved. This system is modulated by pathways originating in the cortex, thalamus, cerebellum, and reticular formation.

1. Chorea and Athetosis

Clinical Findings

Sydenham chorea is a common cause of acute onset of choreoathetoid movements and is a major Jones criteria for rheumatic fever (see Chapter 20 for additional information about rheumatic fever). Hemichorea (involving only one side of the body) occurs in up to 35% of patients. Other symptoms and signs include behavior changes, sleep disturbances, hypotonia, and motor impersistence, such as inability to sustain grip (“milkmaid’s sign”) or tongue protrusion (“tongue darting”). Diagnostic testing should include CBC, ESR, CRP, antistreptolysin O titers, and anti-DNase titer. Strep throat culture should be obtained but is often negative due to the delay between infection and development of chorea. ECG and echocardiography are critical to evaluate for cardiac involvement, which is seen in up to 80% of patients.

Differential Diagnosis

Brain MRI should be obtained in all children with chorea to rule out basal ganglia pathology. Though pediatric autoimmune neuropsychiatric disorder associated with Streptococcal infections (PANDAS) is a controversial diagnosis, other paraneoplastic and other autoimmune disorders can certainly cause acquired movement disorders. Additional laboratory testing should be considered to exclude other causes, such as antineuronal antibodies (to evaluate for lupus), antiphospholipid antibodies (to screen for other autoimmune causes), thyroid screening tests, serum calcium for hypocalcemia, HIV, parvovirus B19, and Epstein-Barr virus infection. Benign hereditary chorea (BHC) is an autosomal dominant genetic disorder that can be associated with intellectual disability, hypotonia, congenital hypothyroidism, and chronic lung disease. Tics can mimic chorea. Rare causes, such as drug-induced extrapyramidal syndromes, dyskinetic cerebral palsy, Huntington chorea, hepatolenticular degeneration (Wilson disease), typically cause subacute-chronic symptoms.

Treatment and Prognosis

Patients with Sydenham chorea require appropriate antibiotic prophylaxis for rheumatic fever, but no other specific treatment for Syndenham chorea has been developed. Prednisone and, in severe cases, IVIg have been successful. Anticonvulsants, such as sodium valproate or levetiracetam, can reduce chorea symptoms. Emotional lability and depression sometimes require psychologic and pharmacologic treatment. Sydenham chorea is a self-limited disease that may last from a few weeks up to 18 months. Relapse of chorea may occur with nonspecific stress or illness - or with breakthrough streptococcal infections. In follow up studies, valvular heart disease occurred in about one-third of patients, particularly if other rheumatic manifestations had been present as part of the childhood illness. Neuropsychologic disturbances were also present in many patients.

2. Tics/Tourette Syndrome

Clinical Findings

Tics are quick, repetitive but irregular, involuntary movements, which are often stereotyped and briefly suppressible. Tics affect up to 20% of school-aged children. Transient tic disorder lasts from 1 month to 1 year. Chronic tic disorder requires more than 1 year of motor or vocal tics. Tourette syndrome is characterized by both motor and vocal tics with no obvious cause, lasting more than 1 year. A premonitory urge (“I had to do it”), transient but effortful suppressibility, and sense of relief after completing the tic are characteristic for tic disorders. Tics generally wax and wane in frequency, and the type of movement evolves over time. Like many movement disorders, tics can be exacerbated by stress or excitement and generally resolve during sleep. Important common comorbidities are attention deficit hyperactivity disorder (AHDH), obsessive-compulsive disorder, academic difficulties, migraine, sleep difficulties, anxiety, and depression.

Motor tics can occur anywhere on the body, but most commonly affect the head, neck, and upper body. Facial tics can include grimaces, twitches, and eye blinking. Complex motor tics are coordinated, sequenced movements that can mimic voluntary motor acts, such as ear/nose scratching or jumping. Vocal tics can manifest as sniffing, grunting, throat clearing, barking, and in complex forms involve the use of words. Coprolalia and echolalia are relatively infrequent. Vocal tics are less common and are highly suggestive of Tourette syndrome. Self-injurious behavior can occur in Tourette syndrome.

Most patients presenting with tics do not require further diagnostic workup. However, a careful history should screen for secondary causes as well as comorbidities and investigate further as indicated.

Differential Diagnosis

Tics may be a symptom of other neurologic diseases such as brain injury, autism, Rett syndrome, and numerous genetic neurodevelopmental disorders. Acute brain lesion such as tumor, stroke, or infection will typically be associated with other symptoms. Post-infectious causes such as PANDAS or pediatric acute-onset neuropsychiatric symptoms (PANS) have been long debated, but can be considered if history suggests.

Treatment and Prognosis

The cornerstone of treatment is reassurance and education for the patient, family, and school about the nature of tic disorders. Importantly, if the tics are not bothersome to the child and are not causing physical or social impairment, no pharmacologic treatment is necessary. However, screening for and treating common comorbidities, such as ADHD, obsessive-compulsive symptoms, and anxiety, can significantly improve quality of life and sometimes lesson tic severity. Stimulant medications do not need to be avoided due to concern that tics might be exacerbated—recent studies have shown that medications such as methylphenidate improved ADHD symptoms without worsening tics. Habit reversal therapy and Comprehensive Behavioral Intervention for Tics (CBIT) can be effective approaches for tics and various comorbidities. Most pediatric patients will have significant improvement or resolution of tics later in life. Tourette syndrome is considered a life-long disorder and may wax and wane, and in some severe cases may be disabling.

If pharmacologic treatment is warranted, the choice of therapy can be tailored to the child’s needs and comorbidities. Clonidine and guanfacine are considered first-line, especially in a child with comorbid ADHD. Topiramate has a mild side effect profile and may be indicated if the patient has headaches or epilepsy. If tics are refractory to first-line agents, pimozide and fluphenazine are recommended next options, followed by antipsychotics, such as risperidone and aripiprazole. Haloperidol is FDA-approved for Tourette syndrome; however, due to the risk of tardive dyskinesia, it is typically reserved for refractory cases.

3. Primary Dystonia and Paroxysmal Dyskinesias

Dystonia is sustained or intermittent involuntary muscle contractions, frequently resulting in twisting movements or abnormal postures. Not all dystonia is due to co-contraction of opposing muscle groups. Secondary causes include cerebral palsy, stroke, tumor, and medication effect. However, primary dystonia can be mistakenly diagnosed as cerebral palsy. Any child with dystonia of unknown cause should have a trial of low-dose L-dopa; a prompt improvement suggests dopa-responsive dystonia (DYT5, also called Segawa disease), a genetic dystonia that is quite sensitive to oral L-dopa. Oppenheim’s dystonia (DYT1) is another genetic cause of dystonia that can manifest in childhood.

Paroxysmal dyskinesias are sudden-onset, short-duration choreoathetosis or dystonia episodes. Most often these episodes are familial or genetic in origin. Episodes may occur spontaneously or be set off by actions (“kinesigenic,” or movement-induced) such as standing up suddenly. Table 25–17 outlines the features of the most common paroxysmal dyskinesias.

4. Tremor

Tremor is a rhythmic, involuntary oscillatory movement across a joint axis and is often due to alternating contraction of opposing muscle groups. Resting tremors are most prominent when the involved muscles are completely at rest. In contrast, action tremors become more prominent when the affected muscles are engaged, for example to maintain a posture (postural tremor) or to move to a target (intention tremor). The most common causes of tremor in the pediatric population are enhanced physiologic tremor, essential tremor, and psychogenic tremor. Numerous medications can exacerbate physiologic tremor, such as asthma medications, antidepressants, stimulants, antipsychotics, and anticonvulsants. Patients with essential tremor often have a family history of tremor, note worsening with caffeine, and have transient improvement with alcohol. Differential diagnosis includes birth asphyxia, Wilson disease, hyperthyroidism, and hypocalcemia; history and laboratory tests rule out these rare possibilities.

CEREBRAL PALSY

The term cerebral palsy is a nonspecific term used to describe a chronic, static impairment of muscle tone, strength, coordination, or movements. The term implies that the condition is nonprogressive and originated from some type of cerebral insult or injury before birth, during delivery, or in the perinatal period. Other neurologic deficits or disorders (eg, blindness, deafness, intellectual disability, or epilepsy) often coexist. Some form of cerebral palsy occurs in about 0.2% of live births. The fundamental course, severity, precise manifestations, and prognosis vary widely.

Clinical Findings

A. Symptoms and Signs

The most common forms of cerebral palsy (75% of cases) involve spasticity of the limbs. A variety of terms denote the limbs affected: monoplegia (one limb); hemiplegia (arm and leg on same side of body, but arm more affected than leg); paraplegia/diplegia (both legs affected with arms unaffected); quadriplegia (all four limbs affected equally). Ataxia is the second most common form of cerebral palsy, accounting for about 15% of cases. The ataxia frequently affects fine coordinated movements of the upper extremities, but may also involve lower extremities and trunk. A dyskinetic movement disorder usually in the form of choreoathetosis or dystonia accounts for 5% of cases and persistent hypotonia without spasticity for 1%.

Depending on the type and severity of the motor deficits, associated neurologic deficits or disorders may occur: epilepsy in 25%, intellectual disability in 50% (that is severe in 25%), disorders of language, speech, vision, hearing, and sensory perception are found in varying degrees and combinations.

The findings on physical examination are variable and are predominantly those of spasticity, hyperreflexia, and, less often ataxia and/or involuntary movements. In patients with hemiplegia, the affected arm and leg may be smaller and shorter than the unaffected limbs. Cataracts, retinopathy, and congenital heart defects may be indicative of congenital infections such as CMV and rubella. It is important to note that, while this is considered a static process, the degree of impairment is not typically visible until the child has at least reached the ages of 3–4 years; children can be said to “grow into” their deficits as they age through infancy and toddlerhood.

B. Laboratory and Imaging Tests

Appropriate studies depend on the history and physical findings. MRI is helpful in understanding the full extent of cerebral injury in about 90% of cases, and occasionally neuroimaging results suggest specific etiologies (eg, periventricular calcifications in congenital CMV, perinatal strokes, or brain malformations). Genetic and metabolic testing should be targeted based on history or MRI findings.

Differential Diagnosis

It should be noted that the diagnosis of cerebral palsy is a descriptor. There must be some underlying etiology that leads to this constellation of symptoms. If identifiable, this is often helpful from a pathologic and prognostic standpoint and should be investigated if an etiology is not clear at diagnosis. No definite etiologic diagnosis is possible in 25% of cases. The incidence is high among infants small for gestational age or with extreme preterm birth. Intrauterine hypoxia is a frequent cause. Other known causes are intrauterine bleeding, infections, toxins, congenital brain malformations, obstetric complications (including birth hypoxia), neonatal infections, kernicterus, neonatal hypoglycemia, metabolic disorders, and a small number of genetic syndromes.

Treatment & Management

Treatment and management are directed at assisting the child to attain maximal neurologic functioning with appropriate physical, occupational, and speech therapy. Orthopedic monitoring and intervention and special educational assistance may all contribute to an improved outcome. Treatment of spasticity (with medications for tone or botulinum toxin) and seizures are needed in many children. Constraint-induced movement therapy can help with the affected extremity. Also important is the general support of the parents and family with counseling, educational programs, and support groups.

Prognosis

The prognosis for patients with cerebral palsy depends greatly on the child’s IQ, severity of the motor deficits, etiology of CP, and degree of disability. In severely affected children, aspiration, pneumonia, or other intercurrent infections are the most common causes of death.

In contrast, patients with mild cerebral palsy may improve with age. Some patients experience resolution of their motor deficits by age 7 years. Ambulatory status at 12 years of age is most predictive of adult functional ability. Many children may have normal intellect, normal life spans, and are able to lead productive, satisfying lives.

Infections and inflammation of the CNS are among the most treatable neurologic conditions. However, they also have a very high potential for causing catastrophic destruction of the nervous system. It is imperative for the clinician to recognize infections and inflammatory disorders of the CNS early to treat and prevent massive tissue destruction.

Clinical Findings

A. Symptoms and Signs

Patients with CNS infections, whether caused by bacteria, viruses, or other microorganisms, present with similar manifestations. These include systemic signs of infection, such as fever, malaise, chills, and organ dysfunction, and specific features suggesting CNS infection including headache, stiff neck, fever or hypothermia, changes in mental status (including hyperirritability evolving into lethargy and coma), seizures, and focal sensory and motor deficits. Meningeal irritation is indicated by the presence of Kernig and Brudzinski signs. In very young infants, signs of meningeal irritation may be absent, and temperature instability and hypothermia are more common than fever. In young infants, a bulging fontanelle and an increased head circumference are common. Papilledema may eventually develop, particularly in older children and adolescents. Cranial nerve palsies may develop acutely or gradually during neurologic infections. No specific clinical sign or symptom is reliable in distinguishing bacterial infections from infections caused by other microbes.

During the initial clinical assessment, conditions that predispose the patient to infection of the CNS should be sought. Infections involving the sinuses or other structures in the head and neck region can result in direct extension of infection into the intracranial compartment. Open head injuries, recent neurosurgical procedures, immunodeficiency, and the presence of a mechanical shunt may predispose to intracranial infection.

B. Laboratory Findings

When CNS infections are suspected, blood should be obtained for a complete blood count, chemistry panel, and culture. Most important, however, is obtaining CSF. In the absence of focal neurologic deficits or signs of brainstem herniation, CSF should be obtained immediately from any patient in whom serious CNS infection is suspected. When papilledema or focal motor signs are present, a lumbar puncture may be delayed until either at CT scan or MRI of the brain has been done to exclude space-occupying lesions. Antimicrobial treatment must be started even if lumbar puncture is delayed. It is generally safe to obtain spinal fluid from infants with nonfocal neurologic examination even if the fontanelle is bulging. Spinal fluid should be examined for the presence of red and white blood cells, protein concentration, glucose concentration, bacteria, and other microorganisms; a sample should be cultured. In addition, serologic, immunologic, and nucleic acid detection (PCR) tests may be performed on the spinal fluid. Many labs have multiplex PCR panels that allow for rapid testing of many pathogens. Identification of a pathogen may allow for customized treatment. Spinal fluid that contains a high proportion of polymorphonuclear leukocytes, a high protein concentration, and a low glucose concentration strongly suggests bacterial infection (see Chapter 42). CSF containing predominantly lymphocytes, a high protein concentration, and a low glucose concentration suggests infection with mycobacteria, fungi, uncommon bacteria, and some viruses such as lymphocytic choriomeningitis virus, herpes simplex virus, mumps virus, and arboviruses (see Chapters 40 and 43). CSF that contains a high proportion of lymphocytes, normal or only slightly elevated protein concentration, and a normal glucose concentration is suggestive of viral infections and CNS inflammatory disorders, although partially treated bacterial meningitis and parameningeal infections may also result in this CSF profile. Typical CSF findings in a variety of infectious and inflammatory disorders are shown in Table 25–2.

Herpes simplex virus infections can be confirmed using PCR to detect for herpes DNA in spinal fluid. This test has 95% sensitivity and 99% specificity. If clinical suspicion is high with a negative result, continue to treat and repeat PCR in 2–3 days. Rarely, brain biopsy may be needed to detect the rare PCR-negative case of herpes simplex, various parasitic infections, or in a suspected parainfectious or postinfectious cause with ambiguous spinal fluid findings (eg, vasculitis).

C. Imaging

Neuroimaging with CT and MRI scans may be helpful in demonstrating the presence of brain abscess, meningeal inflammation, or secondary problems such as venous and arterial infarctions, hemorrhages, and subdural effusions when these are suspected. In addition, these procedures may identify sinus or other focal infections in the head or neck region that are related to the CNS infection.

Although often nonspecific, EEGs may be helpful in the assessment of patients who have had seizures at the time of presentation. In some instances, such as herpes simplex virus or focal enterovirus infection, periodic lateralized epileptiform discharges (PLEDs) may be seen early in the course and may be one of the earliest study abnormalities to suggest the diagnosis. EEGs may also show focal slowing over regions of infarcts or (rare) abscesses.

BACTERIAL MENINGITIS

Bacterial infections of the CNS may present acutely (symptoms evolving rapidly over 1–24 hours), subacutely (symptoms evolving over 1–7 days), or chronically (symptoms evolving over more than 1 week). Diffuse bacterial infections involve the leptomeninges, superficial cortical structures, and blood vessels. Although the term meningitis is used to describe these infections, it should not be forgotten that the brain parenchyma is also inflamed and that blood vessel walls may be infiltrated by inflammatory cells that result in endothelial cell injury, vessel stenosis, and secondary ischemia and infarction. Overall clinical characteristics of bacterial meningitis (and viral meningoencephalitis) are outlined in Table 25–18.

Acutely, this inflammatory process may result in cerebral edema or impaired CSF flow through and out of the ventricular system, resulting in hydrocephalus.

Treatment

A. Specific Measures

(See also Chapters 39, 40, and the section on bacterial infections in Chapter 42.)

While awaiting the results of diagnostic tests, the physician should start broad-spectrum antibiotic coverage. The appropriate antimicrobial varies with age to match the likely pathogens encountered at a given age. After specific organisms are identified, antibiotic therapy can be tailored based on antibiotic sensitivity patterns.

Suspected bacterial meningitis in neonates is treated initially with ampicillin and cefotaxime. Ampicillin and Gentamicin may be used in the case of fever in a neonate. Cefotaxime should be used if a gram-negative organism is suspected. Ampicillin is used to treat Listeria and enterococci infections, which rarely affect immune-competent older children. Thus, children older than 3 months are given ceftriaxone or cefotaxime plus vancomycin to empirically treat for the most common bacterial pathogens, penicillin-resistant S pneumoniae and N meningitides. Rifampin and dexamethasone use should be considered on a case by case basis. Therapy may be narrowed when organism sensitivity is determined. Duration of therapy is 7 days for meningococcal infections, 10 days for Haemophilus influenzae or pneumococcal infection, and 14–21 days for other organisms. Slow clinical response or the occurrence of complications may require prolonged therapy.

Meningitis in a child with a ventriculoperitoneal shunt is most commonly caused by coagulase-negative staphylococci, many of which are methicillin-resistant. In many of these patients who are not seriously ill, therapy should be postponed while awaiting the appropriate shunt fluid for Gram stain and culture. Seriously ill patients should initially be given vancomycin and a third-generation cephalosporin, because Staph aureus and gram-negative rods are also common causes of serious infection.

B. General and Supportive Measures

Children with bacterial meningitis are often systemically ill. The following complications should be looked for and treated aggressively: hypovolemia, hypoglycemia, hyponatremia, acidosis, septic shock, increased intracranial pressure, seizures, disseminated intravascular coagulation, and metastatic infection (eg, pericarditis, arthritis, or pneumonia). Children should initially be monitored closely (cardiorespiratory monitor, strict fluid balance and frequent urine specific gravity assessment, daily weights, and neurologic assessment every few hours), not fed until neurologically stable, isolated until the organism is known, rehydrated with isotonic solutions, and then given intravenous fluids containing dextrose and sodium at no more than maintenance rate (assuming no unusual losses occur).

Complications

Abnormalities of water and electrolyte balance result from either excessive or insufficient production of antidiuretic hormone and require careful monitoring and appropriate adjustments in fluid administration. Monitoring serum sodium every 8–12 hours during the first 1–2 days, and urine sodium if the inappropriate secretion of antidiuretic hormone is suspected, will usually uncover significant problems.

Seizures occur in 20%–30% of children with bacterial meningitis. Most seizures occur early during infection. Seizures tend to be most common in neonates and less common in older children. Persistent focal seizures or focal seizures associated with focal neurologic deficits strongly suggest subdural effusion, abscess, or vascular lesions such as arterial infarct, cortical venous infarcts, or dural sinus thrombosis. Because generalized seizures in a metabolically compromised child may have severe sequelae, early recognition and therapy are critical.

Subdural effusions occur in up to a third of young children with S pneumoniae meningitis. Subdural effusions are often seen on CT scans of the head during the course of meningitis. They do not require treatment unless they are producing increased intracranial pressure or progressive mass effect. Although subdural effusions may be detected in children who have persistent fever, such effusions do not usually have to be sampled or drained if the infecting organism is H influenzae, meningococcus, or pneumococcus. These are usually sterilized with the standard treatment, and slowly waning fever during an otherwise uncomplicated recovery may be followed clinically. Under any other circumstance, however, aspiration of the fluid for documentation of sterilization or for relief of pressure should be considered. Prognosis is not worsened by subdural effusions.

Cerebral edema results in increased intracranial pressure, requiring treatment with dexamethasone, osmotic agents, diuretics, or hyperventilation; intracranial pressure monitoring may be needed.

Long-term sequelae of meningitis result from direct inflammatory destruction of brain cells, vascular injuries, or secondary gliosis. Focal motor and sensory deficits, visual impairment, hearing loss, seizures, hydrocephalus, and a variety of cranial nerve deficits can result. Sensorineural hearing loss in H influenzae meningitis occurs in approximately 5%–10% of patients during long-term follow-up. Early addition of dexamethasone to the antibiotic regimen may modestly decrease the risk of hearing loss in some children with bacterial meningitis (see Chapter 42).

In addition to the disorders mentioned, some patients with meningitis develop mild to severe cognitive impairment and severe behavioral disorders that limit their function at school and later performance in life.

BRAIN ABSCESS

Clinical Findings

Patients with brain abscess often appear to have systemic illness similar to patients with bacterial meningitis, but in addition they may show signs of focal neurologic deficits, papilledema, and other evidence of increased intracranial pressure or a mass lesion. Symptoms may be present for a week or more; children with bacterial meningitis usually present within a few days. Conditions predisposing to development of brain abscess include penetrating head trauma; chronic infection of the middle ear, mastoid, or sinuses (especially the frontal sinus); chronic dental or pulmonary infection; cardiovascular lesions allowing right-to-left shunting of blood (including arteriovenous malformations); and endocarditis.

When brain abscess is strongly suspected, a neuroimaging procedure such as CT or MRI scan with contrast enhancement should be done prior to lumbar puncture. If a brain abscess is identified, lumbar puncture may be dangerous and rarely alters the choice of antibiotic or clinical management since the CSF abnormalities usually reflect only parameningeal inflammation or are normal. With spread from contiguous septic foci, streptococci and anaerobic bacteria are most common. Staphylococci most often enter from trauma or spread from distant infections. Enteric organisms may form an abscess from chronic otitis. Cultures from many brain abscesses are negative, but Gram stain may be informative.

The diagnosis of brain abscess is based primarily on a strong clinical suspicion and confirmed by a neuroimaging procedure. Strongly positive inflammatory markers (erythrocyte sedimentation rate, C-reactive protein) may be supportive as normal results would be unlikely in patients with brain abscess. EEG changes are nonspecific but frequently demonstrate focal slowing in the region of brain abscess.

Differential Diagnosis

Differential diagnosis of brain abscess includes any condition that produces focal neurologic deficits and increased intracranial pressure, such as neoplasms, subdural effusions, cerebral infarctions, and other CNS infections.

Treatment

When a primary source or contiguous focus is suspected Ceftriaxone plus metronidazole is recommended. Penicillin G is an alternative to a cephalosporin and is effective against most mouth flora. In posttraumatic and postsurgical cases, nafcillin or oxacillin plus a third-generation cephalosporin (cefotaxime or ceftriaxone) is recommended. Vancomycin should be considered as a substitute for nafcillin or oxacillin when methicillin-resistant Staphylococcus aureus is suspected. Treatment may include neurologic consultation and anticonvulsant therapy when necessary. In their early stages, brain abscesses are areas of focal cerebritis and can be treated with antibiotic therapies alone. Encapsulated abscesses require surgical drainage.

Prognosis

The surgical mortality rate in the treatment of brain abscess is lower than 5%. Untreated cerebral abscesses lead to irreversible tissue destruction and may rupture into the ventricle, producing catastrophic deterioration in neurologic function and death. Because brain abscesses are often associated with systemic illness, the death rate is frequently high in these patients. Other poor prognostic indicators include rapid progression of disease and alteration of consciousness at the time of presentation.

VIRAL INFECTIONS

Viral infections of the CNS can involve meninges (meningitis) (see Chapter 40) or parenchyma (encephalitis). All patients, however, have some degree of involvement of both the meninges and cerebral parenchyma (meningoencephalitis). Many viral infections are generalized and diffuse, but some viruses, notably herpes simplex and some enteroviruses, characteristically cause prominent focal disease. Focal cerebral involvement is clear on neuroimaging procedures. Some viruses have an affinity for specific CNS cell populations. Poliovirus and other enteroviruses (A71 and D68) can selectively infect anterior horn cells and some intracranial motor neurons.

Although most viral infections of the nervous system have an acute or subacute course in childhood, chronic infections can occur. Subacute sclerosing panencephalitis, for example, represents a chronic indolent infection caused by altered measles virus and is characterized clinically by progressive neurodegeneration and seizures.

Treatment of CNS viral infections is usually limited to symptomatic and supportive measures, except for herpes simplex virus, and some cases of varicella-zoster virus infections where acyclovir is used (see HSV section within the Viral and Rickettsial diseases chapter). West Nile virus is an arthropod-borne flavivirus. It is found in mosquitoes, thus the highest incidence of West Nile virus infections occurs from July to October. The infection is now endemic in United States. This disease is often asymptomatic or mild in pediatric patients; paralysis and death occur mostly in the elderly.

ENCEPHALOPATHY OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION

Neurologic syndromes associated directly with HIV infection include subacute encephalitis, meningitis, myelopathy, polyneuropathy, and myositis. In addition, opportunistic infections of the CNS occur in patients with HIV-induced immunosuppression. Pneumocystis, Toxoplasma, and CMV infections are particularly common. Progressive multifocal leukoencephalopathy caused by a secondary papillomavirus infection, and herpes simplex and varicella-zoster infections also occur frequently in patients with untreated HIV infection. Various fungal (especially cryptococcal), mycobacterial, and bacterial infections occur.

Neurologic abnormalities in these patients can also be the result of noninfectious neoplastic disorders. Primary CNS lymphoma and metastatic lymphoma to the nervous system are the most frequent neoplasms of the nervous system in these patients. See Chapters 33, 39, and 41 for diagnosis and management of HIV infection.

OTHER INFECTIONS

A wide variety of other microorganisms, including Toxoplasma, mycobacteria, spirochetes, rickettsiae, amoebae, and mycoplasma, can cause CNS infections. CNS involvement in these infections is usually secondary to systemic infection or other predisposing factors. Appropriate cultures and serologic testing are required to diagnose these infections. Parenteral antimicrobial treatment for these infections is discussed in Chapter 39.

NONINFECTIOUS INFLAMMATORY DISORDERS OF THE CENTRAL NERVOUS SYSTEM

The differential diagnosis of bacterial, viral, and other microbial infections of the CNS includes disorders that cause inflammation but for which no specific causal organism has been identified. Sarcoidosis, Behçet disease, systemic lupus erythematosus, and other collagen-vascular disorders are examples. In these disorders, CNS inflammation usually occurs in association with characteristic systemic manifestations that facilitate diagnosis. Some CNS inflammatory disorders lead to demyelination syndromes described in Table 25–19. Management of CNS involvement in these disorders is the same as the treatment of the systemic illness.

A. Acute Demyelinating Encephalomyelitis

Inflammatory reactions within the nervous system may occur during the convalescent stage of systemic viral infections. Parainfectious or postinfectious inflammation of the CNS results in several well-recognized disorders: acute disseminated encephalomyelitis (ADEM; 25% of encephalitis), transverse myelitis, optic neuritis, polyneuritis, and GBS.

Clinical Findings

a. Imaging

MRI findings in ADEM are distinctive: demyelinating lesions, seen on T₂ and FLAIR images, are key to the diagnosis. White matter lesions can mimic findings in MS, but more likely are large and ill-defined. White matter lesions may also involve gray matter such as cortex, basal ganglia, and thalamus. Radiologic changes are usually florid when the patient presents but occasionally emerge days later. In cases of uncertain diagnosis, serial or repeat scans may be necessary. Unlike the demyelinating lesions of MS, ADEM lesions usually resolve within months of presentation.

b. Laboratory Findings

Lumbar puncture findings may be normal or mildly abnormal, with mild pleocytosis and elevation of the CSF protein in 25%–50% of cases. Oligoclonal bands are not typically seen in ADEM, but rather are commonly found in chronic, relapsing conditions like MS. Oligoclonal bands may also be seen in chronic infections and viral syndromes.

Treatment

Corticosteroids are the primary treatment for ADEM. Current practice is to administer high-dose, followed by oral prednisone taper over 4–6 weeks. Most pediatric groups initially use intravenous methylprednisolone (10–30 mg/kg/days up to a maximum dose of 1 g/days). In refractory patients, IVIg or plasmapheresis may be effective.

Prognosis

Rarely, ADEM relapses within 3 months of onset. Recurrence more than 3 months after treatment should raise suspicion of MS, neuromyelitis optica spectrum disorder (especially in cases of optic nerve or spinal cord involvement) or alternative cause. Congenital viral infections can also affect the CNS. CMV, herpes simplex virus, varicella, and (rare now, because of immunization) rubella virus are the most notable causes of viral brain injury in utero.

B. Paraneoplastic Syndromes

Paraneoplastic syndromes are increasingly recognized. These immune-mediated disorders are clinically heterogeneous with neurologic effects that can be both central and peripheral. The disorders are identified by autoantibodies to both intraneuronal and cell surface antigens. While the pathogenesis of these disorders is poorly understood, they are thought to result from misdirected immune response to shared epitopes between neuronal antigens and tumor antigens. Anti-NMDA receptor encephalitis is one example of a paraneoplastic syndrome that may precede detection of neoplasm, or result from post-viral immune dysregulation. Recent case reports have identified HSV-1 as a trigger for anti-NMDAR encephalitis. Behavioral changes, autonomic instability, insomnia, aphasia, seizures, and movement disorders are prominent. Detection of the antibody is diagnostic. Immunotherapy, including glucocorticoids, IVIg, and/or plasma exchange are shown to be beneficial. Second-line therapies include rituximab and/or cyclophosphamide for refractory cases.

MULTIPLE SCLEROSIS

Five to ten percent of patients with MS are diagnosed before the age of 18 years. Many patients diagnosed in adulthood report having symptoms attributable to MS prior to age of 18 years. The epidemiology, pathophysiology, diagnosis and treatment of peds MS are areas of study. Several exciting discoveries have highlighted the importance of genetic and environmental risk factors for pediatric MS. Notable examples include HLA subtypes, viral exposures, smoking exposure, childhood obesity, vitamin D deficiency, and others. Importantly, diagnostic criteria, including clinical, MRI, and laboratory studies are different among prepubertal patients when compared to postpubertal patients.

Clinical Findings

The diagnosis of MS in a child remains challenging as the presenting clinical signs and symptoms may be similar or identical to acute disseminated encephalomyelitis, despite the same pathophysiology. An earlier age at disease presentation may be associated with specific features such as encephalopathy, seizures, and brainstem and cerebellar symptoms.

A diagnosis of MS requires demyelination separated in time and space. However, a diagnosis of pediatric MS may be made after one episode of demyelination if the MRI scan meets criteria for dissemination in time and space as described in the McDonald 2010 diagnostic criteria. If these criteria are not met, the child is diagnosed with clinically isolated syndrome, for example, optic neuritis; transverse myelitis; or brainstem, cerebellar, or hemispheric dysfunction. If the patient develops subsequent clinical or radiographic changes that meet criteria for MS, he/she may be diagnosed at that time. Atypical clinical features of pediatric MS include fever and involvement of the peripheral nervous system or other organ systems, elevated erythrocyte sedimentation rate or marked CSF pleocytosis. Encephalopathy is more commonly associated with ADEM. However, in young children, MS exacerbations may present with encephalopathy, making differentiation of the two disorders difficult.

The initial brain MRI scan of younger patients shows more frequent involvement of the posterior fossa and higher numbers of ovoid, ill-defined T2-bright foci that often partially resolve on the follow-up scan. At present, there are several sophisticated MRI criteria to separate pediatric MS diagnosis from alternative diagnoses (eg, ADEM).

Finally, the spinal fluid in younger patients may fail to reveal oligoclonal bands or elevated IgG index at disease onset. There is no FDA-approved therapy for MS in children, but several studies are underway. Current practice is to use disease-modifying therapies that are approved for adults. Retrospective data have shown them to be effective in children.

Differential Diagnosis

Differential diagnosis includes ADEM, idiopathic transverse myelitis, optic neuritis, rheumatologic disorders such as systemic lupus erythematosis, Behcet and Sjogren syndrome and neuromyelitis optica. Many other infections, metabolic disorders, and degenerative diseases can mimic MS. A newly recognized syndrome characterized by antimyelin oligodendrocyte glycoprotein (MOG) antibodies, Anti-MOG Syndrome, may account for cases previously thought to be atypical pediatric MS or ADEM.

Treatment

Acute treatment of relapses includes high dose intravenous methylprednisolone and occasionally plasmapheresis. The use of disease-modifying therapies in children is based on adult randomized controlled trials and retrospective experience. Pediatric clinical trials are underway. Immunomodulatory treatment to prevent relapses in children include injections, oral medications and infusions. Injectable medications include interferon beta-1a, interferon beta-1b, glatiramer acetate, and daclizumab. Oral medications include fingolimod, teriflunomide, and dimethyl fumarate. Intravenous infused drugs include natalizumab, rituximab, ocrelizumab, and alemtuzumab. Cyclophosphamide may be used in refractory patients.

Pathogenesis

Flaccid paralysis in a child can occur as a result of a lesion anywhere along the neuroaxis. The key to diagnosis is localizing the lesion. Associated changes in reflexes, sensory changes, abnormal reflexes such as a positive Babinski’s sign, and bowel and bladder changes can help in localizing the lesion. Mass lesions, infectious or postinfectious causes, toxins (eg, from a tick or due to botulism), and metabolic causes, are only a few of the etiologies that can cause acute weakness. A review of some of the more common causes of acute flaccid weakness and their associated findings are listed in Table 25–20.

Clinical Findings

A. Symptoms and Signs

Features assisting diagnosis are age, a history of preceding illness, rapidity of progression, cranial nerve findings, bowel and bladder changes, and sensory findings (see Table 25–20). The finding of increased reflexes and upgoing toes suggests a CNS lesion. Fatigability when drinking from a bottle and constipation may be seen in infants with botulism. In GBS (also known as acute inflammatory demyelinating polyneuropathy [AIDP]), patients may initially present with an ascending paresthesia and loss of reflexes before they develop overt weakness. Patients with the Miller Fisher variant of GBS may present with a classic constellation of symptoms including ophthalmoplegia, ataxia, and loss of reflexes. Back pain is suggestive of a spinal cord lesion, such as in transverse myelitis or a spinal cord mass.

B. Laboratory Findings

When a spinal cord or brain lesion is suspected, MRI imaging may be helpful, and in fact is essential if a mass lesion is suspected. Once a mass lesion is excluded by imaging, CSF studies, including opening pressure, can be obtained. Viral cultures (CSF, throat, and stool) and titers aid in diagnosing poliomyelitis. A high sedimentation rate may suggest tumor, abscess, or autoimmune disorder.

EMG and nerve conduction studies (NCSs) can be helpful in diagnosing GBS. NCSs are particularly helpful after the first week when delayed or absent H or F reflexes are seen as the first changes. Later, motor NCSs show prolonged distal latency, conduction block or temporal dispersion, with these changes seen in 50% of patients by 2 weeks and 85% by 3 weeks. EMG findings of fibrillation potentials and increased compound muscle action potential amplitudes with high-frequency stimulation are suggestive of botulism. Rarely, elevation of muscle enzymes or even myoglobinuria may aid in diagnosis of acute myopathic weakness.

Differential Diagnosis

Atypical presentations of viral infections such as with influenza A, West Nile virus, and enterovirus should be considered when a patient presents with symptoms of poliomyelitis. Ascending paresthesias and absent reflexes are often early signs of GBS. The weakness of the extremities, respiratory muscles and bulbar muscles can be followed rapidly thereafter. In previously healthy infants who present with acute weakness, botulism should be considered, particularly in endemic areas or with a history of ingesting honey or canned foods. Tick paralysis can be rapidly corrected with removal of the tick, but requires an index of suspicion and a careful search for the offending insect. Patients with transverse myelitis may present with acute weakness and absent reflexes, but in the ensuing weeks will develop hyperreflexia and increased tone in the regions below the area of the lesion.

Complications

A. Respiratory Weakness and Failure

Early careful attention to ventilation is essential, especially in those patients with bulbar weakness and early signs of respiratory failure. Administration of oxygen, intubation, mechanical respiratory assistance, and careful suctioning of secretions may be required. Increasing anxiety and a rise in diastolic and systolic blood pressures are early signs of hypoxia. Cyanosis is a late sign. Deterioration of spirometry testing: forced expiratory volume in 1 second and total vital capacity, may indicate the need for controlled intubation and respiratory support. At the bedside, measurement of negative inspiratory force (NIF) is recommended at frequent intervals in the acute course as this may be more sensitive to early respiratory failure than blood gases.

B. Infections

Pneumonia is common, especially in patients with respiratory weakness. Antibiotic therapy is best guided by results of cultures. Bladder infections occur when an indwelling catheter is required because of bladder paralysis. Recovery from myelitis may be delayed by urinary tract infection.

C. Autonomic Crisis

This may be a cause of death in GBS. Strict attention to vital signs to detect and treat hypotension or hypertension and cardiac arrhythmias in an intensive care setting is advisable, at least early in the course and in severely ill patients.

Treatment

Ticks causing paralysis must be removed. Botulism immune globulin administration shortens the hospitalization course in infant botulism, as can treatment with IVIg or plasmapheresis in GBS. Steroids, IVIg, and/or plasmapheresis have been used in transverse myelitis. Comorbid associated disorders (eg, endocrine, neoplastic, or toxic) should be treated by appropriate means. Supportive treatment is of the essence for all of the diagnoses, including pulmonary toilet, adequate fluids and nutrition, bladder and bowel care, prevention of decubitus ulcers, and in many cases, psychiatric support.

DISORDERS OF CHILDHOOD AFFECTING MUSCLES