CURRENT Diagnosis and Treatment Pediatrics, (Current Pediatric Diagnosis & Treatment) 22nd Edition

25. Neurologic & Muscular Disorders

Sita Kedia, MD

Kelly Knupp, MD

Teri Schreiner, MD MPH

Michele L. Yang, MD

Paul M. Levisohn, MD

Paul G. Moe, MD

NEUROLOGICAL ASSESSMENT & NEURODIAGNOSTICS

1. History

Even in an era of increasingly sophisticated neurodiagnostic testing, the assessment of the child with a possible neurologic disorder begins with history, general physical exam as well as detailed neurologic examination. The standard pediatric history and physical examination are presented in Chapter 9. A careful history will allow the clinician to establish the nature and course of the illness. The progression of the illness, that is, acute, chronic, progressive or static, episodic or continuous, will help to determine the approach to the evaluation. When the developmental history is vague, other resources such as extended family members and baby books may provide clarification of prior development. Episodic events such as headaches or seizures warrant emphasis on precise details preceding and during these events. Often spells can be videotaped and this can provide important details that will assist in diagnosis.

2. Neurologic Examination

A general physical examination is an essential aspect of the assessment. Growth parameters and head circumference should be charted (see Chapter 3). A developmental assessment using an appropriate screening tool is part of every neurologic evaluation of the infant and young child and can be used to document a child’s developmental status. Chapter 3 delineates age-appropriate developmental landmarks (see Tables 3–1 and 3–2). Multiple instruments are available for screening infants and children. Among these The Ages & Stages Questionnaires^®, Third Edition (ASQ-3), a parent-completed screening tool, is widely used when assessing infants and young children. The Modified Checklist for Autism in Toddlers (M-CHAT™) is a screening tool for assessing toddlers between 16 and 30 months of age for risk of autism spectrum disorders. The specifics of the neurologic examination are determined by the age of the child and the ability to cooperate in the examination. Expected newborn-infant reflexes and automations and other examination suggestions pertinent to that age group are included in Chapter 2. The hallmark of neurologic diagnosis is localization, defining where in the nervous system the “lesion” is. While not all childhood neurologic disorders are easily localized, the part of the nervous system involved, for example, central versus neuromuscular, can often be defined and will act as a guide for evaluation and diagnosis.

Table 25–1 outlines components of the neurologic examination. Much of the examination of the frightened infant or toddler is by necessity observational. An organized approach to the examination is thus imperative. Playing games will engage a toddler or preschooler: throwing and catching 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 as will drawing, writing, calculating, and spelling.

1. Electroencephalography

Electroencephalography (EEG) is a noninvasive method for recording cerebral activity. The background patterns of the EEG vary by both age and clinical state of the subject, for example, infant, toddler, adolescent; awake, drowsy, or asleep. Intermittent activity 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 indicate risk for seizures and epilepsy, though not necessarily diagnostic of such. At times, however, the findings on an EEG are diagnostic, as in the hypsarrhythmic pattern of infantile spasms (West syndrome) or generalized three-cycle-per-second spike-wave pattern of absence epilepsy. Synchronized video recording with EEG has increased the utility of the test in assessing episodic disorders. EEG can be very useful in the evaluation of altered mental status and in some encephalopathies.

The EEG itself, in isolation, is rarely diagnostic but is 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 uninterpretable due to artifact from movement, crying, etc. Medications used for sedation of an uncooperative child, especially barbiturates and benzodiazepines, may produce artifact in the tracing, which can confuse interpretation and may decrease the likelihood of recording abnormalities such as epileptiform discharges. Children without a history of epilepsy may 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. When questions arise regarding the clinical significance of EEG findings, consultation with a pediatric neurologist is appropriate.

Due to more prolonged recording duration, ambulatory EEG obtained over 24–48 hours can be useful in assessing events to ascertain if they are due to epileptic seizures. Likewise, recording the EEG during nocturnal polysomnographic studies can help differentiate between nonepileptic sleep-related events from nocturnal epileptic seizures arising from sleep.

Prolonged bedside EEG recordings are useful in the assessment of patients with altered mental status, suspected nonconvulsive status epilepticus, and drug-induced coma (for the treatment of increased intracranial pressure or status epilepticus), as well as infants with hypoxic ischemic encephalopathy. The EEG is less commonly used for determining so-called brain death (electrocerebral inactivity).

Continuous video-EEG monitoring, obtained as an inpatient, allows assessment of the patient with medically intractable epilepsy. The children are admitted to a specialized unit (epilepsy monitoring unit [EMU]) for up to a week or more. When children are admitted to the hospital, medications are often reduced or discontinued, increasing the likelihood of recording an event. Localization of the seizure focus by recording during seizures can lead to resective surgery for the patient who has failed medical therapy. Correlating video with EEG has also proven useful in characterizing spells that may or may not be seizures.

2. 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, which results in cortical response when recorded from the scalp surface using averaging techniques. The presence or absence of evoked potential waves and their latencies from the time of the stimuli are determined and can be useful in some specific situations although they are not routinely obtained for evaluation of neurologic disorders.

However, auditory evoked responses are now the standard for screening hearing in the neonate. Intraoperative somatosensory evoked potentials are often used during spine surgery to assist the surgeon during placement of instrumentation for 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.

3. Lumbar Puncture

Assessing cerebral spinal fluid is a necessity in some clinical situations. 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 evidence of metabolic disorders (Table 25–2). Fluid is often sent for red and white cell counts, for determination of the concentrations of protein and glucose, for viral polymerase chain reaction (PCR), and for viral and bacterial cultures. In some cases, additional information is obtained with special staining techniques for mycobacteria and fungus and by testing for specific viral agents, antibody titer determinations, cytopathologic study, lactate and pyruvate concentrations, and amino acid 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.

4. 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. Microarray testing is diagnostic in almost 8% of children with GDD/ID and in 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.

5. Electromyography & Nerve Conduction Velocity Testing

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

NCV is performed by introducing a small current into peripheral nerves using small discs overlying the nerves. The conduction velocity of the stimulus is calculated. EMG records spontaneous and volitional electrical activity of skeletal muscle tissue. It requires placement of tiny needles into selected muscles. While uncomfortable, the tests are not painful and sedation is only rarely necessary. For more details, refer to section “Disorders of Childhood Affecting Muscles” in the chapter.

1. Computed Tomography

CT scanning is a noninvasive technique, which allows visualization of intracranial contents by obtaining a series of cross-sectional (axial) roentgenograms. Serial images are obtained, which allow computation of x-ray absorption and computation of images which appear as serial slices. Current scanning techniques allow rapid acquisition of data, often without sedation. CT scanning is of 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 presence of intracranial calcifications such as those associated with intrauterine infections, with 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. CT angiography (CTA) is possible using contrast and specialized techniques to visualize vascular anatomy and can replace catheter angiography in evaluation of stroke. Radiation exposure is approximately the same as that from a skull radiographic series and must be considered when obtaining a CT scan.

2. Magnetic Resonance Imaging

MRI is a noninvasive technique that provides high-resolution images of soft tissues. MRI uses the magnetic properties of certain nuclei to produce diagnostically useful signals (Table 25–3). The technique is based on detecting the response (resonance) of hydrogen proton 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, physiologic, and biochemical status of tissues as well as gross anatomic features. Sedation is often necessary for MRI scans in children who are unable to lie still for 45 minutes to avoid any 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 brainstem, blood vessels, and the cranial nerves imaging.

Magnetic resonance angiography (MRA) or venography (MRV) is used to visualize large extra- and intracranial blood vessels (arterial and venous) without injection of dye, though they are not as sensitive as conventional angiography. The lack of radiation exposure is an advantage over CTA (see previous section). 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. For example, MRS can be used to identify brain tumors.

Newer applications of MRI allow for functional assessment of the CNS. Functional MRI (fMRI) is used to localize various brain functions such as language and motor 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.

3. Positron Emission Tomography

Positron emission tomography (PET) is a nuclear medicine imaging technique that utilizes 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 coregistered with a traditional CT scan or MRI allowing more precise localization of functional processes. It is proving to be very useful in preoperative evaluation for epilepsy surgery. PET is most often performed in the interictal state. The information from PET scan complements EEG, single-photon emission computerized tomography (SPECT), and MRI findings to aid in defining the epileptogenic zone (“focus”). PET coregistered with CT scans or MRI scans is used for assessing systemic tumors and is becoming increasingly available for use in evaluation of the CNS.

4. Single-Photon Emission Computerized Tomography

An application of nuclear medicine imaging, 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 in differentiating tumor recurrence from post-treatment changes, in assessing the response to treatment, in directing biopsy, and in planning therapy. Regional cerebral blood flow can be assessed in children with strokes due to vascular stenosis and moyamoya disease.

5. Ultrasonography

Ultrasonography (US) offers a pictorial display of the varying densities of tissues in a given anatomic region by recording the echoes of ultrasonic waves reflected from it. 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. Ultrasonography has been used for in-utero diagnosis of hydrocephalus and other anomalies. In neonates, the thin skull and the open anterior fontanel have facilitated imaging of the brain, and ultrasonography is used to screen and follow infants at risk for intracranial hemorrhage. Other uses in neonates include detection of hydrocephalus, periventricular ischemic lesions, major brain and spine malformations, and calcifications. US of the neonatal spine can be used to determine the presence of anomalies at the lumbosacral level. Once the fontanels start to close, this modality is no longer useful due to inability to penetrate bone.

6. Cerebral Angiography

Arteriography remains useful in the diagnosis of cerebrovascular disorders, particularly cerebrovascular accidents and 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.

7. Myelography

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

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DISORDERS AFFECTING THE NERVOUS SYSTEM IN INFANTS & CHILDREN

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Reduction or alteration in cognitive and affective mental functioning and in arousability or attentiveness

 Acute onset

 General Considerations

Many terms are used to describe the continuum from fully alert and aware, to complete unresponsiveness, including obtundation, lethargy, somnolence, stupor, light coma, and deep coma. Several scales have been used to grade the depth of unconsciousness (Table 25–4). The commonly used Glasgow Coma Scale is summarized in Table 12–5. Physicians should use one of these scales and provide further descriptions in case narratives (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.

The neurologic substrate for consciousness is the ascending reticular activating system in the brainstem, which extends the thalamus and paraventricular nucleus of the hypothalamus. Large lesions of the cortex, especially bilateral lesions, can also cause coma.

• Persistent vegetative state denotes a chronic condition in which there is preservation of the sleep-wake cycle but no awareness of self or the environment and no recovery of mental function. Sleep-wake cycles are present.

• Minimally conscious state denotes patients that do not meet criteria for persistent vegetative state. These patients occasionally may have purposeful movements.

• Brain death refers to patients in coma without brainstem reflexes or spontaneous respirations.

Conditions mistaken for coma:

• Locked-in syndrome describes patients who are conscious but have no access to motor or verbal expression because of massive loss of motor function of the pontine portion of the brainstem. Vertical eye movements may be preserved.

• Akinetic-mutism: Patient is aware, but does not initiate movement or follow commands. Caused by lesions of the frontal lobes.

• Catatonia refers to patients with psychiatric illness. Patients retain ability to maintain trunk and limb postures.

 Treatment

A. Emergency Measures

The clinician must first stabilize the child using the ABCs of resuscitation. The airway must be kept open with positioning; endotracheal intubation is often considered. Breathing and adequate air exchange can be assessed by auscultation. Hand bag respiratory assistance with oxygen may be needed. Circulation must be ensured by assessing pulse and blood pressure. An intravenous line is always necessary. Fluids, plasma, blood, or even a dopamine drip (1–20 mcg/kg/min) may be required in cases of hypotension. Initial intravenous fluids should contain glucose until further assessment disproves hypoglycemia as a cause. An extremely hypothermic or febrile child may require vigorous warming or cooling to save life. The assessment of vital signs may signal the diagnosis. Slow, insufficient respirations suggest poisoning by hypnotic drugs; apnea may indicate diphenoxylate hydrochloride poisoning. Rapid, deep respirations suggest acidosis, possibly metabolic, as with diabetic coma; toxin exposure, such as that due to aspirin; or neurogenic causes, as in Reye syndrome. Hyperthermia may indicate infection or heat stroke; hypothermia may indicate cold exposure, ethanol poisoning, or hypoglycemia (especially in infancy).

The signs of impending brain herniation are another priority of the initial assessment. Bradycardia, high blood pressure, and irregular breathing are signs of severely increased intracranial pressure. Third nerve palsy (with the eye deviated down and out, and a “blown” pupil [unilateral pupillary dilation]) is a sign of impending temporal lobe or brainstem herniation. These signs suggest a need for hyperventilation to reduce cerebral edema, consideration of mannitol, prompt neurosurgical consultation, and head CT. If brainstem herniation or increased pressure is possible, intracranial monitoring may be necessary. Initial treatment of impending herniation includes keeping the patient’s head up (15–30 degrees) and providing moderate hyperventilation. The use of mannitol, diuretics, barbiturates, hypothermia, and drainage of cerebrospinal fluid (CSF) are more heroic measures covered in detail in Chapter 14.

A history obtained from parents, witnesses, or ambulance personnel is desirable. An important point is whether the child is known to have a chronic illness, such as diabetes, hemophilia, epilepsy, or cystic fibrosis. Recent acute illness raises the possibility of coma caused by viral or bacterial meningitis. Trauma is a common cause of coma. Lack of a history of trauma, especially in infants, does not rule it out. Abusive head trauma or an unwitnessed fall may have occurred. In coma of unknown cause, poisoning is always a possibility, especially in toddlers. Absence of a history of ingestion of a toxic substance or of medication in the home does not rule out poisoning as a cause.

Often the history is obtained concurrently with a brief pediatric and neurologic screening examination. After the assessment of vital signs, the general examination proceeds with a trauma assessment. Palpation of the head and fontanel, inspection of the ears for infection or hemorrhage, and a careful examination for neck stiffness are indicated. If circumstances suggest head or neck trauma, the head and neck must be immobilized so that any fracture or dislocation will not be aggravated. The skin must be inspected for petechiae or purpura that might suggest bacteremia, infection, bleeding disorder, or traumatic bruising. Examination of the chest, abdomen, and limbs is important to exclude enclosed hemorrhage or traumatic fractures.

Neurologic examination quantifies the stimulus response and depth of coma, such as responsiveness to verbal or painful stimuli. Are the eye movements spontaneous, or is it necessary to do the doll’s eye maneuver (rotating the head rapidly to see whether the eyes follow in a patient without neck trauma)? Motor and sensory examinations assess reflex asymmetries, Babinski sign, and evidence of spontaneous posturing or posturing induced by noxious stimuli (eg, decorticate or decerebrate posturing).

If the cause of the coma is not obvious, emergency laboratory tests must be obtained. Table 25–5 lists some of the causes of coma in children. Most comas (90%) in children have a medical (vs structural) cause. Infection is a common cause (30%). An immediate blood glucose, complete blood count, urine obtained by catheterization if necessary, pH and electrolytes (including bicarbonate), serum urea nitrogen, and aspartate aminotransferase and ammonia are initial screens. Urine, blood, and even gastric contents must be saved for toxin screen if the underlying cause is not obvious. Blood culture and lumbar puncture often are necessary to rule out CNS infection. However, papilledema is a relative contraindication to lumbar puncture. Often, a blood culture is obtained, antibiotics started, and imaging study of the brain done prior to a diagnostic lumbar puncture. If meningitis is suspected and a lumbar puncture is delayed or believed to be hazardous, antibiotics should be started and the diagnostic lumbar puncture done later. Tests that are helpful in obscure cases of coma include oxygen and carbon dioxide partial pressures, serum and urine osmolality, porphyrins, lead levels, general toxicology screen, serum amino acids, and urine organic acids. Hashimoto encephalopathy is a controversial, yet potentially treatable consideration. A formal metabolic consultation is also useful in this setting.

If head trauma or increased pressure is suspected, an emergency CT scan or MRI is necessary. CT is usually helpful as an initial screening examination, but MRI is more sensitive in finding anoxic brain injury early in the course. Bone windows on the former study or skull radiographs can be done at the same sitting. The absence of skull fracture does not rule out coma caused by closed head trauma. Injury that results from shaking a child is one example. Treatment of head injury associated with coma is discussed in detail in Chapter 12.

Rarely, an emergency EEG aids in diagnosing the cause of coma. Nonconvulsive status epilepticus or a focal finding as seen with herpes encephalitis (periodic lateralized epileptiform discharges) and focal slowing as seen with stroke or cerebritis are cases in which the EEG might be helpful. The EEG also may correlate with the stage of coma and add prognostic information. An EEG should be ordered if seizures are suspected. If obvious motor seizures have occurred, treatment for status epilepticus is given with intravenous drugs (see later section on Seizure Disorders).

B. General Measures

Vital signs must be monitored and maintained. The patient’s response to vocal or painful stimuli and orientation to time, place, and situation are monitored. Posture and movements of the limbs, either spontaneously or in response to pain, are serially noted. Pupillary size, equality, and reaction to light, and movement of the eyes to the doll’s eye maneuver or ice water caloric tests should be recorded (in patients without spine injury). Intravenous fluids can be tailored to the situation, as for treatment of acidosis, shock, or hypovolemia. Nasogastric suction is initially important. The bladder should be catheterized for monitoring urine output and for urinalysis.

 Prognosis

About 50% of children with nontraumatic causes of coma have a good outcome. In studies of adults assessed on admission or within the first days after the onset of coma, an analysis of multiple variables was most helpful in assessing prognosis. Abnormal neuro-ophthalmologic signs (eg, the absence of pupillary reaction or of eye movement in response to the doll’s eye maneuver or ice water caloric testing and the absence of corneal responses) were unfavorable. Delay in the return of motor responses, tone, or eye opening was also unfavorable. In children, the assessment done on admission is about as predictive as one done in the succeeding days. Approximately two-thirds of outcomes can be successfully predicted at an early stage on the basis of 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. Published reports suggest that an anoxic (in contrast to traumatic, metabolic, or toxic) coma, such as that caused by near drowning, has a much poorer outlook.

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 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Recurrent unprovoked seizures.

 Often, interictal electroencephalographic changes.

 General Considerations

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.

Repeated seizures without an evident acute symptomatic cause or provocation (eg, fever) are defined as epilepsy. The incidence is highest in the newborn period and higher in childhood than in later life, with another peak in the elderly. 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. These were revised in 2010. Seizures are classified as either focal, previously called partial (with suspected seizure onset that can be localized to one part of the brain), or generalized (likely involving the whole brain or a network of the brain).

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. Focal seizures are no longer classified as simple and complex; this prior classification was based on loss of awareness which can be difficult to assess with some seizures, particularly if language areas are involved. With the new nomenclature, description of the seizure is most beneficial with suggested terms such as “without impairment of consciousness,” “with motor involvement,” or “hypomotor” seizure. This will allow better description and thus 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. The prior terminology of idiopathic, symptomatic, and cryptogenic is no longer in use with the new ILAE classification system. The recommended terms are now “genetic,” to indicate a known or presumed genetic etiology. “Structural/metabolic” to indicate a known structural or metabolic etiology to an epilepsy syndrome; an example would be tuberous sclerosis or underlying stroke; and lastly “unknown” for those patients for whom a cause has not yet been identified.

1. Seizures & Epilepsy in Childhood

Characterizing the seizure is necessary for accurate diagnosis, which will determine the nature of further evaluation and treatment and help in prognostication (Tables 25–6 and 25–7).

 Clinical Findings

A. History, 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 (partial or focal seizure). Events prior to, during, and after the seizure need to be described, although observers often recall little except generalized convulsive activity because of its dramatic appearance. 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.

Families may not immediately recall the details of the event but asking specific questions can help provide the details needed to determine the seizure type and, if partial, the site of onset. Did the patient become extremely pale before falling? Was the patient able to respond to queries during the episode? Was the patient unconscious or was there just impaired awareness? Did the patient fall stiffly or gradually slump to the floor? Was there an injury? How long did the tonic stiffening or clonic jerking last? Where in the body did the clonic activity take place? Which direction were head and eyes turned? Postictal states can be helpful in diagnosis. After complex partial and generalized convulsive seizures, postictal sleep typically occurs, but postictal changes are not seen after generalized absence seizures. Was there loss of speech after the seizure (suggesting left temporal lobe seizure) or was the patient 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 partial seizures.

Description of the semiology of the event may help determine if the child experienced an epileptic seizure or a nonepileptic event mimicking or misinterpreted as an epileptic seizure. Frequently, the child presenting with a presumed first seizure has experienced unrecognized seizures before the event that brings the child to medical attention. In particular, partial and absence seizures 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.

B. Diagnostic Evaluation

The extent and urgency of the diagnostic evaluation is determined, in general, by 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 are often symptomatic. 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

Appropriate use of EEG requires awareness of its limitations as well as its utility. 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 of time, 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.

1. Diagnostic value—The greatest value of the EEG in convulsive disorders is to help characterize seizure types and epilepsy syndromes. This can aid in prognostication and in selecting appropriate therapy (see Table 25–6). It is sometimes difficult to distinguish between hypomotor seizures due to generalized absence epilepsy vs localization-related epilepsy. The differing EEG patterns of these seizures will then prove most helpful. The presence of a mixed seizure EEG pattern in a child with clinically generalized convulsive seizures or only focal seizures may lead to identification of specific epilepsy syndromes and help the clinician select anticonvulsants effective for the seizure types identified by the EEG. Similarly, the EEG may help in diagnosing seizures in a young infant with minimal or atypical clinical manifestations; it may show hypsarrhythmia (high-amplitude spikes and slow waves with a chaotic background) in infantile spasms or the 1–4/s slow spike-wave pattern of the Lennox-Gastaut syndrome. The EEG may show focal slowing that, if constant, particularly when there are corresponding focal seizure manifestations and abnormal neurologic findings, will alert the physician to the presence of a structural lesion. In this case, brain imaging may establish the cause and help determine further investigation and treatment.

The EEG need not be abnormal in a child with epilepsy. Normal EEGs are seen following a first generalized seizure in one-third of children younger than age 4 years. The initial EEG is normal in about 20% of older children with epilepsy and in about 10% of adults with epilepsy. These percentages are reduced when serial tracings are obtained especially if sleep-deprived. Focal spikes and generalized spike-wave discharges are seen in 30% of close nonepileptic relatives of patients with epilepsy.

2. Prognostic value—EEG following febrile seizures is almost always normal and is not clearly predictive of subsequent seizures and therefore is not useful in these situations. Hypsarrhythmia or slow spike and wave patterns support the diagnosis of infantile spasms and Lennox-Gastaut syndrome, respectively. Both are expressions of diffuse brain dysfunction (epileptic encephalopathy) and are generally of grave significance. Central-temporal (rolandic spikes) and occipital spike-wave activity (occipital paroxysms) are the EEG correlates of idiopathic focal epilepsies of childhood.

Following successful treatment, an abnormal EEG may become normal and may aid in the decision to discontinue medications but is not always present. Normalization can also be seen in infants with infantile spasms who have been successfully treated and, less commonly, in children with other epileptic encephalopathies.

EEG should be repeated when the severity and frequency of seizures increase despite adequate anticonvulsant therapy, when the clinical seizure pattern changes significantly, or when progressive neurologic deficits develop. Emergence of new focal or diffuse slowing may indicate a progressive lesion or a neurodegenerative disorder.

The EEG may be helpful in determining when to discontinue anticonvulsant therapy. The presence or absence of epileptiform activity on the EEG prior to withdrawal of anticonvulsants after a seizure-free period of 2 years on medications has been shown to correlate with the degree of risk of seizure recurrence. However, persistent focal epileptiform discharges are common in children with so-called benign epilepsies until they resolve spontaneously in adolescence and may not be considered a reason to not reduce anticonvulsants.

 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 seizures 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 25–8.

 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 stigma 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 are less likely to complete high school, have less adequate employment, and are less likely to marry. This is also true of populations with well-controlled epilepsy. 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

Untreated seizures can have an impact on cognition and memory. Clearly, epileptic encephalopathy (ie, regression in cognitive ability and development associated with uncontrolled seizures) does occur, particularly in young children with catastrophic 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) 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, reversible on discontinuing the medication. Psychosis can also 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 astatic or akinetic seizures (so-called drop attacks), necessitating protective headgear. In all other seizure disorders in childhood, injuries as a direct result of an attack 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. Bathrooms are a particularly dangerous room for people with uncontrolled epilepsy as the room is usually small and has many hard surfaces. Showers are recommended over bathing as they decrease the likelihood of drowning. Appropriate supervision is recommended.

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 patients with symptomatic 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, especially with symptomatic epilepsy (associated with identifiable CNS etiology). There is no current proven strategy to prevent SUDEP other than seizure control. The mechanism for SUDEP is unclear but is probably most commonly related to either cardiac arrhythmia induced by a seizure or sudden respiratory insufficiency. Vigorous attempts to control intractable seizure disorders remain the most important approach. 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, anticonvulsant 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. Thrusting a spoon handle, tongue depressor, or finger into the clenched 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—Treat with the drug appropriate to the clinical situation, as outlined in Table 25–9.

2. Treatment strategy—The child with a single seizure has a 50% chance of recurrence. Thus, it is usually not necessary to initiate AED 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 (see Table 25–9). Start with one drug in moderate dosage and increase the dosage until seizures are controlled. If seizures are not controlled on the maximal tolerated dosage of one major AED, gradually switch to another before using two-drug therapy. Polytherapy (ie, the use of more than two medications concurrently) is rarely sufficiently effective to warrant the considerable risk of adverse side effects from the synergistic impact of multiple medications.

Dosages and usual target serum levels of commonly prescribed AEDs are listed in Table 25–9. Individual variations must be expected, both in tolerance and efficacy. The therapeutic range may also vary somewhat with the method used to determine levels, and published levels are not always reflective of clinical efficacy and tolerability.

3. Long-term management and discontinuation of treatment—AEDs 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 clonazepam) 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 vast majority of children will again achieve remission of their seizures.

C. Alternative Treatments

1. Adrenocorticotropic hormone (ACTH) and corticosteroids—ACTH is indicated for treatment of infantile spasms. The utility of other immunotherapy is less clear. Duration of ACTH therapy is guided by cessation of clinical seizures and normalization of the EEG. Oral corticosteroids and intravenous immune globulin (IVIG) are occasionally used for pharmacoresistant epilepsy. However, dosing regimens and indications are not well established.

Landau-Kleffner syndrome (acquired epileptic aphasia) is reported to respond to oral steroid treatment. Anecdotal reports of use of immunosuppression in other patients have been published but no controlled clinical trials have been performed.

Precautions: Give additional potassium, guard against infections, provide GI prophylaxis, follow for possible hypertension, and discuss the cushingoid appearance and its disappearance. Do not withdraw oral corticosteroids 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 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. Fatty acids replace glucose as a source of energy for cellular metabolism. Such a diet has been observed to decrease and even control seizures in some children. A ketogenic diet should be considered for children with pharmacoresistant epilepsy. This diet should be monitored very carefully to ensure sufficient protein for body maintenance and growth as well as appropriate vitamin and mineral supplementation. Recent reports suggest 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. A prepared commercial formula is available for children receiving tube feedings.

The mechanism for the anticonvulsant action of the ketogenic diet is not understood. The ketogenic diet requires close adherence full cooperation of all family members is required. However, when seizure control is achieved by this method, acceptance of the diet is usually excellent. Access to other families and patients via Internet has provided support and is particularly useful for providing increased variation of meals for families.

As with all therapies, potential adverse effects can occur with the ketogenic diet. These include acidosis and hypoglycemia, particularly on initiation of the diet. Thus, it is prudent to admit the child for initiation of the diet after screening laboratory studies are performed to rule out underlying metabolic disorders. Renal stones, pancreatitis, and acidosis can occur. 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 on the left and attached to the left vagus nerve. A cycle of electrical stimulation of the nerve is established (typically 30 seconds of stimulation every 5 minutes), which has an antiepileptic effect, reducing seizures by at least 50% in over half the children so treated. In addition, an emergency mode that is activated by the use of a magnet may interrupt a seizure (ie, an anticonvulsant effect). For patients with sufficient warning of an impending seizure, the device can be activated with abortion of the seizure. Many patients also experience an improvement in learning and behavior with use of this device. With current technology, the battery in the stimulator will 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. The evaluation and surgery should be performed at a center with expertise in epilepsy surgery and which has a dedicated neurosurgeon, epileptologists, neuropsychologists, and physiatrists 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 video-EEG monitoring, positron emission tomography (PET), single photon emission computerized tomography (SPECT), and similar noninvasive techniques that can be used to identify the “ictal onset zone” for seizures such as a focal cortical dysplasia that may amenable to resection. Freedom from seizures is reported in as many as 80% who have been treated surgically. Some children without an identifiable onset to seizure 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. Two excellent web sites are http://www.epilepsyfoundation.org and 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 cities 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. Driving is discussed in the next section.

Emotional disturbances, especially depression, are not uncommon, particularly in adolescents with epilepsy, and need to be treated. Loss of sleep should be avoided as sleep deprivation can be a trigger for seizures. Alcohol intake should be avoided because it may precipitate seizures. Prompt attention should be given to intercurrent illnesses as these can 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. Some patients with infrequent seizures, especially if only nocturnal partial seizures (eg, Rolandic seizures) may not need treatment with AEDs.

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 1 year 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 containing folic acid is recommended. 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 http://www.epilepsyfoundation.org/programs/upload/snactionplan.pdf. These plans usually require the approval of the child’s physician. Schools are sometimes hesitant to administer rectal valium or to activate the vagal nerve stimulator. 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 for families in their interactions with the school.

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. 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 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, rectal valium, intranasal midazolam, sublingual lorazepam, and intramuscular diazepam.

Status epilepticus is classified as (1) convulsive (the common tonic-clonic, or grand mal, status epilepticus) 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.

 Treatment

For treatment options, see Table 25–10.

3. Febrile Seizures

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. 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. Immunizations may be a cause. HHV-6 and HHV-7 is a common cause for febrile status epilepticus, accounting for 1/3 of cases. Febrile seizures rarely (1%–3%) lead 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 adverse 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.

 Clinical Findings

A. 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. A white count above 20,000/μL or an extreme left shift may correlate with bacteremia. Complete blood count and blood cultures may be appropriate. Serum sodium is often slightly low but not low enough to require treatment or to cause the seizure. Meningitis and encephalitis must be considered. Signs of meningitis (eg, bulging fontanelle, stiff neck, stupor, and irritability) may all be absent, especially in a child younger than age 18 months.

B. 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 acceptable explanation for elevated cells in the CSF. Although the yield is low, a lumbar puncture should probably be done if the child is younger than age 18 months, if recovery is slow, if no other cause for the fever is found, or if close follow-up will not be possible. Occasionally observation in the emergency department for several hours obviates the need for a lumbar puncture.

C. 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/s 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 & Prognosis

Prophylactic anticonvulsants are not recommended after a febrile seizure. If febrile seizures are complicated or prolonged, or if medical reassurance fails to relieve family anxiety, anticonvulsant prophylaxis may be indicated and appropriately chosen medication may reduce the incidence of recurrent febrile seizures. 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.

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.

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Riviello JJ et al: Practice parameter: diagnostic assessment of the child with status epilepticus (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2006;67:1542 [PMID: 17101884].

Sabaz M et al: The impact of epilepsy surgery on quality of life in children. Neurology 2006;66:557 [PMID: 16505311].

Shany E, Berger I: Neonatal electroencephalography: review of a practical approach. J Child Neurol 2011;26:341–355 [PMID: 21383227].

Shinnar S et al: Phenomenology of prolonged febrile seizures: results of the FEBSTAT study. Neurology 2008;71:170–176 [PMID: 18525033].

Sillanpaa M, Schmidt D: Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study. Brain 2006;129:617 [PMID: 16401617].

Sillanpää M, Shinnar S: Long-term mortality in childhood-onset epilepsy. N Engl J Med 2010;363:2522–2529 [PMID: 21175314].

Silverstein FS, Jensen FE: Neonatal seizures. Ann Neurol 2007;62:112 [PMID: 17683087].

Singh RK, Gaillard WD: Status epilepticus in children. Curr Neurol Neurosci Rep 2009;9:137 [PMID: 19268037].

Steering Committee on Quality Improvement and Management, Subcommittee on Febrile Seizures: Febriles seizures: clinical practice guideline for the long-term management of the child with simple febrile seizures. Pediatrics 2008;121:1281 [PMID: 18519501].

Tuchman R: Autism and epilepsy: what has regression got to do with it? Epilepsy Curr 2006;6:107 [PMID: 17260027].

Wheless JW: Managing severe epilepsy syndromes of early childhood. J Child Neurol 2009;24:24S [PMID: 19666880].

Zaccara G et al: Idiosyncratic adverse reactions to antiepileptic drugs. Epilepsia 2007;48:1223 [PMID: 17386054].

Zawadzki L, Stafstrom CE: Status epilepticus treatment and outcome in children: what might the future hold? Semin Pediatr Neurol 2010;17:201–205 [PMID: 20727491].

Zupanc ML: Clinical evaluation and diagnosis of severe epilepsy syndromes of early childhood. J Child Neurol 2009;24:6S [PMID: 19666878].

Sleep disorders can originate from abnormalities within the respiratory system, the neurologic system and as well as the coordination (or lack thereof) between the 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 Chapters 18 and 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. Onset can occur as early as age 3 years. One half of persons affected by narcolepsy have symptoms in childhood. Of children with narcolepsy, 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, anger, or other emotional upsurge. Consciousness is preserved during these spells and they can last several minutes in duration. Hypnagogic hallucinations are intense dream-like states 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.

Abnormally short latency to rapid eye movement (REM) sleep occurs in subjects with narcolepsy. REM usually occurs after 80–100 minutes or longer in normal subjects. Nocturnal polysomnography and Multiple Sleep Latency Testing (MSLT) demonstrate abnormal REM latency and are used to diagnose the disorder. HLA subtype DQB1∗0602 and DRB1∗1501 are associated with narcolepsy. Absence of a hypothalamic neuropeptide, hypocretin, is associated with the disorder. Low spinal fluid levels of hypocretin-1 are diagnostic.

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 somnolence. Modafinil is an effective treatment in adults and is used at times in children although controlled studies in children are lacking. Cataplexy responds to venlafaxine, fluoxetine, or clomipramine.

2. Benign Neonatal Sleep Myoclonus

Benign neonatal sleep myoclonus is characterized by myoclonic jerks, usually bilaterally synchronous, that occur only during sleep and stop abruptly when the infant is aroused. It is a benign condition that is frequently confused with epileptic seizures. Myoclonic jerks usually occur in the first 2 weeks of life, and resolve spontaneously in the first months of life although 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 is characterized by paroxysmal arousals from NREM sleep with hypermotor seizures with bizarre stereotyped motor movements with dystonic or hyperkinetic features lasting up to 5 minutes. NFLE is a heterogeneous disorder which includes both sporadic and familial forms, the latter related to a genetic abnormality affecting nicotinic receptors. Lack of definitive epileptiform abnormalities on EEG recordings may lead to misdiagnoses of nocturnal dystonia or 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 NREM and REM. The NREM parasomnias consist of partial arousals, disorientation, and motor disturbances and include sleep-walking/somnambulism and sleep terrors/pavor nocturnes among others. These are discussed in more detail in Chapter 3.

5. Restless Legs Syndrome

Restless legs syndrome refers to continuous, bothersome leg movements occurring at rest and producing unpleasant paresthesias (sensory symptoms) that often interfere with restful sleep. 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.

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 ESSENTIALS OF DIAGNOSIS

 The two most common causes of headaches in children are migraine and tension-type headache.

 Diagnosis is based upon a thorough history and physical, excluding secondary causes such as mass or idiopathic intracranial hypertension.

 Warning signs that require further investigation include headache in a young child, new onset and worsening headache, unexplained fever, awakening with headache or vomiting, headache worse with straining or position change, posterior headaches, neurological deficit, or neurocutaneous stigmata.

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 11% of children and 28% of adolescents experience recurrent headaches. First, the clinician must determine if the headache is primary or secondary. Symptoms and signs are the center of evaluation; however, red flags (Table 25–11) 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 2004 International Classification of Headache Disorders-IIR (IHCD-IIR), primary headaches are divided into three major categories: migraine, tension-type, and trigeminal autonomic cephalgia. Clinical features of migraine without aura and tension-type headache are compared in Table 25–12. Migraine headaches are generally episodic unilateral (commonly bilateral in children), throbbing, severe headaches with a combination of photophobia, phonophobia, nausea, and or vomiting. Tension-type headaches (TTH) are a tight band dull sensation that can occur episodically or daily. TTH are not associated with nausea or vomiting but may have photophobia or phonophobia but not both. 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, MSG or nitrites). Trigeminal autonomic cephalgia (or cluster headache) is rare in children, but presents as a unilateral severe headache and autonomic dysfunction (watery eye, congestion, facial sweating, miosis, and ptosis).

According to the IHCD-IIR, migraines include childhood pediatric syndromes such as cyclic vomiting, abdominal migraine, and benign paroxysmal vertigo of childhood. These are precursors to migraines and in an older child with new onset migraines; history of these periodic syndromes/symptoms may be discovered.

B. Laboratory Findings

Laboratory studies are not routinely needed in children presenting with recurrent headaches. History and examination may prompt basic screening studies for thyroid, anemia, or autoimmune disorders.

C. Imaging Studies

Routine neuroimaging is not indicated for children presenting with recurrent headaches unless Red Flags are present as noted in Table 25–11. A single red flag is less worrisome (except for abnormal neurological exam) and usually a combination of red flags will prompt neuroimaging evaluation. Imaging can also be considered for children with historical features that suggest recent onset of severe headache, change in headache, or features to suggest neurological dysfunction.

 Differential Diagnosis

Secondary causes of headache in children include broad categories such as head trauma, infection, vascular, intracranial pressure changes, structural, metabolic, toxic or substance related, and hematologic (Table 25–13). Headaches associated with head trauma are those that start within two 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 or homocystinuria. Headaches that worsen with lying down or vomiting without nausea are concerning for increased intracranial hypertension such as IIH (IIH), sinus venous clot producing increased CSF pressure, hydrocephalus, or mass. 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, spontaneous leak, penetrating trauma, or surgery.

Medication and substance ingestion and withdrawal are both culprits to secondary headaches. Medications directly related to possible headaches include oral contraceptives, steroids, thyroid replacement, caffeine, cold medicines, ergotamines, vasodilators, overuse of vitamin A or D, sympathomimetics, bronchodilators, atypical antipsychotics, SSRIs, ethanol, antibiotics, and tetracycline. Steroids, vitamin A toxicity, oral contraceptives, and tetracycline are all associated with development of 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 headaches. Meningitis and encephalitis will present with a combination of fever, seizures, altered mental status, stiff neck, and headache. However, 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. Headaches 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. Hypothyroidism can cause bilateral nonpulsating continuous mild intensity pain that resolves after thyroid supplementation.

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 dentist, respectively, is indicated. Examination in TMJ dysfunction reveals a click on slow jaw opening and closing in addition to reduced angle of jaw opening.

A thorough history and physical examination helps diagnosing most of these conditions. Several common red flags associated with worrisome secondary causes are listed in Table 25–11. It is not one single symptom or red flag that usually points to a secondary cause; rather, it is a constellation of symptoms.

 Complications

Migraines and tension-type headaches are both episodic headache disorders but may transform into more frequent headaches. When a child has greater than 15 headaches per month for three or more months, the child has chronic headaches. Risk factors for chronicity include psychological comorbidity, excessive medication use leading to Medication Overuse Headache, and possibly signs of central sensitization. During migraines, central sensitization is indicated by presence of cutaneous allodynia (eg, pain with combing hair, wearing a pony tail, or touching the skin). These symptoms are currently being investigated and are thought to be associated with worsened prognosis with respect to treatment response and headache chronicity.

Depression and anxiety are both comorbid with headaches and are associated with increased headache burden and disability such as school absenteeism. Equally, children psychiatric disorders also have increased rates of primary headaches. School absenteeism and poor school performance appears to be one of the most challenging factors in children with recurrent headaches.

 Treatment

Treatment is divided into two categories: acute 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 Treatment

Acute treatment for pediatric migraine includes use of simple analgesics and migraine specific medications. Any abortive medication should be given as early as possible after the onset of headache. The United States FDA approved almotriptan for adolescents 12-17 and rizatriptan for 6-17 year olds. Simple analgesics include acetaminophen (15 mg/kg; max dose 1000 mg) and ibuprofen (10 mg/kg; max dose 800 mg). Studies showing significant benefit for pediatric migraine include rizatriptan, zolmitriptan nasal, sumatriptan nasal, and almotriptan. 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 approximately 1–2 times per month. During a headache biobehavioral techniques include rest and relaxation. 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 centerpoint to treatment. These include sleep hygiene; improved fluid intake and elimination of caffeine; nutritional meals; avoidance of skipping 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, 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 and there are no FDA-approved preventatives in the United States for the treatment of migraine or tension-type headache in children.

Topiramate, propranolol, amitriptyline, and cyproheptadine are the most commonly prescribed medications for pediatric headache. If topiramates started slowly and at low doses, cognitive side effects can be avoided. Peripheral tingling is uncommon and when present can be usually 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. 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.

Coenzyme q10, magnesium oxide, and riboflavin 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.

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Damen L et al: Prophylactic treatment of migraine in children. Part 1. A systematic review of non-pharmacological trials. Cephalalgia 2006;26:373 [PMID: 16556238].

Eiland LS et al: Pediatric migraine: pharmacologic agents for prophylaxis. Ann Pharmacother 2007;41:1181 [PMID: 17550953].

Eiland LD et al: The use of triptans for pediatric migraines. Paediatr Drugs 2010;12:379 [PMID: 21028917].

El-Chammas K et al: Pharmacologic treatment of pediatric headaches: a meta-analysis. JAMA Pediatr 2013:1–11 [PMID: 23358935].

Hershey AD: Current approaches to the diagnosis and management of paediatric migraine. Lancet Neurol 2010;9:190 [PMID: 20129168].

Hershey AD et al: Chronic daily headaches in children. Curr Pain Headache Rep 2006;10:370 [PMID: 16945254].

Lewis DW: Pediatric migraine. Neurol Clin 2009;27:481 [PMID: 19289227].

Lewis DW et al: Efficacy of zolmitriptan nasal spray in adolescent migraine. Pediatrics 2007;120:390 [PMID: 17671066].

Lewis DW et al: Headache evaluation in children and adolescents: when to worry? When to scan? Pediatr Ann 2010;39:399 [PMID: 20666345].

Saadat H, Kain ZN: Hypnosis as a therapeutic tool in pediatrics. Pediatrics 2007;120:179 [PMID: 17606576].

Tepper SJ: Complementary and alternative treatments for childhood headaches. Curr Pain Headache Rep 2008;12:379 [PMID: 18765145].

 ESSENTIALS OF DIAGNOSIS

 Signs and symptoms of increased intracranial pressure: chronic headache, tinnitus, cranial nerve VI palsy, papilledema, visual loss.

 Normal MRI/MRV of the head.

 Elevated opening pressure on lumbar puncture performed in the lateral decubitus position.

 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

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. Symptoms include headache, tinnitus, and visual loss; signs of increased intracranial pressure are outlined in Table 25–14. Visual symptoms are commonly secondary to transient visual obscurations (TVOs), which are transient (less than 1 minute) and reversible alterations of vision in these patients. This must be distinguished from visual field anomalies, which can be permanent. Examine patient for papilledema, cranial nerve VI palsy, visual field deficit.

 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 25–15). 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 25–15, 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 and protein (looking for an infectious mimicker, such as chronic meningitis). In some inflammatory and connective tissue diseases, the CSF protein concentration may be 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, the majority of patients recover from IIH without long-term sequela including visual outcome. Reoccurrence risk is greatest within 18 months.

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Ball AK, Clarke CE: IIH. Lancet Neurol 2006;5:433 [PMID: 16632314].

Bussiere M et al: Unilateral transverse sinus stenting of patients with IIH. AJNR 2010;31:645 [PMID: 19942702].

De Lucia D et al: Benign intracranial hypertension associated to blood coagulation derangements. Thromb J 2006;4:21 [PMID: 17187688].

Kesler A, Bassan H: Pseudotumor cerebri—IIH in the pediatric population. Pediatr Endocrinol Rev 2006;3:387 [PMID: 16816807].

Soiberman U et al: IIH in children: visual outcome and risk of recurrence. Childs Nerv Syst 2011 Nov;27(11):1913-1918 [PMID: 21538129].

Thambisetty M et al: Fulminant IIH. Neurol 2007;68:229 [PMID: 17224579].

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

1. Childhood Arterial Ischemic Stroke

Childhood arterial ischemic stroke (AIS) is emerging as a serious and increasingly recognized disorder, affecting 2–8:100,000 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 24–36 hours after onset; and treatment considerations matter most in the first hours after ischemic stroke onset. When possible, all children who present with ischemic stroke should be transferred to a tertiary care center that specializes in pediatric ischemic 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 25–16). Although many ischemic strokes are not associated with a single underlying systemic disorder, previously diagnosed congenital heart disease is the most common predisposing illness, 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. Symptoms of unilateral weakness, sensory disturbance, dysarthria, and 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, erythrocyte sedimentation rate, C-reactive protein, basic chemistries, blood urea nitrogen, creatinine, prothrombin time/partial thromboplastin time, chest radiography, ECG, urine toxicology, and imaging (see 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 obtundation 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.

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 assess for hemorrhagic ischemic stroke. A CT scan performed early after the onset of neurologic deficits is valuable in excluding 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 (complicated migraine, Todd paralysis, encephalitis, etc.), urgent MRI with 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. Recent 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 paralysis), acute disseminated encephalomyelitis, 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 (particularly cocaine) 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 specialists in hematology 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 ischemic stroke 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/d). Recent AHA guidelines support both of these approaches. In some situations, such as arterial dissection or cardio-embolic 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 U.S. children with ischemic stroke. Cleary, the use of tPA should be limited to practitioner 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 20%, 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 1:4000 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 sometimes 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 prothrombotic states, 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. Recent evidence, however, suggests that as patients progress into their school-age years, they may have previously unrecognized cognitive challenges, such as learning deficits or attention-deficit/hyperactivity disorder. 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 20%–40% 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.

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Malformations of the nervous system occur in 1%–3% of living neonates and are present in 40% of infants who die. Developmental anomalies of the CNS may result from a variety of causes, including infectious, toxic, genetic, metabolic, and vascular insults that affect the fetus. The specific type of malformation that results from such insults, however, may depend 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 after 28 days’ gestation. During this period, lissencephaly, pachygyria, agyria, and agenesis of the corpus callosum may result from genetic, toxic, infectious, or metabolic disruptions.

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. Spina bifida with associated meningomyelocele 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 associated with meningomyelocele usually requires ventriculoperitoneal shunting.

 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 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 increasingly recognized with the advent of MRI techniques and the explosion of newly identified genetic syndromes. They are subdivided into disorders based on (1) neuronal and glial proliferation or apoptosis dysfunction (2) abnormal migration or (3) abnormal post-migrational development. In this section, we provide some common examples of these subtypes.

A. Microcephaly and Megalencephaly

Common examples of neuronal and glial proliferation dysfunction are microcephalies and megalencephaly. Microcephaly is discussed below in abnormal head size section. Megalencephaly results in overdevelopment most commonly one hemisphere (hemimegalencephaly) and results in macrocephaly. Spectrum of clinical findings are broad and depend on the underlying etiology include developmental delay, seizures, and dysmorphisms.

B. Lissencephaly

Lissencephaly is the classic example of abnormal migration. This severe malformation of the brain is characterized by a smooth cortical surface with minimal sulcal and gyral development similar to a fetal brain at the end of the first trimester. Lissencephalic brains have a primitive cytoarchitectural construction with a four-layered cerebral mantle instead of the mature six-layered mantle. Quantities 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); however, there is significant phenotypic heterogeneity. These disorders are autosomal recessive and X-linked disorders. LIS1 mutations on chromosome 17 are associated with dysmorphic features (Miller-Dieker syndrome). Another autosomal recessive mutation, involving the RELN gene, results in a lissencephaly with severe hippocampal and cerebellar hypoplasia. X-linked syndromes involving mutations in DCX (double cortin) and ARX (associated with ambiguous genitalia) affect males with lissencephaly and females with band heterotopias or agenesis of the corpus callosum.

Lissencephaly with hydrocephalus, cerebellar malformations, or muscular dystrophy may occur in Walker-Warburg syndrome (POMT1 mutation), Fukuyama muscular dystrophy (fukutin 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 metabolic peroxisomal abnormality with the presence of elevated concentrations of very-long-chain fatty acids in plasma. No specific treatment for lissencephaly is available, and seizures are often difficult to control with standard medications.

C. Polymicrogyria

Polymicrogyria is a post-migrational disorder. Subcategories of polymicrogyria include those associated with schizencephaly and bilateral perisylvian polymicrogyria. Patients with bilateral perisylvian polymicrogyria pseudobulbar palsy, variable cognitive deficits, facial diplegia with dysarthria and drooling, developmental delay, and epilepsy. Seizures are often difficult to control with anti-epileptic drugs; some patients have benefited from corpus callosotomy. The cause of this syndrome is as yet unknown, although intrauterine cerebral ischemic injury has been postulated. Therapy is aimed at improving speech and oromotor functions and controlling seizures.

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 often occur, including basilar impression (platybasia) and small foramen magnum. Arnold-Chiari malformation type I may remain asymptomatic for years, but in older children and young adults it may cause progressive ataxia, paresis of the lower cranial nerves, and progressive vertigo; rarely may it present with apnea or disordered breathing. Posterior cervical laminectomy may be necessary to provide relief from cervical cord compression. Ventriculoperitoneal shunting may be required for associated hydrocephalus.

Arnold-Chiari malformation type II consists of the malformations found in Arnold-Chiari type I plus an associated lumbar meningomyelocele. Hydrocephalus develops in approximately 90% of children with Arnold-Chiari malformation type II. These patients may also have aqueductal stenosis, hydromyelia or 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 mental retardation in about half of patients, while over 85% of patients with lower level lesions have normal intelligence quotients (IQs). Many patients will develop a latex sensitivity or allergy.

Arnold-Chiari malformation type III is characterized by occipital encephalocele, a closure defect of the rostral (upper) end of the neural tube. Hydrocephalus is extremely common with this malformation.

B. Dandy-Walker Syndrome

Despite being described nearly 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, rostral displacement of the tentorium, and absence or atresia of the foramina of Magendie and Luschka. 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. Diagnosis of Dandy-Walker syndrome is confirmed by CT or MRI scanning of the head. Treatment is directed at the management of hydrocephalus.

4. Agenesis of the Corpus Callosum

Agenesis of the corpus callosum, once thought to be a rare cerebral malformation, is more frequently diagnosed with modern neuroimaging techniques; occurring in 1:4000 births. The cause of this malformation is unknown. Occasionally it appears to be inherited in either an autosomal dominant or recessive pattern. It has been associated with X-linked patterns (ARX as mentioned earlier). Most cases are sporadic. Maldevelopment of the corpus callosum may be partial or complete. No specific syndrome is typical of agenesis of the corpus callosum, although many patients have seizures, developmental delay, microcephaly, or mental retardation.

Neurologic abnormalities may be related to microscopic cytoarchitectural abnormalities of the brain that occur in association with agenesis of the corpus callosum. The malformation may be found coincidentally by neuroimaging studies in otherwise normal patients and has been described as a coincidental finding at autopsy in neurologically normal individuals. A special form of agenesis of the corpus callosum occurs in Aicardi syndrome. In this X-linked disorder, agenesis of the corpus callosum is associated with other cystic intracerebral abnormalities, early infantile spasms, mental retardation, lacunar chorioretinopathy, and vertebral body abnormalities.

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. The presence of radialized thumbs and aqueductal stenosis is suggestive of X-linked hydrocephalus due to the clinically testable neural cell adhesion molecule-L1 deficiency.

Clinical features of hydrocephalus include macrocephaly, an excessive rate of head growth, irritability, bulging or full fontanelle, vomiting, loss of appetite, impaired upgaze, 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.

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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. However, some patients have hereditary disorders, such as Apert syndrome and Crouzon disease that are associated with abnormalities of the digits, extremities, and heart. Craniosynostosis may be associated with an underlying metabolic disturbance such as hyperthyroidism and hypophosphatasia.

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 (“positional”), 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.

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.

2. Microcephaly

A head circumference more than two standard deviations below the mean for age and sex is by definition microcephaly. 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 25–17.

 Clinical Findings

A. Symptoms and Signs

Microcephaly may be suspected in the full-term newborn and in infants up to age 6 months whose chest circumference exceeds the head circumference (unless the child is very obese). 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 25–17 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 25–18.

 Differential Diagnosis

A. Catch-Up Growth

When a neurologically intact premature infant whose rapid head enlargement is most marked in the first weeks of life, or the infant in the early phase of recovery from deprivation dwarfism. 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 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 infants, transillumination of the skull with an intensely bright light in a completely darkened room may disclose 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 (see Table 25–14). 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.

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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 (histologically normal tissue growing abnormally rapidly or in aberrant sites) are common. The most common dysplasias are dominantly inherited. Benign and even malignant tumors may develop in these conditions.

1. Neurofibromatosis Type 1 (Von Recklinghausen Disease)

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 More than six café au lait spots 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals.

 Two or more neurofibromas of any type or one plexi-form neurofibroma.

 Freckling in the axillary or inguinal regions.

 Optic glioma.

 Two or more Lisch nodules (iris hamartomas).

 Distinctive bony lesions, such as sphenoid dysplasia or thinning of long bone with or without pseudarthroses.

 First-degree relative (parent, sibling, offspring) with neurofibromatosis type 1 by above criteria.

Neurofibromatosis is a multisystem disorder with a prevalence of 1:3000. Fifty percent of cases are due to new mutations in the NF1 gene. 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 mental retardation. The history should focus on lumps or masses 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 a check for proptosis and iris Lisch nodules. The optic disk should be examined for atrophy or papilledema. Any progressive or new neurologic deficit calls for studies 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, nonmass 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 glioma occurs 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 vexing to treat. PET scans are helpful to detect malignant transformations (to sarcoma). Experimental trials of interferons and mTOR inhibitors (rapamycin=sirolimus) are ongoing at many centers. Strokes from NF-1 cerebral arteriopathy are noteworthy; 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, with serious complications occasionally seen. Patients sometimes worsen during puberty or pregnancy. Annual or semiannual visits are important in the early detection of school problems, or 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 lesion)

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 are excellent resources. Prenatal diagnosis is probably 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 neoplasia 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 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 the rule 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 (Bourneville Disease)

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 not to 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 (Table 25–19)

1. Dermatologic features—Skin findings bring most patients to the physician’s attention. 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 are often oval or “ash leaf” in shape and follow 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 or 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, so 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 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. The characteristic cortical atrophy, calcifications of the cortex, and meningeal angiomatosis may appear with time, solidifying the diagnosis.

Physical examination may show focal seizures or 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. Hemi-atrophy 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.

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The CNS degenerative disorders of infancy and childhood are characterized by arrest of psychomotor development and loss, usually progressive but at variable rates, of mental, motor, and visual functioning (Tables 25–20 and 25–21). Seizures are common especially in those with gray matter involvement. Symptoms and signs vary with age at onset and primary sites of involvement of specific types.

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 has shown promising results.

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 ESSENTIALS FOR DIAGNOSIS

 Ataxia is most commonly due to cerebellar dysfunction but abnormalities at almost any level of the nervous system can result in motor incoordination.

 It is essential to distinguish between acquired and congenital ataxia as the evaluation, management and outcome is determined by etiology.

 A detailed history and evaluation of truncal vs limb ataxia, mental status, and eye movements can provide the most useful diagnostic points in the formulation of the differential diagnosis.

 Pathogenesis

In general, there are two major categories one should consider in the evaluation of ataxia. Acute acquired ataxia is a common reason for emergent neurological consultation. The best approach in the evaluation of these children is obtaining a detailed history of the antecedent events and current symptoms, as well as a detailed examination of associated neurological symptoms. Typically these patients develop symptoms within 72 hours prior to their presentation to medical care, and they have been previously healthy without developmental delay or neurological abnormalities. In contrast, congenital ataxias may be associated with central nervous system abnormalities, genetic abnormalities, or metabolic disorders. In this section, a brief overview of will be provided of the most common causes of acute and congenital ataxia, and the evaluation and the management of each.

 ESSENTIALS FOR DIAGNOSIS

 Symptoms may include refusal to walk due to ataxia, in addition to sudden development of a wide-based, drunken gait.

 Families may not report unsteadiness of arm movements, ataxia of the trunk, or dysarthria, but these symptoms are essential to localization.

 Serious causes include CNS infections and intracranial mass lesions.

 Pathogenesis

Causes of acute ataxia that require emergent evaluation include increased intracranial pressure due to mass lesions. Therefore, any history suggestive of this should be elicited, such as persistent or recurrent headaches, or vision changes such as blurred or double vision. A history of head of neck trauma should prompt evaluation for vertebral artery dissection. Other common causes include accidental or purposeful ingestion. The evaluation of an acutely ataxic patient can be difficult as the patient may refuse to participate in the examination due to the discomfort of being ataxic, causing them to be irritable or hesitant. Therefore, distinguishing between weakness and ataxia can be difficult, but it is essential to making the correct diagnosis.

 Clinical Findings

A thorough examination should be performed, with attention to signs suggesting a serious central nervous system disorder, such as mass lesions or central nervous system infections. Changes in mental status are particularly important to observe, as this suggests an ingestion, stroke, acute disseminated encephalomyelitis, or opsoclonus-myoclonus syndrome. The presence of papilledema and cranial nerve palsies suggests an intracranial focal lesion or hydrocephalus. Asymmetry in the examination would be unusual for acute cerebellar ataxia.

Once signs of serious CNS disorders have been sought, localization of the cerebellar lesion should be made. A mid-line cerebellar lesion may present with dysarthria or truncal titubation. In contrast, a lesion of the cerebellar hemispheres may present with sparse speech, dysmetria, tremor, or hypotonia. A patient with a hemispheric cerebellar lesion will tend to veer to the side of the lesion. A resting tremor, myoclonus, or opsoclonus will suggest a lesion affecting the deep cerebellar nuclei. Patient with cerebellar ataxia will not worsen with closed eyes, as a patient with sensory ataxia would.

A. Acute Cerebellar Ataxia

 ESSENTIALS FOR DIAGNOSIS

 Symptoms may include refusal to walk due to ataxia, in addition to sudden development of a wide-based, drunken gait.

 Families may not report unsteadiness of arm movements, ataxia of the trunk, or dysarthria, but these symptoms are essential to localization.

 Serious causes include CNS infections and intracranial mass lesions.

This is the most common cause of acute childhood ataxia, accounting for about 40% of all cases. It occurs most commonly in children aged 2–6 years. The onset is abrupt, and the evolution of symptoms is rapid. In about 70% of patients, a prodromal illness occurs with fever, respiratory or gastrointestinal symptoms, or an exanthem within 3 weeks of onset. Associated viral infections include varicella, rubeola, mumps, echovirus infections, poliomyelitis, infectious mononucleosis, and influenza. Bacterial infections such as scarlet fever and salmonellosis have also been incriminated. Typically, the symptoms evolve rapidly, but the severity can vary between patients. Some patients have such severe ataxia that they cannot walk, and others have only mild unsteadiness. Usually the limbs are not as affected as the trunk. Mental status is normal in these patients, as is sensory and reflex testing.

1. Laboratory testing—CSF opening pressure, protein, and glucose levels are typically normal, though a mild pleocytosis with lymphocytic predominance can be seen. Any significant elevation in WBC and protein level should prompt an evaluation for meningitis or encephalitis. Autoantibodies against Purkinje cells and other cerebral and cerebellar tissue have been described, but typically are not clinically useful to obtain.

2. Imaging findings—CT scans are typically normal, as are MR images of the brain. Occasionally focal cerebellar or cerebellopontine demyelinating lesions or enhancement of the meninges can be seen. Decreased regional blood flow in the cerebellum on SPECT without abnormal foci on MRI of the brain has also been reported.

3. Treatment—Treatment for acute cerebellar ataxia is supportive. IVIg has been used. Steroid use does not result in any improvement. About 80%–90% of patients recover without sequelae within 6–8 weeks, though some may demonstrate residual behavioral changes, learning problems, eye movement abnormalities, and speech problems.

B. Toxic Cerebellar Syndrome

Ataxia due to toxins or medications accounts for as many as 32.5% of acute cases. Substances such as anticonvulsants, benzodiazepines, alcohol, and antihistamines, and less commonly organic chemicals and heavy metals can cause ataxia. In these cases, ataxia is usually accompanied by mental status changes, including lethargy, confusion, inappropriate speech and behavior, and in some cases, nystagmus or pupillary changes.

1. Laboratory testing—Urine toxicology screen may not detect specific medications, and therefore a detailed history is always helpful in guiding testing for specific medications. For phenytoin, the toxic level in serum is usually above 25 mcg/mL; for phenobarbital, above 50 mcg/mL; and for primidone, above 14 mcg/mL.

2. Imaging findings—Imaging is usually normal for patients with toxic cerebellar syndrome.

3. Treatment—Treatment is guided by the ingested agent, and requires toxicological consolation.

C. Acute Demyelinating Encephalomyelitis

Ataxia is a common feature of acute demyelinating encephalomyelitis (ADEM), and like acute cerebellar ataxia, can occur after a viral infection or vaccination. However, this entity may be distinguished from acute cerebellar ataxia by the accompanying change in mental status or other associated difficulties such as seizures, cranial nerve palsies, or hemiparesis. These clinical events arise from presumed immune-mediated demyelination of the central nervous system. Refer to later section (Noninfectious Inflammatory Disorders of the Central Nervous System) on ADEM in this chapter.

D. Posterior Circulation Stroke

Though rare, this should be considered as an etiology for ataxia if a history of neck trauma or family history of vascular abnormalities is present. Workup and management are discussed in the stroke section (Cerebrovascular Disorders) of this chapter.

E. Paraneoplastic Syndromes

Acute ataxia can occasionally be seen in the entity known as opsoclonus-myoclonus syndrome (OMS). In its classic form, patients will present with ataxia; rapid chaotic conjugate, multidirectional eye movements (opsoclonus); and nonepileptic jerking of the head, extremities, and face (myoclonus). Some patients may additionally have sleep disturbance, cognitive dysfunction, and behavioral disruption. It is a rare disorder, with an incidence estimated to be 0.18 cases per million children per year in a prospective survey of United Kingdom pediatric neurology centers. Atypical presentations can result in initial erroneous diagnoses, such as of acute cerebellar ataxia, Guillain-Barre syndrome, and epileptic seizures. However, making the diagnosis has significant implications for treatment and prognosis. Forty-eight percent of patients with OMS have a neuroblastoma detected. Traditional methods to detect neuroblastoma with urine catecholamines or metaiodobenzylguanidine scans may be insensitive in patients with opsoclonus-myoclonus syndrome. Therefore, CT or MRI of the entire torso should be obtained in all patients with (OMS). Sometimes repeat testing is necessary to attain the diagnosis. In patients without a neuroblastoma, few will have an identifiable cause, though parainfectious or postinfectious processes have been implicated in some cases.

1. Laboratory testing—Readily available biomarkers would greatly facilitate the diagnosis of OMS. However, only in rare patients have autoantibodies against intracellular antigens been found, such as with anti-Hu or anti-N-methyl-D-aspartate receptor antibodies. None of these antibodies appear to be sensitive for the majority of patients. Relative CSF B-cell expansion has been proposed as a candidate biomarker for OMS, but more data need to be gathered regarding the sensitivity of this biomarker and its relationship to clinical severity. Laboratory evaluation for neuroblastoma or other malignancies should be pursued, with urine catecholamines.

2. Imaging—All patients with OMS should undergo CT or MRI of the entire torso to evaluate for occult malignancies.

3. Treatment—Gold standard treatment for OMS includes corticosteroids and adrenocorticotropic hormone, but no standard formulation or dosing is available, and the short-term benefits do not appear to predict a favorable long-term outcome. Additionally, relapses with dose tapering are common. Therefore, with the poor long-term outcome and the side effects of steroid use, new approaches have been used for treatment, including use of cyclophosphamide, chemotherapy to treat an identified neuroblastoma-associated OMS, and IVIG with ACTH and rituximab.

The long-term outcome for these patients is generally poor for patients both with and without neuroblastoma. From pooled data, 75%–80.6% of patients with OMS had abnormal neurological findings at follow-up, including eye movement abnormalities, dysarthria, ataxia, and myoclonus. In addition, all patients had cognitive impairment, including language, attention, memory, and intellectual disability.

F. Sensory Ataxia

Ataxia can result from loss of sensory input to the cerebellum due to posterior column of the spinal cord, nerve root, or peripheral nerve lesions. Etiologies may include Guillain-Barre syndrome (acute inflammatory demyelinating polyneuropathy) or its variant, Miller-Fisher syndrome; or toxins. These patients, in addition to ataxia, will demonstrate decreased reflexes, a Romberg sign, loss of proprioception and vibratory sensation, and a high steppage gait.

1. Laboratory testing—Testing for suspected Guillain-Barre syndrome should include a lumbar puncture. The CSF findings may show elevated protein with normal cells, known as albuminocytologic dissociation, but very early in the course can be normal in as many as 20% of children. Antibodies against GQ1b should be obtained if Miller-Fisher syndrome is suspected. Electrophysiologic testing with nerve conduction studies may also be helpful, though acutely there may be little in the way of abnormalities.

2. Imaging—MR imaging of the spine may show enhancement of the nerve roots in Guillain-Barre syndrome.

3. Special testing—Electromyography/nerve conduction study may be useful to identify a demyelinating polyneuropathy. Nerve conduction velocities will be slowed into the demyelinating range (motor conduction velocities in the upper extremities ≤ 38 m/s) in a patchy, nonuniform fashion. The sural sensory response is typically spared early in the disease. Conduction block and temporal dispersion are hallmarks of this acquired polyneuropathy.

4. Treatment—Both IVIg and plasmapheresis have been used in treatment of GBS. IVIg is typically used in a regimen of 0.4 g/kg daily for 5 days. The typical regimen for PE is a total exchange of about 5 plasma volumes over a 2 week time period. A Cochrane review of the use of IVIg and PE showed no significant difference between the two treatments with respect to disability after 4 weeks, duration of mechanical ventilation, mortality, or residual disability. Steroid treatment has not been showed to be beneficial in GBS.

G. Basilar Migraine

A basilar migraine may present with ataxia. Typically, other accompanying neurological signs are present, such as vertigo, nausea, vomiting, cranial nerve dysfunction, and headache. The patient’s first episode may be concerning for a focal lesion and may prompt workup for a stroke. However, the description of positive visual phenomenon, such as flashing lights, suggests the migrainous nature of the episodes. Subsequent episodes, in the context of the history, are much easier to identify as basilar migraines.

H. Mass Lesions

Posterior fossa tumors arise from the cerebellum or the brainstem and typically present with slowly progressive ataxia and symptoms of increased intracranial pressure. About 45%–60% of all childhood brain tumors are posterior fossa tumors. Therefore, any patient with a history of nocturnal headaches, chronic headaches, nocturnal emesis, focal neurological deficits, visual changes, or other signs concerning for mass lesion should have neuro-imaging performed immediately.

I. Functional Ataxia

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 neurological examination do not indicate neuroanatomic localization, and therefore suggest a functional ataxia.

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 ESSENTIALS OF DIAGNOSIS

 Establishing an inheritance pattern and temporal course is useful in determining the diagnosis.

 The findings of spasticity, ophthalmologic abnormalities, eye movement abnormalities, peripheral nervous system involvement, and seizures can be helpful in the evaluation of these patients.

 Pathogenesis

In considering congenital causes of ataxia, it is probably easiest for the general pediatrician to classify them by the disease progression, either progressive or intermittent/episodic. For instance, Friedreich’s ataxia and ataxia-telangiectasia are both progressive ataxias, with worsening of the ataxia over years. In contrast, in metabolic disorders such as maple syrup urine disease and channelopathies such as episodic ataxia type 1, ataxia occurs episodically and occasionally in response to a trigger. Further defining the ataxias by inheritance pattern is also useful in determining an etiology.

 Clinical Findings

Similar to the evaluation of a patient with acute onset of ataxia, the examination of a patient with congenital causes of ataxia should include localization of signs to the cerebellum, either the hemispheres or the vermis. Therefore, the presence of ataxia in the trunk and limbs should be noted, of nystagmus, of the quality of eye movements, and of reflexes. Many of the patients may have multisystemic involvement, which may provide diagnostic clues to the etiology.

1. Inborn Errors of Metabolism

Inborn errors of metabolism should be considered when ataxia is either intermittent or progressive. Acute exacerbation or worsening after high protein ingestion, a long period of fasting, febrile illness, or other physical stress is suggestive of a metabolic disorder. Disorders in this category are broad and beyond the scope of this text, but may include amino-acidopathies such as maple syrup urine disease, urea cycle defects such as ornithine transcarbamylase deficiency, lactic acidosis such as in Leigh disease, leukodystrophies, lysosomal disorders such as metachromatic leukodystrophy, peroxisomal disorders, and disorders of glycosylation. Because some of these etiologies, such as maple syrup urine disease, can be treatable, diagnostic studies to consider include MRI of the brain, thyroid studies, vitamins E and B12, serum ammonia, ceruloplasmin, serum amino acids, urine organic acids, serum lactate and pyruvate, serum biotinidase, EMG/NCS, serum cholesterol, very long chain fatty acids, phytanic acid, transferring isoelectric focusing, and lysosomal enzyme profile on leukocytes.

2. Channelopathies

Channelopathies are a broad category of neurological disorders, and result from altered function of a voltage-gated ion channel which subsequently alters membrane excitability in neurons. This group includes the episodic ataxias and familial hemiplegic migraines. There are six recognized genetic forms of episodic ataxia (EA) at this time. They are generally inherited in an autosomal dominant fashion, with episodes of ataxia lasting from seconds to minutes. In some patients, the episodes of ataxia are precipitated by stress, exercise, startle, or fatigue. EA2 is the most common episodic ataxia. It is allelic with familial hemiplegic migraine and spinocerebellar ataxia 6, both of which can also result in ataxia. Typically the attacks in EA2 are more prolonged, lasting from hours to days.

1. Autosomal Dominant Hereditary Ataxias

At this time, there are 29 described dominantly inherited spinocerebellar ataxias. The initial manifestation in infants can be hypotonia and delayed motor development, while in children the symptoms may include nystagmus, truncal and gait ataxia, spasticity, extensor plantar responses, and cognitive delay. Neurological symptoms are progressive, with wheelchair-dependence late in the disorder. In addition, in contrast to the autosomal recessive hereditary ataxias, they may exhibit diverse neurological symptoms, such as retinopathy, optic atrophy, extrapyramidal or pyramidal signs, peripheral neuropathy, cognitive impairment, or epilepsy. The neuroimaging findings can be relatively nonspecific for the various subtypes. However, three general patterns of atrophy on imaging have been described on brain MRI: pure cerebellar atrophy, olivopontocerebellar atrophy, and global brain atrophy. Because many of the spinocerebellar ataxias have overlapping clinical and radiographic phenotypes and there is significant intrafamilial and interfamilial variability in the clinical presentation, confirmation by genetic testing of the subtype of spinocerebellar ataxia needs to be performed. Treatment in these patients is typically symptomatic, with use of acetazolamide for ataxia, and the use of baclofen for spasticity.

2. Autosomal Recessive Hereditary Ataxias

Most autosomal recessive ataxias are early onset, before 20 years of age. These patients, like those with autosomal dominant forms, also develop spinocerebellar ataxia, with poor balance with falls, difficulty with hand coordination, dysarthria, vertigo, and diplopia. In addition, they are generally associated with peripheral neuropathy, with loss of proprioception and vibratory sense. Areflexia is more commonly seen in autosomal recessive ataxias. Unlike the autosomal dominant inherited disorders, they typically do not exhibit other neurological symptoms, such as seizures, but they do tend to involve systems outside of the nervous system. The two most commonly encountered autosomal recessive hereditary ataxias that may be seen by the general pediatrician are Friedreich ataxia and ataxia-telangiectasia and will be discussed below.

A. Friedreich Ataxia

Friedreich ataxia is the most common of the autosomal recessive ataxias, with a prevalence of about 1 in 30,000–50,000, and a carrier rate of 1 in 85. Typically, patients present at the ages of 5–25 years, with progressive gait and limb ataxia, dysarthria, loss of proprioception and vibration, areflexia, abnormal eye movements, and pyramidal weakness of the feet with upgoing toes. In addition, patients develop systemic symptoms, and may have associated pes cavus, cardiomyopathy, diabetes, and scoliosis.

1. Laboratory testing—The diagnosis is made by performing genetic testing. Ninety eight percent of patients have a triplet GAA expansion in the frataxin gene on chromosome 9q13. In general, a greater number of repeats predicts an earlier onset of disease, more severe systemic manifestations, and more severe ataxia.

2. Imaging—Neuroimaging does not show progressive cerebellar degeneration, unlike the other inherited ataxias. Mild atrophy of the cervical spinal cord may be seen.

3. Treatment—Because of the multisystem involvement in Friedreich ataxia, yearly screening needs to be performed with an x-ray to track the scoliosis; serum glucose and hemoglobin A1C to monitor for the onset of diabetes, and echocardiogram to monitor for hypertrophic cardiomyopathy. Current evidence suggests that frataxin has a role in mitochondrial iron handling and respiratory chain function. Therefore, treatment trials have targeted antioxidant protection. Trials have demonstrated that coenzyme Q10 and vitamin E can result in improvement in cardiac symptoms, and low dose idebenone can reduce cardiac hypertrophy. However, none of these have resulted in improvement in neurological symptoms, and therefore treatment of the progressive neurological symptoms remains symptomatic.

B. Ataxia-Telangiectasia

Ataxia-telangiectasia is a multisystem disorder arising from a defect in DNA repair. Patients with classic ataxia-telangiectasia present with slurred speech, truncal ataxia, and oculomotor apraxia between the ages of 1 and 4 years. Choreoathetosis is found in nearly all patients with ataxia-telangiectasia. Deep tendon reflexes are decreased or absent in older patients. Plantar reflexes are upgoing or absent. Nonneurologic manifestations include oculocutaneous telangiectasias, recurrent sinopulmonary infections, and hypersensitivity to ionizing radiation with increased susceptibility to cancers, usually leukemia or lymphoma. Premature aging with strands of gray hair and insulin-resistant diabetes mellitus may also be features. After Friedreich ataxia, this is the most common autosomal recessive ataxia, with an estimated prevalence of 1:40,000 to 1:100,000 live births. Greater than 99% of individuals with classic ataxia-telangiectasias have mutations in the ATM gene.

1. Laboratory testing—The serum alpha-fetoprotein level which is typically elevated in these patients to 10 ng/mL or higher, and can remain normal in unaffected children until age 24 months. Immunodeficiencies of IgA and IgE are common. To establish a diagnosis, an immunoblotting assay of the ATM protein level should be performed. Patients with absent or trace amounts of the ATM protein have a definitive diagnosis of ataxia-telangiectasia. Molecular genetic testing of the ATM gene can identify the disease-causing mutations.

2. Imaging—Though a small cerebellum can be seen in older patients on neuroimaging, it is typically not seen in children.

3. Treatment—To establish the extent of systemic involvement in ataxia-telangiectasia, screening should be performed at diagnosis. This should include screening for infectious and oncologic involvement with chest x-ray, pulmonary function testing, CBC with differential, immunoglobulin levels, B/T levels, and T-cell function. In addition, screening for diabetes should be performed with a urinalysis, fasting blood glucose, and hemoglobin A1C. Neurological evaluation should be performed regularly to monitor for disease progression, including ocular coordination, and MRI of the cerebellum. Patients should report any easy bruising, weight loss, or localized swelling to their physician as this may be an early manifestation of malignancy.

Treatment is symptomatic in these patients, though several compounds are under investigation in clinical trials. IVIg replacement should be considered in patients with frequent and severe infections and very low IgG levels, as well as aggressive pulmonary toilet. The neurological manifestations are treated symptomatically, to minimize drooling and ataxia. Most patients will require a wheelchair by 10 years of age. Contractures and scoliosis can limit function, and physical therapy instituted early and continuously can minimize the development of both. Though steroids may decrease the neurological symptoms, discontinuation of steroids results in return of the neurological symptoms. Mutation-targeted therapy such as with antisense oligonucleotides appears promising.

3. X-Linked Cerebellar Ataxias

Fragile X tremor ataxia syndrome has not been documented to occur before 50 years of age, but will be included here as a rare cause of an X-linked inherited ataxia. Patients typically exhibit tremor or ataxia, in inverse relationship to the number of CGG triplet repeat expansions they harbor. In addition, they may also present with varying combinations of parkinsonism, autonomic dysfunction, polyneuropathy, and cognitive deficits.

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Extrapyramidal disorders are characterized by the presence in the waking state of one or more of the following features: dyskinesias, athetosis, ballismus, tremors, rigidity, and dystonias. For the most part, the precise pathologic and anatomic localization of these disorders is not understood. Motor pathways synapsing in the striatum (putamen and caudate nucleus), globus pallidus, red nucleus, substantia nigra, and the body of Luys are involved and this system is modulated by pathways originating in the thalamus, cerebellum, and reticular formation.

1. Sydenham Post-Rheumatic Chorea

Sydenham chorea is characterized by an acute onset of choreiform movements, variable degrees of psychological disturbance, rheumatic endocarditis, and arthritis. Although the disorder follows infections with group A β-hemolytic streptococci, the interval between infection and chorea may be greatly prolonged; throat cultures may therefore be negative.

 Clinical Findings

A. Symptoms and Signs

Chorea is characterized by rapid involuntary discordinated movements of the limbs and face. Other symptoms and signs include emotional lability, waxing and waning (“milkmaid’s”) grip, darting tongue, “spooning” of the extended hands and their tendency to pronate, and knee jerks slow to return to their prestimulus position (“hung up” knee jerk). Hemichorea occurs in 20% of patients with Sydenham chorea.

B. Laboratory Findings and Special Tests

Anemia, leukocytosis, and an increased erythrocyte sedimentation rate and C-reactive protein may be present. The antistreptolysin O or anti-DNase titer (or both) are usually elevated, and C-reactive protein is present. Throat culture is sometimes positive for group A β-hemolytic streptococci.

ECG and echocardiography are often essential to detect cardiac involvement. If antineuronal antibodies (ANA) are present, chorea may be secondary to lupus. Similarly, antiphospholipid antibody (APA) may be elevated in autoimmune related chorea. Specialized radiologic procedures (MRI and SPECT) may show basal ganglia abnormalities.

 Differential Diagnosis

The diagnosis of Sydenham chorea is usually not difficult. Tics, drug-induced extrapyramidal syndromes, Huntington chorea, and hepatolenticular degeneration (Wilson disease), as well as other rare movement disorders, can usually be ruled out on historical and clinical grounds. Immunologic linkages among chorea, tics, and obsessive-compulsive disorder are being studied in pediatric patients. Thus, other causes of chorea in childhood include dyskinetic, “extrapyramidal” cerebral palsy, benign hereditary chorea, kernicterus, Lupus, postpump cardiac surgery, and, for unilateral chorea, stroke, and tumor. These other causes of chorea can often be ruled out by laboratory tests, such as antinuclear antibody for lupus, thyroid screening tests, serum calcium for hypocalcemia, and immunologic and virologic tests for (rare) HIV, parvovirus B19, and Epstein-Barr virus infection. Relapse of herpes encephalitis rarely manifests as choreoathetosis. Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis may cause chorea or other dyskinesias; detection of NMDAR antibodies is diagnostic. MRI and MRA can help to diagnose or exclude tumor or stroke causing hemichorea.

 Treatment

There is no specific treatment. Prednisone (high-dose IV or orally 0.5–2 mg/kg/d in divided doses) and in severe cases IVIG has been successful. Anticonvulsant sodium valproate (50–60 mg/kg/d in divided doses) and levetiracetam (20–60 mg/kg/d divided into twice a day dosing) is effective in reducing chorea symptoms. Dopaminergic blockers such as haloperidol (0.5 mg/d to 3–6 mg/d) and pimozide (2–10 mg/d) are rarely used because of other effective medications and possible parkinsonian side effects such as rigidity and masked facies, and tardive dyskinesia. Emotional lability and depression sometimes warrant administration of antidepressants. All patients should be given antistreptococcal rheumatic fever prophylaxis with either monthly benzylpenicillin injections or oral penicillin VK 250 mg twice a day.

 Prognosis

Sydenham chorea is a self-limited disease that may last from a few weeks to months. Relapse of chorea may occur with nonspecific stress or illness—or with breakthrough streptococcal infections (if penicillin prophylaxis is not done). One-third of patients relapse one or more times, but the ultimate outcome does not appear to be worse in those with recurrences. In adult longitudinal follow up studies, eventual valvular heart disease occurred in about one-third of patients, particularly if other rheumatic manifestations had been present as part of the childhood illness. Psychoneurotic disturbances were also present in a significant percentage of patients.

2. Tics (Habit Spasms)

 Clinical Findings

A. Symptoms and Signs

Tics, or habit spasms, are quick repetitive but irregular movements, often stereotyped, and briefly suppressible. Coordination and muscle tone are not affected. A premonitory urge (“I had to do it”) is unique to tics. Transient tics of childhood (12%–24% incidence in school-aged children) last from 1 month to 1 year and seldom need treatment. Facial tics such as grimaces, twitches, and blinking predominate, but the trunk and extremities are often involved and twisting or flinging movements may be present. Vocal tics are less common; 90% of tics are “above the neck.”

Tourette syndrome is characterized by multiple fluctuating motor and vocal tics with no obvious cause lasting more than 1 year. Tics evolve slowly, new ones being added to or replacing old ones. Coprolalia and echolalia are relatively infrequent. Complex motor tics are coordinated sequenced movements mimicking normal motor acts or gestures for example ear scratching, head shaking, twisting, and “giving the finger.” Self-injurious behavior is not uncommon in Tourette syndrome.

The usual age for all tic disorders at onset is 4–8 years (median age 6), and the familial incidence is 35%–50%. The disorder occurs in all ethnic groups. Tics may be triggered by stimulants such as methylphenidate and dextroamphetamine. An imbalance of or hypersensitivity to neurotransmitters, especially dopaminergic and adrenergic, has been hypothesized. No single chromosome/gene defect is causative; many “hot spots” have been identified. Either parent can transmit the disease.

In mild cases, tics are self-limited and wane with time. Most pediatric tic patients have transient tics of childhood (tics last less than 1 year), or chronic motor tics (> 1 year). When attention is paid to one tic, it may disappear only to be replaced by another that is often worse. If the tic and its underlying anxiety or compulsive neuroses are severe, psychiatric evaluation and treatment are needed.

Important comorbidities are attention-deficit/hyperactivity disorder and obsessive-compulsive disorder. Learning disabilities, migraine (25%), sleep difficulties, anxiety states, and mood swings are also common. REM sleep is decreased, arousals common. Tics may persist into sleep. Medications such as methylphenidate, amphetamines, and atomoxetine should be carefully titrated to treat attention-deficit/hyperactivity disorder and avoid worsening tics. Fluoxetine, clomipramine, or other selective serotonin reuptake inhibitors (SSRIs) may be useful for obsessive-compulsive disorder and rage episodes in patients with tics.

 Treatment

The most effective medications for treating Tourette syndrome are dopamine blockers; these drugs, however, have a small risk of tardive dyskinesia, and are thus reserved for use in difficult to control tic patients. Many pediatric patients can manage without drug treatment or with less hazardous medications. Medications are generally reserved for patients with disabling symptoms; treatment may be relaxed or discontinued when the symptoms abate (Table 25–22). Medications usually do not eradicate the tics. The goal of treatment should be to reduce the tics to tolerable levels without inducing undesirable side effects. Medication dosage should be increased at weekly intervals until a satisfactory response is obtained. Often a single dose at bedtime is sufficient. Clonidine, guanfacine (probably the two most safe drugs), and dopamine modulators have been used in individual patients with some success.

The two neuroleptic agents used most often are pimozide and risperidone. Sleepiness and weight gain are the most common side effects; rare are prolonged QT interval (ECG), akathisia, and tardive dyskinesia. Sometimes these agents are used in combination (eg, clonidine with pimozide). Clonazepam has the virtue of safety, but sleepiness and slowing of thinking are drawbacks. Topiramate has shown benefit in one controlled animal trial; human experience is limited. Levetiracetam failed in a controlled trial, but showed benefit in open trials. Tetrabenazine is being utilized for Tourette’s syndrome in some university centers. IVIG has been unsuccessful.

Nonpharmacologic treatment of Tourette syndrome includes education of patients, family members, and school personnel. In some cases, restructuring the school environment to prevent tension and teasing may be necessary. Supportive counseling, either at or outside school, should be provided. Habit reversal therapy (“HRT”) is controversial, very labor intensive, variably successful. More recently, comprehensive Behavioral Intervention for Tics (CBIT) is a new intensive (8 weekly visits) therapeutic approach; published results are favorable.

Sydenham chorea is a well-documented pediatric autoimmune disorder associated with streptococcal infections (pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection; PANDAS). Patients with tic disorders occasionally have obsessive-compulsive disorder precipitated or exacerbated by streptococcal infections. Less definite (much less frequent) are tic flare-ups with streptococcal infection. Active prospective antibody (antineuronal and antistreptococcal) and clinical studies are in progress. Research centers have used experimental treatments (IVIG, plasmapheresis, and corticosteroids) in severe cases. At present, most patients with a tic do not worsen with group A streptococcal infections; with rare exceptions, penicillin prophylaxis is not necessary.

3. Paroxysmal Dyskinesias/Chronic Dystonia

Paroxysmal dyskinesias are sudden-onset, short-duration choreoathetosis or dystonia episodes (a sustained muscle contraction of limb or torso, frequently twisting or with abnormal posture). 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 rising from a chair, reaching for a glass, or walking. Sometimes only hard sustained exercise will induce the dyskinesia (Table 25–23). Nocturnal dyskinesia/dystonic episodes are currently thought to be frontal lobe seizures.

The diagnosis is clinical. Onset is usually in childhood; average age, 12 years. The patient is alert and often disconcerted during an episode. Episodes may last seconds to 5–20 minutes and occur several times daily or monthly. Laboratory work is normal. EEG is normal between or during an attack; brain imaging is normal. Inheritance is usually autosomal dominant. Anticonvulsants (eg, carbamazepine) usually prevent further attacks. Patients often grow out of this disease in one or two decades (Table 25–23).

Chronic non-kinesigenic dyskinesia is often secondary to an identifiable brain lesion, less responsive to medications, and may or may not have genetic underpinnings.

Disorders of ion channels underlie many of the genetic cases; some cases are linked to epilepsy and hemiplegic migraine. Chromosome loci are known for the latter. Chronic dystonia in childhood is often “cerebral palsy” a “secondarily caused” movement disorder often from perinatal vicissitudes.

Other chronic dystonias may have an unidentifiable genetic cause: autosomal dominant. DYT-1 is the most common. The diagnosis of chronic persistent dystonia may be aided by spinal fluid neurotransmitter (DYT5) and readily available genetic chromosome studies. Any child with dystonia of unknown cause should have a trial of low-dose L-dopa; a prompt improvement suggests DYT5—a genetic cause with favorable outcome. Long-term oral L-dopa is very effective. Rarely, transient dyskinesia (eg, dystonia) may be precipitated by fever. While the cause of persistent dystonia is often genetic, underlying biochemical and structural causes (eg, Wilson disease, basal ganglia tumor or other pathology, hypoxic ischemic encephalopathy (HIE), glutaric aciduria, etc) must be ruled out. Treatment for chronic dystonia may be specific if a syndrome cause is identified (eg, L-dopa for DYT5). Nonspecific treatment may be physical therapy (eg, for cerebral palsy) or medication trials with anticholinergics trihexyphenidyl (Artane), tetrabenazine, baclofen or botulism injections (eg, for a focal foot, or neck dystonia), or even chronic deep brain stimulation.

Persistent chorea (rarely) may be a benign lifelong genetic disease. Treatment is complex: L-dopa, anticholinergics (trihexyphenidyl, large doses), tetrabenazine, and baclofen are primary medications. A common cause of transient dystonia in childhood (adolescent) is a drug reaction to antipsychotic (eg, chlorpromazine) or antiemetics (phenothiazines, metoclopramide).

4. Tremor

The most common cause of persisting tremors in childhood is essential tremor; average age of onset is 12 years. Tremor is the third most common movement disorder, after restless legs and tics. Of those with this lifelong malady, 4.6% have onset in childhood (2–16 years). A genetic dominant inheritance is probable; 20%–80% afflicted report a relative with tremors. Tremor is worsened by anxiety, fatigue, stress, physical activity, and caffeine, and transiently improved by alcohol. Comorbidities include attention-deficit/hyperactivity disorder, dystonia, and possibly Tourette syndrome. Hand/arm tremor is the major manifestation; voice and head tremors are rare.

Laboratory studies are normal. No single chromosome/gene defect is known. Subtle abnormalities (eg, increased cerebellar blood flow) can be found in 25% in research studies. Progression is usually minimal; some patients develop other movement disorders over a lifetime. Helpful medications (rarely needed long term) include propranolol or primidone.

Differential diagnosis includes birth asphyxia, Wilson disease, hyperthyroidism, and hypocalcemia; history and laboratory tests rule out these rare possibilities.

Recent research studies in adults utilizing proton MRS (magnetic resonance spectroscopy) suggest decreased nerve cells in the cerebellar cortex and increased harmane, a neurotoxin, at the same site. The latter suggests a possible environmental contribution to essential tremor.

5. Wilson Disease

(See also Chapter 22.) Wilson disease is a treatable and reversible genetic disease (AR). Half of patients with Wilson disease present with or have neuropsychiatric diseases; early symptoms may be as non-specific as school work deterioration or mild tremor. Wilson’s should be ruled out in any child with any significant movement disorder or psychiatric disease in school-age children (adolescents, especially) with serum ceruloplasmin, liver function panel, and possibly 24-hour urine copper laboratory assessment. MRI may show hyperintense basal ganglia. Kayser-Fleischer rings seen with slit-lamp eye examination are virtually diagnostic in neurologically involved patients.

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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, or epilepsy) often coexist. Some form of cerebral palsy occurs in about 0.2% of neonatal survivors. 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 specific limb or combination of limbs affected: monoplegia (one limb); hemiplegia (arm and leg on same side of body, but arm more affected than leg); paraplegia (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: seizures in up to 50%, mild mental retardation in 26%, and severe retardation in up to 27%. 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. Microcephaly is frequently present. 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.

B. Laboratory and Imaging Tests

Appropriate laboratory studies depend on the history and physical findings. MRI scans may be helpful in understanding the full extent of cerebral injury, and occasionally neuroimaging results suggest specific etiologies (eg, periventricular calcifications in congenital CMV infections or brain malformations such as pachygyri or lissencephaly). Genetic and metabolic testing should be targeted based on history or MRI findings.

 Differential Diagnosis

The cause is often obscure or multifactorial. No definite etiologic diagnosis is possible in 25% of cases. The incidence is high among infants small for gestational age or with extreme prematurity. 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 neurological 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 or botulinum toxin) and seizures are needed in many children. Constraint-induced movement therapy is being studied in controlled trials. 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 incapacity. 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. Many children may have normal intellect have normal life spans and are able to lead productive, satisfying lives.

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INFECTIONS & INFLAMMATORY DISORDERS OF THE CENTRAL NERVOUS SYSTEM

Infections of the CNS are among the most common neurologic disorders encountered by pediatricians. Although infections are among the CNS disorders most amenable to treatment, they also have a very high potential for causing catastrophic destruction of the nervous system. It is imperative for the clinician to recognize infections early in order 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. Systemic signs of infection include fever, malaise, and impaired heart, lung, liver, or kidney function. General features suggesting CNS infection include 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 manifested 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 often more prominent 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 the course of 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, general 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 a neuroimaging procedure has been done to exclude space-occupying lesions. 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 in an attempt to identify the specific organism. 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.

In some cases, brain biopsy may be needed to identify the presence of specific organisms and clarify the diagnosis. Herpes simplex virus infections can be confirmed using PCR to assay for herpes DNA in spinal fluid. This test has 95% sensitivity and 99% specificity. 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. CT bone windows may demonstrate bony abnormalities such as basilar fractures.

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 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 25–24.

Pathologically, the inflammatory process involves all intracranial structures to some degree. 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. 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 aminoglycoside, usually gentamicin. Cefotaxime may be added if gram negative organisms are suspected. Ampicillin is used to treat Listeria and enterococci infections, which rarely affect 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 allows. 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 prolong the need for therapy.

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 meta-static 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 very stable, isolated until the organism is known, rehydrated with isotonic solutions until euvolemic, 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, usually uncovers significant problems.

Seizures occur in 20%–30% of children with bacterial meningitis. 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 duration, 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. Interestingly, prognosis is not worsened by subdural effusions.

Cerebral edema can participate in the production of increased intracranial pressure, requiring treatment with dexamethasone, osmotic agents, diuretics, or hyperventilation; continuous 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 from meningitis. 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.

 Clinical Findings

Patients with brain abscess often appear to have systemic illness similar to patients with bacterial meningitis, but in addition they 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. Sinus infections more characteristically cause subdural-epidural, orbital and forehead abscesses or empyemas, or cellulitis rather than intrabrain abscesses.

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 often normal. With spread from contiguous septic foci, streptococci and anaerobic bacteria are most common. Staphylococci most often enter from trauma or spread from distant or occult infections. Enteric organisms may form an abscess from chronic otitis. Unfortunately, cultures from a large number of brain abscesses remain negative.

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 CNS infections.

 Treatment

When a primary source or contiguous foci is suspected a 3rd generation cephalosporin (Cefotaxime or Ceftriaxone) plus metronidazole is recommended. Penicillin G is an alternative to a cephalosporin. In posttraumatic and postsurgical cases, nafcillin or oxacillin plus 3rd 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 and edema therapy if 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 and systemic infections, 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 of the CNS can involve primarily meninges (meningitis) (see Chapter 40) or cerebral parenchyma (encephalitis) (see Table 25–24). 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 clearly evident on neuroimaging procedures. Some viruses have an affinity for specific CNS cell populations. Poliovirus and other enteroviruses can selectively infect anterior horn cells (poliomyelitis) 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. 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, secondary opportunistic infections of the CNS occur in patients with HIV-induced immunosuppression. Pneumocystis, Toxoplasma, and CMV infections are particularly common. Progressive multifocal leukoencephalopathy, a secondary papillomavirus infection, herpes simplex and varicella-zoster infections also occur frequently in patients with HIV infection. Various fungal (especially cryptococcal), mycobacterial, and bacterial infections have been described.

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.

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 confirm infections by these organisms. Parenteral antimicrobial treatment for these infections is discussed in Chapter 39.

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 allow proper diagnosis. Some CNS inflammatory disorders lead to demyelination syndromes described in Table 25–25. Management of CNS involvement in these disorders is the same as the treatment of the systemic illness.

1. Acute Demyelinating Encephalomyelitis (ADEM)

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 Guillain-Barré syndrome.

A. Imaging

MRI findings in ADEM are distinctive: demyelinating lesions, seen on T₂ and FLAIR images, are key to the diagnosis. Small and large white matter lesions can mimic findings in multiple sclerosis (MS), but may also involve gray matter such as cortex, basal ganglia, and thalamus. Radiologic changes are usually florid when the patient is first seen but occasionally emerge only days to weeks later. Thus, serial or repeat scans may be necessary.

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. Typically oligoclonal bands are not seen in clinically isolated syndromes, but elevated IgG indices and presence of oligoclonal bands are more often observed in children who subsequently develop multiple sclerosis.

 Treatment

In cases of ADEM, corticosteroids are beneficial. Current practice is to administer high dose therapy, followed by oral prednisone taper over 4–6 weeks. Most pediatric groups initially utilize intravenous methylprednisolone (10–30 mg/kg/d up to a maximum dose of 1 g/d) or dexamethasone (1 mg/kg/d) for 3–5 days (no comparative dose studies are available). 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 strong suspicion of MS, neuromyelitis optica (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.

2. 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. Behavioral changes, autonomic instability, insomnia, aphasia, seizures, and movement disorders are prominent. Detection of the antibody is diagnostic. Immunotherapy, including glucocorticoids, intravenous immunoglobulin, and/or plasma exchange are shown to be beneficial. Second line therapies include rituximab and/or cyclophosphamide for refractory cases.

In association with systemic infections or other illnesses, CNS dysfunction may occur in the absence of direct CNS inflammation or infection. Reye syndrome is a prominent example of this type of encephalopathy that often occurs in association with varicella virus or other respiratory or systemic viral infections. In Reye syndrome, cerebral edema and cerebral dysfunction occur, but there is no evidence of any direct involvement of the nervous system by the associated microorganism or inflammation. Cerebral edema in Reye syndrome is accompanied by liver dysfunction and fatty infiltration of the liver. As a result of efforts to discourage use of aspirin in childhood febrile illnesses, the number of patients with Reye syndrome has markedly decreased. The precise relationship, however, between aspirin and Reye syndrome is unclear.

Pediatric MS accounts for 5%–10% of all MS cases. Over the last 10 years, we have learned more about the epidemiology, pathophysiology, diagnosis, and treatment of multiple sclerosis in children. Several exciting discoveries have highlighted the importance of genetic and environmental factors alone and in combination. Notable examples include HLA subtypes and viral exposures, among 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 multiple sclerosis (MS) in a child remains challenging, given the limited diagnostic criteria and the somewhat poorly defined overlap with acute disseminated encephalomyelitis. Although there are many similarities between pediatric-onset and adult-onset MS, an earlier age at disease presentation seems to be associated with specific features such as more frequent encephalopathy, seizures, and brainstem and cerebellar symptoms during the first event.

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. 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. 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.

In addition, 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 alternatives (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. As a result physicians have started to use off-label drugs approved for adults. Retrospective data has shown them to be effective in children.

 Differential Diagnosis

Differential diagnosis includes ADEM, and neuromyelitis optica. Many other infections, metabolic disorders, and degenerative diseases can mimic MS.

 Treatment

Acute treatment (mainly corticosteroids; sometimes IVIg or plasmapheresis) and prevention or modulation of relapses is extrapolated from adult studies; pediatric trials are in their infancy. Immunomodulatory treatment to prevent relapses in children includes interferon-beta 1a or glatiramer acetate (injections); oral agents fingolimod, teriflunomide and dimethyl fumarate. Natalizumab, rituximab, or cyclophosphamide may be utilized in refractory patients.

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 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 weakness and their associated findings are listed in Table 25–26.

 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 (Table 25–26). The finding of increased reflexes and upgoing toes suggests a CNS lesion. Fatigability in sucking on a bottle and constipation may be seen in patients with botulism. In Guillain-Barré syndrome (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 are 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 or abscess; the presence of antinuclear antibody may suggest lupus arteritis.

EMG and nerve conduction studies (NCSs) can be helpful in diagnosing polyneuropathy. In GBS, NCSs are particularly helpful after the first week when delayed or absent H or F reflexes are seen are the first changes. Later, motor NCS 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 myopathic weakness.

 Differential Diagnosis

While the differential diagnosis for acute weakness is broad, a short list of common and potentially treatable causes of acute weakness is listed in Table 25–26. Atypical presentations of viral infections such as with influenza A and West Nile virus 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 presents with acute weakness, botulism should be considered, particularly in endemic areas or with a history of using 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 and 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. Deteriorating spirometric findings (forced expiratory volume in 1 second and total vital capacity) may indicate the need for controlled intubation and respiratory support and is an important mode of monitoring as blood gases may be normal even in late stages of respiratory failure.

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 Guillain-Barré syndrome. 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

Most of these syndromes have no specific treatment, and therefore, supportive treatment is of the essence. Ticks causing paralysis must be removed. Other therapies include the use of erythromycin in Mycoplasma infections and botulism immune globulin in infant botulism. Recognized associated disorders (eg, endocrine, neoplastic, or toxic) should be treated by appropriate means. Supportive care also involves pulmonary toilet, adequate fluids and nutrition, bladder and bowel care, prevention of decubitus ulcers, and in many cases, psychiatric support.

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Borchers AT, Gershwin ME. Transverse myelitis. Autoimmun Rev 2012;11:231-248 [PMID 21621005].

Cortese I et al: Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2011;76:294 [PMID: 21242498].

Dalakas MC: Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA 2004;291:2367 [PMID: 15150209].

Defresne P et al: Acute transverse myelitis in children: clinical course and prognostic factors. J Child Neurol 2003;18:401 [PMID: 12886975].

Francisco AM, Arnon SS: Clinical mimics of infant botulism. Pediatrics 2007;119:826 [PMID: 17403857].

Frohman EM, Wingerchuk DM: Transverse myelitis. N Engl J Med 2010;363:564 [PMID: 23818891].

Greenberg BM et al: Idiopathic transverse myelitis. Neurology 2007;68:1614 [PMID: 17485649].

Hughes RA, Cornblath DR: Guillain-Barré syndrome. Lancet 2005;366:1653 [PMID: 16271648].

Hughes RA, Swan AV, Van Doom PA: Intravenous immunoglobulin for Guillain-Barre syndrome. Cochrane Database Syst Rev 2010;Jun 16:CD002063 [PMID: 20556755].

Kincaid O, Lipton HL: Viral myelitis: an update. Curr Neurol Neurosci Rep 2006;6:469 [PMID: 17074281].

Li Z, Turner RP: Pediatric tick paralysis: discussion of two cases and literature review. Pediatr Neurol 2004;31:304 [PMID: 15464647].

Mori M, Kuwabara S: Fisher syndrome. Curr Treat Options Neurol 2011;13:71 [PMID: 21104459].

Risko W: Infant botulism. Pediatr Rev 2006;27:36 [PMID: 16473839].

Roodbol J et al: Recognizing Guillain-Barre syndrome in pre-school children. Neurology 2011;76:807 [PMID: 21357832].

Sejvar JJ et al: West Nile virus-associated flaccid paralysis. Emerg Infect Dis 2005;11:1021 [PMID: 16022775].

Thompson JA et al: Infant botulism in the age of botulism immune globulin. Neurology 2005;64:2029 [PMID: 15917401].

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Wingerchuk DM: Diagnosis and treatment of neuromyelitis optica. Neurologist 2007;13:2 [PMID: 17215722].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Usually painless, symmetric proximal more than distal muscle weakness (positive Gowers sign, excessive lordosis with walking, waddling gait).

 Preserved deep tendon reflexes compared with muscle weakness.

 Normal to elevated serum creatine kinase (CK) levels.

 Generally normal NCSs; myopathic findings on EMG.

 Clinical Findings

A. Laboratory Findings and Special Tests

1. Serum enzymes—Serum creatine kinase (CK) levels reflect muscle damage or “leaks” from muscle into plasma. Generally, CK levels are normal to mildly elevated in myopathies, and markedly elevated in muscular dystrophies, up to 50–100 times, as in Duchenne muscular dystrophy. Medications and activity level may affect CK levels, for instance after an EMG or muscle biopsy procedure. Corticosteroids may suppress levels despite very active muscle disease, for example, as in polymyositis.

2. Electrophysiologic studies—Nerve conduction study (NCS) and needle electromyography (EMG) are often helpful in grossly differentiating myopathic from neurogenic processes. Generally, NCSs are normal in muscle disorders. In demyelinating polyneuropathies, NCSs may show slowing of conduction velocities or conduction block. EMG involves inserting a needle electrode into muscle to record muscle electrical potentials. The examination includes assessment of abnormal spontaneous activity (eg, fibrillation and fasciculation potentials, myotonic discharges, myokymic discharges, and complex repetitive discharges) and motor unit action potentials (MUAPs). In the myopathies, MUAPs during contraction characteristically are of short duration, polyphasic, and increased in number for the strength of the contraction (increased interference pattern). In neuropathic processes, MUAPs are polyphasic, are of large amplitude, and show decreased recruitment.

3. Muscle biopsy—A muscle biopsy can be helpful in the diagnosis of a muscle disorder, if properly executed. It is important to consider the timing of the biopsy and the biopsied muscle should be chosen based upon the degree of weakness (ie, weaker muscles will show more pathology than strong muscles). Imaging with MRI or ultrasound may guide the choice of an appropriate site. Biopsies performed in the newborn period may be of limited utility as pathologic changes may not be evident in immature muscle. Care should be taken to avoid sites of prior needle EMG examinations or injections as this may cause spurious areas of focal inflammation pathologically. Findings common to the muscular dystrophies include variation in the size and shape of muscle fibers, increase in connective tissue, interstitial infiltration of fatty tissue, areas of degeneration and regeneration, focal areas of inflammatory changes, and centralized nuclei. Myopathies typically do not have the vigorous cycles of degeneration/regeneration and inflammation is seen in dystrophies.

Immunostaining for proteins of the sarcolemmal membrane, surrounding collagen matrix, and intracellular components of the myofiber is a valuable tool. For instance, demonstration of absent collagen VI is virtually diagnostic of Ullrich congenital muscular dystrophy. In the past, absent dystrophin staining at the sarcolemmal membrane on muscle biopsy was diagnostic of Duchenne muscular dystrophy, but mutation analysis of the dystrophin gene is the preferred initial step given the ready availability of commercial testing.

4. Genetic testing and carrier detection—Mutation analysis for Duchenne and Becker muscular dystrophy is considered the initial step in diagnosis, though it should be noted that readily available commercial testing is not exhaustive, and an initial negative result does not exclude the diagnosis. Full characterization of the mutation is critical, as newer treatments targeting specific mutations are emerging. Carrier testing should be offered to all mothers, not only for genetic counseling purposes but also because carriers are at increased risk for developing cardiomyopathy.

Genetic testing for other myopathies and muscular dystrophies should be guided by the clinical findings, serum CK levels, and muscle biopsy results. Commercially available tests are available for many of these disorders (see Table 25–27).

Genetic counseling is particularly important for families of patients with spinal muscular atrophy. Testing for the survival motor neuron (SMN)1 gene deletion has a sensitivity of 95% and a specificity of 100%. Carrier testing, along with genetic counseling, should also be offered, as the carrier rate is 1 in 25 to 1 in 50, depending upon ethnicity.

 Complications

Though skeletal muscle weakness may be profound in muscle disorders, the greatest morbidity and mortality arises from cardiorespiratory complications. Advances in supportive care, especially in critical care management of these patients, have had a tremendous impact in the care of these patients. Noninvasive ventilation, better management of secretions, and generation of effective cough are a few examples. Other complications include delayed gastrointestinal motility which can lead to debilitating constipation or pseudo-obstruction. Contractures are a particularly frustrating complication which can limit mobility of these patients, cause pain, and affect quality of life. Some DMD patients may have a nonprogressive mental retardation with IQ scores one standard deviation below normal means.

 Treatment

Treatment for patients with muscle disorders is predominantly supportive, and medications altering disease progression is, at this time, limited. Patients with Duchenne muscular dystrophy (DMD)/Becker muscular dystrophy (BMD) should be offered treatment with corticosteroids (prednisone/prednisolone and deflazacort) which have been shown to extend the period of independent ambulation by approximately 2.5 years, and to preserve respiratory strength and cardiac function into the second decade. Instituting steroid treatment between 4 and 8 years, when motor function plateaus or is in decline, appears to have the greatest impact on muscle strength and cardiorespiratory function, according to recent practice parameter guidelines. Additional promising treatments targeting the mutation more specifically have been developed over the last decade and are currently in clinical trials, including exon-skipping and read-through strategies that target specific mutations.

In the past, the prognosis for infantile Pompe disease was uniformly grim, with death by age 1 year, but enzyme replacement therapy with recombinant alglucosidase alpha has changed the outlook for many of these patients. Published short-term studies of infants with Pompe disease show significant improvement after treatment with alglucosidase alpha; with improved survival, respiratory performance, cardiomyopathy, and attainment of motor skills.

Until curative treatments for muscle diseases are available, the emphasis on management ought to be on slowing the progressive deterioration in muscle strength and cardio-respiratory function, and to improve quality of life.

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Bushby K et al: Diagnosis and management of Duchenne muscular dystrophy part 2. Lancet Neurol 2010;9(2):177–189 [PMID: 19945914].

Finder JD: A 2009 perspective on the 2004 American Thoracic Society statement, “respiratory care of the patient with Duchenne muscular dystrophy.” Pediatrics 2009;123(Suppl 4):S239–S241 [PMID: 19420152].

Kinali M et al: Congenital myasthenic syndromes in childhood: diagnostic and management challenges. J Neuroimmunol 2008;201–202:6–12 [PMID: 18707767].

Kirschner J, Bonnemann CG: The congenital and limb-girdle muscular dystrophies. Arch Neurol 2004;61:189–199 [PMID: 14967765].

Kishnani PS et al: Pompe disease diagnosis and management guideline. Genet Med 2006;8:267–288 [PMID: 16702877].

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Schara U et al: Myotonic dystrophies type 1 and 2: a summary on current aspects. Semin Pediatr Neurol 2006;13:71 [PMID: 17027856].

Tawil R et al: Facioscapulohumeral muscular dystrophy. Muscle Nerve 2006;34:1 [PMID: 16508966].

Wang CH et al: Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol 2007;22:1027–1049 [PMID: 17761659].

Wang CH et al: Consensus statement on standard of care for congenital muscular dystrophies. J Child Neurol 2010;25(12):1559–1581 [PMID: 21078917].

Yang ML, Finkel RS: Overview of paediatric neuromuscular disorders and related pulmonary issues. Paediatr Resp Rev 2010;11(1):9–17 [PMID: 20113986].

Benign acute childhood myositis (myalgia cruris epidemica) is characterized by transient severe muscle pain and weakness affecting mainly the calves and occurring 1–2 days following an upper respiratory tract infection. Although symptoms involve mainly the gastrocnemius muscles, all skeletal muscles appear to be invaded directly by virus; recurrent episodes are due to different viral types. By sero-conversion or isolation of the virus, acute myositis has been shown to be largely due to influenza types B and A and occasionally due to parainfluenza and adenovirus.

Agyeman P et al: Influenza-associated myositis in children. Infection 2004;32:199 [PMID: 15293074].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Asymmetric, variable weakness, usually coming on or increasing with use (fatigue).

 Involves extraocular, bulbar, and respiratory muscles.

 Positive response to neostigmine and edrophonium.

 General Considerations

Myasthenic syndromes are characterized by easy fatigability of muscles, particularly the extraocular, bulbar, and respiratory muscles. In the neonatal period, however, or in early infancy, the weakness may be so constant and general that an affected infant may present nonspecifically as a “floppy infant.” Three general categories of myasthenic syndromes are recognized: transient neonatal myasthenia, autoimmune myasthenia gravis, and congenital myasthenia.

 Clinical Findings

A. Symptoms and Signs

1. Neonatal (transient) myasthenia—This disorder occurs in 12%–19% of infants born to myasthenic mothers as a result of passive transfer of maternal acetylcholine receptor antibody across the placenta. Neonates present before the third day of life with bulbar weakness, difficulty feeding, weak cry, and hypotonia.

2. Juvenile myasthenia gravis—Like the adult form of myasthenia gravis, juvenile myasthenia gravis is characterized by fatigable and asymmetric weakness. However, more than half of patients present with ocular symptoms (ptosis or ophthalmoplegia), unlike adult patients who typically present with limb weakness. Weakness may remain limited to the extraocular muscles in 10%–15% of patients, but approximately half of children develop systemic or bulbar symptoms within 2 years and 75% within 4 years. Symptoms of weakness tend to recur and remit, and can be precipitate by illness or medications such as aminoglycoside antibiotics. Typical signs include difficulty chewing foods like meat, dysphagia, nasal voice, ptosis, ophthalmoplegia, and proximal limb weakness. Other autoimmune disorders such as rheumatoid arthritis and thyroid disease may be associated findings.

3. Congenital myasthenic syndromes—These syndromes are a heterogenous group of hereditary, nonimmune disorders of presynaptic, synaptic, or postsynaptic neuromuscular transmission. Patients present with symptoms similar to that of myasthenia gravis, but onset is earlier, before the age of 2 years, and can vary from mild motor delay to dramatic episodic apnea. Serum acetylcholine receptor antibody testing is negative. Response to anticholinesterases is variable, depending on the type of congenital myasthenic syndrome, and some forms may paradoxically worsen. The distinction between this group of disorders and myasthenia gravis is important, as these patients will not benefit from a thymectomy, steroids, or immunosuppressants, but it may be clinically difficult to distinguish between the two.

B. Laboratory Findings

1. Anticholinesterase inhibitor testing

A. NEOSTIGMINE TEST—In newborns and very young infants, the neostigmine test may be preferable to the edrophonium (Tensilon) test because the longer duration of its response permits better observation, especially of sucking and swallowing movements. There is a delay of about 10 minutes before the effect may be manifest. The physician should be prepared to suction secretions, and administer atropine if necessary.

B. EDROPHONIUM TEST—Testing with edrophonium is used in older children who are capable of cooperating in certain tasks and who exhibit easily observable clinical signs, such as ptosis, ophthalmoplegia, or dysarthria. Maximum improvement occurs within 2 minutes. Both cholinesterase inhibitor tests can be limited by patient cooperation and lack of an easily observable clinical sign.

2. Antibody testing—Serum acetylcholine receptor binding, blocking, and modulating antibodies typically, though not always, are found in autoimmune juvenile myasthenia gravis. Though not specifically studied in the pediatric population, in the general myasthenia gravis population at large, about 40% of the seronegative patients have muscle-specific receptor tyrosine kinase (MuSK) antibodies. Serum acetylcholine receptor antibodies or MuSK antibodies are often found in the neonatal and juvenile forms. In juveniles, thyroid studies are appropriate.

3. Genetic testing—Commercially available genetic testing is limited for patients with congenital myasthenic syndromes.

C. Electrophysiologic Studies

Electrophysiologic studies may be helpful when myasthenic syndromes are considered. Repetitive stimulation of a motor nerve at slow rates of 2–3 Hz with recording over an appropriately chosen muscle reveals a progressive fall in compound muscle action potentials by the fourth to fifth repetition in myasthenic patients. At higher rates of stimulation of 50 Hz, there may be a transient repair of this defect before the progressive decline is seen. Both studies may be technically difficult to perform in infants and younger children as repetitive stimulation can be painful and requires cooperation. If this study is negative, single-fiber EMG in older cooperative children may be helpful diagnostically, but it is technically challenging and time intensive, and requires concentration on the part of the child. Stimulated single-fiber EMG may be performed by trained electromyographers.

D. Imaging

Chest radiograph and CT scanning in older children may show thymic hyperplasia. Thymomas are rare in children.

 Treatment

A. General and Supportive Measures

In the newborn or in a child in myasthenic or cholinergic crisis (see the following section Complications), supportive care is essential and the child should be monitored in a critical care setting. A careful search for signs of respiratory failure is crucial: simple bedside tests include evaluation of cough and counting to 20 in a single breath. An inability to do either signals respiratory failure. Neck flexion weakness, nasal speech, and drooling are other important signs to observe. Management of secretions and respiratory assistance should be monitored by trained critical care staff.

B. Anticholinesterase Inhibitors

1. Pyridostigmine bromide—Pyridostigmine is the first-line treatment in patients with juvenile myasthenia gravis and mild weakness. Anticholinesterase inhibitors do not modify disease progression but transiently improve muscle strength. For younger children, the starting dose is 0.5–1 mg/kg every 4–6 hours. In older children, the initial dose is 30–60 mg every 4–6 hours. The maximal daily dose is 7 mg/kg/d with an absolute maximum dose of 300 mg/d. The dosage must be adjusted for each patient based on clinical symptoms and side effects.

2. Neostigmine—Fifteen milligrams of neostigmine are roughly equivalent to 60 mg of pyridostigmine bromide. Neostigmine often causes gastric hypermotility with diarrhea, but it is the drug of choice in newborns, in whom prompt treatment may be lifesaving. It may be given parenterally.

C. Immunomodulatory Treatment

Patients with more severe weakness not responding to cholinesterase inhibitors alone require long-term treatment with immunomodulation. There are four therapeutic options in this category: (1) plasmapheresis, (2) intravenous immunoglobulins (IVIg), (3) steroids, and (4) immunosuppressants. The mainstay of treatment is steroids, but some patients who either cannot tolerate or do not respond to steroids require treatment with other immunosuppressants such as azathioprine, cyclosporine, or mycophenolate mofetil. Both plasmapheresis and IVIg may be given on a long-term basis, depending on the severity of symptoms, as well as in the acute setting, with myasthenic crises. Special note must be made to the use of steroids, which can transiently worsen symptoms before any benefit is noted, particularly with large starting doses.

 Complications

A. Myasthenic Crisis

Respiratory failure can develop swiftly due to critical weakness of respiratory muscle, bulbar muscles or both, resulting in a myasthenic crisis. Crises are generally not fatal as long as patients receive timely respiratory support and appropriate immunotherapy. Particular vigilance, however, needs to be maintained as crises can occur in the setting of medical illnesses or surgical procedures. Patients and their caregivers should also be alerted that certain medications can exacerbate myasthenia gravis, including aminoglycoside antibiotics, muscle relaxants, and anesthetics.

B. Cholinergic Crisis

Cholinergic crisis may result from overmedication with anticholinesterase drugs. The resulting weakness may be similar to that of myasthenic crises, and the muscarinic side effects (diarrhea, sweating, lacrimation, miosis, bradycardia, and hypotension) are often absent or difficult to evaluate. If suspected, cholinesterase inhibitors should be discontinued immediately, and improvement afterward suggests cholinergic crisis. As in myasthenic crisis, supportive respiratory care and appropriate immunotherapy should be given.

C. Surgical Measures

Data for efficacy of thymectomy in the pediatric population are few. Some studies suggest that thymectomy within 2 years of diagnosis results in a higher rate of remission in Caucasian children. Experienced surgical and postsurgical care are prerequisites.

 Prognosis

Prognosis for neonatal (transient) myasthenia is generally good, with complete resolution of symptoms in 2–3 weeks. However, immediate treatment with appropriate respiratory support in the acute presentation period is crucial, primarily because of the risk of secretion aspiration. No further treatment is required thereafter. The prognosis for congenital myasthenic syndromes is variable by subtype. Some subtypes show improvement in weakness with age. Others demonstrate life-threatening episodic apnea, including those with rapsyn mutations, fast-channel mutations, and choline acetyltransferase mutations. Patients with juvenile myasthenia gravis generally do well, with greater spontaneous remission rates than adult patients. Improvements in respiratory and critical care support has improved prognosis for these patients.

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Hennessey IA et al: Thymectomy for inducing remission in juvenile myasthenia gravis. Pediatr Surg Int 2011;27(6):591–594 [PMID: 21243366].

Juel VC, Massey JM: Autoimmune myasthenia gravis: recommendations for treatment and immunologic modulation. Curr Treat Opt Neurol 2005;7:3 [PMID: 15610702].

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Kinali M et al: Congenital myasthenic syndromes in childhood: diagnostic and management challenges. J Neuroimmunol 2008;201–202:6–12 [PMID: 180707767].

Mehndiratta MM, Pandey S, Kuntzer T: Acetylcholinesterase inhibitor treatment for myasthenia gravis. Cochrane Database Syst Rev 2011;16(2):CD006986 [PMID: 21328290].

 Facial Weakness

 ESSENTIALS OF DIAGNOSIS

 Central vs peripheral facial nerve lesions need to be distinguished in order to determine workup, treatment, and prognosis. The inability to raise the eyebrows indicates peripheral involvement of the facial nerve.

 Pathogenesis

The most common cranial mononeuropathy is facial nerve palsy. Cranial nerve VII is a complex nerve that carries several different nerve fibers, including motor fibers to all muscles of facial expression, parasympathetic motor fibers supplying the mucosa of the soft palate and the salivary and lacrimal glands, taste fibers to the anterior 2/3 of the tongue, parasympathetic sensory fibers for visceral sensation from the salivary glands and the nasal and pharyngeal mucosa, and somatic sensory fibers supplying a small part of the external auditory meatus and the skin of the ear. Facial weakness can occur as the result of a lesion anywhere along the path of the nerve. A central lesion, proximal to the facial nerve nuclei, causes contralateral weakness of the lower face, sparing the forehead and orbicularis oculi muscles which are bilaterally innervated. Peripheral lesions, at or distal to the facial nerve nuclei, cause ipsilateral facial weakness that affects both the upper and lower facial muscles, resulting in an inability to wrinkle the forehead, close the eye or smile. In addition, there may be dysfunction in the ability of tearing and saliva production, hyperacusis, and absent taste sensation over the anterior two-thirds of the tongue.

 Clinical Findings

The inability to wrinkle the forehead may be demonstrated in infants and young children by getting them to follow a light moved vertically above the forehead. Loss of taste of the anterior two-thirds of the tongue on the involved side may be demonstrated in cooperative children by age 4 or 5 years. Playing with a younger child and the judicious use of a tongue blade may enable the physician to note whether the child’s face puckers up when something sour (eg, lemon juice) is applied with a swab to the anterior tongue.

 Differential Diagnosis

Injuries to the facial nerve at birth occur in 0.25%–6.5% of consecutive live births. Forceps delivery is the cause in some cases; in others, the side of the face affected may have abutted in utero against the sacral prominence. Often, no cause can be established.

Acquired peripheral facial weakness (Bell palsy) is common in children. Some cases are postinfectious, although an increasing body of evidence suggests that Bell palsy is a viral-induced cranial neuritis caused by herpes virus. It may be a presenting sign of Lyme disease, infectious mononucleosis, herpes simplex, or Guillain-Barré syndrome and is usually diagnosable by the history, physical examination, and appropriate laboratory tests. Chronic cranial nerve VII palsy may be a sign of brainstem tumor.

Bilateral facial weakness in early life may be due to agenesis of the facial nerve nuclei or muscles (part of Möbius syndrome) or may even be familial. Myasthenia gravis, polyneuritis (Miller-Fisher syndrome), fascioscapulohumeral muscular dystrophy, and myotonic dystrophy must be considered.

Asymmetrical crying facies, in which one side of the lower lip depresses with crying (ie, the normal side) and the other does not, is usually an innocent form of autosomal dominant inherited congenital malformation. The defect in the parent (the asymmetry often improves with age) may be almost inapparent. EMG suggests congenital absence of the depressor angularis muscle of the lower lip. Forceps pressure is often erroneously incriminated as a cause of this innocent congenital anomaly. Occasionally other major (eg, cardiac septal defects) congenital defects accompany the palsy. Congenital unilateral lower lip paralysis with asymmetric crying facies, most often attributed to congenital absence of the depressor anguli oris, is associated with major malformations, most commonly heart defects, in 10% of cases.

 Treatment & Prognosis

In the vast majority of cases of isolated peripheral facial palsy—both those due to birth trauma and those acquired later—improvement begins within 1–2 weeks, and near or total recovery of function is observed within 2 months. In severe palsy with inefficient blinking, methylcellulose drops, 1%, should be instilled into the eyes to protect the cornea during the day; at night the lid should be taped down with cellophane tape. Upward massage of the face for 5–10 minutes three or four times a day may help maintain muscle tone. Prednisone therapy (2–4 mg/kg orally for 5–7 days) likely does not aid recovery. In the older child, acyclovir or valacyclovir (herpes antiviral agent) therapy or antibiotics (Lyme disease) may have a role in Bell palsy.

In the few children with permanent and cosmetically disfiguring facial weakness, plastic surgical intervention at age 6 years or older may be of benefit. New procedures, such as attachment of facial muscles to the temporal muscle and transplantation of cranial nerve XI, are being developed.

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Ashtekar CS et al: Best evidence topic report. Do we need to give steroids in children with Bell’s palsy? Emerg Med J 2005;22:505 [PMID: 15983089].

Gilden DH: Clinical practice. Bell’s palsy. N Engl J Med 2004;351:1323 [PMID: 15385659].

Hato N et al: Valcyclovir and prednisolone treatment for Bell’s palsy: a multicenter, randomized, placebo-controlled study. Otol Neurotol 2007;28:408 [PMID: 17414047].

Kawaguchi K et al: Reactivation of herpes simplex virus type 1 and varicella-zoster virus and therapeutic effects of combination therapy with prednisolone and valacyclovir in patients with Bell’s palsy. Laryngoscope 2007;117:147 [PMID: 17202945].

Salinas RA et al: Corticosteroids for Bell’s palsy (idiopathic facial paralysis). Cochrane Database Syst Rev 2004;(4):CD001942 [PMID: 15495021].

Sapin SO et al: Neonatal asymmetric crying facies: a new look at an old problem. Clin Pediatr (Phila) 2005;44:109 [PMID: 15735828].

Terada K et al: Bilateral facial nerve palsy associated with Epstein-Barr virus infection with a review of the literature. Scand J Infect Dis 2004;36:75 [PMID: 15000569].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Insidious onset of weakness and fatigability of the limbs, sometimes with pain or numbness; decreased strength and reflexes.

 General Considerations

Polyneuropathy is usually insidious in onset and slowly progressive. Children present with disturbances of gait and easy fatigability in walking or running, and slightly less often, weakness or clumsiness of the hands. Pain, tenderness, or paresthesias are mentioned less frequently. Neurologic examination discloses muscular weakness, greatest in the distal portions of the extremities, with steppage gait and depressed or absent deep tendon reflexes. Cranial nerves are sometimes affected. Sensory deficits occur in a stocking-and-glove distribution. The muscles may be tender, and trophic changes such as glassy or parchment skin and absent sweating may occur. Rarely, thickening of the ulnar and peroneal nerves may be felt. In sensory neuropathy, the patient may not feel minor trauma or burns, and thus allows trauma to occur.

Known causes include (1) toxins (lead, arsenic, mercurials, vincristine, and benzene); (2) systemic disorders (diabetes mellitus, chronic uremia, recurrent hypoglycemia, porphyria, polyarteritis nodosa, and lupus erythematosus); (3) inflammatory states (chronic inflammatory demyelinating polyneuropathy and neuritis associated with mumps or diphtheria); (4) hereditary, often degenerative conditions, which in some classifications include certain storage diseases, leukodystrophies, spinocerebellar degenerations with neurogenic components, and Bassen-Kornzweig syndrome; and (5) hereditary sensory or combined motor and sensory neuropathies. Polyneuropathies associated with malignancies, vitamin deficiencies, or excessive vitamin B₆ intake are not reported or are exceedingly rare in children.

The most common chronic motor neuropathy of insidious onset often has no identifiable cause. This chronic inflammatory demyelinating neuropathy (CIDP) is assumed to be immunologically mediated and may have a relapsing course. Sometimes facial weakness occurs. CSF protein levels are elevated. Nerve conduction velocity is slowed, and findings on nerve biopsy are abnormal. Immunologic abnormalities are seldom demonstrated, although nerve biopsy findings may show round cell infiltration. Corticosteroids, repeated IVIG, and, occasionally, immunosuppressants may give long-term benefit.

 Clinical Findings

Hereditary neuropathy is the most common documented cause of chronic neuropathy in childhood. A careful genetic history (pedigree) and examination and electrical testing (motor and sensory nerve conduction and EMG) of patient and relatives are keys to diagnosis. Genetic tests are available for many of the variants. Nerve biopsy is rarely necessary.

Other hereditary neuropathies may have ataxia as a prominent finding, often overshadowing the neuropathy. Examples are Friedreich ataxia, dominant cerebellar ataxia, and Marinesco-Sjögren syndrome. Finally, some hereditary neuropathies are associated with identifiable and occasionally treatable metabolic errors (see Tables 25–20 and 25–21). These disorders are described in more detail in Chapter 36.

Laboratory diagnosis of chronic polyneuropathy is made by measurement of motor and sensory nerve conduction velocities. EMG may show a neurogenic pattern. CSF protein levels are often elevated, sometimes with an increased IgG index. Nerve biopsy, with teasing of the fibers and staining for metachromasia, may demonstrate loss of myelin, and to a lesser degree, loss of axons and increased connective tissue or concentric lamellas (so-called onion-skin appearance) around the nerve fiber. Muscle biopsy may show the pattern associated with denervation. Other laboratory studies directed toward specific causes mentioned above include screening for heavy metals and for metabolic, renal, or vascular disorders.

 Treatment & Prognosis

Therapy is directed at specific disorders whenever possible. Corticosteroid therapy is used first when the cause is unknown or neuropathy is considered to be due to chronic inflammation (this is not the case in acute Guillain-Barré syndrome [AIDP; acute inflammatory demyelinating neuropathy]). Prednisone is initiated at 2–4 mg/kg/d orally, with tapering to the lowest effective dose; it may need to be reinstituted when symptoms recur. (Prednisone should probably not be used for treatment of hereditary neuropathy.) Immunomodulating therapy may be safer or “steroid-sparing”; IVIG, plasmapheresis, mycophenolate mofetil, and rituximab are choices.

The long-term prognosis varies with the cause and the ability to offer specific therapy. In the corticosteroid-dependent group, residual deficits are more frequent.

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MISCELLANEOUS NEUROMUSCULAR DISORDERS

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Classic maneuvers to evaluate a floppy infant include checking vertical suspension, horizontal suspension, and traction response.

 Correct interpretation of neurological findings in a hypotonic infant is dependent on a thorough knowledge of normal childhood development.

 Pathogenesis

An infant may present with hypotonia due to dysfunction at any place along the neuroaxis, from the brain, spinal cord, nerve, neuromuscular junction, and muscle. Additionally, systemic disorders, metabolic disease and genetic disorders may cause an infant to appear “floppy.” The evaluation of the hypotonic infant is therefore one of the most challenging diagnostic problems that a pediatrician is often faced with. The diagnostic workup requires a thorough knowledge of normal developmental milestones at each stage of a developing infant and child, and careful assessment of the pre- and perinatal history, family history, developmental history, and presence of other systemic involvement (see Table 25–28).

 Clinical Findings

A. Signs and Symptoms

In the young infant, horizontal suspension (ie, supporting the infant with a hand under the chest) normally results in the infant’s holding its head slightly up (45 degrees or less), the back straight or nearly so, the arms flexed at the elbows and slightly abducted, and the knees partly flexed. The “floppy” infant droops over the hand like an inverted U. The normal newborn attempts to keep the head in the same plane as the body when pulled up from supine to sitting by the hands (traction response). Marked head lag is characteristic of the floppy infant. In vertical suspension, the hypotonic infant will slip through the examiner’s hands when held under the armpits. Hyperextensibility of the joints is not a dependable criterion.

B. Laboratory Findings

A general rule for laboratory testing is to localize the etiology of the hypotonia. For instance, if a lower motor neuron etiology is suspected, a serum CK, EMG/NCS, and/or muscle biopsy may be appropriate as first tier testing. Many neuromuscular disorders may be diagnosed by clinical findings alone, as is often the case with spinal muscular atrophy and congenital myotonic dystrophy, and in those cases, genetic testing is often the first testing warranted. If the hypotonic is accompanied by language or cognitive delay, a CNS or genetic disorder is most likely, and MR imaging of the brain may be the most useful diagnostic test.

 Differential Diagnosis

The most common etiology of hypotonia in the neonate is hypoxic ischemic encephalopathy. Dysmorphic features may suggest a genetic etiology such as Down syndrome and Prader-Willi syndrome. Abnormalities of the hair or skin, which form from the neuroectoderm in development with the brain, may prompt an evaluation for brain malformations. Often seizures or language or cognitive delay may be accompanying features. Regression in development is often a clue for mitochondrial or metabolic disorders. Neuromuscular disorders including congenital myotonic dystrophy and spinal muscular atrophy can present as hypotonic in the infant. While the list of differential diagnosis in Table 25–28 is not complete, it describes the clinical features of some of the more common causes of hypotonia in infants and children.

 Treatment

Treatment for many of these disorders is supportive. Physical and occupational therapy can facilitate some progress to a varying degree. Accompanying seizures and other systemic manifestions should be controlled to optimize development.

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